CN101327196A - Dosage form and method for administering drug - Google Patents
Dosage form and method for administering drug Download PDFInfo
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- CN101327196A CN101327196A CNA2008101379378A CN200810137937A CN101327196A CN 101327196 A CN101327196 A CN 101327196A CN A2008101379378 A CNA2008101379378 A CN A2008101379378A CN 200810137937 A CN200810137937 A CN 200810137937A CN 101327196 A CN101327196 A CN 101327196A
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Abstract
A dosage form and a method are disclosed and claimed for administering a drug in a sustained and constantly ascending rate per unit time to provide an intended therapeutic effect while concomitantly lessening the development of unwanted effects.
Description
The application is that JIUYUE in 1997 was submitted on the 16th, and the China national application number is 97198342.9, and the invention exercise question is divided an application for " dosage form and application method ".
Technical field
The present invention relates to be used to produce the novel form and the new application method of therapeutic effect.More particularly, the present invention relates to the dosage form of continuous increasing speed dispenser forming specific therapy, and relate to by producing the method for therapeutic effect to form specific therapy with the dispenser of continuous increasing speed at the fixed time.The invention still further relates to a kind of dosage form and a kind of method, is then to be applied to the medicine that prolongs continuous increasing dosage in time by the medicine that is applied to predose earlier to reach curative effect.
Background technology
For a long time, use medicine in each social medicament and the medical treatment to pain, emotion, thinking, sensation, behavior and psychological personality generation effect.These medicines refer to opioid, barbituric acid salt, sleeping pill, central nervous system stimulant, central nervous system depressant, psychostimulant, alcohols, Fructus Cannabis lipid and catecholamine.In present medical treatment, there is a class to become the standard contrivance of treatment distractibility disease in these medicines, promptly be central nervous system stimulant.Though the present invention provides medicine for central nervous system in more detail, should understand that the present invention has universality, it comprises the medicine that application dosage form of the present invention and method are extensively used.
Father and mother, teachers, doctors, psychologists, social worker and clinicist have found out the remarkable benefit of medicine for central nervous system, and this has caused the general acceptable application of central nervous system's medication treatment distractibility disease.In 1994, promptly collect the nearest time of data, find the female population at school age about 2% and school age male's population about 6% (amounting to about 2,000,000 patients) accept medication with treatment distractibility disease.
Before the present invention occurred, the dosage form and the method for dispenser (for example central nervous system's drugs with function) were the application standard pharmaceutical dosage forms.For example, a kind of prior art dosage form of drug administration (as the medicine for central nervous system methylphenidate) and method are to use the tablet that contains this medicine of instant-free.This instant-free dosage form is sent drug delivery by emitting medicine at once, and this just produces with crest and trough is the unsettled blood levels of feature.To produce the curative effect of anticipation as for the instant-free dosage form that contains methylphenidate (it is characterized in that beginning rapidly and lacking half life), need multidose every day, cause the fluctuation of behavior and attention like this, because medication loses its curative effect.This dosage form can not provide required curative effect for a long time.
The prior art dosage form that another kind is used to offer medicine is a slow release formulation.May be cumulative when the medicine of throwing in from the prior art slow release formulation begins, but can not increase at whole dosing interval, in fact it may prolong in time and reduce.That is to say that these slow release formulations are thrown in medicine with the distribution that does not increase in time, because they do not provide the rate of release that per hour increases continuously in whole long-time administration process.In addition, this dosage form can not provide required treatment phase and suitable blood graphic.As for from the non-medicine (as methylphenidate) that the central nervous system is worked that increases progressively dosage form dispensing of slow release, the normal acute tolerance that forms medicine of patient, this is confirmed by the reduction of the required curative effect intensity of the persistent period that shortens and acceptable therapy.Previous slow release send to pass and also lacks the wherein means of inherent defect that compensate.
Above-mentioned explanation enlightenment, urgent need have overcome the novel form and the new application method of the known shortcoming of prior art.Need requirement to dosage form with to this of method is long-expected: (1) reduces the number of times of dispensing every day simultaneously with the speed dispenser that continues to increase; (2) with the dosage form of the dosage dispenser that continues compensation and method to compensate acute tolerance basically, so keep the clinical response of preliminary election to medicine; (3) with the dosage form of the lasting increase distribution form dispenser of treatment distractibility disease clinical needs, and (4) beginning dispenser and be dosage form and the method that continues the distribution form dispenser that increases in whole school day.
Therefore, in view of as above explanation, instant purpose of the present invention provides the dosage form that has overcome shortcoming known in the state of the art.
Summary of the invention
Another object of the present invention provides a kind of novel unique dosage form, and it is offerd medicine with the ascending-dose that is control in time to the patient.
Another purpose of the present invention provides a kind of dosage form, it executes the medicine of dose to keep curative effect for the patient obtained the toleration of medicine, promptly, avoid forming simultaneously acute tolerance basically by offeing medicine to keep curative effect with the ascending-dose that is control in time.
Another purpose of the present invention provides a kind of dosage form, and the medicine that its delivers dose is avoided substantially or reduced the formation that causes the toleration that the patient obtained of acute tolerance because of dispenser, by this dosage form to be the dosage dispenser of continuous increasing in time.
Another purpose of the present invention provides a kind of dosage form that is used for to central nervous system's dispenser, and it has overcome known disadvantage of the prior art.
