AU672177B2 - Medication vehicles made of solid lipid particles (solid lipid nanospheres - SLN) - Google Patents

Abstract

Medication vehicles have particles made of lipids, lipid-like (lipoid) materials or mixtures thereof, with a diameter from 10 nm to 10 $g(m)m, that are solid at the ambient temperature. Because or their solid core, these medication vehicles allow active substances to be controllably released over a longer period, allow hydrophilic medicaments to be incorporated into the solid core and are relatively quickly decomposable, producing no toxic by-products.

Description

OIDATE 27/04/93 AOJP DATE 24/06/93 APPLN. ID 25615/92 PCT NUMBER PCT/EP92/02132 AU9225615 (51) Internationale Patentklassiikation 5 (11) Internationale Verbffentlichungsnummer: WO 93/05768 A61K 9/16, 9151 Al (43) Internationales Verbffcntlichungsdatum: 1. April 1993 (01.04.93) (21) Internationales Aktenzeichen: PCT/EP92/02132 (74) Anwalt: G RAF ZiJ STOLBERO, Ulrich Uexkill Stolberg, Beselerstr. 4, D-2000 Hamburg 52 (DE).

(22) Internationales Anmeldedatumn: 16. September 1992 (16.09.92) (81) Bestimmungsstaaten: AU, CA, CS, HU, JIP, KR, PL, RU, US, europfiisches Patent (AT, BE, CH, DE, DK, ES, FR, Prioritfitsdaten: GB, GR, IE, IT, LU, MC, NL, SE).

P 41 31 562.6 lB. September 1991 (18.09.91) DE Ver~ffentlicht (71) Anmelder (flir alle Bestimmungsslaaten ausser US): MEDAC Mit internafionalent Reclierchenberichi.

GESELLSCHAFT FUR KLINISCHE SPEZIALPRA- PARATE QwWBH [DE/DE]; Fehlandtstrasse 3, D-2000 R4' Hamburg 36 (DE).

(72) Erfinder; mid Erfinder/Anxnelder (nurfiir US) LUCKS, Stefan [DE/DE]; Deliusstrasse 23A, D-2300 Kiel I MULLER, Rainer [DE/DE]; Samwerstrasse 8, D-2300 Kiel I (DE).

(54)Title: MEDICATION VEHICLES MADE OF SOLID LIPID PARTICLES (SOLID LIPID NANOSPHERES SLN) (54) Bezeichnung: ARZNEISTOFFTRXGER AUS FESTEN LIPIDTEILCHEN (FESTE LIPIDNANOSPH&REN (SLN)) (57) Abstract Medication vehicles have particles made of lipids, lipid-like (lipoid) materials or mixtures thereof, with a diameter from nm to 10 .tm, that are solid at the ambient temperature. Because or their solid core, these medication vehicles allow active substances to be controllably released over a longer period, allow hydrophilic medicaments to be incorporated into the solid core and are relatively quickly decomposable, producing no toxic by-products.

(57) Zusammnenfassung Arzneistofftrflger, der Teilchen aus Lipid, lipidghnfichemn (lipoidem) Material oder Mischungen davon umfagt, die cinen Durchmesser von 10 nm bis 10 im aufweisen und bei Raumntemperatur fest sind. Dieser Arzneistofftrflger erm~5gliclit aufgrund semnen festen Kerns eine kontrollierbare Freisetzung von Wirkstoffen Oiber einen Iingeren Zeitraum, die Einarbeitung von hydrophilen Arzneistoffen in den festen Kern und eine relativ schnell Abbaubarkeit, A obei keine toxischen Nebenprodukte entstehen.

1 Drug carrier consisting of solid lipid particles Solid lipid nanospheres curueouo> The invention relates to a drug carrier, its dispersion in a-wate4 medium, a method to produce it, as well as its use. It concerns in particular a drug carrier consisting of lipid or lipoid particles.

