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WO2005070332A1 - Long-term delivery formulations and methods of use thereof - Google Patents

Long-term delivery formulations and methods of use thereof Download PDF

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Publication number
WO2005070332A1
WO2005070332A1 PCT/US2005/000884 US2005000884W WO2005070332A1 WO 2005070332 A1 WO2005070332 A1 WO 2005070332A1 US 2005000884 W US2005000884 W US 2005000884W WO 2005070332 A1 WO2005070332 A1 WO 2005070332A1
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WO
WIPO (PCT)
Prior art keywords
drug
formulation
plga
risperidone
kit
Prior art date
Application number
PCT/US2005/000884
Other languages
French (fr)
Inventor
Steven Siegel
Karen Winey
Original Assignee
The Trustees Of The University Of Pennsylvania
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Trustees Of The University Of Pennsylvania filed Critical The Trustees Of The University Of Pennsylvania
Priority to EP05705510A priority Critical patent/EP1711124A4/en
Priority to CA2553254A priority patent/CA2553254C/en
Priority to JP2006549540A priority patent/JP5306599B2/en
Priority to US10/585,611 priority patent/US20080305140A1/en
Priority to KR1020117025349A priority patent/KR101242486B1/en
Priority to AU2005206143A priority patent/AU2005206143B2/en
Priority to KR1020067016248A priority patent/KR101197540B1/en
Priority to US11/183,232 priority patent/US8221778B2/en
Priority to US11/195,845 priority patent/US8329203B2/en
Publication of WO2005070332A1 publication Critical patent/WO2005070332A1/en
Priority to US11/988,137 priority patent/US8741327B2/en
Priority to US13/490,787 priority patent/US8802127B2/en
Priority to US14/286,168 priority patent/US9439905B2/en
Priority to US14/540,828 priority patent/US9717799B2/en
Priority to US15/627,349 priority patent/US9925268B2/en
Priority to US15/627,389 priority patent/US9895447B2/en
Priority to US15/863,483 priority patent/US10111960B2/en
Priority to US16/174,083 priority patent/US10736965B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • This invention provides long-te ⁇ n delivery formulations comprising a it) biodegradable matiix and an agent of interest, methods of producing the same, and methods of use thereof.
  • the invention also relates to long-term formulations of Rispeiidone and 9-OH-Risperidone compositions for the treatment of psychotic disorders
  • Psychotic disoiders are pathological conditions of the biain characterized by identifiable symptoms that lesull in abnormalities in cognition, emotion or mood, or in particular, in temis of ones ability to work, interact and be intimate with other0 people These disorders may vary in severity of symptoms, duration, and functional impairment. Psychiatric disorders afflict millions of people of all ages worldwide, foi extensive periods of time, resulting in tremendous human suffering and economic burden due to lost productivity In some cases the psychiatric disorder may be acute, iasting only foi several weeks to months. In other instances the disorder is chronic,5 lasting for years or even decades.
  • Medication non-compliance is a pervasive problem with many forms of illness.
  • Non-compliance causes particular medical and social problems when the diugs concerned aie neuroleptics (anti-psychotics) such as chlorpromazine or haloperidol (Rogcis, A et al. [1998], "The meaning and management of neuroleptic medication: A study of patients with a diagnosis of schizophienia," Social Science and Medicine 47(9): 1313-1323)
  • aie neuroleptics anti-psychotics
  • chlorpromazine or haloperidol Rogcis, A et al. [1998], "The meaning and management of neuroleptic medication: A study of patients with a diagnosis of schizophienia," Social Science and Medicine 47(9): 1313-1323)
  • Schuchait EK Relapse and rehospitalization lates in patients with schizophrenia effects of second generation antipsychotics CNS Drugs 2002, 16:473-484.
  • tins invention provides a method of treating a Nervous System disorder in a subject in need theieof, the method comprising administering to the subject a first formulation of a drug in complex with a biodegradable polymer, wherein said formulation deliveis said drug with pseudo zero-order kinetics in-vivo; and administering to the subject a second formulation of said drug in complex with a biodegradable polymei, wherein the second formulation delivers the diug at a faster late, in-vivo, than the first formulation, whereby administering said fust and second formulation results in therapeutic circulating levels of said diug, thereby being a method of treating a nervous system disorder,
  • this invention provides a method comprising administering to the subject a first foimulalion of a drug in complex with a biodegradable polymei, wherein said formulation delivers said drug with pseudo zero- oider kinetics in-vivo; and administering to the subject a second formulation of said drug in complex with a biodegradable polymei, wherein the second formulation delivers the diug at a fastei rate, in-vivo, than the first formulation, whereby administering said fust and second formulation results in therapeutic circulating levels of said drug indefinitely upon re implanting.
  • the invention provides a kit foi sustained deliveiy of a drug comprising a fust foimulalion of said drug in complex with a biodegradable polymer, wherein said foimulation delivers said diug with pseudo zeio-oider kinetics in-vivo, and a second formulation of said drug in complex with a biodegradable polymer wheiein said second formulation has a late of lelease which is fastei than said first foimulation, in-vivo.
  • the present invention provides a composition for use in the treatment of psychotic disorders, comprising a poly(d,I-lactide/glycolide) (PLGA) copolymei at a concentration of from about 95-98% (w/w), and an antipsychotic agent (al a concentration of from about 2 to about 5% w/w), wherein the lactide:glycolide ratio of said po!y(iactide/glycolide) copolymer is from about 100:0 to 50:50 and wheiein said antipsychotic agent is Risperidone or 9-OH-Risperidone
  • FIG. 1 is a graph showing Haloperidol release for total of 443 days from PLGA disk implanted in monkeys.
  • FIG. 2A is a graph showing Haloperidol release for total of 379 days from single PLGA disk system implanted in Rabbits.
  • FIG 2B is a graph showing Haloperidol release for total of 379 days from combination PLGA disk system implanted in Rabbits.
  • FIG 3 is a graph showing In-vilro cumulative Risperidone lelease from implants containing expressed as total mass of Risperidone released
  • FIG 4A is a graph of cumulative release of 20, 40 or 60% (w/w) Risperidone dispersed in 85:15 PLGA leleased from 50 mg implant
  • FIG 4B is a graph of cumulative release of 20, 40 or 60% (w/w) Risperidone dispersed in 85:15 PLGA Release expressed as percentage of the amount of drug in each implant
  • FIG. 5 is a graph showing cumulative hi-viiro release from disk and rod-shaped implants. Diffeiences in release profile were statistically insignifacnt.
  • FIG. 6 is a graph showing a model for continuous delivery from biodegradable implants projected to oscillate around a target serum level as long as implantations occui eceiy 6 months,
  • FIG. 7A is a giaph showing expected seium release from a single polymer
  • FIG. 7B is a graph showing expected serum release from leimplantalion of a single polymer matrix eveiy 6 months
  • FIG 7C is a giaph showing expected serum release pattern from leimplantalion of a single polymer system every 6 months, along with a maintenance set with 3 month peak release
  • FIG. 7D is a graph showing the expected release from a staiter polymer set, abridging the first 4 months of therapy
  • FIG. 7E is a graph showing the expected release from a combination therapy comprising staiter polymer set, abridging the first 4 months of therapy with reimplantation of a single polymer system every 6 months, along with a maintenance set with 3 month peak telease
  • FIG. 8 A is a g aph showing 40% haloperidol release from Implants made from 75:25 PLGA:
  • FIG 8b is a giaph showing 40% haloperidol release from Implants made from 85:15 PLGA:
  • FIG 8C is a graph showing cumulative release from a hypothetical two-polymer system over a period of 154 days.
  • FIG 9 is a graph showing locomotor activity (total distance in meters over twenty minutes) tested prior to implant removal and then again 48 hours following implant
  • FIG. 10 shows the Western blot of D2 receptor piotein in striatal membranes from tats treated with haloperidol-PLA or PLA alone implants for 3 months.
  • FIG I lA is a graph of cumulative ielease of Risperidone dispersed in PLGA biodegiadable matrix.
  • FIG 1 1 B is a graph of cumulative release of 9-OH-Risperidone dispersed in PLGA biodegradable matiix.
  • FIG. 12 is a graph of cumulative release of 20% (w/w) 9-OH-Risperidone dispersed in 85:15 PLA:PGA block copolymer biodegradable matiix.
  • FIG. 13 is a graph of cumulative release of 20% (w/w) Risperidone dispersed in 85:15 PLA:PGA block copolymer biodegradable matrix.
  • FIG 14 A Is a giaph showing the effect of Implants in rats or mice for in vivo behavioral testing with piepulse inliibition of startle (PPI).
  • FIG 14B Is a graph showing the effect of Implants in rats or mice for in vivo behavioral testing with prepulse inhibition of startle (PPI) following Amphetamine administration
  • FIG 14C Is a graph showing the effect of Risperidone Implants in rats or mice for in vivo behavioial testing with prepulse inliibition of startle (PPI) pre and post Amphetamine administration.
  • FIG 14D Is a graph showing the cumulative Risperidone ielease from 85:15 (PLA:PGA) PLGA implants as a function of time
  • FIG 14E Is a giaph showing the effect of Risperidone Implants in rats oi mice on in vivo behavioral testing with prepulse inliibition of startle (PPI).
  • FIG 14F Is a graph showing the effect of Risperidone Implants in rats or mice on in vivo behavioral testing with prepulse inliibition of startle (PPI) following vehicle injection
  • FIG 14G Is a graph showing the effect of Risperidone Implants in rats or mice on in vivo behavioral testing with piepulse inhibition of staitle (PPI) following amphetamine administration,
  • FIG. 15 A Is a giaph showing the cumulative quetiapine release from 85:15 (PLA:PGA) PLGA implants as a function of time.
  • FIG. 15B Is a graph showing the effect of Quetiapine ielease from implant before and after injection of apomorphine, relative to control on PPL
  • FIG. 15C Is a graph showing the effect of Quetiapine injection before and after injection of apomorphine, lelative to control and sham apomorhine injection on PPI
  • FIG 16A Is a graph showing the cumulative clozapine release from 85:15 (PLA:PGA) PLGA implants as a function of time
  • FIG 16B Is a graph showing the effect of Clozapine Implants before and after placebo injection of apomoiphine, relative to control and sham apomorhine injection on PPI
  • FIG 16C Is a graph showing the effect of Clozapine Implants befoie and after injection of apomoiphine, lelative to control and sham apomorhine injection on PPI
  • FIG 17A Is a giaph showing the cumulative haloperidol release from 85:15 (PLA:PGA) PLGA implants as a function of time
  • FIG 17B Is a graph showing the effect of haloperidol release from PLGA implants on PPI
  • FIG 17C Is a graph showing the effect of haloperidol Implants in lats or mice on in vivo behavioral testing with piepulse inliibition of staitle (PPI)
  • FIG. ISA Is a graph showing the effect of initial drug load on cumulative Risperidone ielease from 85:15 (PLA:PGA) PLGA implants in-vitro
  • FIG. 18B Is a graph showing the effect of initial drug load on fractional Risperidone ielease from 85:15 (PLA:PGA) PLGA implants in-vitro
  • This invention provides in one embodiment, long-term sustained delivery formulations and methods of use thereof
  • this invention provides a method of ti eating a Neivous System disoider in a subject in need thereof, the method comprising administering to the subject a fust formulation of a drug in complex with a biodegradable polymer, wherein said fust formulation delivers said drug with pseudo zeio-ordei kinetics in- vivo; and administering to said subject a second formulation of said drug in complex with a biodegradable polymei, wherein the second formulation delivers said drug substantially faster, in-vivo, than the first foimulation, whereby administering said first and second formulation results in therapeutic circulating levels of said drug, thereby being a method of treating a nervous system disorder.
  • this invention provides a method of treating a Nervous System disoider in a subject in need thereof, wherein the method uses a kit comprising the formulations as described further hereinbelow
  • the method may further comprise administrating at least one additional foimulation comprising the drug in complex with a biodegiadable polymei, wherein the late of release of the drug from said one additional formula is fastei than the fust formulation and in one embodiment, is faster than the second foimulation, or in anothei embodiment is slower than the second formulation, or in anothei embodiment is slower than the fust formulation.
  • the one additional formulation has a peak diug release which is piior to the pealc release of either the first formulation, or in anothei embodiment, the second formulation.
  • the one additional foimulation has a peak drug release which coincides with the peak release of either the first formulation, or in another embodiment, the second foimulation, oi in another embodiment follows the peak rel ease of sai d fu st foi mul ation.
  • the methods, kits and compositions of this invention comprise or make use of a first formulation, which is in complex with a biodegradable polymer that is metabolized, oi in another embodiment produces non-toxic, oi in another embodiment sub-pathologically toxic by-products.
  • the degiadation products of PLGA, lactic acid and glycolic acid in one embodiment are water soluble, non-toxic products of normal metabolism that are either excieted oi further metabolized to carbon dioxide and water in the Krebs cycle
  • the terms "in complex” or “complexes” refer to the drug molecules being interdispeised within a biodegradable polymer's matrix.
  • the drug is located within interstitial spaces within the polymer matrix, which may be accomplished, in antoher embodiment, via fast solvent extraction, wheiein, following extraction, a les ⁇ lting increase in polymer concentration occurs, which causes a rapid inciease in polymer viscosity, and in anothei embodiment, lowers diffusivity of the thus entiapped drug
  • the term "fast solvent extraction” refeis to solvent removal at a late in which the resulting increase in polymer concenti ation and subsequent increase in viscosity are such that allignment of the polymer chains to the point of lecrystallization is kinetically unfeasible
  • any factor which may affect the entrapment of the subject diug in the biodegradable polymer matrix, and thereby affect its initial loading, in one embodiment, oi, in another embodiment, subsequent release, or in another embodiment, a combination theieof, may be utilized according to the methods of this invention, and in kits and compositions of this invention
  • such factois may comprise inter-alia, the initial solvent concentration, its moleculai size and polarity, the lempeiature and piessure under which the solvent is lemoved, molecular weight numbei (MWn) average of the biodegradable polymer matrix, its polydispeisity index, the size and polarity of the drug, the monomer ratio and distribution along the copolymei's chain, or a combination thereof.
  • D/L ratio within each monomer of a biodegiadable polymer will affect release rates.
  • the term D/L ratio refers to the ratio of monomer molecules that affect the direction (D-iight, L-left), in which a cross-polarized lense will be rotated when obseiving a single optically active monomei , like lactic acid. Since most mammals have D-specific enzymes, that ratio will affect the digestion late of the biodegradable biopolymer, affecting its molecular weight and consequently its viscosity, thereby affecting release rate of any entrapped drug
  • the term "theiapeutic” means the produced desired biological, or in another embodiment, prophylactic response, as a consequence of a method, or administi ation of a kit or composition of this invention
  • the desired response can be a reduction (complete or in another embodiment partial) of symptoms associated with a particular disease or disordei, such as, schizophienia, depiession, psychotic anxiety or combination thereof
  • this invention provides for the administration of appropriate palliative drugs during the tieatment regimen
  • a nervous system disorder like schizophrenia can be treated with a diug, which in one embodiment, is Risperidone, by complexing the drug with a biodegradable polymer exhibiting the release profile shown in Figuie 7A.
  • a foimulation comprising a di ug in complex with 5 different polymers may be used simultaneously wherein 3 complexes comprise a "starter set", referring in one embodiment to the formulations administered to bridge the lag oi ielease from the sustained release implants ( Figures 7D and 7E)
  • the startei set comprises 3 complexes the fust of which has an immediate release profile, which is taken simultaneously with two other fast release complexes, each with a slightly slower release profile.
  • the starter set is taken concurrent with or just prior to the "maintenance set", which comprises at least one, or in anotliei embodiment, 2, oi in another embodiment, 3, or in another embodiment, 4 complexes, which provides for constant theiapeutic circulating level of Risperidone
  • the maintenance set is provided at a point when complete release, referring in one embodiment to 100% of the drug is released from the starter set complexes
  • the maintenance set may comprise a 5 lh complex, which in one embodiment, is an implant comprising the diug and biodegradable matrix, which, has a higher absolute drug content, as compared to the other complexes
  • the 5" complex peak release coincides with a decline in diug release from the other complexes comprising the "maintenance set".
  • the release profiles from each complex are combined at an optimum to provide for a constant desired circulating Risperidone level (Figure 7E).
  • the maintenance sets may be leadministered to a subject indefinitely, to provide for prolonged therapy.
  • the method of this invention includes repeated use, e g the use of the method according to the invention includes administi ation of one or more of the foimulalions as a repeated discrete treatment for a given period.
  • the method of this invention includes cyclical use, e.g , one or more of the formulations of the invention may be administered at fixed time inleivals.
  • the method may comprise evaluation of therapy midcourse, and formulations may be changed as a function of any sign of improvement of the subject, including lessening of symptoms, or in another embodiment, lessening of pathology, etc , as will be appreciated by one skilled in the art
  • formulations may be changed as a function of any sign of improvement of the subject, including lessening of symptoms, or in another embodiment, lessening of pathology, etc , as will be appreciated by one skilled in the art
  • theiapies may be altered following an indication of a lack of lesponse to particular administeied formulations
  • formulation of drug and polymer implants aie designed without siufactants or emulsifiers, instead using solvent casting from acetone followed by compression molding.
  • acetone is chosen as the solvent for asting, oi in anothei embodiment, other FDA Class III solvents (low toxicity with minimal need foi lemoval of residual solvent) aie used, in which, in one embodiment, the diug and biodegradable polymers are soluble at greater than 100 mg/ml
  • implants thus produced are tolerable, and bioactive, and can be demonstrated as such, for example in rodents wheie a demonstration of tolerabiiity and bioactivity following implantation in mouse and rat can be evaluated ovei a course of time, foi example for 3 weeks to 3 months post-implantation.
  • solvent casting is accomplished with solvents chosen from table I (FDA Class III solvents (FDA Guidance document Q3C): Table I FDA Class III solvents (FDA Guidance document Q3C
  • the methods, kit and compositions of this invention provide for drug release profiles, which are a function of the interaction of each drug with the respective polymer
  • other factors which may affect the patterns of release from the polymeric systems include diug diffusion rate, drug/polymer affinity, pH, source/sink concentrations, molecular weight average (MW W ), polymer numbei average (MW ⁇ ), their ratio (Polydispersity index [PDI]) and the capability of physiological fluids to plasticize tire biopolymer. .
  • the methods, kit and compositions of this invention provide that the first foi ulation and second formulation are administered within 1-48 houis of each othei.
  • administration of the fust foimulation is done simultaneously with administration of the second foimulation.
  • administration of the fust formulation is done before administration of the second formulation
  • administration of the fast formulation is done after administi ation of the second foimulation.
  • the methods, kit and compositions of this invention make use of a biodegradable polymer, which is in one embodiment Poly(d,l-lactide- glycolide) copolymer [PLGA].
  • a biodegradable polymer which is in one embodiment Poly(d,l-lactide- glycolide) copolymer [PLGA].
  • the biodegiadable PLGA polymei s may be as described by ( Kitchell .IP, Wise DL (1985) Poly(lactic/glycolic acid) biodegradable diug-polymer matrix systems. Methods Enzymol 112:436-448)
  • the biodegradable polymei is a polylactide, a polyglycolide, a polycapiolactone, a copolymer thereof, a terpolymer thereof, or any combination thereof.
  • the copolymer theieof is atactic, oi in another embodiment syndiotactic
  • the biodegradable thermoplastic polyester is a polylactide, a polyglycolide, a copolymei thereof, a terpolymer theieof, oi a combination thereof
  • the biodegradable thermoplastic polyester is 50/50 poly (DL-lactide-co-glycolide). In another embodiment, the biodegradable thermoplastic polyestei is 75/25 poly (DL-lactide-co-glycolide). In another embodiment, the biodegradable thermoplastic polyester is 85/15 poly (DL-lactide-co-glycolide). In another embodiment, the biodegiadable thermoplastic polyester is 60/40 poly (DL- lactide-co-glycolide). In another embodiment, the biodegradable thermoplastic polyester is 90/10 poly (DL-lactide-co-glycolide).
  • the biodegradable thermoplastic polyester comprises any combination of poly (DL- lactide-co-glycolide), which produces a desired release profile when in complex with a drug.
  • the biodegradable thermoplastic polyestei can be present in any suitable amount, provided the biodegradable thermoplastic polyester is at least substantially insoluble in aqueous medium or body fluid.
  • the biodegradable thermoplastic polyester is preferably present in about 50 wt % to about 98 wt % of the flowable composition, or in one embodiment is piesent in about 50 wt % to about 60 wt % of the flowable composition, or in another embodiment in about 60 wt % to about 75 wt. % of the flowable composition, or in anothei embodiment in about 75 wt. % to about 90 wt. % of the flowable composition, or in another embodiment, in about 90 wt. % to about 95 wt. % of the flowable composition, or in another embodiment, in about 95 wt % to about 98 wt. % of the flowable composition.