Another purpose of the present invention provides the improvement measure to dosage form, wherein should the improvement measure comprises being used for the treatment of distractibility disease to continue the constant dosage form that increases progressively the distribution form dispenser.
Another purpose of the present invention provides the pharmaceutical composition that is solid dosage forms, and it comprises the 1mg～500mg medicine with pharmaceutically acceptable carrier fusion, and this medicine is slow release and the release of ascending-dose form is used for the treatment of psychological personality disorder.
Another purpose of the present invention provides a kind of dosage form, is used for the per hour amount of application that increased central nervous system's drugs with function in 4～8.5 hours in school's day.
Another purpose of the present invention provides a kind of dosage form, is used for using under the minimum doses with the speed that continue to increase and in every day the medicable medicine to the central nervous system.
Another purpose of the present invention provides a kind of dosage form, and the medicine that is used for the relevant toleration of medicine that obtains with compensation send to be passed pattern and use central nervous system's drugs with function.
Another purpose of the present invention provides a kind of dosage form of medicine of administering therapeutic distractibility disease, and it comprises this disease for the treatment of the people with this medicine of oral dose of the 100ng～375mg of continuous increasing in 16 hours to the people who is suffered from this disease by diagnosis.
Another purpose of the present invention provides a kind of novelty and unique method is obtaining the curative effect among the patient of this medicine toleration to keep medicine, wherein this method comprises to the patient and uses this dosage form, it send drug delivery to keep curative effect with the form that prolongs the ascending-dose that is control in time, avoids forming in the patient simultaneously acute tolerance basically.
Another purpose of the present invention provides a kind of method, be used for avoiding basically or reduce the formation of the toleration that the patient obtains, described patient has been applied in the medicine that forms acute tolerance among the patient, and wherein this method comprises the effect of envisioning with generation with the dosage dispenser of continuous increasing in time.
Another purpose of the present invention provides the improvement measure to application method, and improvement measure wherein comprises to prolong in time to be and continues the constant distribution form dispenser that increases progressively with treatment distractibility disease.
Another purpose of the present invention provides a kind of application method, and it uses central nervous system's drugs with function per hour to increase progressively rate of release continuously during 4～8.5 hours whole school day.
Another purpose of the present invention provides the acute tolerance development that a kind of new method compensates and can tolerific medicine is relevant in the patient, promptly by with the dosage per os dispenser of continuous increasing greatly to reduce the effect of unwanted acute tolerance.
Another purpose of the present invention provides one and is using the improvement that has aspect the method for medicine that the central nervous system stimulates curative effect, wherein this improvement comprise with prolong in time be continuous increasing the form dispenser with treatment distractibility disease, also provide the treatment of the acquired tolerance relevant to compensate in addition with medicine.
Another purpose of the present invention provides the method for treatment distractibility disease, it comprises to the people who is suffered from this disease by diagnosis with the oral dose medicine for central nervous system of 100ng～500mg of being continuous increasing in 16 hours with this disease among the treatment people patient, and with minimum dosage number every day.
Another purpose of the present invention is to use central nervous system's drugs with function with treatment distractibility disease (ADD) and distractibility hyperkinetic syndrome (ADHD) by a kind of method, increases when medicine is initial in the method and increases continuously at whole dosing interval.
Description of drawings
Below will make these purposes of the present invention and other purpose, feature and advantage become more obvious to the detailed open and accompanying Claim book of the present invention.
In Fig. 1, solid line has been described the plasma concentration of the central nervous system stimulant used from the instant-free dosage form, and dotted line is represented from continuing the non-plasma concentration that increases the central nervous system stimulant that dosage form discharges.
In Fig. 2, comprise that the solid line of crest and trough has been described the instant-free dosage form, what be shown in dotted line then is that slow release increases progressively dosage form.
Among Fig. 3,4 and 5, described the release result of medicine for central nervous system, wherein open circles is represented placebo, black circle expression instant-free type, and black shape represents to continue the non-release profile that increases, and square hollow represents that then the continuous increasing rate of release distributes.
In Fig. 6, solid line has been described continuous increasing and has been discharged plasma concentration, comprises that the dotted line of crest and trough has then been described the instant-free plasma concentration.
In Fig. 7, filled circles is represented placebo, and open circles represents that continuous increasing distributes, and solid squares is drawn the dispenser scheme of identical medicine for central nervous system one day three times.
Fig. 8 has described: the placebo that black circle expression is a day three times, and black shape is represented instant-free, open circles is represented to discharge about the continuous increasing of the essentially no toleration of same medicine.
The blood plasma methylphenidate concentration that gets by by following three kinds of mode dispensers has been described in Fig. 9～11: three dispensers in a day, with the ascending-dose dispenser, and send the dosage form of passing distribution by control.
The blood plasma methylphenidate concentration that gets by with a kind of dosage form dispenser has been described in Figure 12～16, and this dosage form comprises: the outer coating of medicine predose then is the medicine internal layer of ascending-dose in time.