In the field of medicinal agents there is a continuous search for carriers which allow drug application in various ways, i.e. carriers which are available in a form that permits the respective drug to be administered as deemed most suitable, e.g. in an intravenous, intraarthricular, intramuscular or subcutaneous maimer.

Carriers are known which consist, e.g. of solid microparticles, microspheres and mircrocapsules (mean diameter in the micrometer range), as well as nanoparticles and nanocapsules (mean diameter in the nanometer range). Microparticles and nanoparticles consist of a solid polymer matrix. With respect to microcapsules and nanocapsules, liquid or solid phases are enclosed by film-forming polymers. Such particles consist of or have coatings of polymers, such as polylactides (PLA), polylactide-glycolides (PLA/GA) or polyalkyl cyanoacrylates. Polylactide and polylactide-glycolide as particle matrix and as coatings have, however, the disadvantage of degrading only very slowly, i.e. the degradation takes weeks up to months. Multiple applications of a drug with such a carrier lead to an accumulation of polymer ion the organism and possibly cause toxic effects. Although particles based on polymers, such aF polyalkyl cyanoacrylates, metabolize up to 80% in the organism within a period of 24 hours, toxic formaldehyde is set free during the decomposition. To produce the polymeric particles, carbon hydrogen chlorides, such as dichlormethane, have to be used as solvents for the polymer, and these solvents in turn are toxic on their part Tice and D.H. Lewis, Microencapsulation Process, US-PS 4,389,330), Furthermore, on account of their size, microparticles may cause embolisms when injected intravenously, and therefore one usually refrains from this procedure.

Another disadvantage of polymeric particles is the fact that when sterilising in an autoclave, the glass temperature is exceeded, thus resulting in an aggregation of particles. Such drug carriers or drugs can therefore not be sterilised in this manner and have to be subjected to the disadvantageous procedure of gamma irradiation.

20 Also known to serve as drug carriers are fat emulsions. Fat emulsions are oil-in-water emulsions in which the dispersed (inner) phase is •liquid. In the trade literature such fatty emulsions are also referred to as "lipid microspheres", and highly disperse fat emulsions with a mean particle size in the nanometer range are also called "nano-emulsions" H.G. Weder 25 and M. Muetsch. Eur. Pat. EP 90-810436, June 1990). These fat emulsions comprise two liquid phases. After diluting with body fluids, fat emulsions S: set incorporated medicinal agents free within a relatively fast time g. after injection into the blood). The t is in the 30 to range, which is correlated to the rate of diffusion of the medicinal agents in the oil that is of relatively low viscosity. Furthermore, the liquid, dispersed phase of the fat emulsions oil) will be completely metabolized in the body within a few hours, which liberates from the oil also extremely lipophile substances. Such quick liberations may also lead to the so-called peaks of the medicinal agents in the plasma so that toxic side effects are possible due to this brief overdosing. In addition, the loss of active substance before it reaches the target organ is relatively large when passively aiming at macrophages of the liver and spleen.

Through P. Eldem, P. Speiser and A. Hincal, Pharmaceutical Research 8, 47-54 (1991) micropellets on a lipid basis have become known, the mean diameter of which again is in the micrometer range.

Known are also drug carriers in which liposomes or substances which resemble or are analogous to liposomes, such as niosomes, having an aqueous liquid core, are enclosed by one or several phospholipid double membranes.

Furthermore, subparticulate or semiparticulate systems are known in which substances are dissolved with the help of solving agents, such as tensides, to an extent that micells or mixed micells will form. What they are here are no longer dispersions but already solutions.

zforo, 0 zobjet fqAhe-inv'ention i o t make ava!iable a drn..carrier which can .form a 4 The present invention consists in a process for the manufacture of a drug carrier which comprises tenside-containing or tenside-free particles of lipid or lipid-like (lipoid) material or mixtures thereof and having a diameter range of 10n to 10|i, whereby the particles have an average diameter of between 40 and 1000 nm and are solid at room temperature characterised in that the particles when in a melted or softened state are homogenised under high pressure in a dispersion medium, being water, aqueous solution or a liquid miscible with water or the particles when in a solid state are dispersed under high pressure in the dispersion medium, whereby the particles arc finely dispersed.