  • the biodegradable thermoplastic polymer has an average molecular weight of about 10,000 to about 200,000, or in another embodiment from about 15,000 to about 25,000, or in another embodiment from about 25,000 to about 45,000, or in another embodiment from about 45,000 to about 75,000, oi in another embodiment from about 75,000 to about 100,000, oi in another embodiment from about 100,000 to about 150,000, oi in another embodiment from about 150,000 to about 200,000.
  • the lactic monomer comprising the PLGA is at a concentration of between 50-100%, or in another embodiment between 50-60%, or in another embodiment between 60-70%, or in another embodiment between 70-80%, or in anothei embodiment, between 80-90%, or in another embodiment, between 90- 100% of the PLGA polymer, or in another embodiment comprises 100% PLA.
  • the teim "about” refers to a deviation from the lange of 1- 20%, or in anothei embodiment, of 1-10%, or in anothei embodiment of 1-5%, or in another embodiment, of 5-10%, or in another embodiment, of 10-20%.
  • the drug-polymer complex in a given formulation is such that the diug content is between 2 and 75% (w/w), or in another embodiment between 2 and 5% (w/w), or in another embodiment between 5 and 10% (w/w), or in another embodiment between 10 and 25% (w/w), or in anotlier embodiment between 25 and 35% (w/w), or in anothei embodiment between 35 and 50% (w/w), oi in another embodiment between 50 and 75% (w/w).
  • the complexes may be formed via covalent attachment of watei-soluble polymeis such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxy ethyl cellulose, dextian, polyvinyl alcohol, polyvinylpyrrolidone oi polyproline
  • modifications may increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, leduce the immunogemcity or leactivity of the compound or combination thereof
  • the methods, kit and compositions of the piesent invention provide foi the treatment of any disease or disorder wherein deliveiy of at least one diug ovei a sustained period of time is desiied.
  • any condition, disease or disoider, wheieby a treatment regimen with a particular compound or combination of compounds which comprises providing an initial formulation, which achieves therapeutic cii dilating levels, of the particular compound or combination of compounds, which is concurrent with or followed by treatment with a second formulation, which achieves therapeutic circulating levels, wheiein the circulating levels attained by the second foimulation, coincide with decline of such levels by the fust formulation, and the circulating levels are achieved over a prolonged course of time, is to be considered as part of this invention [00037]
  • the first formulation of the methods, kit and compositions of the present invention deliver the diug with pseudo-zero order kinetics which in one embodiment refers to a "steady state" (zero oider) release profile, or almost steady state, oi in one embodiment with a variation of ⁇ 5-10% from steady state, which delivers a therapeutically effective amount of diug over a given time period, In another embodiment, oscillation of ⁇ 5%,
  • the release profile from the formulation used in the methods, kit and compositions of the piesent invention may parallel that shown in Figure 7A, or in anothei embodiment Figure 7B, or in anothei embodiment Figuie 7C, oi in anothei embodiment, Figure 7C, or in anothei embodiment Figure 7D or in another embodiment Figuie 7E, or in another embodiment, approximate such profiles.
  • the formulation may be administered as a controlled release patch
  • the subject theiapeutic drug is delivered by way of a transdeimal patch
  • a patch is in one embodiment, a flat hollow device with a peimeable membrane on one side, and, also may comprise an adhesive to maintain the patch in place on the patient's skin, with the membrane in contact with the skin so that the medication can permeate out of the patch leservoir and into and through the skin.
  • the outei side the patch is formed, in one embodiment of an impenneable layer of material, and the membrane side and the outer side are joined around the perimeter of the patch, forming a reservoir for the medication and ca ⁇ iei between the two layeis Patch technology enables the active ingredient to be in constant contact with the epideimis Over substantial periods of lime, diug molecules, held in such a state, will diffuse into the bloodstream, due, in one embodiment to a concentration gradient, in another embodiment, tiansdermal drug delivery can be accomplished using patch technology
  • These conventional drug deliveiy systems comprise a patch with an active ingredient such as a drug incorporated therein, the patch also including an adhesive for attachment to the skin so as to place the active ingredient in close proximity to the skin
  • Exemplary patch technologies aie available from Ciba-Geigy Corporation and Alza Corpoiation.
  • transdermal delivery devices can be leadiiy adapted for use with the subject amphetamine compounds.
  • a maintenance set of the drug is administered once eveiy 3 months in a patch form.
  • release from and in another embodiment diffusion of the diug from the implant vary substantially foi diffeient drugs
  • design specifications foi one compound may not be directly translated to another
  • an antipsychotic or in another embodiment 9-OH- Risperidone are used as part of the methods, kit and compositions of the present invention to tieal a Nervous System disorder, which in one embodiment is Bipolar disoidei.
  • the methods, kits and compositions of this invention may be used in ordei to deliver thyrotiopin-releasing hormone, or L-dopa, in order to treat Paikinson's Disease
  • the methods, kits and compositions of this invention may be used in ordei to deliver naltrexone , in order to treat narcotic addiction
  • formulations used in the methods, kit and compositions of the piesent invention may comprise combination of drugs, which in one embodiment may be a part of the tieatment regimen of the disordei.
  • the present invention provides a method foi treating neivous system disorders, wherein the diug is at a concentration of between about 2 to about 50 percent by weight of said first or second formulation.
  • the drug is at a concentration of between about 2 to about 5 percent by weight of said first or second formulation.
  • the drug is at a concenti ation of between about 5 to about 10 percent by weight of said first or second foimulation
  • the drug is at a concentration of between about 10 to about 15 percent by weight of said first oi second formulation.
  • the drug is at a concentiation of between about 15 to about 20 percent by weight of said first or second formulation.
  • the drug is at a concentiation of between about 20 to about 30 percent by weight of said first or second formulation In one embodiment, the drug is at a concentration of between about 30 to about 40 percent by weight of said first or second formulation. In another embodiment, the diug is at a concentiation of between about 40 to about 50 percent by weight of said first oi second formulation
  • the piesent invention provides a method for ti eating nervous system disoideis, wheiein the drug used is Risperidone, 9-OH-Risperidone, haloperidol, oianzapine, clozapine, aiipiprazole, quetiapine, ziprasidone oi a combination theieof
  • the fiist and second foimulation have at least one diug m- common
  • the first formulation comprises Risperidone and 9-OH- Risperidone and the second foimulalion comprises 9-OFI-Risperidone
  • the fust foimulation comprises Risperidone and haloperidol
  • the second foimulation comprises haloperidol
  • the first formulation comprises quetiapine and 9-OH-Rispe ⁇ idone and the second formulation comprises 9-OH-Rispe ⁇ idone.
  • the first formulation contain drugs that aie therapeutic in chronic diseases.
  • the second formulation comprises drug that aie therapeutic foi an acute phase of the chronic disease
  • relapsing and l emitting diseases such as Multiple Sclerosis
  • each foimulation will comprise Copaxon
  • the first formulation may additionally comprise ⁇ -i ⁇ terferon, or in anothei embodiment, an immunomodulating compound
  • the second formulation has a late of release which is fastei than the first foimulation
  • the % drug released as a function of time is graphically depicted in Figure 4B
  • the second foimulation may be administered as a depot injection
  • the second formulation is administered as microspheres containing the drug entrapped within the biodegradable polymer matiix.
  • the f ⁇ st formulation of the methods, kit and composaitions of the pisenl invention is such that the rate of release of drugs is substantially slow, in order to provide for prolonged sustained release
  • substantially slow refers in one embodiment to an oidei of magnitude, relative to an average under noimal formulation
  • the present invention provides a method for treating neivous system disorders, wherein the fust formulation is an implant, and is administeied subcutaneously, and said second formulation comprises oral drug form, a parentei al form, or an inti avenous form .
  • the phiases "administered pixieerally" as used herein means mode of administration other than enteial and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, inlraaiteriai, intrathecal, intracapsular, i ⁇ traorbital, inlracardiac, intradermal, intraperitoneal, translracheal, subcutaneous, subcuticular, intraarticular, intraiumoral, subcapsular, subarachnoid, inlraspinal and intrasteinal injection and infusion.
  • the present invention provides for the cyclic administration of the first and second foimulations to said subject. It is to be undei stood that ordei of adminislarlion of first, second or in another embodiment, any additional administration of formulas containing the drug is within the scope of the piesent invention and may be varied to provide a designed ciiculating level of the diug, as will be appreciated by one skilled in the art,
  • the first and second formulations are administeied to said subject when the ciiculating levels of the drug serum levels are below the therapeutic threshold level foi that drug. In another embodiment, the first and second formulations are administered to said subject when the circulating levels of said drug serum levels are below 1 ng/mL.
  • the present invention provides a method for treating nervous system disordeis, wherein the first and second formulations are administered to said subject as described hereinabove from about 160-200 days, following a first administration of the formulations.
  • the first and second foimulations aie administered to said subject from about 160-180 days, following a first administration of the formulations
  • the first and second formulations are administeied to said subject from about 180-200 days, following a first administration of the foimulations.
  • the present invention provides a method for treating neivous system disordeis, wherein the method addresses the need for more sustained treatment adherence, or in one embodiment a methods of long-term medication delivery using implantable systems for the treatment of schizophienia.
  • Implantable systems have in anothei embodiment, the capability to optimize a medication's theiapeulic properties, which in one embodiment renders treatments that are more safe, efficacious or reliable
  • the present invention provides a method for healing nervous system disorders, wherein less medication may be generally lequired and side effects can be minimized
  • implantable systems can be removed by a physician in case of adverse side effects, offering a degree of reversibility.
  • the present invention provides a method for treating nervous system disorders, wherein mandatory removal at the end of the delivery interval is eliminated with biodegradable systems, cutting in half the inheient invasiveness to the patient .
  • the present invention provides a method for treating nervany diseases or disoideis where a prolonged therapy period is needed
  • the drugs are used to treat: HIV and other viral diseases, mycobacterial infection, cancer, multiple sclerosis, diabetes, kidney disease, or any other wherein the methods, kits or compositions of this invention prove useful
  • the present invention provides a method for treating nervous system disoideis, wherein said disorder is AIDS -related dementia, schizophienia, bipolar disorder, bordeiline personality disorder (BPD), Alzheimer's disease (AD), psychotic depression or othei mental disordeis causing confusion, disoiganization oi psychosis
  • the drug used according to the methods, kits or compositions of this invention may be any drug which is applicable for such lieatmenl regimens, as described herein.
  • the drug is a peplide, protein, nucleic acid, or compound.
  • tire term "drug” refers to a molecule that alleviates a symptom, disease or disorder when administered to a subject afflicted theieof
  • a drug is a synthetic molecule, or in another embodiment, a drug is a natuially occurring compound isolated from a source found in nature.
  • drugs may comprise antihypertensives, anlidepiessants, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, anti- inflammaloiies, antipsychotic agents, cognitive enlianceis, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Par kinsonism in agents, antibiotics, antiviral agents, anli-neoplastics, barbituates, sedatives, nutritional agents, beta blockeis, emetics, anti-emetics, diuretics, anticoagulants, cardi ⁇ tonics, andiogens.
  • corticoids anabolic agents, growth hormone secretagogues, anti-infective agents, coronary vasodilators, carbonic anhydrase inhibitors, antipiotozoals, gastrointestinal agents, serotonin antagonists, anesthetics, hypoglycemic agents, dopamineigic agents, anti-Alzheimer's Disease agents, anti-ulcer agents, platelet inhibitors and glycogen phosphorylase inhibitors
  • examples of the drugs used accoiding to this invention include, inter-alia, antihypertensives including piazosin, nifedipine, trimazosin, amlodipine, and doxazosin mesylate; the antianxiety agent hydroxyzine; a blood glucose lowering agent such as glipizide; an anti -impotence agent such as sildenafil citrate; anti-neoplasties such as chlorambucil, lomustine or echinomycin; anti-inflammatory agents such as betamethasone, prednisolone, piroxicam, aspirin, flurbiprofen and (+)_N- ⁇ 4-[3-(4- fluorophenoxy)phenoxy]-2-cycIopenten-l-yl ⁇ -N-hyroxyurea; antivirals such as acyclovir, nelfmavir, or virazoie; vitamins/nutrit
  • drugs for use according to this invention are the glucose- lowering drug chlorpropamide, the anti-fungal fluconazole, the anti- hypercholesterolemic atoivastatin calcium, the antipsychotic thiothixene hydrochloride, the anxiolytics hydroxyzine hydrochloride or doxepin hydrochloride, the anti-hypertensive amlodipine besylate, the antiinflammatories piroxicam and celicoxib and valdicoxib, and the antibiotics carbenicillin indanyl sodium, bacampicillin hydrochloride, troleandomycin, and doxycycline hyclate
  • a drug of this invention may comprise othei anlineoplastic agents such as platinum compounds (e.g., spiroplatin, cisplatin, and carboplatin), methotrexale, fiuorouracil, adriamycin, mitomycin, ansamitocin, bleomycin, cylosine arabinoside, arabinosyl adenine, mercaptopolylysine, vincristine, busulfan, chlorambucil, melphalan (e.g., PAM, L-PAM or phenylalanine mustard), meicaptopurine, mitotane, piocai'bazine hydrochloride daclinomycin (actinomycin D), daunorubicin hydrochloride, doxorubicin hydrochloride, paclitaxel and other taxenes, lapamyci ⁇ , manumycin A, TNP-470, plicamycin
  • platinum compounds e.g.
  • mitotic inhibitors such as etoposide, colchicine, and the vinca alkaloids, radiopharmaceuticals such as radioactive iodine and phosphorus products; hormones such as progeslins, estrogens and antiestrogens; anti-helmintics, antimalarials, and antit ⁇ berculosis drugs; biologicals such as immune serums, antitoxins and antivenoms; rabies prophylaxis products; bacterial vaccines; viral vaccines; respiratory products such as xanthine derivatives theophylline and aminophylline; thyroid agents such as iodine products and anti-thyroid agents; cardiovascular products including chelating agents and mercurial diuretics and cardiac glycosides; glucagon; blood products such as parenteral iron, hemin, hematopoiphyrins and their derivatives; biological response modifiers such as muramyldipeptide, muramyltripeptid
  • the methods, kits and compositions of this invention provide foi combined use of di ⁇ gs, as described herein, wherein such combinations may diffei within the respective foimulations, so long as a single drug is in common amongst foimulations administeied to a subject, at one point in time.
  • the methods of this invention may be affected via the use of a kit comprising the forumulations as described,
  • the invention provides a kit for sustained delivery of at least one drag comprising a first formulation of said drug in complex with a biodegradable polymer, wherein said formulation delivers said drug with pseudo zero- ordei kinetics in-vivo, and a second formulation of said drug in complex with a biodegiadable polymer wherein said second formulation has a rate of release which is faster than said first formulation, in-vivo.
  • the invention provides a kit foi sustained delivery of a drug, wheiein the combination of the first and second formulation of the kit gives sustained delivery, once administered over a period of about 1 week to about 14 months.
  • the combination of the first and second formulation of the kit gives sustained delivery, once administeied over a period of about 1 week to about 1 month In another embodiment, the combination of the first and second formulation of the kit gives sustained delivery, once administered over a period of about 1 to about 3 months In one embodiment, the combination of the first and second foimulation of the kit gives sustained deliveiy, once administered over a period of about 3 to about 6 months. In another embodiment, the combination of the first and second foimulation of the kit gives sustained deliveiy, once administered over a period of about 6 to about 9 months. In anothei embodiment, the combination of the fust and second foimulation of the kit gives sustained deliveiy, once administered ovei a period of about 9 to about 12 months. In another embodiment, the combination of the first and second formulation of the kit gives sustained deliveiy, once administered over a period of about 1 to about 14 months.
  • kit and compositions as described herein are used according to the methods of this invention, and in another embodiment, such use may include combination with othei kits or in anothei embodiment, compositions as a part of systemic therapy, and in anothei embodiment, may comprise use of only part of a given kit. oi particulai formulations theiein contained
  • kit of the piesent invention may be used with any of the methods described hereinabove, and in another embodiment, may make use of any of the compositions or foimulations described herein
  • the piesent invention provides a composition for use in the tieatment of psychotic disoiders, comprising a poly(d,l-lactide/glycolide) (PLGA) copolymei al a concentration of from about 95-98% (w/w), and an antipsychotic agent, at a concentration of from about 2 to about 5% (w/w), wherein the lactide:glycolide latio of said poly(lactide/glycolide) copolymer is from about 100:0 to 50:50 and wherein said antipsychotic agent is Risperidone or 9-OH-Rispe ⁇ idone, [00073]
  • the formulations of the present invention may be given in one embodiment orally, pixieerally, topically, or subcutaneously.
  • formulations aie given by foims suitable for each administration route are administered in tablets or capsule form, or in anothei embodiment by injection, infusion, inhalation, eye lotion, ointment, rectal suppository, or controlled ielease patch
  • the therapeutic circulating levels of said drug range from 0 1 - 10 ng/mL In another embodiment, the therapeutic circulating levels of said daig range from 0.1 - 0 5 ng/mL In one embodiment, the therapeutic circulating levels of said drug range from 0 5 - 1 0 ng/mL. In another embodiment, the therapeutic ciiculating levels of said drug lange from 1 0 - 1.5 ng/mL In one embodiment, the therapeutic ciiculating levels of said drug lange from 1.5 - 2 5 ng/mL In another embodiment, the therapeutic circulating levels of said drug range from 2.5- 5 ng/mL. In one embodiment, the therapeutic circulating levels of said drug range from 5 - 10 ng/mL.
  • this invention provides, wherein administering the second foimulation iesults in said circulating levels within a period of about 1-31 days. In another embodiment, administering the second formulation results in said ciiculating levels within a period of about 1-7 days. In one embodiment, administering the second foimulation results in said circulating levels within a period of about 7-14 days. In another embodiment, administering the second formulation results in said ciiculating levels within a period of about 14-21 days In one embodiment, administering the second formulation results in said circulating levels within a period of about 22-31 days.
  • this invention wheiein administering the fiist formulation results in acheiving circulating levels within a period of about 21-180 days.
  • administering the first foimulation results in acheiving circulating levels within a period of about 21-31 days
  • administering the first formulation results in acheiving circulating levels within a period of about 31-60 days
  • administering the first foimulation results in acheiving circulating levels within a period of about 60-90 days.
  • administering the fust foimulalion results in acheiving circulating levels within a period of about 90-120 days.
  • administering the first foimulation results in acheiving ciiculating levels within a period of about 120-150 days
  • administering the first foimulation lesulls in acheiving circulating levels within a peiiod of about 150-180 days
  • this invention provides for circulating levels of at least one desired diug, which is sustained for about from 1-420 days. In one embodiment, this invention provides for circulating levels of at least one desired drug, which is sustained for about from 14-420 days In one embodiment, this invention provides, wherein said circulating levels are sustained for about from 75-420 days In another embodiment, said circulating levels aie sustained for about from 75-180 days. In one embodiment, said ciiculating levels aie sustained for about from 180-270 days. In anothei embodiment, said ciiculating levels are sustained for about from 270-365 days In one embodiment, said ciiculating levels are sustained for about from 365-420 days
  • tire present invention provides for the use of implants inserted subculaneously
  • procedures for implantation could be easily tolerated with local anesthetic befoie subcutaneous placement.
  • using rigid implants obviate the need foi a tool to guide implants under the skin, reducing risk of intramuscular placement.
  • the foimulations may be such as to be suitable for implantation at any desired tissue site, in the form of a patch, or for injection, intiavenously, intracavitarily, intranodally, or any other appropriate site, and may be in the foim of a depot injection.
  • the route of administration and inleivals between administration may be individually adjusted for a given subject
  • the time inteival may involve administration of the formulations once every six months
  • treatment regimens according to the methods of this invention, and using the kits/compositions of this invention may be accompanied by other forms of treatment, which do not involve administration of a drug, such as subject interaction with psychiatrists and/or therapists.
  • the piesent invention provides a method foi treating a disease oi disorder, wherein at least one formulation is in the form of an implant, which in one embodiment is is disk shaped, or, in another embodiment, rod shaped.
  • Polymers and drugs are mixed in a proportion of 60/40 by mass and solvent cast from acetone
  • the resulting film may be compression molded to disk-shaped implants of 20 mm diameter with aveiage thickness of 1.22 ⁇ 0.0 mm, mass of 493 ⁇ 2 mg and density of 1.28 ⁇ 0.0 glee, such as for example, the implants exemplified hereinbelow
  • Rod-shaped implants are prepared as described in example 10 hereinbelow, having in anotlier embodiment a diameter of about 1 to about 2 mm, a length of between about 10 and about 40 mm, or a combination thereof.