By enforcement of the present invention, having now found that can provide by a kind of formulation of new departure dispenser and a kind of Method, greatly alleviate or full remuneration patient's tolerance. Brill "Pharmacology in the medical science Learn " (Pharmacology in Medicine)P.227 define among (1965) McGraw-Hill ' tolerance ' expression dispenser after the reduction of effect. When behind dose or in very short time When forming tolerance behind the interior several dosage, be called as acute tolerance. Longer time is aobvious after dispenser When showing the tolerance of obvious degree, be called as chronic tolerance. Medical literature, as Goodman and Gilman "Therapeutic pharmacological basis”(
The Pharmacological Bases of Therapeutics), the 8th edition, p.72 among (1990) Pergamon Press, reported from But the effect acquired tolerance of a lot of medicines, the document based on time of acquired tolerance with tolerance Be divided into acute or chronic. That is to say that acute tolerance is the administration phase dose or one day Interior formation, chronic tolerance then is because long-term dispenser (being generally several weeks, several months and several years) And obtain. The chronic tolerance of the most normal finger of tolerance that proposes in the medical literature is as seen in for a long time Use more heavy dose of, normally because the liver enzyme that relates in the increase of body sizes, bio-transformation etc. Cause.
The present invention includes the pharmaceutical dosage form that ascending-dose is provided. Exemplary dosage form comprise contain many little The hydrogel matrix of little ball. This hydrogel matrix comprises the hydrophilic polymer that is selected from lower group of material: Polysaccharide, agar, agarose, natural gum, alkaline alginates (such as mosanom), Irish moss gather Sugar, fucoidin, furcellaran, laminarin, husky Lepidium, gum arabic, Indian gum, thorn Karaya, tragacanth, locust bean gum, pectin, amylopectin, gelatin and hydrophilic colloid. This hydrogel matrix comprises a lot of 4～50 small balls, and each small ball comprises from 100ng Increased dosage amount is to the agent that increases progressively such as 0.5mg, 1mg, 1.2mg, 1.4mg, 1.6mg, 1.8mg etc. Amount group. This small ball comprises that the thick rate of release of 0.0mm～10mm control wall regularly passs guaranteeing Increase release amount of medicine. The representative of wall-forming material comprises the triglycerides that is selected from lower group of material: three tristearin Acid glyceride, glycerin monostearate, glycerol-1,3-dipalmitate, glyceryl laurate ester, two decene Acid glyceride and three decylenic acid glyceride. Other wall-forming material comprises poly-(acetic acid phthalic acid Vinyl acetate), methyl cellulose phthalate ester and porous vinyl olefins. Prepare small The method of ball be disclosed in United States Patent(USP) Nos. 4,434,153; 4,721,613; 4,853,229; 2,996,431; In 3,139,383 and 4,752,470.
Be used for sending the formulation of the present invention of the medicine that increases progressively long dosage to comprise that medicine discharges pearl. This medicine Discharge pearl and be characterised in that such stripping curve, namely wherein 0～20% of this pearl experience stripping and Discharge medicine in 0～2 hour, 20～40% experience strippings also discharged medicine in 2～4 hours, 40～60% showed stripping and discharged medicine in 4～6 hour, 60～80%, and in 6～8 hours, 80～100%, in 8～10 hours. This medicine discharges pearl and comprises center composition or core, it Comprise that medicine and pharmaceutically acceptable composition batching (comprises lubricant, antioxidant and buffering Agent). This pearl comprises the medicine of ascending-dose, and for example 1mg, 2mg, 5mg and 10mg are increased to 40mg. These integuments are coated rate of release control polymer, can use top disclosed stripping and distribute Select this polymer. Following document discloses the preparation of this pearl: Liu,International pharmacy magazine
(
Inter.J.of Pharm.), Vol.112, pp.105-116 (1994); Liu And Yu,International pharmacy magazine，Vol.112，pp.117-124(1994)；Remington，
The pharmacy science(
Pharm.Sci.), the 14th edition, pp.1626-1628 (1970); Fincher,The pharmacy Scientific Magazine(
J.Pharm.Sci.), Vol.57, pp1825-1835 (1968); And U.S. Patent No. 4,083,949.
A kind of formulation provided by the invention comprises the drug concentration gradient from 1mg to 100mg, in the past Person's low dosage is coated on the polymer substrate to the latter's high dose. This polymer can be erosion property Maybe can not erosion property polymer. The matrix of coating is around himself latter's high dose winding from formulation central authorities Expose the former low dosage of outer end to this matrix. The matrix of this coating is from high dose to the low dosage winding To guarantee when solution is unclamped or lost to matrix, from the low dosage to the high dose, discharging medicine. For example, with 1mg～The 25mg methylphenidate is coated in erosion property polymer (for example polypeptide, collagen, gelatin or polyvinyl alcohol) On, again with the coaxially winding of this matrix, inwardly roll volume with centre of compliance position, then from high dose Outwards volume forms outer position to low dosage. In application, this formulation is lost solution and is thrown at any time Between the ascending-dose methylphenidate that discharges.
Another kind of formulation provided by the invention comprises a lot of layers, and wherein the feature of each layer is passing of medicine Increase dosage. " a lot of layer " this vocabulary shows 2～6 layers of the contact that coincides. These many layers are put continuously Put, namely one deck connects one deck in order, and ground floor exposes, and layer 6 contacts with layer 5, layer 6 Exposed surface coating medicine impermeability polymer. The coated medicine impermeability of layer 6 polymer with Assurance discharges medicine from the ground floor to the layer 6. Ground floor comprises 1～5mg medicine, and each successive layer Comprise the 1～5mg medicine that adds in addition. This biodegradable polymer experience chemical breakdown and form can Soluble monomers or soluble polymer unit. The biodegradation of polymer generally includes chemical catalysis Or the hydrolysis of enzyme-catalyzed change. Representational biodegradable polymers is fit to every one deck Chinese traditional medicine load Increase by 5% to 50wt% than ground floor and adjoining course, wherein ground floor contains 100ng. Typically can give birth to The thing degradation polymer comprises and is selected from a kind of of lower group of material: biodegradable polyamide, polyaminoacid, Polyester, PLA, polyglycolic acid, poe, polyanhydride, biodegradable poly-(dehydrogenation pyrans) With poly-(two English ketone) (polydioxinones). These polymer are known in the art, See following document: Rosoff, "The control of medicine discharges”(
Controlled Release of Drugs), the 2nd chapter, pp.53-95 (1989); And United States Patent(USP) Nos. 3,811,444; 3,962,414; 4,066,747; 4,070,347; 4,079,038 and 4,093,709.