With respect to the drug carrier it concerns particles that are solid at room temperature about 20°C) and the size of which is in the nanomneter range. Such particles can be defined as "solid lipid nanosphered" (SLN).

These particles can be dispersed in an aqueous medium, thus resulting in a solid/liquid dispersion. The particle size of the dispersed phase is in the range of 10nm up to a few micrometers [about 10mun), The average particle size (diameter determined by photon correlation spectroscopy) is predominantly in the 100 to 100Onm range and especially in the 100 to 800onm r-ange. By selecting suitable processing parameters and by choosing 20 appropriate exipients a higher tenside concentration), it is possible to make the SLN smaller than 10Onm, especially in the 40 to 80nm range.

S.

*e *e• The SLN consists of lipid or lipid-like substances which canl be degraded by the organism like fat from foodstuffs. The degradation of lipids occurs at a faster rate than the decomposition of synthetic polymers such as PLA, PLA/GA. Another advantage is that in the degradation or in the mietabolisation of lipids, no toxic metabolites are produced, as is the case in particles of a polyalkyl cyanacrylate base. Reference is made in this connection to the toxicity of fatty emulsions used in parenteral nutrition since the 1950's.

Since in SLN it concerns solid, lipid particles with a relevantly high the rate of diffusion and liberation of anl active substance embedded therein is reduced. Trhus, contrary to the fat emulsions, consisting of a liquid-dispersed phase it is possible to achieve a controlled liberation over a longer period. Onl a,.:Lount of thle longer liberation period, the formation of plasma peaks of the respective active substance is prevented and side effects, which occur as a result of such peak values, are eliminated. Due to the delayed liberation, the loss of active substance after application and before reaching the respective target organ is smaller than iii fat enulsions in which the active substances are liberated comparatively fast.

The active substance or substances are dissolved or dispersed in thle lipid or 0 lhipoid particles. Furthermore, the active substances canl be adsorbed at the 00 surface of thle particles. On account of the solid matter character it is also 0 possible to incorporate in the lipid or lipoid phase hydrophilic sub stances in .0the form of anl aqueous solution of the active substance. After incorporating 0, 0 25 and subsequently dispersing the obtained SLN in thle aqueous dispersion medium, a W/F/W system water-in-fat water) is produced. Onl account of its solid aggregate state, 6 the lipid core incorporates the -watey~drug solution better than it is possible in comparable, multiple emulsions of water-in-oil-in water Another advantage of the solid, lipid nanospheres is the fact that, in contrast to the polymeric particles, they can be sterilized in an autoclave without causing an aggregation of the particles.

coT.cc r-c3A\cs &en In this way the disadvantages connected to cA:iseagliaatieacan be avoided.

Contrary to microparticles of the micrometer range, the SLN can be injected intravenously without difficulty and without the risk of embolism due to their small particle size in the nanometer range. When producing the SLN, no toxic adjuvants have to be used such as e.g.

slightly volatile solvents of chlorohydrocarbons.

The drug carrier according to the invention can be produced in the following manner: 1. by dispersing the inner phase (of the lipid or lipoid) in a melted or softened state. The dispersing is carried out above room temperature and can be achieved by various procedures such as, for example, the methods described below; 2. by dispersing the solid inner phase in a solid state. For this purpose, the solid phase is o-c eLoL-s finely broken down and dispersed in water or in a wa tey medium.

Prior to this, the dispersed lipid or lipoid core, which is solid at room temperature, was loaded with one or more medicinal agents. This can be achieved by dissolving or dispersing the active substance in the lipid/lipoid, by adsorbing the active substance at the surface of the lipid/lipoid, or by dispersing it in the lipid/lipoid in the form of a watery solution.