  • the geometry of the implant may be varied to any foim which provides for a desired release profile, as will be appreciated by one skilled in the art, with dimensions which may vary in order to accommodate, in one embodiment, a desiied drug load, or in anothei embodiment, to suit the environment wheiein the material will be implanted, or any other consideration which will affect the methods of this invention, as will be appreciated by one skilled in the art
  • the invention provides a kit for sustained delivery of a diug comprising a first formulation of said drag in complex with a biodegradable polymei, wherein said foimulation delivers said drug with pseudo zero-order kinetics in-vivo, and a second formulation of said drug in complex with a biodegradable polymei wherein said second formulation has a rate of release which is faster than said fast formulation, in-vivo
  • the invention provides a kit for sustained delivery of a drug, wherein the combination of the first and second formulation of the kit gives sustained delivery, once administered over a peiiod of about 1 week to about 14 months
  • the combination of the first and second foimulation of the kit gives sustained delivery, once administeied over a period of about 1 week to about 1 month
  • the combination of the first and second foimulation of the kit gives sustained delivery, once administered over a period of about 1 to about 3 months.
  • the combination of the first and second formulation of the kit gives sustained delivery, once administered over a period of about 3 to about 6 months In another embodiment, the combination of the first and second formulation of the kit gives sustained delivery, once administered over a pei iod of about 6 to about 9 months In another embodiment, the combination of the fust and second formulation of the kit gives sustained delivery, once 5 administeied over a period of about 9 to about 12 months. In another embodiment, the combination of the first and second formulation of the kit gives sustained delivery, once administered over a period of about 12 to about 14 months.
  • the invention piovides a kit for sustained delivery of a 15 drug, wheiein the formulation is in a foim of a rod-shaped implant as described in one embodiment hereinabove, said rod-shaped disk has a diameter of about 1 to about 2 mm, a length of between about 10 and about 40 mm, or a combination thereof.
  • the present invention provides a flowable composition0 that is suitable for use as a controlled release implant of Risperidone or 9-OH- Risperidone
  • the flowable composition includes a biodegiadable theimoplastic polyester that is at least initially substantially insoluble in an aqueous medium or body fluid
  • the flowable composition is formulated as an injectable subcutaneous deliveiy system.
  • the inj ⁇ ctable composition5 piefeiabiy has in anothei embodiment a volume of about 0.20 mL to about 0.40 mL or about 0 30 mL to about 0 50 mL,
  • the injectable composition is preferably formulated for administration about once per month, or in another embodiment about once per thiee months, oi in another embodiment about once pei four months to about once pei six months
  • the flowable composition is a liquid or a gel composition,0 suitable foi injection into a patient
  • the piesent invention provides a composition for use in the treatment of psychotic disorders, in the form of microparticles, which in another embodiment, are fabricated as described in example 11 hereinbelow.
  • the microparticles of the present invention have a mean diameter (D 3 _ 2 ) of about 150 ⁇ rn ⁇ 50 ⁇ m, or in another embodiment a mean diameter (D 3>2 ) of about 0.75 ⁇ 25 nm
  • the formulations of this invention, for use in the methods oi incorporation in the kits or compositions of this invention may comprise nanoparticles, which comprise the drug in complex with a biodegradable matrix, as herein described,
  • compositions of the present invention may be administered in one embodiment to humans and othei animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intiavaginally, pendederally, intracisteinally and topically, as by powders, ointments oi drops, including buccally and sublingually,
  • the composition can be deliveied in a controlled release system.
  • the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration,
  • a pump may be used (see Langer, supra; Sefton, CRC Crit Ref. Biomed Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al, N Engl I. Med. 321 :574 (1989).
  • polymeric materials can be used
  • a controlled release system can be placed in proximity to the therapeutic taiget, i.e., the brain, thus lequiring only a fi action of the systemic dose (see, e.g , Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Othei controlled release systems are discussed in the review by Langer (Science 249: 1527-1533 (1 90).
  • the composition is in a form suitable for oral, intravenous, intraaorterial, intiamuscular, subcutaneous, parenteial, tiansmucosal, tiansdermal, oi topical administration.
  • the composition is a controlled release composition.
  • the composition is an immediate release composition
  • the composition is a liquid dosage foim.
  • the composition is a solid dosage form.
  • compositions of this invention may be in the form of a pellet, a table a capsule, a solution, a suspension, a dispersion, an emulsion, air elixii, a gel, an ointment, a cream, a patch or a suppositoiy,
  • the pharmaceutical pieparations of the invention can be prepared by known dissolving, mixing, gianulating, extrusion, coextrusion oi tablet-forming processes.
  • the active ingredients, or their physiologically tolerated derivatives in another embodiment such as salts, esters, N-oxides, and the like are mixed with additives customary foi this memepose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable foims for administration, such as tablets, coaled tablets, haid or soft gelatin capsules, aqueous, alcoholic or oily solutions
  • suitable inert vehicles are conventional tablet bases such as lactose, sucrose, or comstaich in combination with binders such as acacia, comstarch, gelatin, with disintegrating agents such as comstarch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
  • composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient
  • An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, foi example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trim ⁇ thylamine, 2-ethylamino ethanol, hislidine, procaine, and the like
  • compositions of the present invention are formulated in one embodiment foi oral delivery, wherein the active compounds may be incorporated with excipients and used in the fonn of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tiagacanth, acacia, comstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegiating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppeimint, oil of winter green, or cherry flavoring.
  • a binder as gum tiagacanth, acacia, comstarch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegiating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactos
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of tire above type, a liquid carriei Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, oi both. Syrup of elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. In addition, the active compounds may be incorporated into sustained-ielease, pulsed release, controlled ielease oi postponed release preparations and formulations.
  • Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatly acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e g,, poloxamers or poloxamines).
  • compositions of this invention comprise one or more, phaimaceulically acceptable carrier materials
  • the carriers for use within such compositions are biocompatible, and in anothei embodiment, biodegradable.
  • the foimulation may provide a relatively constant level of release of one active component In othei embodiments, however, a moie rapid rate of release immediately upon administration may be desired In othei embodiments, release of active compounds may be event-triggeied The events triggering the release of the active compounds may be the same in one embodiment, or different in anothei embodiment.
  • Events triggering the release of the active components may be exposuie to moisture in one embodiment, lower pH in anothei embodiment, or temperatuie threshold in anothei embodiment.
  • the foimulalion of such compositions is well within the level of oidinary skill in the art using known techniques.
  • Illustrative carriers useful in this regard include microparticles of poly(lactide-co-glycolide), poiyacrylate, latex, starch, cellulose, dextran and the like.
  • illustrative postponed-release carrieis include supiamolecuiai biovectors, which comprise a non-liquid hydrophilic core (e.g., a cross-linked polysacchaiide or oligosaccharide) and, optionally, an external layer comprising an amphiphilic compound, such as phospholipids
  • a non-liquid hydrophilic core e.g., a cross-linked polysacchaiide or oligosaccharide
  • an external layer comprising an amphiphilic compound, such as phospholipids
  • the methods, kits or compositions of the present invention may be used to improve the therapeutic efficiency of a cancer therapy, or treatment of HIV, Heipes simplex, Fleipes Zoster, mycobacterial infection, cancel, psychotic disordeis, multiple sclerosis, diabetes, kidney disease, chronic pain, Flepatitis or any other applicable disease or disordei, such as, in another embodiment, a chronic disease, wheie a prolonged therapeutic legimen involving repeated administration of at least one drug is beneficial
  • Each implant was made from a single polymer of Poly(d,l-lactic-glycoiic acid) copolymer (PLGA) in ratios of 75:25, 85:15, 90:10 (high and low inherent viscosity), 95:5 and 100:0 (Medisoib® Aldermes, Cincinnati, OH), lesepectively, polylactic acid (PLA):poiygIycoIic acid (PGA).
  • PLGA Poly(d,l-lactic-glycoiic acid) copolymer
  • PGA Poly(d,l-lactic-glycoiic acid) copolymer
  • haloperidol release was measuied over a total of 443 days Average serum concentration during the fust 224 days is 10.5 ⁇ 1 5 ng/ml. During the subsequent 176 days, serum haloperidole level is sustained at lower concentration befor the end of release. Mean concentration during this period is 4.0 ⁇ 0.4 ng/ml. During the last 45 days, release follows 1 st order decay release with a mean serum level of 1.2 ⁇ 0,3 ng/ml
  • Five additional animals leceived implants comprising a combined polymer system including 75:25, 85:15, 90:10 high inherent viscosity, 90:10 low inherent viscosity and 100:0 PLGA.
  • the average dose in this group was 473 ⁇ 4 mg/kg with an expected delivery over 365 days yielding an average daily dose of 1.29 ⁇ 0.03 mg/kg/day.
  • Two labbils leceived implants without drug as a control One control received 100% PLA implants to mimic the single polymer condition, while the other received implants composed of 75:25, 85:15, 90:10 high inherent viscosity, 90:10 low inherent viscosity and 100:0 PLGA to minor the combined polymer system.
  • Implant fabrication
  • Risperidone Stability [0010I]Risperidone (10 mg) was dissolved in 100 ⁇ l of Acetonitrile for subsequent dissolution in 1000 ml of phosphate buffered saline, pH 7.0 to yield a final solution of 10,000 ng/ml Risperidone solution was then sloied in a light-safe amber bottle at 37 °C and shaken at 40 rpm. 1ml samples were taken 3 times per week and examined by UV spectroscopy (Amersham Biosciences, Buckinghamshire, UK) for drug content. Analysis indicated that the concentiation of drug remained stable with an overall decrement of 0.12% over 285 days, equivalent to 0.05 ng/day.
  • Example 4 Determination of maximum load of Risperidone in the implants Determination of maximum Risperidone drug Load [00104] Studies examining the effect of diug concentiation on Risperidone release profile are done with the purpose of establishing the maximum concentration of Risperidone that can be used in implants. Maximum drug loading per implant system is used to minimize implant system size, thereby making it more tolerable
  • Figure 5 shows the cumulative in-vitro release from disk and rod- shaped implants Each point represents the mean of triplicate observations of disks or rods Each implant was disposed in 500 ml of phosphate buffeted saline, pH 7 0 at 37 °C at 40 RPM in the dark. Rods and disks weie matched for weight No appreciable differences in ielease profile weie found, between the two implant geometries evaluated under these conditions
  • Figuie 6 shows a model for continuous deliveiy from biodegradable implants.
  • the release profile from 100% poly(lactic Acid) (PLA) implants in rabbits is superimposed temporarily at 6 months intervals (gray trendlines) to model reimplntatio ⁇ intervals Projected serum levels are summed at each time point, resulting in an anticipated total release plot (Xs)
  • the black trendlines model total ielease data
  • the system oscillates around a target serum level as long as reimplantations occur eveiy 6 months
  • Example 7 Sealing of sustained release drug therapy to human patients
  • Risperidone Stability of Risperidone is evaluated following solvent casting from acetone and slow extrusion molding, theieby ensuring that the compounds can withstand commercial processing into implants. Subsequently, a shelf-life study is conducted wherin Risperidone content is examined in a series of implants stored at 4°C for various intervals up to 1 year. Risperidone is stable in a physiologic aqueous environment (37 °C, phosphate bufferred 0.9% saline, pH 7.0) for over 10 months when examined with UV spectroscopy.
  • Risperidon retains its characteristic HPLC- MS pealc retention time and mass, following solvent casting and compression molding. In addition, Risperidone displays less than 1% degradation during 1 year storage and similarly, Risperidone displays less than 1% degradation during 1 year storage in a physiologic aqueous environment (37 °C, phosphate buffeired 0.9% saline, pH 7.0) as assessed by quantitative HPLC equipped with UV detector.
  • PLGA stability is evaluated by measuring inherent viscosity and glass transition temperature (Tg). PLGA polymers display less than 5% change in inherent viscosity and less than 2°C change in Tg following solvent casting and extrusion molding in a dry environment at 4°c for 1 year 1 .
  • Risperidone is synthesized using GMP methods. Commercially available, medical-grade Risperidone and acetone (USP/EP) is used.
  • Risperidone solution is prepared as follows: Risperidone (lOmg) is dissolved in 100 ⁇ l of Acetonitrile foi subsequent dissolution in 1000 ml of phosphate buffeied saline, pH 7.0 to yield a final solution of 10,000 ng ml. Risperidone solution is then stored in a light-safe amber bottle al 37 °C. Three aliquots (lOO ⁇ l) of each sample will be drawn at monthly intervals for HPLC analysis. The concentration of Risperidone is then plotted against time and the slope of the resulting line reflects the stability of the compound .
  • Risperidone [00I06]Risperidone implants composed of 5% drug and 95% polymer (w/w) aie made by solvent casting from acetone followed by slow extrusion molding into rods measuring 3.6mm in diameter and 20 ⁇ 10 mm le ⁇ gtii al 60°C and 5mm/sec piston speed, The resulting material undergoes quantitative in vitro analysis with HPLC for Risperidone content. The resulting measurements are expressed as as a ratio of the original mass of Risperidone in the implant material.
  • Typical release of Risperidone is shown in Figure I lA depicting cumulative ielease of Risperidone dispersed in PLGA biodegradable matrix Similar profile is shown for 9_OH-Risperidone in Figuie 11B, similaily, Figure 12 shows the cumulative release of 20% (w/w) 9-OH-Risperidone dispersed in 85:15 PLA:PGA block copolymei biodegradable matrix.
  • Figuie 13 shows the graph of cumulative release of 20% (w/w) Risperidone dispersed in 85:15 PLA:PGA block copolymer biodegiadable matrix.
  • Implants were fabricated through solvent casting and compression-molding. Two polymers, 75% polylactide with 25% polyglycolide (75:25 PLGA) and 85% polylactide with 15% polyglycolide (85:15 PLGA) were presented in a combined system of release during a 5-month period. Each copolymer had a distinctive period of degradation that was determined by the ratio of lactide to glycolide and the moleculai weight of the resulting molecule produced. An additional polymer of 100% polylactide (PLA) was used for in vivo testing in rats.
  • PLA polylactide
  • Implantation/removal surgery [001 13]Mice and rats were anesthetized with ketamine/xylazine (100/10 mg/kg, i.p,). A 1- cm scalpel incision was made in the skin on the dorsal aspect of the animal. The subdermal space was visualized with hemostats and a single implant was placed between dermis and muscle with forceps The wound was then closed with a surgical staple. Foui weeks aflei implantation, implants were localized by palpation and removal was performed with identical anesthesia and incision In-tact implants weie easily removed with forceps.
  • Blots were then incubated overnight with a ⁇ ti-D2-Receptor antibody, washed with TBS, and incubated with goat anti rabbit horseiadish peroxidase conjugate (BioRad, 1:4800) for 1 hour. Blots were then incubated with chemilu inesce ⁇ t substrate (Pierce) for 1 min, wrapped with plastic and exposed to autoiadiographic film Quantification:
  • Figuie 8 graphically depicts individual implants that are placed in phosphate buffered saline, pH 7, at 37°C on a shaker. Samples of buffer are drawn at weekly / biweekly intervals and evaluated with GCMS for haloperidol concentration. Cumulative release is expressed as the percent of total drug load measuied in buffer solution at each time point. Cumulative haloperidol concentration from 75:25 and 85:15 PLGA polymers. Each graph displays data from three implants (circle, squaie and triangle) with a 4th degree polynomial average line for the three values.
  • Implants made of 85:15 PLGA with 40% haloperidol displayed a similai pattern of release with a phase of slow release (approximately 0,26% / day / implant) from 0 to 56 days A second phase of more rapid release occurred between 56 and 140 days (0 95% / day / implant)
  • Implants made from 85:15 PLGA released half of the haloperidol load in 88 days ( Figure 8B) Release from the theoretical composite system of 75:25 and 85:15 PLGA, 40% haloperidol, shows an early phase from 0 to 28 days with an average of 0 34%/day and moie rapid release between 28 to 140 days with 0.82%/day.
  • In-vivo Locomotor activity [001 19]Locomolor activity for mice that received either haloperidol or blank polymer implants is demonstrated in Figuie 9 All animals were tested 3 weeks after- receiving implants made of 75:25 PLGA alone or 75:25 PLGA with 20% haloperidol Baseline locomotor activity was measured for twenty minutes. Animals with control implants traveled a mean of 12223 ⁇ 433 cm, while those with haloperidol containing implants traveled an average of 7664 ⁇ 450 cm. Thus, mice with haloperidol implants traveled significantly less distance than controls (p ⁇ 0 01) Implants were then lemoved and all animals were allowed to recover for 48 hours One animal with a control implant died from anesthetic during removal surgeiy.
  • mice Forty-eight houis after removal of implants, animals received apomorphine 0.5 mg/kg i.p. twenty minute prioi to locomotor testing, which has been shown to inciease locomotor activity in mice (Ninan and Kulkarni 1999) After apomoiphine challenge, animals that had control implants traveled a mean of 4721 ⁇ 476 cm, while those with haloperidol containing implants traveled an average of 8531 ⁇ 2536 cm. Therefore, following lemoval of implants and exposure to apomorphine, mice that had haiopetidol implants traveled more distance than control mice (p ⁇ 0.01).
  • Risperidone Disk implant may be fabricated tluough solvent casting and/or compression-molding. Two polymers, 75% polylactide with 25% polyglycolide (75:25 PLGA) and 85% polylactide with 15% polyglycolide (85:15 PLGA) are presented in a combined system of release during a 12- 14-month period.
  • Each copolymer has a distinctive period of degradation thai is determined by the ratio of lactide to glycolide and the molecular weight of the lesulting molecule produced All polymers (Alkermes Inc., Cincinnati, OH) aie with an inheient viscosity of 0 66 0.80 DL/g in chloroform and a molecular weight distribution between 120,000-140,000.
  • Individual polymers and Risperidone (Sigma, St. Louis, MO) may be dissolved in acetone and solvent cast at 60°C for 72 hrs. Solvent-cast material was made into disks measuring 20 mm in diameter and 1.2 ⁇ 0 00 mm thickness, with final density of 1.2 ⁇ 0.1 g/cc.
  • Rod Implants may be fabricated through compiession-molding.
  • PLGA polymer, 50% polylactide with 50% polyglycolide (50:50 PLGA) are presented in a system of release during a 2-month period
  • Polymer (Alkermes Inc., Cincinnati, OH) is with an inherent viscosity of 0,66 ⁇ 0,1 DL/g in chloroform and a molecular weight distribution between 120,000-140,000, Polymer and Risperidone (Sigma, St.
  • the first group of control subjects receive 6 months of risperidone exposure from a multiple polymer system
  • the second group of control subjects receive an initial multi-polymer system followed by reimplantalion of "maintenance" implants at six months to provide 12 months of continuous medication prior to necropsy.
  • C) The third group of control subjects receive an initial multi-polymer system to provide six months of steady state delivery, but will not receive leimplantalion of maintenance implants. These control subjects are then be tested at 12 months post implantation to provide toxicological evaluation after the system has ceased to delivery medication
  • D) The fourth group of control subjects receive broken implants to evaluate the consequences of mechanical damage to implants during the delivery inteival.
  • the fifth group of control subjects serve as positive control and they leceive daily oral risperidone or risperidone injections to reveal toxicological effects of the drag that are independent of the deliveiy system being tested, F) The final group of control subjects receive blank implants with no drug as a negative control to assess the effects of polymer materials, independent of risperidone.
  • Rod Implant Disposition Implants varying in release profiles are inserted subcutanously to a patient in need thereof
  • the implans may be disposed at the shoulder through a 4 mm incision. Since the implants aie rigid, no implant-guides are necessary,
  • BPRS Brief Psychiatric Rating Scale
  • Example 11 Microparticles for Oral-delivery of 9-OH-Risperidone for bipolar disorder, short term therapy (1-3 weeks).
  • the microparticles are made from poly(glycolic acid) and poIy(d,l -lactic acid) copolymer at a 75:25 ratio of lactide to glycolide with 9-hydroxy-Rispe ⁇ idone, as an active agent at 98:2 w/w ratio PLGA copolymer and 9-hydroxy-Risperidone aie dissolved in acetone and EVA as the dispersed phase.
  • the continuous phase is made with PVA, water, ethyl acetate, and benzyl alcohol.
  • the dispersed and continuous phases at a 20:80 latio are pumped through a static mixer (Kenics ® KM Series Static Chcmineer, Dayton, OH) to form an emulsion.
  • Final microspheie size may be controlled by phase ratio, flowrate, temperature and continuous phase composition.
  • the resulting emulsion is passed into a quenching liquid. After being allowed to settle, the lesulting microspheres are then filtered and washed repeatedly with a series of appropriate solvents and then dried.
  • Microspheres are incoprorated in capsules and orally administered to a patient in need theieof,
  • the microspheres may be incorporated with excipients and used as ingeslible capsules, which also contain a binder, excipients, a lubricant and possibly a liquid ca ⁇ ier
  • Treatment efficiency [00128] Patients undergoing long-term therapy exhibit improvement of at least 7 points above baseline based on Clinical Global Impression (CGI), and mean Global Assessment of Functioning (GAF) scores. Treatment is well tolerated, and no patient experiences worsening of mood symptoms while receiving 9-OH-Risperidone (Ghaemi, S,N, [1997] Acute Treatment of Bipolar Disorder with Adjimclive Risperidone in Outpatients Can J Psychiatry, Vol 42,pp. 196-199.