The present invention has further used a kind of formulation that comprises polymer, it by diffusion, opening, Or discharge medicine by breaking of polymer substrate. This medicine send to be passed polymeric system and comprises one Concentration gradient, wherein this gradient is to pass to the concentration of last or higher concentration from beginning or initial concentration Increase, namely the concentration of 100ng～250mg increases progressively. This formulation comprises the exposed surface of starting dose and The remote non-exposed surface of post dose. This non-exposed surface is coated pharmaceutically acceptable thing Matter, this material do not allow medicine see through. This formulation structure has guaranteed that the flux of delivering drugs increases, from Begin to be incremented to and send at last the dosage of passing.
This formulation matrix can be by known method preparation in the polymer technology. In a kind of preparation method, Prepare independently 3～5 or more casting composition, wherein each casting composition comprises one The drug dose that increases progressively, each composition is stacked from the low dosage to the high dose. Provide so a series of Layer, they consist of the unit polymer substrate with concentration gradient together. In another kind of preparation method, The higher dosage of casting then provides with stacking the closing of the dosage that falls progressively to have the drug concentration gradient earlier Polymer substrate. Provide an example of this formulation to comprise: with pharmaceutically acceptable carrier (such as polyethylene glycol) raising with the medicine (such as central nervous system stimulant) of known dose The lower blending of temperature (such as 37 ℃) is added to it the silicon rubber that contains crosslinking agent (such as stannous octoate) again In the pharmaceutical grade elastomer, then in mould, cast. All repeat this step for follow-up every layer. Will This system is placed 1 hour so that this formulation to be provided. The representative polymers for preparing this formulation is drawn together a kind of Be selected from lower group material: olefin polymer and polyvinyl, condensation polymer, carbohydrate polymer and Silicon polymer, for example polyethylene, polypropylene, polyvinyl acetate, PMA, poly-first Base isobutyl acrylate, poly-alginate esters, polyamide and polysiloxanes. These polymer and preparation side Method is known, sees following document: Coleman etc.,Polymer(
Polymers) Vol.31, Pp.1187-1230 (1990); Roerdink etc.,The pharmaceutical carrier system(
Drug Carrier Systems), Vol.9, pp.57-109 (1989); Leong etc.,Medicine send the exhibition of going forward one by one Comment(
Adv.Drug Delivery Rev.), Vol.1, pp.199-233 (1987); The editors such as Roff, "The Common Polymers handbook”(
Handbook of Common Polymers), (1971) CRC Press publishes; And U.S. Patent No. 3,992,518.
In addition, by enforcement of the present invention, method of the present invention is used described disclosed formulation and is given possibility Obtain patient's dispenser of acute or chronic tolerance to reduce and/or to avoid described tolerance, now Show that the method can be used for treating the patient that may obtain acute tolerance. Also have, by of the present invention Implement, in one embodiment, equally having found to provide a kind of method, uses the method and gives The dispenser of people's per os is with treatment distractibility disease, namely reaches in time institute as the function dispenser of time The drug concentration that needs. Drug concentration is relevant with drug dose (representing with mg/h), and this dosage is Time per unit (in hour) send the confession of passing to be absorbed into the dosage of body circulation. Method of the present invention This method is provided uniquely, namely during the acute tolerance that obtains when curative effect descends, lead to Crossing continuous regulating drug send the speed of passing and keeps required effect of drugs.
Medicine should provide curative effect at whole dosing interval, and this is general medical practice. Yet, When forming or obtained tolerance to medicine, the art methods that guarantees the treatment response be with Instant dosage discharging modes increase the dosage of using, and with regard to this administering mode, possibly Produce relevant side effect, may produce the different tolerance of produce effect, and treatment Index may descend. Prior art be used for to reduce other method that tolerance takes place be number of times less So drug administration dosage has been avoided acquired tolerance, lack at official hour but use the method Treatment.
In medical science, generally believe that the central nervous system drugs with function is applicable to treatment distractibility disease. The medicine that is fit to this therapy is slight central nervous system stimulant, comprises catecholamines and energy mould Imitate the medicine of their effect. The medicine that is applicable to this therapy comprises a kind of material that is selected from lower group: Amphetamine, dextro-amphetamine, Metamfetamine, methylphenidate, racemic methylphenidate, threo form Methylphenidate, propyloxy phenyl amine, risperidone and pemoline. This medicine also comprises their medicine Upper acceptable salt, for example a kind of salt that is selected from lower group: hydrochloride, sulfate, phosphate, second Hydrochlorate, hydrobromate, embonate and maleate. The patient who accepts these medicines obtains usually Must be to the tolerance of this effect of drugs. For example, accept the methylphenidate of every day twice 5mg dosage The patient has obtained tolerance, thus must use bigger dosage because need single-bolus high-dose with Overcome tolerance and form, this will cause undesirable side effect. In some patient, although Keep methylphenidate at the constant density of non-increase, but the treatment of methylphenidate is responded 4～5 Reduced in hour. That is to say, obtained to the piperazine ester methyl ester with usually to incitantia The tolerance of Behavioral effect and psychological effects. The present invention also finds, distributes the still constant of non-compensation The sustained release goods of the medicine of concentration can not be clinically effective, because be designed to produce constant The sustained release forms of for example methylphenidate concentration of blood plasma especially lacks the effect of anti-acquired tolerance Really.