As dispersed phase, lipids and lipoids can be in the widest sense as individual compounds or as mixtures. Examples of these include the following: natural or synthetic triglycerides or mixtures thereof, mono and diglycerides alone or in mixtures thereof or with e.g. triglycerides, natural and synthetic waxes, fatty alcohols, including their esters and ethers, as well as lipid peptides. Especially suitable are synthetic monoglycerides, diglycerides and triglycerides as individual substances or as mixtures hard fat), glycerin trifatty acid ester (e.g.

glycerintrilaurate, glycerinmyristate, glycerinpalmitate, glycerinstearate and glycerinbehenate) and waxes such as, for example, cetylpalmitate and cera alba (bleached wax, DAB 9).

The of the inner or lipid phase, related to the basic preparation, is 0.1 to 30% by weight and preferably 1 to 10% by weight.

Should it be necessary to use dispersion-stabilizing additives to produce stable dispersions, these can be incorporated to stabilize the particles in the form of pure substances or in the form of mixtures. The quantitity to be used in relation to the total weight of the watery dispersion ranges in per cent by weight from 0.01 to 20 and preferably from 0.5 to 5. The following substances come into consideration as stabilizing agents: a) tensides, particularly ethoxylated sorbitaa fatty acid ester, blockpolymers and blookcopolymers (such as e.g. poloxamers and poloxamines), polyglycerin ethers and polyglycerin esters, lecithins of various origin g. egg-lecithin or soya-lecithin), chemically modified lecithins hydrated lecithin), as well as phospholipids and sphingolipids, mixtures of lecithins with phospholipids, sterols cholesterin and cholesterin derivatives, as well as stigmasterin), esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols saccharosemonosteatarate); b) sterically stabilising substances, such as poloxamers and polyoxyethylene-polyoxypropylene-blockpolymers), ethoxylated sorbitan fatty acid ester, ethoxylated mono- and diglycerides, ethoxylated lipids and lipoids, ethoxylated fatty alcohols or fatty acids, and c) charge enhancing or charged compounds such as dicetylphosphate, phosphatidylglycerin, as well as saturated and unsaturated fatty acids, sodium cholate, sodium glycolcholate, sodium taurocholate or mixtures thereof, amino acids or anti-flocculants such as sodium citrate (see J.S. Lucks, W. Miller, RI-H. Miller, Int. J. Pharmaceutics 63, 183-188 (1990)); 20 d) viscosity increasing substances such as cellulose ethers and cellulose esters methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose), polyvinyl derivatives, such as polyvinyl alcohol, polyvinyl pyrrolidon, polyvinyl acetate, alginates, polyacrylates carbopol), xanthenes and pectins.

The charge enhancing stabilisers are incorporated, if necessary, in relation to the basic preparation, preferably in a quantity of 0.01 to 10% and most preferably in a quantity of 0.05 to The viscosity increasing substances are likewise incorporated, if necessary, in relation to the basic preparation, 30 preferably in a quantity of 0.01 to 10%, and even more preferably in a quantity of 0.1 to 10% and most preferable at 0.5 to

°A

I***14J SQ As outer phase (continuous phase, dispersion medium) water, aqueous solutions or liquids miscible with water, such as glycerin or polyethylene glycol, are used. The aqueous solutions can be non-isotonic or isotonic for this purpose. To be taken into consideration as aqueous solutions are mixtures of water with one or several other components such as the following: glycerin, mniannose, glucose, fructose, xylose, trehalose, mannitol sorbitol, xylotol or other polyols such as polyethylene glycol, as well as electrolytes such as sodium chloride, These components are then put proportionately into the basic preparation in a quantity of 0.1 to 50% and preferably 1 to The SLN are produced generally by dispersing the inner phase (of the lipid or lipoid) into the outer phase (water, aqueous solution or a liquid that is miscible with water) at above room temperature When dispersing it is preferable to avoid using ultrasonic probes in order to prevent contamination by metal particles Ti), The temperature shall be selected so that the substance to be dispersed is in a liquid state or at least in a softened state. Thus, many lipids are dispersed at 70"C to 80 0 C. The production is usually accomplished in two stages: *e 20 1, by making a pre-dispersion, e.g. with a stirrer or with a rotor-statordisperser Ultra Turrax), If necessary, one or several dispersionstabilising substances are added; S2. by subsequently dispersing in a high-pressure homogeniser at an increased pressure a gap homogeniser, such as APV Gaulin or French Press, a jet stream homogeniser such as the microfluidizer).