  • Example 12 Sustained release therapy of psychotic disorder using second generation antipsychotic agent; Starter formulation:
  • a patient exhibiting symptoms of psychotic disoider is given a formulation containing the antipsychotic drug in the form of an injectible for practically immediate elevation of blood serum level to above theiapeutic levels.
  • the injectible formulation is followed by oral dose of microparticles of PLGA containing the antipsychotic drug, wherein fast release of the drug, to above-therapeutic leveis is obtained in a day and peak delivery is obtained over a two-week period.
  • Implants Single polymer implant: [00130] Implants fabricated as described above are made from a single copolymer containing the antipsychotic agent Release profile is designed to achieve therapeutic levels within 3 weeks of implantation and last from 6-8 months until ftill degradation, with peak ielease occurring 5-7 months following implantation In older to compensate for the high amplitude oscillation around optimal serum level of the antipsychotic agent that may result from a single implant, a second maintenance set of a single copolymei composition may be added, with peak delivery al 10- 14 weeks and full degradation within 4-5 months from implantation Examples of cumulative ielease profile for seveial antipsychotic agents from PLGA implants are shown graphically in Figures 14D, 15A, 16A and 17A 5 Multiple copolymer compositions implant: [O0I31]Using coexti ⁇ sion, a high-load core PLGA (85:15 PLA:PGA, high IV) copolymer with prolonged ielease profile is incorporated as the core of composite implant with external low
  • !5[00132]2 ml of blood are taken from the subject eveiy three months or as needed based on the implantation/reimplantation legimen. Blood is then centrifuged and the serum separated Antipsychotic agent concentration is determined following solid-state extraction (MCX, Waters) and HPLC/UV detection by comparison against a known standaid0 Monitoring treatment efficacy: [00133]Monitoring efficacy will depend on the psychotic disorder being tieated. Patients generally show improvement in cognitive tasks, stable emotion or mood swings, or in particular, improvement in ones ability to work, interact and be intimate with5 other people and society. No significant side effect are evident and rehospitalization frequency is reduced. Effects of antipsychotic agents released from implants is shown in Figuies 14-17.
  • Figures 18 A-B shows cumulative risperidone release from implants containing 85:15 PLGA with 20, 40 or 60% drag load by weight, Each point represents the mean of thiee replicates with a trendline to demonstrate overall pattern of release, A) Release expressed in total g of risperidone from each 50 mg implant B) Release expressed as a percentage of the amount of drug in each type of implant.

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Abstract

The present invention provides a method, a kit and compositions for long-term release of a drug at a constant therapeutically effective level for nervous system disorders where adherence to therapeutic regimen is problematic. In particular, to the therapy of psychotic disorders.

Description

LONG-TERM DELIVERY FORMULATIONS AND METHODS OF USE THEREOF
FIELD OF INVENTION
[0001] This invention provides long-teπn delivery formulations comprising a it) biodegradable matiix and an agent of interest, methods of producing the same, and methods of use thereof. The invention also relates to long-term formulations of Rispeiidone and 9-OH-Risperidone compositions for the treatment of psychotic disorders
15 BACKGROUND OF THE INVENTION
Psychotic disoiders are pathological conditions of the biain characterized by identifiable symptoms that lesull in abnormalities in cognition, emotion or mood, or in particular, in temis of ones ability to work, interact and be intimate with other0 people These disorders may vary in severity of symptoms, duration, and functional impairment. Psychiatric disorders afflict millions of people of all ages worldwide, foi extensive periods of time, resulting in tremendous human suffering and economic burden due to lost productivity In some cases the psychiatric disorder may be acute, iasting only foi several weeks to months. In other instances the disorder is chronic,5 lasting for years or even decades.
[0002] The use of pharmacological agents to treat psychotic disorders has greatly increased due to teseaich advances in both neuroscience and molecular biology. In addition, advances in the field resulted in production of new drugs and deliveiy0 mechanisms, which aie more effective in treating psychosis and other pathological conditions of the brain, and yet have fewer accompanying side effects.
[0003] Medication non-compliance is a pervasive problem with many forms of illness. Non-compliance causes particular medical and social problems when the diugs concerned aie neuroleptics (anti-psychotics) such as chlorpromazine or haloperidol (Rogcis, A et al. [1998], "The meaning and management of neuroleptic medication: A study of patients with a diagnosis of schizophienia," Social Science and Medicine 47(9): 1313-1323) There are numerous reasons patients with psychotic disorders choose not to comply with a prescribed medication legimen. Between one- quartei and two-thirds of patients cite side effects as theii primary leason foi medication discontinuance (del Campo, E I et al. [1983], "Rehospitalized schizophrenics: what they report about illness, treatment and compliance," J. of Psychosocial Nurs. and Mental Health Serv. 21(6):29-33). Others cite lack of family support (Robinson et al , 2002) Other studies have directly linlced the severity of psychopathology with non-compliance in both inpalient and outpatient settings (Fenton, W S et al [1997], "Determinants of medication compliance in schizophienia: empirical and clinical findings," Schizophrenia Bull. 23(4):637-651) The most powerful predictor of relapse and hospitalization among patients with schizophrenia is non-adherence with antipsychotic treatment regimens (Csernansky ΪG. Schuchait EK: Relapse and rehospitalization lates in patients with schizophrenia effects of second generation antipsychotics CNS Drugs 2002, 16:473-484. Doeiing S, Mullei E, Kopckc W, Pietzcker A, Gaebel W, Linden M, Mullei P, Muller-Spahn F. Tegeler J, Sch ussier G: Predictors of relapse and lehospitalization in schizophrenia and schizoaffective disoider. Schizoplir. Bull 1998, 24:87-98.). Other studies have leporled an even gieater incidences of non-compliance (up to 55%) In England, wheie adheience rates foi neuroleptics converge at a 50% level, lesearchers concluded, "This late of non-consumption of prescribed medications suggests that, foi many individuals, non-compliance holds more benefits than compliance" (Rogers et al [1998], supra, p 1315).
10004] With an economic and social burden of healthcare cost, foi nonadherence in mental health estimated at $2 3 Billion annualy (Menzin et al , 2003), therapy that helps patients adhere to medication legimens for extensive periods of time, or alternatively, removes the patient from the decision making process, would improve clinical outcome substantially
SUMMARY OF THE INVENTION [0005] In one embodiment, tins invention provides a method of treating a Nervous System disorder in a subject in need theieof, the method comprising administering to the subject a first formulation of a drug in complex with a biodegradable polymer, wherein said formulation deliveis said drug with pseudo zero-order kinetics in-vivo; and administering to the subject a second formulation of said drug in complex with a biodegradable polymei, wherein the second formulation delivers the diug at a faster late, in-vivo, than the first formulation, whereby administering said fust and second formulation results in therapeutic circulating levels of said diug, thereby being a method of treating a nervous system disorder,
[0006] In another embodiment, this invention provides a method comprising administering to the subject a first foimulalion of a drug in complex with a biodegradable polymei, wherein said formulation delivers said drug with pseudo zero- oider kinetics in-vivo; and administering to the subject a second formulation of said drug in complex with a biodegradable polymei, wherein the second formulation delivers the diug at a fastei rate, in-vivo, than the first formulation, whereby administering said fust and second formulation results in therapeutic circulating levels of said drug indefinitely upon re implanting.
[0007] In another embodiment, the invention provides a kit foi sustained deliveiy of a drug comprising a fust foimulalion of said drug in complex with a biodegradable polymer, wherein said foimulation delivers said diug with pseudo zeio-oider kinetics in-vivo, and a second formulation of said drug in complex with a biodegradable polymer wheiein said second formulation has a late of lelease which is fastei than said first foimulation, in-vivo.
[0008] In one embodiment, the present invention provides a composition for use in the treatment of psychotic disorders, comprising a poly(d,I-lactide/glycolide) (PLGA) copolymei at a concentration of from about 95-98% (w/w), and an antipsychotic agent (al a concentration of from about 2 to about 5% w/w), wherein the lactide:glycolide ratio of said po!y(iactide/glycolide) copolymer is from about 100:0 to 50:50 and wheiein said antipsychotic agent is Risperidone or 9-OH-Risperidone
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing Haloperidol release for total of 443 days from PLGA disk implanted in monkeys.
FIG. 2A is a graph showing Haloperidol release for total of 379 days from single PLGA disk system implanted in Rabbits.
FIG 2B is a graph showing Haloperidol release for total of 379 days from combination PLGA disk system implanted in Rabbits.
FIG 3 is a graph showing In-vilro cumulative Risperidone lelease from implants containing expressed as total mass of Risperidone released,
FIG 4A is a graph of cumulative release of 20, 40 or 60% (w/w) Risperidone dispersed in 85:15 PLGA leleased from 50 mg implant
FIG 4B is a graph of cumulative release of 20, 40 or 60% (w/w) Risperidone dispersed in 85:15 PLGA Release expressed as percentage of the amount of drug in each implant
FIG. 5: is a graph showing cumulative hi-viiro release from disk and rod-shaped implants. Diffeiences in release profile were statistically insignifacnt.
FIG. 6: is a graph showing a model for continuous delivery from biodegradable implants projected to oscillate around a target serum level as long as implantations occui eceiy 6 months,
FIG. 7A: is a giaph showing expected seium release from a single polymer FIG. 7B: is a graph showing expected serum release from leimplantalion of a single polymer matrix eveiy 6 months
FIG 7C: is a giaph showing expected serum release pattern from leimplantalion of a single polymer system every 6 months, along with a maintenance set with 3 month peak release
FIG. 7D: is a graph showing the expected release from a staiter polymer set, abridging the first 4 months of therapy, FIG. 7E: is a graph showing the expected release from a combination therapy comprising staiter polymer set, abridging the first 4 months of therapy with reimplantation of a single polymer system every 6 months, along with a maintenance set with 3 month peak telease FIG. 8 A is a g aph showing 40% haloperidol release from Implants made from 75:25 PLGA:
FIG 8b is a giaph showing 40% haloperidol release from Implants made from 85:15 PLGA: FIG 8C: is a graph showing cumulative release from a hypothetical two-polymer system over a period of 154 days.
FIG 9: is a graph showing locomotor activity (total distance in meters over twenty minutes) tested prior to implant removal and then again 48 hours following implant
FIG. 10 shows the Western blot of D2 receptor piotein in striatal membranes from tats treated with haloperidol-PLA or PLA alone implants for 3 months.
FIG I lA is a graph of cumulative ielease of Risperidone dispersed in PLGA biodegiadable matrix.
FIG 1 1 B is a graph of cumulative release of 9-OH-Risperidone dispersed in PLGA biodegradable matiix.
FIG. 12 is a graph of cumulative release of 20% (w/w) 9-OH-Risperidone dispersed in 85:15 PLA:PGA block copolymer biodegradable matiix.
FIG. 13 is a graph of cumulative release of 20% (w/w) Risperidone dispersed in 85:15 PLA:PGA block copolymer biodegradable matrix.
FIG 14 A: Is a giaph showing the effect of Implants in rats or mice for in vivo behavioral testing with piepulse inliibition of startle (PPI). FIG 14B: Is a graph showing the effect of Implants in rats or mice for in vivo behavioral testing with prepulse inhibition of startle (PPI) following Amphetamine administration
FIG 14C: Is a graph showing the effect of Risperidone Implants in rats or mice for in vivo behavioial testing with prepulse inliibition of startle (PPI) pre and post Amphetamine administration.
FIG 14D: Is a graph showing the cumulative Risperidone ielease from 85:15 (PLA:PGA) PLGA implants as a function of time
FIG 14E: Is a giaph showing the effect of Risperidone Implants in rats oi mice on in vivo behavioral testing with prepulse inliibition of startle (PPI).
FIG 14F: Is a graph showing the effect of Risperidone Implants in rats or mice on in vivo behavioral testing with prepulse inliibition of startle (PPI) following vehicle injection
FIG 14G: Is a graph showing the effect of Risperidone Implants in rats or mice on in vivo behavioral testing with piepulse inhibition of staitle (PPI) following amphetamine administration,
FIG. 15 A: Is a giaph showing the cumulative quetiapine release from 85:15 (PLA:PGA) PLGA implants as a function of time. FIG. 15B: Is a graph showing the effect of Quetiapine ielease from implant before and after injection of apomorphine, relative to control on PPL
FIG. 15C: Is a graph showing the effect of Quetiapine injection before and after injection of apomorphine, lelative to control and sham apomorhine injection on PPI
FIG 16A: Is a graph showing the the cumulative clozapine release from 85:15 (PLA:PGA) PLGA implants as a function of time FIG 16B: Is a graph showing the effect of Clozapine Implants before and after placebo injection of apomoiphine, relative to control and sham apomorhine injection on PPI
FIG 16C: Is a graph showing the effect of Clozapine Implants befoie and after injection of apomoiphine, lelative to control and sham apomorhine injection on PPI
FIG 17A: Is a giaph showing the cumulative haloperidol release from 85:15 (PLA:PGA) PLGA implants as a function of time FIG 17B: Is a graph showing the effect of haloperidol release from PLGA implants on PPI
FIG 17C: Is a graph showing the effect of haloperidol Implants in lats or mice on in vivo behavioral testing with piepulse inliibition of staitle (PPI)
FIG. ISA: Is a graph showing the effect of initial drug load on cumulative Risperidone ielease from 85:15 (PLA:PGA) PLGA implants in-vitro
FIG. 18B: Is a graph showing the effect of initial drug load on fractional Risperidone ielease from 85:15 (PLA:PGA) PLGA implants in-vitro
DETAILED DESCRIPTION OF THE INVENTION
[0009] This invention provides in one embodiment, long-term sustained delivery formulations and methods of use thereof
[00010] In one embodiment, this invention provides a method of ti eating a Neivous System disoider in a subject in need thereof, the method comprising administering to the subject a fust formulation of a drug in complex with a biodegradable polymer, wherein said fust formulation delivers said drug with pseudo zeio-ordei kinetics in- vivo; and administering to said subject a second formulation of said drug in complex with a biodegradable polymei, wherein the second formulation delivers said drug substantially faster, in-vivo, than the first foimulation, whereby administering said first and second formulation results in therapeutic circulating levels of said drug, thereby being a method of treating a nervous system disorder.
[000 I I] In anothei embodiment, this invention provides a method of treating a Nervous System disoider in a subject in need thereof, wherein the method uses a kit comprising the formulations as described further hereinbelow
[00012] In one embodiment, the method may further comprise administrating at least one additional foimulation comprising the drug in complex with a biodegiadable polymei, wherein the late of release of the drug from said one additional formula is fastei than the fust formulation and in one embodiment, is faster than the second foimulation, or in anothei embodiment is slower than the second formulation, or in anothei embodiment is slower than the fust formulation. In one embodiment, the one additional formulation has a peak diug release which is piior to the pealc release of either the first formulation, or in anothei embodiment, the second formulation. In another formulation the one additional foimulation has a peak drug release which coincides with the peak release of either the first formulation, or in another embodiment, the second foimulation, oi in another embodiment follows the peak rel ease of sai d fu st foi mul ation.
[00013] In one embodiment, the methods, kits and compositions of this invention, as further described hereinbelow comprise or make use of a first formulation, which is in complex with a biodegradable polymer that is metabolized, oi in another embodiment produces non-toxic, oi in another embodiment sub-pathologically toxic by-products.
[00014] The degiadation products of PLGA, lactic acid and glycolic acid in one embodiment, are water soluble, non-toxic products of normal metabolism that are either excieted oi further metabolized to carbon dioxide and water in the Krebs cycle
[00015] In one embodiment, the terms "in complex" or "complexes" refer to the drug molecules being interdispeised within a biodegradable polymer's matrix. In one embodiment, the drug is located within interstitial spaces within the polymer matrix, which may be accomplished, in antoher embodiment, via fast solvent extraction, wheiein, following extraction, a lesυlting increase in polymer concentration occurs, which causes a rapid inciease in polymer viscosity, and in anothei embodiment, lowers diffusivity of the thus entiapped drug
[00016] In one embodiment, the term "fast solvent extraction" refeis to solvent removal at a late in which the resulting increase in polymer concenti ation and subsequent increase in viscosity are such that allignment of the polymer chains to the point of lecrystallization is kinetically unfeasible
[00017] In one embodiment, any factor, which may affect the entrapment of the subject diug in the biodegradable polymer matrix, and thereby affect its initial loading, in one embodiment, oi, in another embodiment, subsequent release, or in another embodiment, a combination theieof, may be utilized according to the methods of this invention, and in kits and compositions of this invention In other embodiments, such factois may comprise inter-alia, the initial solvent concentration, its moleculai size and polarity, the lempeiature and piessure under which the solvent is lemoved, molecular weight numbei (MWn) average of the biodegradable polymer matrix, its polydispeisity index, the size and polarity of the drug, the monomer ratio and distribution along the copolymei's chain, or a combination thereof. In addition, D/L ratio within each monomer of a biodegiadable polymer will affect release rates. In one embodiment, the term D/L ratio refers to the ratio of monomer molecules that affect the direction (D-iight, L-left), in which a cross-polarized lense will be rotated when obseiving a single optically active monomei , like lactic acid. Since most mammals have D-specific enzymes, that ratio will affect the digestion late of the biodegradable biopolymer, affecting its molecular weight and consequently its viscosity, thereby affecting release rate of any entrapped drug
[00018] In one embodiment, the term "circulating level" rofeis to the concentiafion of the drug in blood serum as measured by separating the serum and determining drug concentration
[0001 ] In one embodiment, the term "theiapeutic" means the produced desired biological, or in another embodiment, prophylactic response, as a consequence of a method, or administi ation of a kit or composition of this invention In one embodiment, the desired response can be a reduction (complete or in another embodiment partial) of symptoms associated with a particular disease or disordei, such as, schizophienia, depiession, psychotic anxiety or combination thereof, In another embodiment, on the appearence of undesirable side effects (e g. patients exhibit immunodeficiency from treatment), due to use of the method, kit or composition of this invention, this invention provides for the administration of appropriate palliative drugs during the tieatment regimen
[00020] As an example as described in Example 12 hereinbelow, a nervous system disorder like schizophrenia can be treated with a diug, which in one embodiment, is Risperidone, by complexing the drug with a biodegradable polymer exhibiting the release profile shown in Figuie 7A. In anothei embodiment, a foimulation comprising a di ug in complex with 5 different polymers may be used simultaneously wherein 3 complexes comprise a "starter set", referring in one embodiment to the formulations administered to bridge the lag oi ielease from the sustained release implants (Figures 7D and 7E) According to this aspect of the invention, the startei set comprises 3 complexes the fust of which has an immediate release profile, which is taken simultaneously with two other fast release complexes, each with a slightly slower release profile. In one embodiment, the starter set is taken concurrent with or just prior to the "maintenance set", which comprises at least one, or in anotliei embodiment, 2, oi in another embodiment, 3, or in another embodiment, 4 complexes, which provides for constant theiapeutic circulating level of Risperidone The maintenance set is provided at a point when complete release, referring in one embodiment to 100% of the drug is released from the starter set complexes In anothei embodiment, the maintenance set may comprise a 5lh complex, which in one embodiment, is an implant comprising the diug and biodegradable matrix, which, has a higher absolute drug content, as compared to the other complexes In one embodiment, the 5" complex peak release coincides with a decline in diug release from the other complexes comprising the "maintenance set". According to this aspect of the invention, the release profiles from each complex are combined at an optimum to provide for a constant desired circulating Risperidone level (Figure 7E).
[00021] In one embodiment, the maintenance sets may be leadministered to a subject indefinitely, to provide for prolonged therapy. [00022] In another embodiment, the method of this invention includes repeated use, e g the use of the method according to the invention includes administi ation of one or more of the foimulalions as a repeated discrete treatment for a given period. In one embodiment the method of this invention includes cyclical use, e.g , one or more of the formulations of the invention may be administered at fixed time inleivals. In one embodiment, the method may comprise evaluation of therapy midcourse, and formulations may be changed as a function of any sign of improvement of the subject, including lessening of symptoms, or in another embodiment, lessening of pathology, etc , as will be appreciated by one skilled in the art In anotlier embodiment, theiapies may be altered following an indication of a lack of lesponse to particular administeied formulations
[00023] In another embodiment, formulation of drug and polymer implants aie designed without siufactants or emulsifiers, instead using solvent casting from acetone followed by compression molding. In one embodiment, acetone is chosen as the solvent for asting, oi in anothei embodiment, other FDA Class III solvents (low toxicity with minimal need foi lemoval of residual solvent) aie used, in which, in one embodiment, the diug and biodegradable polymers are soluble at greater than 100 mg/ml In another embodiment, implants thus produced are tolerable, and bioactive, and can be demonstrated as such, for example in rodents wheie a demonstration of tolerabiiity and bioactivity following implantation in mouse and rat can be evaluated ovei a course of time, foi example for 3 weeks to 3 months post-implantation.