The present invention provides the method for a kind of formulation and treatment distractibility disease in its purpose, described distractibility disease comprises distractibility/hyperactivity, mating type, mainly being not note type, mainly is hyperactive impulsive style, and these are also referred to as minimum brain dysfunction, hyperkinetic syndrome, behavior syndrome, MCD and minor's cerebral disorder, as be disclosed in "Smart Refreshing obstacle diagnosis and statistic handbook”(
Diagnostic and Statistical Manual of Mental Disorders) the 3rd edition, in pp.49～56 (1987), by the American Psychiatric Association, Washington, D.C. publish, by provide formulation and Methods for the treatment of is namely by providing the compensation of continuous medicine basically to eliminate acute tolerance and roughly disappear Except the undesirable result of prior art, so make curative effect stable.
The pharmacological effect of medicine is relevant with its acceptor site concentration. So, if with the effect of medicine Fruit is regarded the function (f) that send the time of passing (t) as, and the steady dynamic mechanics of some drugs may be rapid , and concerning other medicines, along with response reduce the effect instability, it is expressed as formation To the tolerance of medicine. Latter event is fit to the central nervous system drugs with function (such as piperazine vinegar first Ester). The present invention send by the suitableeest medicine that its operation is provided and passs the acute tolerance that distributed compensation obtains The property. Concerning some drugs, tolerance initial very fast, for example methylphenidate number after being applied Just form tolerance in hour. The processing scheme that the present invention provides for this reason is to provide this medicine Sending and pass pattern, send the medicine of passing doses to reach immediate treatment when namely beginning, then is at any time Between the releasing dosage that continue to increase to keep this effect.
The medicine methylphenidate can be slow release formulation
Be purchased, use this commercialization form Methylphenidate can cause acute tolerance. When obtaining acute tolerance, in the possibility repetitive administration Need the no medicine of a few hours to remove the phase before this formulation. Yet the present invention is by providing a kind of sending to pass The curative effect loss of speed (with expression in mg/ hour) method compensation medicine (such as methylphenidate) should Method is by regarding medicine as shown in the following equation 1 medicine at the clinical effectiveness (E) of time (t) The function of substrate concentration (C) and the formation of Continuous Compensation acute tolerance
Effect=f (t, C) equation 1
In addition, the speed (A) (with expression in mg/ hour) of sending drug delivery directly and concentration multiply by The elimination factor of medicine is proportional. Along with effect time to time change and this functionality are expressed, in Be by the present invention, (A) can be controlled to guarantee curative effect is maintained clinical value. If clinical The effect of existing medicine descends in time, and then this decline may be linear, shown in equation 2:
Effect(t)=effect(ini)-k
Effect* t equation 2
Wherein, effect(ini)The clinical effectiveness that original observed arrives when dispenser begins, effect(t)The effect of hour observing in the time (t), kEffectBe the proportionality constant that obtains like this, namely pass through minute (t1) hour clinical effectiveness (E1) and time (t2) hour (E2) keeps constant simultaneously PC, then will (E1) subtract (E2) and subtract (t2) divided by (t1) afterwards. In order to keep Constant effect, must use the same functions adjusting (A) of equation 3:
A
(t)＝A
(ini)+k
Effect* t equation 3
A wherein(ini)Initial medicine input amount when being the treatment beginning (with expression in mg/ hour), A(t)The medicine input amount in time (t) hour, kEffectIt is the proportionality constant that proposes previously. Treat if find Effect is in time exponential relationship and descends, and represents this relation with equation 4:
Effect
(t)=effect
(ini)X exp
(the k effect * t)Equation 4 is effect wherein
(ini)And effect
(t)Definition as described above, k
EffectBe speed constant (h
-1), it is the units of inverse of hourage, can obtain like this: clinical effectiveness (E1) by minute (t1) hour and time (t2) hour (E2) keeps constant plasma concentration simultaneously, subtracts (t2) divided by (t1) after then the natural logrithm of (E1) being subtracted the natural logrithm of (E2).In order to keep constant effect, must press equation 5 and regulate (A)
A
(t)=A
(ini)* exp
(the k effect * t)Equation 5
A wherein
(ini)And A
(t)Definition as described above.k
EffectBe the speed constant (h that provides above
-1).These equations are by Holford N.H.G and Sheiner, and L.E. is set forth in
Drug therapy(
Pharmac.Ther.) Vo1.16, among the pp.143-166 (1982).
" effect " that this paper defines refers to the pharmacological effect of medicine performance, as the effect of determining by clinical subjective observation (for example SKAMP and CLAM), perhaps as by objective activity monitors the effect of determining (for example mathematics testing and school's achievement).The CLAM test is by Conners, a kind of behavior evaluation method of Lonez and Milch design, compliance that its expression is social or rebellion property; SKAMP also is a kind of evaluation methodology of mensuration behavior, is designed and is reported in by Swanson
The psychopharmacology circular(
Psychopharmacological Bulletin), Vol.21 is among the pp.887-890 (1985).