In systems with good dispersible capacity, step 1 can be eliminated.

Tenside-free SLN is produced by dispersing the lipid or lipoid phase in an aqueous solution which contains one or several viscosity increasing substances either alone or in combination with other substances, such as sugars, sugar alcohols, especially glucose, mannose, trehalose, mannitol, sorbitol, as well as others. Furthermore, it is possible to use a combination of the viscosity increasing substance(s) or the combination thereof with sugars or sugar alcohols, or in a further combination with charged compounds. Suitable charged compounds, for example, are the following: sodium citrate, sodium pyrophosphate, sodium sorbate.

The active substance(s) can be incorporated by various methods, as for example: 1. by dissolving the active substance in the inner phase; 2. by dissolving the active substance in a solvent that is mixable with the inner phase and by adding this solution to the inner phase. The solvent will subsequently be partially or completely removed, if required; 3. by dissolving the active substance in the inner phase by -dispersing a solid matter or by controlled precipitation of the active substance in the inner phase); 4. by dissolving the active substance in the outer, water phase (e.g.

amphiphilous substances) and enclosing the active agent during the :production process in a particle-stabilising tenside film; 5. by adsorption of the active substance on the surface of the particles; o 0• 000.° 6. by dissolving the active substance in the lipid/lipoid phase by means of aisolvng agent a blockcopolymer or a sorbitan fatty acid ester), and subsequently dispersing the lipid/lipoid phase in order to produce the preliminary dispersion. The active substance is then present in the SLN as a solid solution; 7. by incorporating wat.wsolutions of the active substance into the lipid/lipoid phase and subsequently dispersing the lipid/lipoid phase in order to make the preliminary dispersion, thus -producing a W/F/W system which is analogous to the multiple emulsions.

The sterilization can be accomplished according to the procedures outlined in the pharmacopeia, as for example by means of autoclaves (121 C, 2 bar, DAB 9) or according to other recognized procedures.

The realms of use of the drug carrier according to the invention with the solid liquid nanospheres are manifold. For example, it can be used for the following drug applications: parenteral, enteral, pulmon"ry, topical (nasal, dermal, intra-ocular) and in body cavities.

With respect to the parenteral application, it concerns in particular the following: 1. Intravenous drese(targeting the liver, spleen and bone marrow, particles circulating in the blood and the controlled liberation of active substances, such as peptide drugs, cytostatics, immunostimulants, growth factors, such as the colony stimulating factor (regulation of leucocytes) and the growth factor.

12 2. Intramuscular administration (depot dosage forms for extended or prolonged release of the active substances, e.g. peptide drugs or hormones).

3. Intra-arthricular administration for antirheumatics and immunosuppressives for arthritis).

4. Intracavital administration for cytostatics and peptide drugs for forms of cancer in the peritoneum and in the pleura cavity), Subcutaneous administration slow release of the drug for cytostatics in skin cancer).

The enteral forms of application are suited especially to the following: 1. incorporation of lipid-soluble vitamins; 2. lymphatic adsorption drug-targeting of cytostatics to the lymph nodes); 3. presentation of antigens oral immunisation with the help of Peyer's plaques), and 4. uptake of peptide medicinal agents with the help of M-cells.