[00024] In one embodiment solvent casting is accomplished with solvents chosen from table I (FDA Class III solvents (FDA Guidance document Q3C)): Table I FDA Class III solvents (FDA Guidance document Q3C
Figure imgf000011_0001
[00025] In another embodiment, the methods, kit and compositions of this invention provide for drug release profiles, which are a function of the interaction of each drug with the respective polymer In another embodiment, other factors which may affect the patterns of release from the polymeric systems include diug diffusion rate, drug/polymer affinity, pH, source/sink concentrations, molecular weight average (MWW), polymer numbei average (MWπ), their ratio (Polydispersity index [PDI]) and the capability of physiological fluids to plasticize tire biopolymer. .
[00026] In one embodiment, the methods, kit and compositions of this invention provide that the first foi ulation and second formulation are administered within 1-48 houis of each othei. In another embodiment, administration of the fust foimulation is done simultaneously with administration of the second foimulation In one embodiment, administration of the fust formulation is done before administration of the second formulation In another embodiment, administration of the fast formulation is done after administi ation of the second foimulation.
[00027] In one embodiment, the methods, kit and compositions of this invention make use of a biodegradable polymer, which is in one embodiment Poly(d,l-lactide- glycolide) copolymer [PLGA]. In one embodiment, the biodegiadable PLGA polymei s may be as described by ( Kitchell .IP, Wise DL (1985) Poly(lactic/glycolic acid) biodegradable diug-polymer matrix systems. Methods Enzymol 112:436-448)
[00028] In one embodiment, the biodegradable polymei is a polylactide, a polyglycolide, a polycapiolactone, a copolymer thereof, a terpolymer thereof, or any combination thereof. In one embodiment the copolymer theieof is atactic, oi in another embodiment syndiotactic In one embodiment, the biodegradable thermoplastic polyester is a polylactide, a polyglycolide, a copolymei thereof, a terpolymer theieof, oi a combination thereof
[00029] In one embodiment the biodegradable thermoplastic polyester is 50/50 poly (DL-lactide-co-glycolide). In another embodiment, the biodegradable thermoplastic polyestei is 75/25 poly (DL-lactide-co-glycolide). In another embodiment, the biodegradable thermoplastic polyester is 85/15 poly (DL-lactide-co-glycolide). In another embodiment, the biodegiadable thermoplastic polyester is 60/40 poly (DL- lactide-co-glycolide). In another embodiment, the biodegradable thermoplastic polyester is 90/10 poly (DL-lactide-co-glycolide). In another embodiment, the biodegradable thermoplastic polyester comprises any combination of poly (DL- lactide-co-glycolide), which produces a desired release profile when in complex with a drug. In one embodiment, the biodegradable thermoplastic polyestei can be present in any suitable amount, provided the biodegradable thermoplastic polyester is at least substantially insoluble in aqueous medium or body fluid.
[00030] In anothei embodiment the biodegradable thermoplastic polyester is preferably present in about 50 wt % to about 98 wt % of the flowable composition, or in one embodiment is piesent in about 50 wt % to about 60 wt % of the flowable composition, or in another embodiment in about 60 wt % to about 75 wt. % of the flowable composition, or in anothei embodiment in about 75 wt. % to about 90 wt. % of the flowable composition, or in another embodiment, in about 90 wt. % to about 95 wt. % of the flowable composition, or in another embodiment, in about 95 wt % to about 98 wt. % of the flowable composition.
[00031] In one embodiment, the biodegradable thermoplastic polymer has an average molecular weight of about 10,000 to about 200,000, or in another embodiment from about 15,000 to about 25,000, or in another embodiment from about 25,000 to about 45,000, or in another embodiment from about 45,000 to about 75,000, oi in another embodiment from about 75,000 to about 100,000, oi in another embodiment from about 100,000 to about 150,000, oi in another embodiment from about 150,000 to about 200,000.
[00032] In one embodiment, the lactic monomer comprising the PLGA is at a concentration of between 50-100%, or in another embodiment between 50-60%, or in another embodiment between 60-70%, or in another embodiment between 70-80%, or in anothei embodiment, between 80-90%, or in another embodiment, between 90- 100% of the PLGA polymer, or in another embodiment comprises 100% PLA.
[00033] In one embodiment, the teim "about" refers to a deviation from the lange of 1- 20%, or in anothei embodiment, of 1-10%, or in anothei embodiment of 1-5%, or in another embodiment, of 5-10%, or in another embodiment, of 10-20%. [00034] In one embodiment, the drug-polymer complex in a given formulation is such that the diug content is between 2 and 75% (w/w), or in another embodiment between 2 and 5% (w/w), or in another embodiment between 5 and 10% (w/w), or in another embodiment between 10 and 25% (w/w), or in anotlier embodiment between 25 and 35% (w/w), or in anothei embodiment between 35 and 50% (w/w), oi in another embodiment between 50 and 75% (w/w).
[00035] In one embodiment, the complexes may be formed via covalent attachment of watei-soluble polymeis such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxy ethyl cellulose, dextian, polyvinyl alcohol, polyvinylpyrrolidone oi polyproline In one embodiment modifications may increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, leduce the immunogemcity or leactivity of the compound or combination thereof
[00036] In another embodiment, the methods, kit and compositions of the piesent invention provide foi the treatment of any disease or disorder wherein deliveiy of at least one diug ovei a sustained period of time is desiied.
It is to be understood that any condition, disease or disoider, wheieby a treatment regimen with a particular compound or combination of compounds, which comprises providing an initial formulation, which achieves therapeutic cii dilating levels, of the particular compound or combination of compounds, which is concurrent with or followed by treatment with a second formulation, which achieves therapeutic circulating levels, wheiein the circulating levels attained by the second foimulation, coincide with decline of such levels by the fust formulation, and the circulating levels are achieved over a prolonged course of time, is to be considered as part of this invention [00037] The first formulation of the methods, kit and compositions of the present invention, deliver the diug with pseudo-zero order kinetics which in one embodiment refers to a "steady state" (zero oider) release profile, or almost steady state, oi in one embodiment with a variation of ±5-10% from steady state, which delivers a therapeutically effective amount of diug over a given time period, In another embodiment, oscillation of ±5%, oi in another embodiment ±10%, or in another embodiment ±20%, or in another embodiment ±30% is observed around a target serum level. In one embodiment, the time period is from 3-10 months post administration In one embodiment, the time period is from 14 days-6 months post administration
[00038] In one embodiment, the release profile from the formulation used in the methods, kit and compositions of the piesent invention may parallel that shown in Figure 7A, or in anothei embodiment Figure 7B, or in anothei embodiment Figuie 7C, oi in anothei embodiment, Figure 7C, or in anothei embodiment Figure 7D or in another embodiment Figuie 7E, or in another embodiment, approximate such profiles.
[00039] In one embodiment, the formulation may be administered as a controlled release patch In another embodiment, the subject theiapeutic drug is delivered by way of a transdeimal patch, A patch is in one embodiment, a flat hollow device with a peimeable membrane on one side, and, also may comprise an adhesive to maintain the patch in place on the patient's skin, with the membrane in contact with the skin so that the medication can permeate out of the patch leservoir and into and through the skin. The outei side the patch is formed, in one embodiment of an impenneable layer of material, and the membrane side and the outer side are joined around the perimeter of the patch, forming a reservoir for the medication and caπiei between the two layeis Patch technology enables the active ingredient to be in constant contact with the epideimis Over substantial periods of lime, diug molecules, held in such a state, will diffuse into the bloodstream, due, in one embodiment to a concentration gradient, in another embodiment, tiansdermal drug delivery can be accomplished using patch technology These conventional drug deliveiy systems comprise a patch with an active ingredient such as a drug incorporated therein, the patch also including an adhesive for attachment to the skin so as to place the active ingredient in close proximity to the skin Exemplary patch technologies aie available from Ciba-Geigy Corporation and Alza Corpoiation. Such transdermal delivery devices can be leadiiy adapted for use with the subject amphetamine compounds. In one embodiment, a maintenance set of the drug is administered once eveiy 3 months in a patch form. [00040] In one embodiment, the formulations aie in a form of an implant. In another embodiment, release from and in another embodiment diffusion of the diug from the implant vary substantially foi diffeient drugs In one embodiment design specifications foi one compound may not be directly translated to another
[00041] In one embodiment an antipsychotic, or in another embodiment 9-OH- Risperidone are used as part of the methods, kit and compositions of the present invention to tieal a Nervous System disorder, which in one embodiment is Bipolar disoidei.
[00042] In one embodiment, the methods, kits and compositions of this invention may be used in ordei to deliver thyrotiopin-releasing hormone, or L-dopa, in order to treat Paikinson's Disease In another embodiment, the methods, kits and compositions of this invention may be used in ordei to deliver naltrexone , in order to treat narcotic addiction
[00043] It is to be understood that the formulations used in the methods, kit and compositions of the piesent invention, may comprise combination of drugs, which in one embodiment may be a part of the tieatment regimen of the disordei.
[00044] In one embodiment, the present invention provides a method foi treating neivous system disorders, wherein the diug is at a concentration of between about 2 to about 50 percent by weight of said first or second formulation. In another embodiment, the drug is at a concentration of between about 2 to about 5 percent by weight of said first or second formulation. In one embodiment, the drug is at a concenti ation of between about 5 to about 10 percent by weight of said first or second foimulation In another embodiment, the drug is at a concentration of between about 10 to about 15 percent by weight of said first oi second formulation. In one embodiment, the drug is at a concentiation of between about 15 to about 20 percent by weight of said first or second formulation. In another embodiment, the drug is at a concentiation of between about 20 to about 30 percent by weight of said first or second formulation In one embodiment, the drug is at a concentration of between about 30 to about 40 percent by weight of said first or second formulation. In another embodiment, the diug is at a concentiation of between about 40 to about 50 percent by weight of said first oi second formulation
[00045] In one embodiment, the piesent invention provides a method for ti eating nervous system disoideis, wheiein the drug used is Risperidone, 9-OH-Risperidone, haloperidol, oianzapine, clozapine, aiipiprazole, quetiapine, ziprasidone oi a combination theieof
[00046] In one embodiment, the fiist and second foimulation have at least one diug m- common
[00047] In another embodiment the first formulation comprises Risperidone and 9-OH- Risperidone and the second foimulalion comprises 9-OFI-Risperidone, or in another embodiment, the fust foimulation comprises Risperidone and haloperidol, and the second foimulation comprises haloperidol, oi in another embodiment the first formulation comprises quetiapine and 9-OH-Rispeιidone and the second formulation comprises 9-OH-Rispeιidone.
[00048] In one embodiment, the first formulation contain drugs that aie therapeutic in chronic diseases. In another embodiment, the second formulation comprises drug that aie therapeutic foi an acute phase of the chronic disease For example, in one embodiment, relapsing and l emitting diseases such as Multiple Sclerosis, may thus be tieated, wheie in one embodiment, each foimulation will comprise Copaxon, while the first formulation may additionally comprise β-iπterferon, or in anothei embodiment, an immunomodulating compound
[00049] In anothei embodiment, the second formulation has a late of release which is fastei than the first foimulation In one embodiment the term "faster late of release lefeis to the increase in relative concentration of circulating serum levels of the subject diug, as a function of time In one embodiment, the % drug released as a function of time is graphically depicted in Figure 4B [00050] In another embodiment, the second foimulation may be administered as a depot injection In another embodiment the second formulation is administered as miciospheres containing the drug entrapped within the biodegradable polymer matiix.
[00051] In one embodiment, the fπst formulation of the methods, kit and composaitions of the pisenl invention is such that the rate of release of drugs is substantially slow, in order to provide for prolonged sustained release Substantially slow, refers in one embodiment to an oidei of magnitude, relative to an average under noimal formulation
[00052] In one embodiment, the present invention provides a method for treating neivous system disorders, wherein the fust formulation is an implant, and is administeied subcutaneously, and said second formulation comprises oral drug form, a parentei al form, or an inti avenous form .
[00053] In one embodiment, the phiases "administered paienterally" as used herein means mode of administration other than enteial and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, inlraaiteriai, intrathecal, intracapsular, iπtraorbital, inlracardiac, intradermal, intraperitoneal, translracheal, subcutaneous, subcuticular, intraarticular, intraiumoral, subcapsular, subarachnoid, inlraspinal and intrasteinal injection and infusion.
[00054] In another embodiment, the present invention provides for the cyclic administration of the first and second foimulations to said subject. It is to be undei stood that ordei of adminislarlion of first, second or in another embodiment, any additional administration of formulas containing the drug is within the scope of the piesent invention and may be varied to provide a designed ciiculating level of the diug, as will be appreciated by one skilled in the art,
[00055] In one embodiment, the first and second formulations are administeied to said subject when the ciiculating levels of the drug serum levels are below the therapeutic threshold level foi that drug. In another embodiment, the first and second formulations are administered to said subject when the circulating levels of said drug serum levels are below 1 ng/mL.
[00056] In anothei embodiment, the present invention provides a method for treating nervous system disordeis, wherein the first and second formulations are administered to said subject as described hereinabove from about 160-200 days, following a first administration of the formulations. In one embodiment the first and second foimulations aie administered to said subject from about 160-180 days, following a first administration of the formulations In another embodiment, the first and second formulations are administeied to said subject from about 180-200 days, following a first administration of the foimulations.
[00057] In another embodiment, the present invention provides a method for treating neivous system disordeis, wherein the method addresses the need for more sustained treatment adherence, or in one embodiment a methods of long-term medication delivery using implantable systems for the treatment of schizophienia. Implantable systems have in anothei embodiment, the capability to optimize a medication's theiapeulic properties, which in one embodiment renders treatments that are more safe, efficacious or reliable In another embodiment, the present invention provides a method for healing nervous system disorders, wherein less medication may be generally lequired and side effects can be minimized In one embodiment implantable systems can be removed by a physician in case of adverse side effects, offering a degree of reversibility. In another embodiment, the present invention provides a method for treating nervous system disorders, wherein mandatory removal at the end of the delivery interval is eliminated with biodegradable systems, cutting in half the inheient invasiveness to the patient .
[00058] In one embodiment, the present invention provides a method for treating nervany diseases or disoideis where a prolonged therapy period is needed In one embodiment the drugs are used to treat: HIV and other viral diseases, mycobacterial infection, cancer, multiple sclerosis, diabetes, kidney disease, or any other wherein the methods, kits or compositions of this invention prove useful [00059] In another embodiment, the present invention provides a method for treating nervous system disoideis, wherein said disorder is AIDS -related dementia, schizophienia, bipolar disorder, bordeiline personality disorder (BPD), Alzheimer's disease (AD), psychotic depression or othei mental disordeis causing confusion, disoiganization oi psychosis
[00060] In one emboidment, the drug used according to the methods, kits or compositions of this invention, may be any drug which is applicable for such lieatmenl regimens, as described herein. In one embodiment, the drug is a peplide, protein, nucleic acid, or compound.
[00061] In one embodiment, tire term "drug" refers to a molecule that alleviates a symptom, disease or disorder when administered to a subject afflicted theieof In one embodiment, a drug is a synthetic molecule, or in another embodiment, a drug is a natuially occurring compound isolated from a source found in nature.
[00062] In one embodiment, drugs may comprise antihypertensives, anlidepiessants, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, anti- inflammaloiies, antipsychotic agents, cognitive enlianceis, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Par kinsonism in agents, antibiotics, antiviral agents, anli-neoplastics, barbituates, sedatives, nutritional agents, beta blockeis, emetics, anti-emetics, diuretics, anticoagulants, cardiαtonics, andiogens. corticoids, anabolic agents, growth hormone secretagogues, anti-infective agents, coronary vasodilators, carbonic anhydrase inhibitors, antipiotozoals, gastrointestinal agents, serotonin antagonists, anesthetics, hypoglycemic agents, dopamineigic agents, anti-Alzheimer's Disease agents, anti-ulcer agents, platelet inhibitors and glycogen phosphorylase inhibitors
[00063] According to this aspect of the invention, and in one embodiment, examples of the drugs used accoiding to this invention include, inter-alia, antihypertensives including piazosin, nifedipine, trimazosin, amlodipine, and doxazosin mesylate; the antianxiety agent hydroxyzine; a blood glucose lowering agent such as glipizide; an anti -impotence agent such as sildenafil citrate; anti-neoplasties such as chlorambucil, lomustine or echinomycin; anti-inflammatory agents such as betamethasone, prednisolone, piroxicam, aspirin, flurbiprofen and (+)_N-{4-[3-(4- fluorophenoxy)phenoxy]-2-cycIopenten-l-yl}-N-hyroxyurea; antivirals such as acyclovir, nelfmavir, or virazoie; vitamins/nutritional agents such as retinol and vitamin E; emetics such as apomoiphine; diuretics such as chlorlhalidone and spironolactone; an anticoagulant such as dicumarol; cardiotonics such as digoxin and digitoxin; andiogens such as 17-methyltestosteιone and testosterone; a mineral corticoid such as desoxycorticosterone; a steroidal hypnotic/anesthetic such as alfaxalone; an anabolic agent such as fiuoxymesteione or methanslenolone; antidepression agents such as fluoxeline, pyroxidine, venlafaxine, sertraline, paroxetine, sulphide, [3,6-dimelhyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]- (letlιyipropyl)-amine or 3,5-dimethyl-4-(3'-pentoxy)-2-(2',4',6'- trimethylpheπoxy)pyιidiιιε; an antibiotic such as ampicillin and penicillin G; an anli- infective such as benzalkonium chloride or chlorhexidine; a coronary vasodilator such as nitioglyceiin or mioflazine; a hypnotic such as etomidale; a carbonic anhydrase inhibitor such as acetazolamide or chlorzolamide; an antifungal such as econazole, tercoπazole, fluconazole, voiiconazole or griseofulvin; an antiprotozoal such as metronidazole; an imidazole-type anti-neoplastic such as lubulazole; an aπthelmiπtic agent such as thiabendazole or oxfendazole; an antihistamine such as astemizole, levocabastine, cetirizine, or cinnarizine; a decongestant such as pseudoephediine; anlipsychotics such as fluspirilene, penfluridole, risperidone or ziprasidone; a gastrointestinal agent such as lopei amide or cisapride; a serotonin antagonist such as ketaπserin or mianserin; an anesthetic such as lidocaine; a hypoglycemic agent such as acetohexamide; an anti-emetic such as dimenhydrinate; an antibacterial such as colrimoxazole; a dopaminergic agent such as L-DOPA; anti-Alzheimer agents such as THA or' donepezil; an anti-ulcer agenι/H2 antagonist such as famotidine; a sedative/hypnotic such as chlordiazepoxide or triazolam; a vasodilator such as alprostadil; a platelet inhibitor such as prostacyclin; an ACE inliibilor/anlihyperlensive such as enalaprilic acid or lisinopril; a tetracycline antibiotic such as oxytetiacycline or minocyciine; a macrolide antibiotic such as azithromycin, clarilhro ycin, erythromycin or spiramycin; and glycogen phosphorylase inhibitors such as [R-(R*S*)]-5-chloiO-N-[2-hydroxy- 3 {methoxymelhylamino}-3-oxo-l-(phenylmethyl)-piOpyl]-IH-indole-2-cai"boxamide or 5-chloro-l -Hindole-2-carboxylic acid [(IS)-benzyl(2R)-hydroxy-3- ((3R,4S)dihydroxy-pyrrolidin- 1 -yl-)-oxypropyl]amide,
[00064] Further examples of drugs for use according to this invention are the glucose- lowering drug chlorpropamide, the anti-fungal fluconazole, the anti- hypercholesterolemic atoivastatin calcium, the antipsychotic thiothixene hydrochloride, the anxiolytics hydroxyzine hydrochloride or doxepin hydrochloride, the anti-hypertensive amlodipine besylate, the antiinflammatories piroxicam and celicoxib and valdicoxib, and the antibiotics carbenicillin indanyl sodium, bacampicillin hydrochloride, troleandomycin, and doxycycline hyclate
[00065] In anothei embodiment a drug of this invention may comprise othei anlineoplastic agents such as platinum compounds (e.g., spiroplatin, cisplatin, and carboplatin), methotrexale, fiuorouracil, adriamycin, mitomycin, ansamitocin, bleomycin, cylosine arabinoside, arabinosyl adenine, mercaptopolylysine, vincristine, busulfan, chlorambucil, melphalan (e.g., PAM, L-PAM or phenylalanine mustard), meicaptopurine, mitotane, piocai'bazine hydrochloride daclinomycin (actinomycin D), daunorubicin hydrochloride, doxorubicin hydrochloride, paclitaxel and other taxenes, lapamyciπ, manumycin A, TNP-470, plicamycin (mithramycin), aminoglutethin ide,eslramustine phosphate sodium, flutamide, leuprolide acetate, megestrol acetate, tamoxifen citiate, teslolaclone, trilostane, amsacrine (m-AMSA), asparaginase (L-asparaginase) Erwina asparaginase, interferon .alpha.-2a, interferon alpha, -2b, teniposide (VM-26), vinblasline sulfate (VLB), vincristine sulfate, bleomycin sulfate. hydroxyurea ,procarbazine, and dacarbazine; mitotic inhibitors such as etoposide, colchicine, and the vinca alkaloids, radiopharmaceuticals such as radioactive iodine and phosphorus products; hormones such as progeslins, estrogens and antiestrogens; anti-helmintics, antimalarials, and antitυberculosis drugs; biologicals such as immune serums, antitoxins and antivenoms; rabies prophylaxis products; bacterial vaccines; viral vaccines; respiratory products such as xanthine derivatives theophylline and aminophylline; thyroid agents such as iodine products and anti-thyroid agents; cardiovascular products including chelating agents and mercurial diuretics and cardiac glycosides; glucagon; blood products such as parenteral iron, hemin, hematopoiphyrins and their derivatives; biological response modifiers such as muramyldipeptide, muramyltripeptide, microbial cell wall components, lymphokines (e.g., bacterial endotoxin such as lipopolysaccharide, macrophage activation factor), sub-units of bacteria (such as Mycobacteria, Corynebacteria), the synthetic dipeptide N-acetyl-muramyl-L-alanyl-D-isoglutamine; anti-fungal agents such as ketoconazole, nystatin, griseofulvin, flucytosine (5-fc), miconazole, amphotericin B, ricin, cyclosporins, and β-lactam antibiotics (e.g , sulfazecin); hormones such as growth hormone, melanocyte stimulating hoimone, estradiol, beclomethasone dipropioπate, betamelhasone, betamethasone acetate and betamethasone sodium phosphate, vetamelhasone disodium phosphate, vetamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate. dexamethasone sodium phosphate, fiunisolide, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinaie, methylpiednisolone, methylprednisolone acetate, melhyipiednisolone sodium succinate, paramethasone acetate, prednisolone, piednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, Iriamcinolone, triamcinolone acelonide, triamcinolone diacetate, tiiamcinolone hexacetonide, fludrocortisone acetate, oxytocin, vassopressin, and their derivatives; vitamins such as cyanocobalamin neinoic acid, retinoids and derivatives such as lelinol palmitate, and .alpha -tocopherol; peptides, such as manganese supei oxide dismutase; enzymes such as alkaline phosphatase; anti-allergic agents such as amelexanox; anti-coagulation agents such as phenprocoumon and heparin; circulatory drugs such as propianolol; metabolic potentiators such as glutathione; antituberculars such as para-aminosalicylic acid, isoniazid, capreomycin sulfate cycloserine, elhambutol hydrochloride ethionamide, pyrazinamide, rifampin, and sheptomycin sulfate; antivirals such as amantadine azidothymidine (AZT, DDI, Foscarnet, oi Zidovudine), ribaviiin and vidaiabine monohydiate (adenine arabinoside, ara-A); antianginals such as diltiazem, ni edipine, veiapamil, eiythritol tetranitrate, isosorbide dinitrate, nitrogiycerin (glyceryl triiiitrale) and pentaerytluitol tetranitiate; anticoagulants such as phenprocoumon, heparin; antibiotics such as dapsone, chloramphenicol, πeo ycin, cefaclor, cefadroxil, cephalexin, cepliradine erythromycin, clindamycin, lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin, dicloxacillin, cyclacillin, picloxacillin, hetacillin, ethicillin, nafcillin, oxaciilin, penicillin including penicillin G and penicillin V, ticarcillin rifampin and tetiacycline; antiinflammatoriεs such as diflunisal, ibuprofen, indomethacin, meclofenamate, mefenamic acid, napioxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac, tolmetin, aspirin and salicylates; antiprotozoans such as chloroquine,hydιoxych]oroqυiπe, metronidazole, quinine and meglumine antimonate; antirheumatics such as penicillamine; narcotics such as paregoric;opiates such as codeine, heroin, methadone, moiphine and opiiun; cardiac glycosides such as deslanoside, digitoxin, digoxin, digitalin and digitalis; neuromuscular blockers such as atiacuiium mesylale, gallamine triethiodide, hexafluorenium bromide, metocurine iodide, pancuroniυm bromide, succinylcholine chloride (suxamethonium chloride), tubocuraiine chloride and vecuronium bromide; sedatives (hypnotics) such as amobarbital, amobarbital sodium, aprobarbital, butabaibital sodium, chloral hydrate, elhchlorvynol, ethinamate, flurazepam hydrochloride, glutethimide, methotrimcprazine hydrochloride, methyprylon, midazolam hydrochloride, pai aldehyde, pεntobarbital, penlobarbital sodium, phenobarbital sodium, secobarbital sodium, talbutal, temazepam and tiiazolam; local anesthetics such as bupivacaine hydrochloride, chioroprocaine hydrochloride, etidocaine hydrochloride, lidocaine hydrochloride, mepivacaine hydrochloride, procaine hydrochloride and tetracaine hydrochloride; general anesthetics such as droperidol, etomidate, fenlanyl citrate with droperidol, ketamine hydrochloride, methohexital sodium and thiopental sodium; and radioactive particles or ions such as strontium, iodide rhenium and yttrium.