Effect measuring in this research is: the performance that (1) is tested with the mathematics of computer operation observer's evaluation and (2) of SKAMP degree (in time in classroom).Before the research beginning, the mathematics level of testing each child under study for action, provides the mathematics test that is fit to each capabilities of children based on this pre-test.The result is used to identify Deviant Behavior with the father and mother CLAM estimation of morning and evening.Evening, father and mother CLAM was used to determine the existence of time internal therapy effect at night, and especially at the therapeutic effect of time of child's sleep, and whether child's sleep is interrupted.All children put on activity monitor (Actigraph), and it writes down child's activity of all day.Write down active situation (the movable number of times of per minute) by electronic machine, and set up the function model of effect of drugs.
Following embodiment just sets forth the present invention, they can not be regarded as by any way to limit the scope of the invention, because according to the disclosure and the accompanying claims book, these embodiment and equivalents thereof will be obvious to those skilled in the art.
The specific embodiment
The commercially available immediate release tablet of containing the 5mg methylphenidate for 36 child of school administered twice every day is mapped the plasma concentration (ng/ml represents) of prediction, shown in black solid line among Fig. 1 to the time.Crest and trough appear in the plasma concentration curve of this tablet methylphenidate.The non-increase scheme of slow release of using the 20mg methylphenidate is included in 0 hour 8.3mg, then at 1.5 hours 0.9mg, at 2 hours 0.9mg, at 2.5 hours 0.9mg, at 3 hours 0.9mg, at 3.5 hours 0.9mg, at 4 hours 0.9mg, at 4.5 hours 0.9mg, at 5 hours 0.9mg, at 5.5 hours 0.9mg, at 6 hours 0.9mg, at 6.5 hours 0.9mg, at 7 hours 0.9mg, at 7.5 hours 0.9mg, form the slow release dotted line that is parallel to the x axle, see Fig. 1.With this immediate release tablet and slow release formulation and the slow release formulation that is that increasing progressively distributes and uses methylphenidate contrast.Slow release increases progressively distribution corresponding to used 4.2mg at 0 hour, at 1.5 hours 1.1mg, at 2 hours 1.1mg, at 2.5 hours 1.2mg, at 3.0 hours 1.2mg, at 3.5 hours 1.3mg, at 4 hours 1.3mg, at 4.5 hours 1.5mg, at 5 hours 1.5mg, at 5.5 hours 1.8mg, at 6 hours 1.8mg, and at 6.5 hours 2.0mg, form continuous increasing and discharge dashed line view, see Fig. 2.
Clinical research is the result show, the patient who uses the dosage form (placebo) that does not contain methylphenidate shows behavior fluctuation high, that raise, and the behavior is activeness, unsuitable behavior, low attention, lower mathematics mark and study lost interest in for example.Be applied the minimizing that the patient of the methylphenidate that continues non-increased dosage amount shows activeness, the higher mathematics mark and the minimizing of improper department.Yet, follow these effects in the patient, to form acute tolerance.Use the methylphenidate that is the distribution of control continuous increasing by the present invention to the patient, then the patient shows the required curative effect of no toleration.Provided above-mentioned result of study in the accompanying drawing.In Fig. 3,4 and 5, there is the line of open circles to represent placebo, twice instant-free dosage form was used in black circle expression in one day, and black shape represents that the non-increased dosage amount of slow release distributes, and square hollow then refers to continuous increasing release profile provided by the invention.SKAMP mark and CLAM mark have defined in the front of this description, and the time is as pointing out among the figure.Fig. 3 represents the behavior observed, and Fig. 4 represents careless over-activity, and Fig. 5 represents that then this studies bonded attention result.
Reported in the present embodiment and comprised the clinical research result who send the scheme of passing to use methylphenidate by two kinds of differences.In this research, continuous increasing distributes corresponding to using methylphenidate like this: at 0 hour 8mg, at 1.5 hours 1.4mg, at 2.0 hours 1.4mg, at 2.5 hours 1.7mg, at 3.0 hours 1.7mg, at 3.5 hours 2.0mg, at 4.0 hours 2.0mg, at 4.5 hours 2.2mg, at 5.0 hours 2.2mg, at 5.5 hours 2.2mg, at 6.0 hours 2.2mg, at 6.5 hours 2.4mg, at 7.0 hours 2.4mg, at 7.5 hours 2.6mg, at 8.0 hours 1.9mg.Be coated with the capsule shape formula beyond the methylphenidate and use, it comprises common 36mg methylphenidate, accounts for 22% in external coating.The ascending-dose of using is to be the dosage first time constantly 0730, follows per 30 minutes increased dosage amount until 1530 moment, forms the plasma concentration that increases progressively of expection.This research comprise with every day three times instant dosage form send and pass methylphenidate, constantly send 0730,1130 and 1530 and passed the 10mg methylphenidate.32 children that suffer from the distractibility hyperkinetic syndrome carry out this researchs.Accompanying drawing 6 has provided the plasma concentration of methylphenidate, and wherein chain-dotted line is drawn by continuous increasing dispenser scheme, and dotted line is then drawn by instant dosage form.In accompanying drawing 7, filled circles is represented placebo, and open circles is represented continuous increasing dispenser scheme, and solid squares is represented three times dispenser scheme every day, and observed parameter is the behavior that there is not the toleration of acquisition in continuous increasing dispenser scheme.Accompanying drawing 8 has provided bonded attention parameter, and wherein filled circles is a placebo, follows the toleration of acquisition; Solid squares be every day three times immediate release broadcast and pass, follow the toleration of acquisition; Open circles is that continuous increasing discharges the toleration of essentially no formation.