SAs pulmonary forms of application, especially the following come into 20 consideration: 1. aerosols, dosing aerosols (spraying of the aqueous SLN-dispersion), 2. installation of the dispersion, i e ,7 ,,2 0 Examples of topical applications: 1. dermatological drugs for application of corticoids and antinaycotics; 2. Eye drops or eye gels, e.g. for lB-blocker, but also for 3. cosmetics analogous to the Uposornal preparations, Examples of drugs to be incorporated into the SIN (as salt, ester, ether or in a 1hf4 for Analgetics/Antirheumatics Morphine, codeine, piritamide, fentanyl and fentanyl derivatives, levomethadon, tramadol, diclofenac, ibuprofen, indometacin, naproxen, piroxicam, penicillamaine Andi-allergies Pheniramine, dimetinden, terfenadine, astemnizol, loratidine, doxylamirie, tneclozine, bainipin, clexnastin.

Antibiotics/Chemotherapeutics from these: polypeptide antibiotics such as colistin, polyuiyxini B, teicplanin.

vuncomycin; antimalarial such as quinine, halofanatrin, mefloquine, chloroquine; virustatics such as ganciclovir, foscarniet, zidovudin, ac;-.avir and others such as dapson, .14 fosfomycin, fusafungin, timetroprim, Anti-epileptics Phenytoin, mesuximide, ethosuximide, primidon, phenobarbital, valproin acid, carbamazpin, clonazepam Antimycotics a) internal: Nystain natarnycin, amphotericin B, flucytosine, miconazole, fluconazole, itraconazole b) external, in addition: Clotriniazle, econazole, tioconazole, fenticonawole, bifonazole, oxiconazole, ketoconazole, isoconaole, tolnaftate Corticoid (inrernal) Aldosterone, fiudrocortisone, betamnetasone. dexametasorie, triamcinolone, fluocortolone, hydroxycortisone, prednisolorie, prednylidene, cloprednole, methyiprednisolone Dertuatics, a) Antibiotics: Tetracylinc, erythromycin, neomycin, gentamycin, clindam3ycin, frantycetin, tyrothricin, chioretetracyline, inipirocin, fusidin acid Virustatics as above, but in addition: Podophyllotoxin., vidarabine, tromantadine c) Corticoids as above, but in addition: Aincinonide, flupredniden, alciometason, clobetasol, diflorason, balcinionide, fluocinolone, clpcortoloue, flumetason, difluocortolone, flurandrenolide, halometason, desoxinietason, fluocinolide, fluocortinbutyl, flupreniclen, prednicarbate, desonide Diagnostics a) radioactive isotopes such as Te99m, WI or 1131, covalently bound to lipids or lipoids or other molecules or in complexes b) highly substituted iodine-containing compounds such as, lipids HaemostypticsfAntihiaemorrhagics Blood clotting factors VIII, IX Hypnotics, Sedatives Cyclobarbital, pentobarbital, phenobarbital, methaqualone, beuzodiazepines (flurazepam, midazolain, nitrazepam, lorznetazepam, flunitrazepain, triazolam, brotizolam, temazepaM, loprazolam) Pituitary hormones, hypothalamic hormones, regulatory peptides and their inhibiting agents Corticotrophin, tetracosactide, choriongonadotropin, urofolitropin, urogonadotropin, somatropin, metergoline, bromocriptin, terlipressin, desmopressin, oxytocin, argipressin, 16 ornipressin, leuprorelin, triptorelin, gonadorelin, buserelin, nafarelin, goselerin, somatostatin Immunotherapeutics and Zytokine Dimepranol-4-acetate amido benzoate, thymopentin, a-interferon, 1-interferon, yinterferon, filgrastim, interleukin, azathioprine, ciclosporin Local Anaesthetics internal: Butanilicaine, mepivacaine, bupivacaine, etidocaine, lidocaine, articaine, prilocaine, external, in addition: Propipocaine, oxybuprocaine, tetracaine, benzocaine Migraine Agent Proxibarbal, lisuride, methysergide, dihydroergotamine, clonidine, ergotamine, pizotifen Anaesthetic Agent Mvlethohexital, propofol, etomidate, ketamine, alfentanil, thiopental, droperidol, fentanyl Parathyroid Gland Hormones, Calcium Metabolism Regulators Dihydrotachysterol, calcitonin, clodron acid etidron acid 17 Opthalmics atropine, cyclodrin, cyclopentolate, homatropine, tropicamide, scopolamine, poledrin, edoxudine, tromantadine, aciclovir, acetazolamide, diclofenamide, carteolol, timolol, metipranolol, betaxolol, pindolol, befunolol, bupranolol, levobunuol, carbachol, pilocarpine, clonidine, neostigmine, idouridin.