[00066] In one embodiment, the methods, kits and compositions of this invention provide foi combined use of diυgs, as described herein, wherein such combinations may diffei within the respective foimulations, so long as a single drug is in common amongst foimulations administeied to a subject, at one point in time.
[00067] In one embodiment, the methods of this invention may be affected via the use of a kit comprising the forumulations as described,
[00068] In one embodiment, the invention provides a kit for sustained delivery of at least one drag comprising a first formulation of said drug in complex with a biodegradable polymer, wherein said formulation delivers said drug with pseudo zero- ordei kinetics in-vivo, and a second formulation of said drug in complex with a biodegiadable polymer wherein said second formulation has a rate of release which is faster than said first formulation, in-vivo. [00069] In anothei embodiment, the invention provides a kit foi sustained delivery of a drug, wheiein the combination of the first and second formulation of the kit gives sustained delivery, once administered over a period of about 1 week to about 14 months. In one embodiment, the combination of the first and second formulation of the kit gives sustained delivery, once administeied over a period of about 1 week to about 1 month In another embodiment, the combination of the first and second formulation of the kit gives sustained delivery, once administered over a period of about 1 to about 3 months In one embodiment, the combination of the first and second foimulation of the kit gives sustained deliveiy, once administered over a period of about 3 to about 6 months. In another embodiment, the combination of the first and second foimulation of the kit gives sustained deliveiy, once administered over a period of about 6 to about 9 months. In anothei embodiment, the combination of the fust and second foimulation of the kit gives sustained deliveiy, once administered ovei a period of about 9 to about 12 months. In another embodiment, the combination of the first and second formulation of the kit gives sustained deliveiy, once administered over a period of about 1 to about 14 months.
[00070] In one embodiment, the kit and compositions as described herein are used according to the methods of this invention, and in another embodiment, such use may include combination with othei kits or in anothei embodiment, compositions as a part of systemic therapy, and in anothei embodiment, may comprise use of only part of a given kit. oi particulai formulations theiein contained
[00071] It is to be understood that the kit of the piesent invention may be used with any of the methods described hereinabove, and in another embodiment, may make use of any of the compositions or foimulations described herein
[00072] In one embodiment, the piesent invention provides a composition for use in the tieatment of psychotic disoiders, comprising a poly(d,l-lactide/glycolide) (PLGA) copolymei al a concentration of from about 95-98% (w/w), and an antipsychotic agent, at a concentration of from about 2 to about 5% (w/w), wherein the lactide:glycolide latio of said poly(lactide/glycolide) copolymer is from about 100:0 to 50:50 and wherein said antipsychotic agent is Risperidone or 9-OH-Rispeιidone, [00073] The formulations of the present invention may be given in one embodiment orally, paienterally, topically, or subcutaneously. In another embodiment the formulations aie given by foims suitable for each administration route For example in one embodiment, they are administered in tablets or capsule form, or in anothei embodiment by injection, infusion, inhalation, eye lotion, ointment, rectal suppository, or controlled ielease patch
[00074] In one embodiment, the therapeutic circulating levels of said drug range from 0 1 - 10 ng/mL In another embodiment, the therapeutic circulating levels of said daig range from 0.1 - 0 5 ng/mL In one embodiment, the therapeutic circulating levels of said drug range from 0 5 - 1 0 ng/mL. In another embodiment, the therapeutic ciiculating levels of said drug lange from 1 0 - 1.5 ng/mL In one embodiment, the therapeutic ciiculating levels of said drug lange from 1.5 - 2 5 ng/mL In another embodiment, the therapeutic circulating levels of said drug range from 2.5- 5 ng/mL. In one embodiment, the therapeutic circulating levels of said drug range from 5 - 10 ng/mL.
[00075] In one embodiment, this invention provides, wherein administering the second foimulation iesults in said circulating levels within a period of about 1-31 days. In another embodiment, administering the second formulation results in said ciiculating levels within a period of about 1-7 days. In one embodiment, administering the second foimulation results in said circulating levels within a period of about 7-14 days In another embodiment, administering the second formulation results in said ciiculating levels within a period of about 14-21 days In one embodiment, administering the second formulation results in said circulating levels within a period of about 22-31 days.
[00076] In one embodiment, this invention, wheiein administering the fiist formulation results in acheiving circulating levels within a period of about 21-180 days. In another embodiment, administering the first foimulation results in acheiving circulating levels within a period of about 21-31 days In one embodiment, administering the first formulation results in acheiving circulating levels within a period of about 31-60 days In anothei embodiment, administering the first foimulation results in acheiving circulating levels within a period of about 60-90 days. In one embodiment, administering the fust foimulalion results in acheiving circulating levels within a period of about 90-120 days. In another embodiment, administering the first foimulation results in acheiving ciiculating levels within a period of about 120-150 days In anothei embodiment, administering the first foimulation lesulls in acheiving circulating levels within a peiiod of about 150-180 days,
[00077] In one embodiment, this invention provides for circulating levels of at least one desired diug, which is sustained for about from 1-420 days. In one embodiment, this invention provides for circulating levels of at least one desired drug, which is sustained for about from 14-420 days In one embodiment, this invention provides, wherein said circulating levels are sustained for about from 75-420 days In another embodiment, said circulating levels aie sustained for about from 75-180 days. In one embodiment, said ciiculating levels aie sustained for about from 180-270 days. In anothei embodiment, said ciiculating levels are sustained for about from 270-365 days In one embodiment, said ciiculating levels are sustained for about from 365-420 days
[00078] In anothei embodiment, tire present invention provides for the use of implants inserted subculaneously In one embodiment, procedures for implantation could be easily tolerated with local anesthetic befoie subcutaneous placement. In anothei embodiment, using rigid implants obviate the need foi a tool to guide implants under the skin, reducing risk of intramuscular placement.
[00079] In another embodiment, the foimulations may be such as to be suitable for implantation at any desired tissue site, in the form of a patch, or for injection, intiavenously, intracavitarily, intranodally, or any other appropriate site, and may be in the foim of a depot injection. In another embodiment, the route of administration and inleivals between administration may be individually adjusted for a given subject In one embodiment, the time inteival may involve administration of the formulations once every six months In another embodiment, treatment regimens according to the methods of this invention, and using the kits/compositions of this invention may be accompanied by other forms of treatment, which do not involve administration of a drug, such as subject interaction with psychiatrists and/or therapists. [00080] In one embodiment, the piesent invention provides a method foi treating a disease oi disorder, wherein at least one formulation is in the form of an implant, which in one embodiment is is disk shaped, or, in another embodiment, rod shaped. In another embodiment, Polymers and drugs are mixed in a proportion of 60/40 by mass and solvent cast from acetone The resulting film may be compression molded to disk-shaped implants of 20 mm diameter with aveiage thickness of 1.22 ± 0.0 mm, mass of 493 ± 2 mg and density of 1.28 ± 0.0 glee, such as for example, the implants exemplified hereinbelow In one embodiment, Rod-shaped implants are prepared as described in example 10 hereinbelow, having in anotlier embodiment a diameter of about 1 to about 2 mm, a length of between about 10 and about 40 mm, or a combination thereof. It is to be understood that the geometry of the implant may be varied to any foim which provides for a desired release profile, as will be appreciated by one skilled in the art, with dimensions which may vary in order to accommodate, in one embodiment, a desiied drug load, or in anothei embodiment, to suit the environment wheiein the material will be implanted, or any other consideration which will affect the methods of this invention, as will be appreciated by one skilled in the art
[00081] In one embodiment, the invention provides a kit for sustained delivery of a diug comprising a first formulation of said drag in complex with a biodegradable polymei, wherein said foimulation delivers said drug with pseudo zero-order kinetics in-vivo, and a second formulation of said drug in complex with a biodegradable polymei wherein said second formulation has a rate of release which is faster than said fast formulation, in-vivo
[00082] In anothei embodiment, the invention provides a kit for sustained delivery of a drug, wherein the combination of the first and second formulation of the kit gives sustained delivery, once administered over a peiiod of about 1 week to about 14 months In one embodiment, the combination of the first and second foimulation of the kit gives sustained delivery, once administeied over a period of about 1 week to about 1 month, In anothei embodiment, the combination of the first and second foimulation of the kit gives sustained delivery, once administered over a period of about 1 to about 3 months. In one embodiment, the combination of the first and second formulation of the kit gives sustained delivery, once administered over a period of about 3 to about 6 months In another embodiment, the combination of the first and second formulation of the kit gives sustained delivery, once administered over a pei iod of about 6 to about 9 months In another embodiment, the combination of the fust and second formulation of the kit gives sustained delivery, once 5 administeied over a period of about 9 to about 12 months. In another embodiment, the combination of the first and second formulation of the kit gives sustained delivery, once administered over a period of about 12 to about 14 months.
[00083] In one embodiment, the kit and compositions of the formulations described I D heieinbelow aie used in the methods described above in their entirety, partially or in combination with othei kits oi in anothei embodiment, composition as a part of systemic therapy
[00084] In one embodiment, the invention piovides a kit for sustained delivery of a 15 drug, wheiein the formulation is in a foim of a rod-shaped implant as described in one embodiment hereinabove, said rod-shaped disk has a diameter of about 1 to about 2 mm, a length of between about 10 and about 40 mm, or a combination thereof.
[00085] In one embodiment, the present invention provides a flowable composition0 that is suitable for use as a controlled release implant of Risperidone or 9-OH- Risperidone In another embodiment, the flowable composition includes a biodegiadable theimoplastic polyester that is at least initially substantially insoluble in an aqueous medium or body fluid In one embodiment, the flowable composition is formulated as an injectable subcutaneous deliveiy system. The injεctable composition5 piefeiabiy has in anothei embodiment a volume of about 0.20 mL to about 0.40 mL or about 0 30 mL to about 0 50 mL, The injectable composition is preferably formulated for administration about once per month, or in another embodiment about once per thiee months, oi in another embodiment about once pei four months to about once pei six months Preferably, the flowable composition is a liquid or a gel composition,0 suitable foi injection into a patient
[00086] In one embodiment, the piesent invention provides a composition for use in the treatment of psychotic disorders, in the form of microparticles, which in another embodiment, are fabricated as described in example 11 hereinbelow. In another embodiment, the microparticles of the present invention have a mean diameter (D3_2) of about 150 μrn ± 50 μm, or in another embodiment a mean diameter (D3>2) of about 0.75 ± 25 nm In another embodiment, the formulations of this invention, for use in the methods oi incorporation in the kits or compositions of this invention may comprise nanoparticles, which comprise the drug in complex with a biodegradable matrix, as herein described,
[00087] The compositions of the present invention may be administered in one embodiment to humans and othei animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intiavaginally, paienterally, intracisteinally and topically, as by powders, ointments oi drops, including buccally and sublingually,
[00088] In one embodiment, the composition can be deliveied in a controlled release system. For example, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration, In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit Ref. Biomed Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al, N Engl I. Med. 321 :574 (1989). In anothei embodiment, polymeric materials can be used In another embodiment, a controlled release system can be placed in proximity to the therapeutic taiget, i.e., the brain, thus lequiring only a fi action of the systemic dose (see, e.g , Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Othei controlled release systems are discussed in the review by Langer (Science 249: 1527-1533 (1 90).
[00089] In another embodiment, the composition is in a form suitable for oral, intravenous, intraaorterial, intiamuscular, subcutaneous, parenteial, tiansmucosal, tiansdermal, oi topical administration. In one embodiment the composition is a controlled release composition. In another embodiment, the composition is an immediate release composition In one embodiment, the composition is a liquid dosage foim. In another embodiment, the composition is a solid dosage form. [00090] In one embodiment, the compositions of this invention may be in the form of a pellet, a table a capsule, a solution, a suspension, a dispersion, an emulsion, air elixii, a gel, an ointment, a cream, a patch or a suppositoiy,
[00091] The pharmaceutical pieparations of the invention can be prepared by known dissolving, mixing, gianulating, extrusion, coextrusion oi tablet-forming processes. For oial administration, the active ingredients, or their physiologically tolerated derivatives in another embodiment, such as salts, esters, N-oxides, and the like are mixed with additives customary foi this puipose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable foims for administration, such as tablets, coaled tablets, haid or soft gelatin capsules, aqueous, alcoholic or oily solutions Examples of suitable inert vehicles are conventional tablet bases such as lactose, sucrose, or comstaich in combination with binders such as acacia, comstarch, gelatin, with disintegrating agents such as comstarch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
[00092] In addition, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient
[00093] An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, foi example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimεthylamine, 2-ethylamino ethanol, hislidine, procaine, and the like
[00094] The compositions of the present invention are formulated in one embodiment foi oral delivery, wherein the active compounds may be incorporated with excipients and used in the fonn of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tiagacanth, acacia, comstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegiating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppeimint, oil of winter green, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of tire above type, a liquid carriei Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, oi both. Syrup of elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. In addition, the active compounds may be incorporated into sustained-ielease, pulsed release, controlled ielease oi postponed release preparations and formulations.
[00095] Such compositions are in one embodiment liquids or lyophilized or otlierwise dried formulations and include diluents of various buffer content (e.g., Tris-HCL, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g , Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., giycerol, polyethylene glycerol), anti- oxidanls (e g , ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifieis (e.g., lactose, maπnitol), covalent attachment of polymers such as polyetiryleπe glycol to the protein, complexation with metal ions, or incorpoiation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydiogels, etc , or onto liposomes, microemulsions, micelles, unilamellar or multilamellai vesicles, erythiocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo cleaiaπce. Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatly acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e g,, poloxamers or poloxamines).
[00096] In another embodiment, the compositions of this invention comprise one or more, phaimaceulically acceptable carrier materials [00097] In one embodiment, the carriers for use within such compositions are biocompatible, and in anothei embodiment, biodegradable. In other embodiments, the foimulation may provide a relatively constant level of release of one active component In othei embodiments, however, a moie rapid rate of release immediately upon administration may be desired In othei embodiments, release of active compounds may be event-triggeied The events triggering the release of the active compounds may be the same in one embodiment, or different in anothei embodiment. Events triggering the release of the active components may be exposuie to moisture in one embodiment, lower pH in anothei embodiment, or temperatuie threshold in anothei embodiment. The foimulalion of such compositions is well within the level of oidinary skill in the art using known techniques. Illustrative carriers useful in this regard include microparticles of poly(lactide-co-glycolide), poiyacrylate, latex, starch, cellulose, dextran and the like. Other illustrative postponed-release carrieis include supiamolecuiai biovectors, which comprise a non-liquid hydrophilic core (e.g., a cross-linked polysacchaiide or oligosaccharide) and, optionally, an external layer comprising an amphiphilic compound, such as phospholipids The amount of active compound contained in one embodiment, within a sustained release formulation depends upon the site of administration, the rate and expected duration of release and the natuie of the condition to be tieated suppressed or inhibited.
[00098] In one embodiment, the methods, kits or compositions of the present invention may be used to improve the therapeutic efficiency of a cancer therapy, or treatment of HIV, Heipes simplex, Fleipes Zoster, mycobacterial infection, cancel, psychotic disordeis, multiple sclerosis, diabetes, kidney disease, chronic pain, Flepatitis or any other applicable disease or disordei, such as, in another embodiment, a chronic disease, wheie a prolonged therapeutic legimen involving repeated administration of at least one drug is beneficial
[00099] The following examples aie presented in order to more fully illustrate the prefen'ed embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention,
EXAMPLES Example 1: Haloperidol Release from PLGA implants in Monkeys
In-vivo release of haloperidol in monkey: [000100] Studies to evaluate 1 year of continuous haloperidol delivery in primates weie performed Effects of long-term haloperidol exposure on cortical anatomy in primates, as a control for antipsychotic exposure in post mortem human schizophienia studies were evaluated The study demonstrated 14 months of haloperidol release in monkeys. Subjects:
[0010i]The Institutional Animal Caie and Use Committee at the University of Pittsburgh approved all protocols. Two monkeys (Macaco fascicularis, Rangos Research Facility) leceived implants. One animal received control implants with no drug, while the other received implants with 40% haloperidol by mass. Haloperidol (Sigma, St. Louis, MO) dosing was approximately 1 mg/kg/day over 12 months to achieve a seium concentiation of 2-10 ng/mL Each implant was made from a single polymer of Poly(d,l-lactic-glycoiic acid) copolymer (PLGA) in ratios of 75:25, 85:15, 90:10 (high and low inherent viscosity), 95:5 and 100:0 (Medisoib® Aldermes, Cincinnati, OH), lesepectively, polylactic acid (PLA):poiygIycoIic acid (PGA).