Provide a kind of method by using the dosage form that is processed into oral tablet, this method is used to use the central nervous system stimulant methylphenidate that is the continuous increasing dosage form with treatment distractibility disease, follows the toleration that reduces to obtain.This dosage form comprises the polyanhydride polymeric film of one deck decanedioic acid and Azelaic Acid, coats the compositions that comprises the 20mg methylphenidate of admixing with pharmaceutically acceptable gelatin.The coated methylphenidate compositions of this pharmaceutically acceptable film is the thickness form around the increase of self spiral winding.Oral go into gastrointestinal tract after, this film prolongs in time and is separated by erosion, discharges with constant increasing velocity so comprise the said composition of methylphenidate.The polymer of this dosage form is described in United States Patent(USP) Nos. 2,668, and in 162 and 2,676,945, this dosage form is described in U.S. Patent No. 3,625, in 214.
Of the present inventionly can biological erosion separate dosage form (comprising central nervous excitation agent pemoline) a kind of method is provided by using, this method is used for the treatment of the distractibility hyperkinetic syndrome, be aided with psychology and instruct and educate guiding, in the child, play stablizing effect by using pemoline, follow the toleration that does not obviously have acquisition.This dosage form comprises that 5 can bioerodiblely be gathered (lactide-Acetic acid, hydroxy-, bimol. cyclic ester) contact layer, every layer of 4,6,8,10 and 12mg pemoline that contains incremental change.These layers are pressed into the structure of lamination tablets, and the surface that one deck is opened wide exposes that layer that contains the 2mg pemoline, and all the other each layer quilts of this tablet can not bioerodible ethylene vinyl acetate copolymer surround.So these layers are separated the corresponding pemoline that discharges constant ascending-dose in time by constant order by the biology erosion.This can bioerodible polymer as can be known from following patent, and promptly U.S. Patent No. 3,773, and 919; EP00-052-510; And Canadian Patent No.1,169,090.
Provide a kind of method, promptly by using the dosage form that connects the preparation of capsule (comprising a lot of spherical-shaped beads) form with pharmaceutically acceptable gelatin two joints with the dispenser of continuous increasing rate of release.This capsule comprises a series of beadlet, contain in the variant beadlet is 1,1.25,1.5,1.75,2 and the 2.25mg medicine in succession, these beadlet are correspondingly coated be in succession 0.5,1,1.5,2.5,3 and 3.25mm poly-(2,2-dioxy-anti--1,4-cyclohexanedimethyleterephthalate oxolane) this polymer.Along with these beadlet are separated by erosion in the gastrointestinal environment, they are with the rate of release dispensing of continuous increasing in time.The medicine that available this method is thrown in comprises one of medicine that is selected from down group: amfetamine, dextro-amphetamine, metamfetamine, methylphenidate, propyloxy phenyl amine and pemoline.Coating method is disclosed in
American Pharmaceutical Association can will(
J.Am.Phar.Assoc.), Sci.Ed., Vol.48 is among the pp.451-454 (1959); And in the U.S. Patent No. 2,799,241.
The invention provides a kind of system of passing of sending, its discharges medicine and causes increasing progressively blood plasma methylphenidate concentration to the distribution of time, has overcome toleration substantially and has made the required pharmacological effect of analeptic methylphenidate keep reaching the persistent period of requirement.For example, effect-time is distributed reach and be similar to three instant-free dosage every day (per 4 hours once, totally 12 hours), i.e. TID (every day three times), a kind of system of passing (it causes in the scope that blood plasma methylphenidate concentration lists below) of sending will overcome toleration and keep pharmacological effect.Produce a kind of twice instant-free dosage that send the system of passing to make it to be equivalent to provide in per 4 hours, can reduce rate of release; Similarly, reach the longer persistent period just can increase concentration.This send, and passing distributes has illustrated medicine and pharmacological effect.Yet the notion that increases concentration still keeps identical.
The scope that table 1 provides is as the part of mimic TID concentration.Accompanying drawing illustrates and is attached to TID and increases progressively changes in distribution with reference to increasing progressively (ASCEND) on handle distributing.
Table 1
Accompanying drawing has been drawn the treatment benefit that obtains by the present invention.Fig. 9 has illustrated: about the mimic blood plasma methylphenidate CONCENTRATION DISTRIBUTION (solid line) of one day three 30mg dosage, (dotted line) handled in the increase of 36mg, and the 36mg dosage (chain-dotted line) of infiltration control.Figure 10 has drawn the blood plasma methylphenidate concentration as among Fig. 9, and different is that the dosage that infiltration is controlled among Figure 10 is 38mg.Figure 11 has drawn the blood plasma methylphenidate concentration as among Fig. 9, and just the dosage of infiltration control is 40mg among Figure 11.Figure 12 has illustrated to send for one day three times and has passed 30mg (solid line), send the increased dosage amount of passing (dotted line) from the dosage form that comprises the 36mg medicine once a day, and the dosage form (chain-dotted line) that comprises instant 8mg dosage and lasting 26mg ascending-dose.Figure 13 has drawn the blood plasma methylphenidate concentration similar to Figure 12, and just the dosage form represented of chain-dotted line comprises the instant-free dosage of 9mg methylphenidate and the ascending-dose of 24mg methylphenidate.Figure 14 is similar to the figure of front, and just chain-dotted line is represented the instant-free dosage of 8mg and the ascending-dose of 25mg methylphenidate.Figure 15 is similar to the figure of front, and just chain-dotted line has been illustrated the instant dosage of 8mg methylphenidate, then is the continuous increasing dosage of 25mg methylphenidate.Figure 16 is similar to earlier figures, and clinical condition is the instant dosage that chain-dotted line has been illustrated the 8mg methylphenidate in this research with what stipulate previously, then is the control ascending-dose of 24mg methylphenidate.