Psycho-Drugs Benzodiazepines (lorazepam, diazepam), clomethiazol Tyroid Gland Therapeutics 1-thyroxin, carbimazole, thiamazole, propylthiouracil Serums, Immunoglobulins, Vaccines a) Immunoglobulins in general, and specifically such as heptatitis types, German measles, cytomegaly, rabies, FSME, chickenpox/shingles, tetanus, rhesus factors b) Immunoserums such as botulism-antitoxin, diphteria, gas gangrene, snake poison, scorpion poison c) Vaccines such as, influenza, tuberculosis, cholera, diphteria, hepatitis types, FSME, German measles, haemophilus influenzae, measles, neisseria, mumps, poliomyelitis, tetanus, rabies, typhoid 'yI/I Sex hormones and their inhibiting agents Anabolics, androgens, anti-androgens, gestagens, estrogens, anti-estrogens (tamoxifen, etc.) Cystostatics and Metastasis Inhibitors a) Alkylants such as nimustine, melphalane, carmustine, lomustine, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, busulfan, treosulfan, prednimustine, thiotepa b) Antimetobolites such as cytarabine, fluorouracil, methotrexate, mercaptopurine, tioguanine c) Alkaloids such as vinblastine, vincristine, vindesine d) Antibiotics such as aclarubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, plicamycin e) Complexes of secondary group elements Ti, Zr,V, Nb, Ta, Mo, W, Pt) such as carbo-platinum, cis-platinum and metallocene compounds such as titanocendichloride f) Amsacrine, dacarbazine, estramustine, etoposide, hydroxycarbamide, mitoxanthrone, procarbazine, temiposide g) Alkyl amido phospholipids (described in J.M. Zeidler, F. Emling, W.

Zimmermann and H.J. Roth, Pharmacy Archives, 324 (1991, 687) h) Etherlipids such as hexadecylphosphocholine, ilmofosin and analoga, described in R. Zeisig, D. Arndt and H. Brachwitz, Pharmacy 45 (1990), 809-818.

The invention is explained in greater detail by the following examples.

19 Example I

I

10.0 g cera alba (bleached wax) g poloxamer 188 (polyoxyethylene-polyoxypropylene-block-copolymer) 0.1 g dicetylphosphate 87.4 g water for injection purposes Cera alba and dicetylphosphate were heated to 70 0 C and mixed with a solution of poloxamer 188, in water for injection purposes which was likewise heated to 70C. The mixture was predispersed at 70 0 C with the help of an Ultra Turrax. The resulting preliminary dispersion subsequently put through an APV Gaulin high-pressure homogeniser which had been temperature adjusted to 70 0 C (5 cycles with 500 bar). A SLN-dispersion was attained with a mean diameter of 216 nm. The polydispersity index, serving as measure for the width of the particle size distribution, was 0.143 (PCSphoton correlation spectroscopy). All particles were smaller than 60 Fim (measured with a Sympatek laser diffractometer).

Example 2 10.0 g cetulpalmitate 2.5 g poloxamer 188 20 87.5 g water for injection purposes e eo e e** e• se i *e *oo The production was done as described in example 1. The mean diameter was 215 nm and the polydispersity index was 0.131 (PCS-data). All particles were smaller than 4.2 rim (laser Example 3: 10.0 g cetylpalmitate g lipoid S 75 (soyalecithin with 75% of phosphatidylcholin) 0.1 g dicetylphosphate 87.4 g water for injection purposes The production was done as described in example 1. However, lipoid S 75 was dispersed in the heated lipid phase. The mean diameter was 183 nm, and the polydispersity index was 0.1333 (PCS-data). All particles were smaller than 8.6 um (laser diffraction meter).