Implant fabrication:
[00102]Polymeιs and haloperidol were mixed in a proportion of 60/40 by mass and solvent cast from acetone (Fisher Scientific, Pittsburgh, PA), The resulting film was compiession molded to disk-shaped implants of 20 nun diameter with average thickness of 1.22 ± 0 0 mm, mass 493 ± 2 nig and density of 1 28 ± 0.0 g/cc.
Pharmacokinetic determination:
[00103]Blood was drawn twice pel month. Specimens were separated by centrifugation and haloperidol levels assayed were done by high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detection (Figure 1). Assays from control animals yielded no drug detected Results
[00104] As depicted giaphically in Figure 1, haloperidol release was measuied over a total of 443 days Average serum concentration during the fust 224 days is 10.5 ±1 5 ng/ml. During the subsequent 176 days, serum haloperidole level is sustained at lower concentration befor the end of release. Mean concentration during this period is 4.0 ±0.4 ng/ml. During the last 45 days, release follows 1st order decay release with a mean serum level of 1.2±0,3 ng/ml
Example 2: Release of Haloperidol from two-polymer PLGA system in Rabbit implants
Haloperidol release in Rabbit:
[00105]Implants in rabbits were tetheied to assist in locating implant sites at necropsy- Two different implant systems were tested One contained an amalgam of five different polymers to affiim previous findings in monkey (see example 1). The other was composed of a single long-lasting polymer system, aimed at reducing the initial spike while maintaining release for one year. These studies demonstrated haloperidol release for' 13 months in rabbit Subjects:
[00106] Rabbits (N=12, Covance, Denver, PA) ranged from 4 0 to 5 7 kg. Five animals received implants comprising a single polymer, 100% Poly(Lactic Acid) (PLA), with a 40% (w/w) haloperidol load foi an average dose of 418±7 mg/kg yielding a daily dose of 1.13±0.02 mg/kg/day for anticipated delivery over 365 days. Five additional animals leceived implants comprising a combined polymer system including 75:25, 85:15, 90:10 high inherent viscosity, 90:10 low inherent viscosity and 100:0 PLGA. The average dose in this group was 473±4 mg/kg with an expected delivery over 365 days yielding an average daily dose of 1.29±0.03 mg/kg/day. Two labbils leceived implants without drug as a control. One control received 100% PLA implants to mimic the single polymer condition, while the other received implants composed of 75:25, 85:15, 90:10 high inherent viscosity, 90:10 low inherent viscosity and 100:0 PLGA to minor the combined polymer system. Implant fabrication:
[0 107]I plants foi rabbits weie made using procedures described in example 1 for monkeys with an average mass of 536±2 mg and density of 1 ,24±0.00 g/cc, Pharmacokinetic determination:
[00I08]Blood samples were diawn twice per month. Serum haloperidol was detennined by HPLC with UV detection following solid phase extraction (Oasis MCX columns, Waters, Milfoid, MA) (Figure 2), Histopatlwlogy:
[00109] Five rabbits weie sacrificed after nine months to obtain interim pathological analyses The remaining seven rabbits weie sacrificed after an additional four months of study Remains of implants were found tethered in place upon sacrifice in ail animals except controls. HPLC/UV and NMR spectroscopy confirmed the presence of haloperidol and PLGA breakdown products in residual implants Histological analyses showed all organ systems in control and treated rabbits were within normal limits.
Results:[001 10] As depicted graphically in Figuie 2A, haloperidol release from a single Polymei system in Rabbits over a total of 379 showed average serum concentiation during the first 224 days was 2.5 ±0.4 ng/ml. Between days 57 and 274, mean concentration was 3.8±0.4 ng/ml,
[001 1 1] As depicted giaphically in Figure 2B, haloperidol release from a combination Polymei system in Rabbits over a total of 379 showed average serum concentration during the first 224 days of 2.5 ±0 4 ng/ml Between days 57 and 274, mean concentiation was 3 ,8±0.4 ng/ml [001 12]In multiple polymer systems design, higher serum levels were apparent in the first seven months in comparison to the subsequent seven months (Fig 2B). It is likely that implants made from faster-degrading polymers such as 75:25 PLGA contributed to a Iargei initial phase of release. Therefore, the mass of 75:25 PLGA implants could be I educed in future studies to achieve lower initial dosing Example 3: Release of Risperidone from PLGA implants
Risperidone Stability:[0010I]Risperidone (10 mg) was dissolved in 100 μl of Acetonitrile for subsequent dissolution in 1000 ml of phosphate buffered saline, pH 7.0 to yield a final solution of 10,000 ng/ml Risperidone solution was then sloied in a light-safe amber bottle at 37 °C and shaken at 40 rpm. 1ml samples were taken 3 times per week and examined by UV spectroscopy (Amersham Biosciences, Buckinghamshire, UK) for drug content. Analysis indicated that the concentiation of drug remained stable with an overall decrement of 0.12% over 285 days, equivalent to 0.05 ng/day.
In-vitro Risperidone release from individual polymers:
[00I02]Rispeιidone ielease profile from three polymers were evaluated. Implants were fabricated as described in examples 1 above, with 20% Risperidone (w/w) (RBI Flanders, I) and 80% polymer (MEDISORB®, Alkeimes Inc Cincinati, OH), where the polymer consisted of 50:50 (PLA: PGA) High inherent viscosity (IV), 65:35 Low IV and 75:25 High IV PLGA . Three implants weie placed in a separate light-safe amber bottle (500 ml) of phosphate buffer saline at 37 °C and shaken at 40 rpm 1ml aliquotes were taken 3 times per week from each bottle and analyzed by UV spectroscopy (Ameisham Biosciences, Buckinghamshire, UK) for drug content, after which 1 mi of buffer was reintioduced to maintain constant volume
Results:[00103]As depicted giaphically in Figure 3, cumulative Risperidone release from implants containing either 50:50 High IV, 65:35 Low IV and 75:25 High IV PLGA with 20% diug load, expressed as total mass of Risperidone released, follow a typical satui ation curve. Diug release is a function of the fractional concentration of PGA in the polymer matrix, wherein the lower the fractional concentration of PGA, the slower the release of Risperidone,
Example 4: Determination of maximum load of Risperidone in the implants Determination of maximum Risperidone drug Load [00104] Studies examining the effect of diug concentiation on Risperidone release profile are done with the purpose of establishing the maximum concentration of Risperidone that can be used in implants. Maximum drug loading per implant system is used to minimize implant system size, thereby making it more tolerable
Methodology: [00105]Implants aie prepared using a single polymer (85:15 PLGA High IV) combined with Risperidone at ratios of 20, 40 or 60% drug (w/w), The polymer has an anticipated degradation time of 4 months Each implant has a mass of 50 ±10 mg yielding drug mass of 10, 20 and 30 mg lespectively. Representative release profile expressed as total mg Risperidone from each 50 mg implant, over 40 days is depicted graphically in Figure 4A. Representative release profile expressed as precentage of the amount of Risperidone in each 50 mg implant, over 40 days is depicted giaphically in Figuie 4B
Example 5; Release of Haloperidol from PLGA implants as a function of implant geometiT
Background:[00106]The laige incision associated with disk-shaped implants may reduce their applicability to human subjects, under some circumstances. Therefore, implant fabrication was modified to produce rod-shaped implants that can be inserted through a 4 mm hole Rigid PLGA implants obviate the need for a tool to guide the implants tinder the skin, to ensure subcutaneous, rather than intramuscular insertion Preliminary studies weie then carried out to examine the effect of implant geometry on haloperidol release
Methodology: f00!07]Haloperidol (40% w/w) was combined with 50:50 PLGA (60% w/w) by solvent casting. Material was then compiession molded into discs or slowly extruded using high pressure piston extruder (DACA Instiuments, Goleta, CA).
Results: [00108] Release profiles from these two geometries are shown in Figure 5. As depicted graphically, Figure 5 shows the cumulative in-vitro release from disk and rod- shaped implants Each point represents the mean of triplicate observations of disks or rods Each implant was disposed in 500 ml of phosphate buffeted saline, pH 7 0 at 37 °C at 40 RPM in the dark. Rods and disks weie matched for weight No appreciable differences in ielease profile weie found, between the two implant geometries evaluated under these conditions
Example 6: Control of release profiles to maintain consistent serum drug level
Gaussian Release profiles:
[00109]Release profiles from the single-polymei system in labbit (Figure 2A) suggest that biodegiadable implants can deliver antipsychotic medication for an extended therapy peiiod While this design avoids early periods of high serum concentiation, the Gaussian pattern of release results in a 3-month lag to achieve target serum concentration Nevertheless, the symmetrical nature of the release profile opens the possibility of using overlapping implantations every six months to sustain drug deliveiy throughout the peiiod of therapy (Figure 6) thereby offsetting the steady decline from one set of implants with the gradual onset from a subsequent set
[001 10] Figuie 6 shows a model for continuous deliveiy from biodegradable implants. The release profile from 100% poly(lactic Acid) (PLA) implants in rabbits is superimposed temporarily at 6 months intervals (gray trendlines) to model reimplntatioπ intervals Projected serum levels are summed at each time point, resulting in an anticipated total release plot (Xs) The black trendlines model total ielease data The system oscillates around a target serum level as long as reimplantations occur eveiy 6 months
Example 7: Sealing of sustained release drug therapy to human patients
Scaling to Human:
[00101]The substantial interspecies differences in the metabolism of many drugs, including haloperidol, with both rabbits and monkeys lequiring approximately 15 to 30 fold higher doses than humans for equivalent plasma concent! ations are considered (Bacopoulos et al., 1980; Jibiki el al., 1993; Klintenberg et al., 2002). Humans require approximately 1 mg/kg/month of haloperidol when given as a depot prepai ation, an implant system containing 600 mg provides one year of treatment for a 50 kg patient. Thus, implant design has 1,5 gm of material with 40% drug load for one year of medication. High potency agents such as Risperidone showing promise foi this approach aie used as well. Release profiles for Risperidone indicate that an in-vivo system can attain long-term delivery for six months or more when incorporated to a PLGA delivery system Example S: Long term release of Risperidone
Physico-chemical characteristics of Risperidone in long-term delivery system: Stability of Risperidone [00102] The stability of Risperidone is evaluated following solvent casting from acetone and slow extrusion molding, theieby ensuring that the compounds can withstand commercial processing into implants. Subsequently, a shelf-life study is conducted wherin Risperidone content is examined in a series of implants stored at 4°C for various intervals up to 1 year. Risperidone is stable in a physiologic aqueous environment (37 °C, phosphate bufferred 0.9% saline, pH 7.0) for over 10 months when examined with UV spectroscopy. Risperidon retains its characteristic HPLC- MS pealc retention time and mass, following solvent casting and compression molding. In addition, Risperidone displays less than 1% degradation during 1 year storage and similarly, Risperidone displays less than 1% degradation during 1 year storage in a physiologic aqueous environment (37 °C, phosphate buffeired 0.9% saline, pH 7.0) as assessed by quantitative HPLC equipped with UV detector.
Stability of PLGA copolymers:
[00103]The stability of ten (10) PLGA polymers during fabrication storage is evaluated by measuring inherent viscosity and glass transition temperature (Tg). PLGA polymers display less than 5% change in inherent viscosity and less than 2°C change in Tg following solvent casting and extrusion molding in a dry environment at 4°c for 1 year1.
Methods: Materials [00104] Risperidone is synthesized using GMP methods. Commercially available, medical-grade Risperidone and acetone (USP/EP) is used
' The following PLGA polymeis are used:
Figure imgf000041_0001
Temporal stability of Risperidone in physiologic solution:
[00105]Three replicates of Risperidone solution is prepared as follows: Risperidone (lOmg) is dissolved in 100 μl of Acetonitrile foi subsequent dissolution in 1000 ml of phosphate buffeied saline, pH 7.0 to yield a final solution of 10,000 ng ml. Risperidone solution is then stored in a light-safe amber bottle al 37 °C. Three aliquots (lOOμl) of each sample will be drawn at monthly intervals for HPLC analysis. The concentration of Risperidone is then plotted against time and the slope of the resulting line reflects the stability of the compound .
Stability of Risperidone and PLGA polymers during implantation: Risperidone: [00I06]Risperidone implants composed of 5% drug and 95% polymer (w/w) aie made by solvent casting from acetone followed by slow extrusion molding into rods measuring 3.6mm in diameter and 20 ± 10 mm leπgtii al 60°C and 5mm/sec piston speed, The resulting material undergoes quantitative in vitro analysis with HPLC for Risperidone content. The resulting measurements are expressed as as a ratio of the original mass of Risperidone in the implant material. Polymeis: [00107]StabiIity of PLGA polymers is assessed following fabrication procedures, Control implants are piepared without diugs, using solvent casting from acetone followed by slow extrusion molding. The lesulting material (5-10 mg) undergoes analysis for alterations in IV in acetone, using an Ubbelhode suspended-level viscometei at constant temperatuie (25 °C) and changes in Tg using deferential scanning calorimetiy between 20-100°C at 10 min. Both IV and Tg are determined pre and post implant fabrication Determinins in-vivo release profile for Risperidone as a function of blodesradable copolymer physico-chemical properties:
Release patterns for individual polymers: Single polymer systems containing 100% PLA and 50% drug load result in Gaussian release profile, with peak concentration at 6 months and within therapeutic range (above 1 ng/L) between 2-8 months post-implantation (Figure 7A). The symmetrical natuie of the ielease profile opens the possibility of using overlapping implantations every six months to sustain drug delivery throughout the therapy period Such a system provides sustained therapeutic drag delivery because each reimplantation is offsetting the steady decline from one set of implants with the gradual onset of ielease from a subsequent set. Typical release of Risperidone is shown in Figure I lA depicting cumulative ielease of Risperidone dispersed in PLGA biodegradable matrix Similar profile is shown for 9_OH-Risperidone in Figuie 11B, similaily, Figure 12 shows the cumulative release of 20% (w/w) 9-OH-Risperidone dispersed in 85:15 PLA:PGA block copolymei biodegradable matrix. Figuie 13 shows the graph of cumulative release of 20% (w/w) Risperidone dispersed in 85:15 PLA:PGA block copolymer biodegiadable matrix.
[OOlOSjTo avoid relatively extensive initial lag lime and high-amplitude oscillation around the desired therapeutic concentration, additional polymer implants or fast release formulations are combined and their implantation is staggered throughout the therapy period yielding a pseudo — zero-order release wherein therapeutic drug levels are sustained throughout the therapy period (Figures 7B-7E). Example 9; Release of Haloperidol from PLGA implants
Implant fabrication:
[001 10] Implants were fabricated through solvent casting and compression-molding. Two polymers, 75% polylactide with 25% polyglycolide (75:25 PLGA) and 85% polylactide with 15% polyglycolide (85:15 PLGA) were presented in a combined system of release during a 5-month period. Each copolymer had a distinctive period of degradation that was determined by the ratio of lactide to glycolide and the moleculai weight of the resulting molecule produced. An additional polymer of 100% polylactide (PLA) was used for in vivo testing in rats. All polymers (Alkeimes Inc., Cincinnati, OH) had an inherent viscosity of 0,66 - 0.80 DL/g in chloroform and a molecular weight distribution between 120-140 IcD. Individual polymers and haloperidol (Sigma, St. Louis, MO) were dissolved in acetone and solvent cast at 60°C for 72 hours Solvent-cast material was compression molded at 80°C and 25,000 psi to a final density of 1 1 ±0,05 g/cc)
In-vitro assay:
[001 11] Individual implants were placed in 1 liter of phosphate buffered saline (PBS), pH 7,0 al 37°C on a shaker. Haloperidol concentration was measured by GCMS (National Medical Services, Willow Grove, PA) Each assay included negative controls of implants made of polymei alone and a 100 ng/ml haloperidol standard to assess stability of haloperidol in solution over time.
Animals [001 12] Implants were tested in rats (Hailan, Indianapolis, IN) (π=9) and mice (Jackson Labs, Bar Harbor, ME)(n = 1 ). Ail animals were housed in an AAALAC accredited animal facility at the University of Pennsylvania. The Institutional Animal Care and Use Committee (IACUC) approved all protocols. Animals were maintained with a 12:12 lightidark cycle with all testing and procedures peifoimed during the light cycle.
Implantation/removal surgery: [001 13]Mice and rats were anesthetized with ketamine/xylazine (100/10 mg/kg, i.p,). A 1- cm scalpel incision was made in the skin on the dorsal aspect of the animal. The subdermal space was visualized with hemostats and a single implant was placed between dermis and muscle with forceps The wound was then closed with a surgical staple. Foui weeks aflei implantation, implants were localized by palpation and removal was performed with identical anesthesia and incision In-tact implants weie easily removed with forceps.
Behavioral testing: [001 14] Sixteen C57bl/6 mice received implants made of 75:25 PLGA alone (n = 8) or 75:25 with 20% haloperidol (n = 8) to assess the effects of implants on locomotion. Following thiee weeks of implantation, total distance traversed was assessed over a twenty-minute period. Implants were then removed and animals allowed to recover for 48 hours prior to le-testing 20 minutes after apomorphine challenge (0.5 mg/kg i p.) (Sigma, St Louis, MO) Western blot:
[001 15]Six Sprague Dawley rats leceived implants made of PLA with 30-40% haloperidol, Thiee rats leceived implants of PLA alone Implants remained in all animals for thiee months prior to removal Seventy-two hours after implant removal, rats were sacrificed and brains rapidly lemoved, dissected into four regions (cortex, hippocampus, stiiatum and ceiebellum) then frozen in liquid nitrogen. Western blots foi quantitative analysis of D2 receptor protein were performed on striatum. Three concentiations of cortex protein from a single animal (2,5, 5 and 10 μg) were run with all blots as an internal control to insure intensity of labeling was within linearity of quantitative software. Only those blots in which the density of samples was within the linear range of internal standaids weie used for analyses. Western blots were perfoimed using polyclonal antibody WR-3526, raised against amino acids 272-282 of the D2 receptor protein (Research and Diagnostic Antibodies, Berkeley, Ca). Slriata were homogenized in homogenization buffer (20 mM HEPES, 2mM EGTA, 1 mM PMSF, 2 μM Aprotinin and 2mM DTE), followed by a 30- second sonication Samples were centrifuged 100,000 g for 1 hour at 4°C. Pellets were resuspended and solubilized in homogenization buffer containing 0 1% Triton X-100. Proteins were extracted on ice for 45 minutes with occasional agitation. After extiaction, proteins were centrifuged at 30,000 g for 30 minutes at 4°C. Protein samples were prepared with 25% 4x NuPAGE sample buffer plus 10% reducing agent (Invitro en) and heat shocked at 70°C for 1Q_ minutes. Samples were separated on a 10% precasted mini-gel at 200 volts for 50 min. Proteins were transferred to PVDF at 30 volts foi 1 hour. Blots were blocked with 5% milk in TBS (20 mM Tris, pH = 7 5, 0 5 M NaCl), then washed for 15 minutes. Blots were then incubated overnight with aπti-D2-Receptor antibody, washed with TBS, and incubated with goat anti rabbit horseiadish peroxidase conjugate (BioRad, 1:4800) for 1 hour. Blots were then incubated with chemilu inesceπt substrate (Pierce) for 1 min, wrapped with plastic and exposed to autoiadiographic film Quantification:
[001 16] The intensity of each band was quantified using a densitometer model 7100 and quantitative analysis software (Bio Rad, Heicules, CA) and expressed as a ratio to the corresponding band in rat 1 to yield a ratio of intensity (rat 1 = ratio of 1), All samples were processed simultaneously on a single blot to allow for quantitative comparisons between conditions,
In-vitro:
[001 17]Haloperidol concentration for two polymers, as well as combined values are shown in Figure 8 A-C. Figuie 8 graphically depicts individual implants that are placed in phosphate buffered saline, pH 7, at 37°C on a shaker. Samples of buffer are drawn at weekly / biweekly intervals and evaluated with GCMS for haloperidol concentration. Cumulative release is expressed as the percent of total drug load measuied in buffer solution at each time point. Cumulative haloperidol concentration from 75:25 and 85:15 PLGA polymers. Each graph displays data from three implants (circle, squaie and triangle) with a 4th degree polynomial average line for the three values.