Method of the present invention further guaranteed by the foregoing description drug administration, wherein this medicine be reached 8 hours or reached 12 hours on class day during use by dosage form of the present invention with the speed and the slow release pattern of control.
Though described and pointed out the features and advantages of the present invention, as be applied to described embodiment, but the technical staff in the medical field can understand and can do various modifications, change, augment and delete the method for describing in this description and do not depart from spirit of the present invention.
Claims (12)
1. be a kind of forms of pharmaceutical compositions, it comprises the drug dose of the Concentraton gradient form that is from the low dosage to the high dose, so this dosage form is with the form release medicine of low dosage to high dose.
2. be used to send the dosage form of the claim 1 of drug delivery, wherein this dosage form comprises: the compositions that contains polymer, the medicine that is present in the doses in the compositions with the Concentraton gradient form from the low dosage to the high dose, and wherein when being applied, this dosage form discharges low-dose drugs, then is high dose medicament.
3. be used to send the dosage form of the claim 1 of drug delivery, wherein this dosage form comprises: a lot of layers comprise the compositions of polymer, the medicine that in a lot of layers, is the doses that increases progressively dosage, and wherein when this dosage form is applied, it send to pass and is the medicine that increases progressively dosage in time.
4. be used to send the dosage form of the claim 1 of drug delivery, wherein this dosage form comprises: comprise a kind of a lot of layers that comprise the compositions of different polymer, the medicine that in a lot of layers, is the doses that increases progressively dosage, and wherein when this dosage form is applied, it send to pass and is the medicine that increases progressively dosage in time.
5. be used to send the dosage form of the claim 1 of drug delivery, wherein this dosage form comprises: contain can bioerodible polymer compositions, the medicine of the doses that exists with predose and final dose form in the said composition, this dosage form send thus in time passs predose and final dose.
6. be used to send the dosage form of the claim 1 of passing the ascending-dose medicine, wherein this dosage form comprises: contain can bioerodible polymer a lot of layers, in these layers, be the medicine that increases progressively dosage, this dosage form is sent thus to pass and is the medicine that increases progressively dosage in time.
7. be used to send the dosage form of the claim 1 of passing the ascending-dose medicine, wherein this dosage form comprises: contain can bioerodible different polymer a lot of layers, in different layers, be the medicine that increases progressively dosage, this dosage form is sent thus to pass and is the medicine that increases progressively dosage in time.
8. be used to send the dosage form of the claim 1 of passing the ascending-dose medicine, wherein this dosage form comprises the small ball that contains medicine, and these small balls send the medicine of passing predose in time and are the medicine that increases progressively dosage in succession.
9. as a kind of pharmaceutical composition of claim 1 of dosage form, wherein this pharmaceutical composition comprises and the medicine of the doses of pharmaceutically acceptable carrier blending, and this medicine is released with slow release and ascending-dose form.
10. the pharmaceutical composition of claim 1, wherein this pharmaceutical composition comprises 1mg～500mg medicine.
11. the pharmaceutical composition of claim 1, wherein this medicine was released with the continuous increasing dosage from 100ng to 375mg during 16 hours.
12. the application of the pharmaceutical composition of claim 1 aspect the treatment mental illness.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2872696P | 1996-09-30 | 1996-09-30 | |
| US60/028,726 | 1996-09-30 | ||
| US3051496P | 1996-11-12 | 1996-11-12 | |
| US60/030,514 | 1996-11-12 | ||
| US4412197P | 1997-04-22 | 1997-04-22 | |
| US60/044,121 | 1997-04-22 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97198342A Division CN1231603A (en) | 1996-09-30 | 1997-09-16 | Dosage form providing a sustained and ascending drug release |
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| Publication Number | Publication Date |
|---|---|
| CN101327196A true CN101327196A (en) | 2008-12-24 |
| CN101327196B CN101327196B (en) | 2014-05-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810137937.8A Expired - Lifetime CN101327196B (en) | 1996-09-30 | 1997-09-16 | Dosage form and method for administering drug |
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| Country | Link |
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| CN (1) | CN101327196B (en) |
| ZA (1) | ZA977873B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4083949A (en) * | 1973-07-17 | 1978-04-11 | Byk Gulden Lomberg Chemische Fabrik Gmbh | New oral form of medicament and a method for producing it |
-
1997
- 1997-09-02 ZA ZA9707873A patent/ZA977873B/en unknown
- 1997-09-16 CN CN200810137937.8A patent/CN101327196B/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4083949A (en) * | 1973-07-17 | 1978-04-11 | Byk Gulden Lomberg Chemische Fabrik Gmbh | New oral form of medicament and a method for producing it |
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| Publication number | Publication date |
|---|---|
| ZA977873B (en) | 1998-04-23 |
| CN101327196B (en) | 2014-05-14 |
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