[001 18]Implants made of 75:25 PLGA with 40% haloperidol resulted in a pattern of release characterized by an initial phase of slow release (approximately 0,29% / day / implant) from 0 to 28 days A second phase of more rapid release occurred between 28 and 84 days (approximately 1.28% / day / implant). Implants made with 75:25 PLGA released 50% of the total haloperidol load in 66 days (Figuie 8A). Implants made of 85:15 PLGA with 40% haloperidol displayed a similai pattern of release with a phase of slow release (approximately 0,26% / day / implant) from 0 to 56 days A second phase of more rapid release occurred between 56 and 140 days (0 95% / day / implant) Implants made from 85:15 PLGA released half of the haloperidol load in 88 days (Figure 8B) Release from the theoretical composite system of 75:25 and 85:15 PLGA, 40% haloperidol, shows an early phase from 0 to 28 days with an average of 0 34%/day and moie rapid release between 28 to 140 days with 0.82%/day. The combined system of 75:25 and 85:15 PLGA demonstrates a period of 78 days to release half of the total haloperidol load (Figure 8C) The value for the positive control solution (100 ng/ml) remained stable throughout the period of 154 days (0 days = 106, 154 days = 100, mean ± sd throughout study inteival = 106 ±11 ng/ml).
In-vivo Locomotor activity: [001 19]Locomolor activity for mice that received either haloperidol or blank polymer implants is demonstrated in Figuie 9 All animals were tested 3 weeks after- receiving implants made of 75:25 PLGA alone or 75:25 PLGA with 20% haloperidol Baseline locomotor activity was measured for twenty minutes. Animals with control implants traveled a mean of 12223 ± 433 cm, while those with haloperidol containing implants traveled an average of 7664 ± 450 cm. Thus, mice with haloperidol implants traveled significantly less distance than controls (p < 0 01) Implants were then lemoved and all animals were allowed to recover for 48 hours One animal with a control implant died from anesthetic during removal surgeiy. Forty-eight houis after removal of implants, animals received apomorphine 0.5 mg/kg i.p. twenty minute prioi to locomotor testing, which has been shown to inciease locomotor activity in mice (Ninan and Kulkarni 1999) After apomoiphine challenge, animals that had control implants traveled a mean of 4721 ± 476 cm, while those with haloperidol containing implants traveled an average of 8531 ± 2536 cm. Therefore, following lemoval of implants and exposure to apomorphine, mice that had haiopetidol implants traveled more distance than control mice (p<0.01).
Western blots: [00120] Western blots of stiiatal membranes from all rats levealed a band at an apparent molecular weight of approximately 50 kD (Figure 10) corresponding to the piedicted molecular weight of the full-length D2 receptor protein (Expert Protein Analysis System, Swiss Institute of Bioinformatics, http://www.expasy.ch/) (Bunzow et al 1988) , Mean optical density of bands was quantified relative to the corresponding band in lane 1 (haloperidol treated rat). Results based on 3 blots yielded a mean ± SD relative density for haloperidol implant treated rats of 0,90 ± 0.07 for the 50 kD band, while the mean relative density for control rats was 0 64 ± 0,02 (p<0 001, two tail t-test ),
Example 10. Risperidone Implant Long-term Therapy for Scizopherenia
Implant Fabrication: Risperidone Disk implant [00121]Implaπls may be fabricated tluough solvent casting and/or compression-molding. Two polymers, 75% polylactide with 25% polyglycolide (75:25 PLGA) and 85% polylactide with 15% polyglycolide (85:15 PLGA) are presented in a combined system of release during a 12- 14-month period. Each copolymer has a distinctive period of degradation thai is determined by the ratio of lactide to glycolide and the molecular weight of the lesulting molecule produced All polymers (Alkermes Inc., Cincinnati, OH) aie with an inheient viscosity of 0 66 0.80 DL/g in chloroform and a molecular weight distribution between 120,000-140,000. Individual polymers and Risperidone (Sigma, St. Louis, MO) may be dissolved in acetone and solvent cast at 60°C for 72 hrs. Solvent-cast material was made into disks measuring 20 mm in diameter and 1.2 ± 0 00 mm thickness, with final density of 1.2 ± 0.1 g/cc. Risperidone Rod implant
[00122]Rod Implants may be fabricated through compiession-molding. PLGA polymer, 50% polylactide with 50% polyglycolide (50:50 PLGA) are presented in a system of release during a 2-month period Polymer (Alkermes Inc., Cincinnati, OH) is with an inherent viscosity of 0,66±0,1 DL/g in chloroform and a molecular weight distribution between 120,000-140,000, Polymer and Risperidone (Sigma, St. Louis, MO) are dissolved in acetone at a 95:5 ratio (w/w) and extruded using high pressure piston extruder (DACA Instruments, Goleta, CA) at 60°C and 5mm/sec piston speed psi to a final density of 1 1 ± 0.1 g/cc. And 3,5 ± 0.5 mm diameter and 20 ± 10 mm length Release profile may be altered by varying monomer ratio (lactide:glycolide), initial drug loading and fabrication procedures
Experimental Controls and Monitoring: A) The first group of control subjects receive 6 months of risperidone exposure from a multiple polymer system B) The second group of control subjects receive an initial multi-polymer system followed by reimplantalion of "maintenance" implants at six months to provide 12 months of continuous medication prior to necropsy. C) The third group of control subjects receive an initial multi-polymer system to provide six months of steady state delivery, but will not receive leimplantalion of maintenance implants. These control subjects are then be tested at 12 months post implantation to provide toxicological evaluation after the system has ceased to delivery medication D) The fourth group of control subjects receive broken implants to evaluate the consequences of mechanical damage to implants during the delivery inteival. E) The fifth group of control subjects serve as positive control and they leceive daily oral risperidone or risperidone injections to reveal toxicological effects of the drag that are independent of the deliveiy system being tested, F) The final group of control subjects receive blank implants with no drug as a negative control to assess the effects of polymer materials, independent of risperidone.
Rod Implant Disposition [0012 ] Implants varying in release profiles are inserted subcutanously to a patient in need thereof The implans may be disposed at the shoulder through a 4 mm incision. Since the implants aie rigid, no implant-guides are necessary,
Determination of therapeutic effect in Schizopherenia:
[00124] Patients, while undrgoing therapy, have improved Brief Psychiatric Rating Scale (BPRS) scores (Dinakar, H.S. et al , [2002] Efficacy of Olanzapϊne and Risperidone for Treatment-Reft acto y Schizophrenia Among Long-Stay State Hospital Patients, Psychiatric Services, Vol. 53 No 6, pp 755-757) and show no significant side effects such as weight gain. Improvement is also observed with regards to negative symptoms (alogia, affective flattening, avolition, apathy, social withdrawal and atlentional impairment) and performance of cognitive tasks (Honey, G.D., et al , [1999] Differences in Fiontal Cortical Activation by a Working Memory task after Substitution of Risperidone for Typical Antipsychotic Drugs in Patients with Schizophrenia, PNAS, vol, 96, No. 23, pp. 13432-13437)
Blood Serum Levels of Risperidone:
[00125]2 ml of blood are taken from the subject every tliree months or as needed based on the impiantation/ieimplantation regimen. Blood is then centrifuged and the seium separated Risperidone concentration is determined following solid-state extraction (MCX, Waleis) and HPLC/UV detection.
Example 11. Microparticles for Oral-delivery of 9-OH-Risperidone for bipolar disorder, short term therapy (1-3 weeks).
Microparticles fabrication:
[00126] The microparticles are made from poly(glycolic acid) and poIy(d,l -lactic acid) copolymer at a 75:25 ratio of lactide to glycolide with 9-hydroxy-Rispeιidone, as an active agent at 98:2 w/w ratio PLGA copolymer and 9-hydroxy-Risperidone aie dissolved in acetone and EVA as the dispersed phase. The continuous phase is made with PVA, water, ethyl acetate, and benzyl alcohol. The dispersed and continuous phases at a 20:80 latio are pumped through a static mixer (Kenics® KM Series Static Chcmineer, Dayton, OH) to form an emulsion. Final microspheie size may be controlled by phase ratio, flowrate, temperature and continuous phase composition. The resulting emulsion is passed into a quenching liquid. After being allowed to settle, the lesulting microspheres are then filtered and washed repeatedly with a series of appropriate solvents and then dried. Adminisu ation of microspheres: [00127]Microspheres are incoprorated in capsules and orally administered to a patient in need theieof, The microspheres may be incorporated with excipients and used as ingeslible capsules, which also contain a binder, excipients, a lubricant and possibly a liquid caπier
Treatment efficiency: [00128] Patients undergoing long-term therapy exhibit improvement of at least 7 points above baseline based on Clinical Global Impression (CGI), and mean Global Assessment of Functioning (GAF) scores. Treatment is well tolerated, and no patient experiences worsening of mood symptoms while receiving 9-OH-Risperidone (Ghaemi, S,N, [1997] Acute Treatment of Bipolar Disorder with Adjimclive Risperidone in Outpatients Can J Psychiatry, Vol 42,pp. 196-199. Example 12; Sustained release therapy of psychotic disorder using second generation antipsychotic agent; Starter formulation:
[00129] To compensate for the lelatively long lag time associated with attaining theiapeutic blood-serum level in rigid implants, a patient exhibiting symptoms of psychotic disoider is given a formulation containing the antipsychotic drug in the form of an injectible for practically immediate elevation of blood serum level to above theiapeutic levels. The injectible formulation is followed by oral dose of microparticles of PLGA containing the antipsychotic drug, wherein fast release of the drug, to above-therapeutic leveis is obtained in a day and peak delivery is obtained over a two-week period.
Implants: Single polymer implant: [00130] Implants fabricated as described above are made from a single copolymer containing the antipsychotic agent Release profile is designed to achieve therapeutic levels within 3 weeks of implantation and last from 6-8 months until ftill degradation, with peak ielease occurring 5-7 months following implantation In older to compensate for the high amplitude oscillation around optimal serum level of the antipsychotic agent that may result from a single implant, a second maintenance set of a single copolymei composition may be added, with peak delivery al 10- 14 weeks and full degradation within 4-5 months from implantation Examples of cumulative ielease profile for seveial antipsychotic agents from PLGA implants are shown graphically in Figures 14D, 15A, 16A and 17A 5 Multiple copolymer compositions implant: [O0I31]Using coextiυsion, a high-load core PLGA (85:15 PLA:PGA, high IV) copolymer with prolonged ielease profile is incorporated as the core of composite implant with external low-load, fast ielease PLGA (50:50 15 PLA:PGA, low IV) which may 10 eliminate the maintenance set and inciease degradation lime, such that therapeutic levels are sustained for an extensive amount of time allowing for eithei leimplantalion once eveiy 9 months or alternatively reducing implant size.
Monitoring of blood serum for antipsychotic agent concentration:
!5[00132]2 ml of blood are taken from the subject eveiy three months or as needed based on the implantation/reimplantation legimen. Blood is then centrifuged and the serum separated Antipsychotic agent concentration is determined following solid-state extraction (MCX, Waters) and HPLC/UV detection by comparison against a known standaid0 Monitoring treatment efficacy: [00133]Monitoring efficacy will depend on the psychotic disorder being tieated. Patients generally show improvement in cognitive tasks, stable emotion or mood swings, or in particular, improvement in ones ability to work, interact and be intimate with5 other people and society. No significant side effect are evident and rehospitalization frequency is reduced. Effects of antipsychotic agents released from implants is shown in Figuies 14-17.
[00134] While various embodiments of the present invention have been described above, it0 should be understood that they have been presented by way of example only, and not limitation. Thus the bieadth and scope of the present invention should not be limited by any of the above described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents. Example 13: Drug loading optimization;
Background
[0OI35]Studies to examine the effects of drug concentration on risperidone ielease profile were done The purpose of these studies was to establish the maximum concentration of risperidone that can be used in implants. Implants will utilize the maximum concentration so as to make implants as small as possible and theiefore moie easily tolerated. Implants were prepared using a single polymer (85:15 PLGA High IV) combined with risperidone at ratios of 20%, 40% or 60% drug by weight (Figure 18A) This polymer has an anticipated degradation inteival of 4 months. Each implant has a mass of approximately 50 mg, yielding drug mass of 10, 20 and 30 mg respectively for the 20%, 40% and 60% drag load conditions, These studies were replicated and additional percentages were tested. Results
[00136] Figures 18 A-B shows cumulative risperidone release from implants containing 85:15 PLGA with 20, 40 or 60% drag load by weight, Each point represents the mean of thiee replicates with a trendline to demonstrate overall pattern of release, A) Release expressed in total g of risperidone from each 50 mg implant B) Release expressed as a percentage of the amount of drug in each type of implant.

Claims

What is claimed is:
1 A method of treating a Nervous System disorder in a subject in need, the 5 method comprising: a. Administering to said subject a first foimulation of a drug in complex with a biodegradable polymer, wherein said formulation delivers said drug with pseudo-zero order kinetics in-vivo; and it) b Administering to said subject a second formulation of said drag in complex with a biodegradable polymer, wherein said formulation deliveis said drug substantially fastei, in-vivo, than said first formulation, Whereby administering said fust and second foimulation results in therapeutic 15 ciiculating levels of said drug, for a period of about 14-420 days, thereby being a method of treating a nervous system disorder.
2 The method of claim I , wheiein said therapeutic circulating levels of said drug lange from 0.1 - 10 ng/mL.0 3. The method of claim 2, wherein administering said second formulation results in said circulating levels within a peiiod of about 1 -30 days,
4 The method of claim 2, wheiein administering said first foimulation results in5 said cii dilating levels within a period of about 21-180 days
5 The method of claim 2, wherein said circulating levels is sustained for about 34-420 days 0 6, The method of claim 2, wherein the formulations are in a form of an implant,
7 The method of claim 6, wherein said implant is inserted subcutaneously. 8 The method of claim 1 , wheiein said first foimulation comprises complexes of said drag and two or more biodegradable polymers
9. The method of claim 8, wherein said complexes vary in terms of drug concentiation, polymer composition, or combination thereof
10 The method of claim 1 , wheiein said second formulation comprises complexes of said drug and two or moie biodegradable polymers. I I. The method of claim 10, wherein said complexes vary in teims of drug concentiation. polymei composition, oi combination theieof
12 The method of claim 1, wherein said disorder is AIDS-related dementia, schizophrenia, bipolar disorder, bordeiline personality disordei (BPD), Alzheimer's disease (AD), psychotic depression or other mental disorders causing confusion, disorganization or psychosis
1 The method of claim 6, wherein said implant is disk or rod shaped
14 The method of claim 13, wheiein said rod shaped implant has a diameter of about 1 to about 2 mm, a length of between about 10 and about 40 mm, oi a combination theieof
15 The method of claim 1, wherein said drug is at a concentration of between about 2 to about 50 percent by weight of said first or second formulation.
16. The method of claim 2, wherein said diug is is Risperidone, 9-OH- Risperidone, haloperidol, olanzapine, clozapine, aripiprazole, quetiapine, ziprasidone or a combination thereof.
17 The method of claim 2, wheiein said first formulation and said second foimulation aie administered within 1-24 houis of each other
18 The method of claim 2, wherein said first and second formulations are administeied to said subject cyclically 19 The method of claim 18, wherein said fust and second formulations are administered to said subject when said circulating levels of said drug serum levels are below 1 ng/mL
20. The method of claim 18, wherein said first and second formulations are administered to said subject from about 160-200 days, following a first administration of the formulations.
21 A kit for sustained delivery of a drug comprising: a first foimulation of said drug in complex with a biodegradable polymer, wherein said formulation delivers said drug with pseudo-zero oidei kinetics in-vivo, and a second formulation of said drug in complex with a biodegradable polymei wherein said second formulation has a rate of release which is faster than said fust formulation, in-vivo,
22. The kit of claim 21, wherein the combination of said fust and second foimulation of the kit gives sustained delivery, once administered over a peiiod of about 1 week to about 14 months.
23. The kit of claim 21, wheiein said biodegradable polymer is copolymer of poly(laclide-glycolide) (PLGA)
24. The kit of claim 23, wherein said PLGA is an ataclic or syndiotactic block copolymer of PLA and PGA
25 The kit of claim 23, wherein said PLGA has a molecular weight of from about 10,000 to about 200,000.
26 The kit of claim 23, wherein the concentiation of d,I-lactide monomer comprising said PLGA ranges from 50% - 100%.
27 The kit of claim 21, wherein said biodegradable polymei is polylactide.
28. The kit of claim 21, wherein said drug is Risperidone, 9-OH-Risperidone, Haloperidol, Olanzapine, Clozapine, Quetiapine, or a combination thereof.
29. The kit of claim 21 , wherein the drag content is between 2 and 75% (w/w)
30. The kit of claim 21 , wherein said first formulation is in the form of an implant
31 . The kit of claim 30, wherein said implant is for subcutaneous insertion.
32. The kit of claim 30, wheiein said implant is rod or disk shaped,
33 The lcit of claim 32, wheiein said rod-shaped disk has a diameter of about 1 to about 2 mm, a length of between about 10 and about 40 mm, or a combination thereof.
34. Use of the kit of claim 21 in treating a psychotic disorders in a subject in need thereof.
35. A composition for use in the treatment of psychotic disorders, comprising a poly(laclide/gIycolide) (PLGA) copolymer at a concentration of from about 95-98% (w/w), and an antipsychotic agent, at a concentration of from about 2 to about 5% (w/w), wherein the lactide:glycolide ratio of said poly(laclide/glycolide) copolymer is from about 100:0 to 50:50 and wherein said antipsychotic agent is Risperidone or 9-OH-Risperidone.
36. The composition of claim 35, wherein said PLGA copolymer concentiation is 98% (w/w).
37. The composition of claim 35, wherein said PLGA copolymer concentration is 95% (w/w).
38. The composition of claim 35, wherein said antipsychotic is 9-OH-Risperidone. 39 The composition of claim 38, wherein said PLGA has a molar ratio of lactic monomer to glycolic monomer is 85:15.
40. The composition of claim 38, wherein said PLGA has a molar ratio of lactic monomer to glycolic monomer is 75:25.
41. The composition of claim 38, wherein said PLGA has a molar ratio of lactic monomer to glycolic monomer is 65:35.
42. The composition of claim 38, wherein said PLGA has a molar ratio of lactic monomer to glycolic monomer is 50:50.
43. The composition of claim 38, in the form of a solid implant
44. The composition of claim 43, wherein said implant is in a disk or rod shape.
45. The composition of claim 44, wherein said rod shaped implant has a diameter of about 1 to about 4 mm, a length of between about 10 and about 40 mm, or a combination thereof
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JP2006549540A JP5306599B2 (en) 2004-01-12 2005-01-12 Long-term delivery formulation
US10/585,611 US20080305140A1 (en) 2004-01-12 2005-01-12 Long-Term Delivery Formulations and Methods of Use Thereof
KR1020117025349A KR101242486B1 (en) 2004-01-12 2005-01-12 Long-term delivery formulations and methods of use thereof
AU2005206143A AU2005206143B2 (en) 2004-01-12 2005-01-12 Long-term delivery formulations and methods of use thereof
KR1020067016248A KR101197540B1 (en) 2004-01-12 2005-01-12 Long-term delivery formulations and methods of use thereof
US11/183,232 US8221778B2 (en) 2005-01-12 2005-07-18 Drug-containing implants and methods of use thereof
US11/195,845 US8329203B2 (en) 2004-01-12 2005-08-03 Drug-containing implants and methods of use thereof
US11/988,137 US8741327B2 (en) 2004-01-12 2006-07-18 Method of maintaining therapeutic risperidone levels in a PLA:PLGA implant
US13/490,787 US8802127B2 (en) 2004-01-12 2012-06-07 Risperidone-containing PLA:PGA implants and methods of use thereof
US14/286,168 US9439905B2 (en) 2004-01-12 2014-05-23 Risperidone-containing implants and methods of use thereof
US14/540,828 US9717799B2 (en) 2004-01-12 2014-11-13 Drug-containing implants and methods of use thereof
US15/627,349 US9925268B2 (en) 2004-01-12 2017-06-19 Drug-containing implants and methods of use thereof
US15/627,389 US9895447B2 (en) 2004-01-12 2017-06-19 Drug-containing PLA implants and methods of use thereof
US15/863,483 US10111960B2 (en) 2004-01-12 2018-01-05 9-OH-risperidone controlled release composition
US16/174,083 US10736965B2 (en) 2004-01-12 2018-10-29 Risperidone biodegradable implant

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US13/490,787 Continuation-In-Part US8802127B2 (en) 2004-01-12 2012-06-07 Risperidone-containing PLA:PGA implants and methods of use thereof
US14/286,168 Continuation-In-Part US9439905B2 (en) 2004-01-12 2014-05-23 Risperidone-containing implants and methods of use thereof
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