Example 4: 10.5 g g 87.5 g glycerintrilaurate (Dynasan(R) 112) poloxamer 188 water for injection purposes The production was done as described in example 1. The mean diameter was 199 nm and the polydispersity index was 0.180 (PCS-data). All particles were smaller than 7.2 Jtm (laser diffraction meter).

Example 10.0 g g g 87.0 g cetylpalmitate poloxamer 188 dicetylphosphate water for injection purposes 22 The production was done as described under example 1. The characteristic data before and after the autoclaving substantiates the applicability of the sterilization method.

mean polydispersity diameter index all particles smaller than before sterilization after sterilization 215 nm 214 nm 0.131 0.109 4.2 .m 3.0 uzm Example 6: As a model drug, 0.25g of tetracaine base were incorporated in preparation No. The production was done as described in example 1. The mean diameter was 218 nm and the polydispersity index was 0.186 (PCS-data). All particles were smaller than 10.2 /m (laser The drug tefwas 92.8%.

23 Example 7: As a model drug, tetracaine base was incorporated in the following preparation: 10.0 g g to 100.0 g glycerin trilaurate (Dynasan 112) lipoid S tetracaine base of 0.1 g, 0.5 g, 1.0 g or 2.0 g water for injection purposes The production was done as described in example 1. However the high-pressure homogenization was carried out at 1500 bar (three cycles). The following values were achieved as mean diameter (PCS-data).

Drug Content (related to lipid phase) 1% PCS-diameter (nm) 103 102 101 125 Example 8: The preparations, as mentioned under example 7, were autoclaved (A 121) according to DAB39.

Drug Content (related to bLnd bhase) PCS-dianieter before autoclaving PCS-diameter after autoclavinz 1% 103 n 102 am 101 rn 101 =m 102 nm.

95 run When active substances are used which are sensitive to lyophilized or dried by spraying.

hydrolysis, the particles can also be 10.0Og g g 84.5 ml Example 9: glycerintrilaurate (Dynasan 112) lipoid S tetracaine base watery glucose solution (30% mX') The production was done as described under example 1. However, the high-pressure homogenization was carried out at 1500 x W0 pa (1500 bar) (three cycles). Asmean diameter -(PCS-data), the following values -were obtained before and after lyophilization: meanL ditameter Polydispersity index 0.277 before lyophilization after.1yophilization 90 n 481 nrn 0.289 As another drug, the active substance hexadecylphosphocholin (HPC) was incorporated in a model preparation.

EXaMPle 10.0 g glycerintrilaurate (Dynasan 112) g poloxamer 188 0.1 g hexadecyiphosphocholin 84.9 g water for injection purposes The production was done as described in example 1. The attained SLN-dispersion had a mean PCS diameter f 178 nm. Jmoyiprsity index was 0. 1653. All particles werae smalJler than 3.6 A~m (laser) By varying the tenside content or the tenside components it was possible'to produce SLN-dispersions with a h C-content of 0. 1 to 50 mg/g.

fly using viscosity increasing substances, it is possible to produce tenside-free SLN-distpersions.

Example 11: g glycerintrilaurate (Dynasan 112) g tylose M 300 89.5 g water for injection purposes The production was done as described in example 1. However, the high-pressure homogenization was carried out at 500 x 101 pa (500 bar) (three cycles). The PCS-diameter of the main population was 879 nin with a polydispersity index of 0.367.

By varying the processing conditions it is possible to produce SLN-dispersions with a mean PCSdiameter below 100 '3m.

26 Example 12: 10.0 g glycerintrilaurate (Dynasan 112) g lipoid S 85.0 g water for injection purposes The production was done as described under example 1. However, the high-pressure homogenization was carried out at 1500 x 105 pa (1550 bar) (three cycles).

The PCS-diameter of the main population was 88 nm (attaied through polydispersity analysis by means of Fourier's transformation of the astilaecorrelation function).

The invention also includes the procedure to produce the described drug carrier as well as its use for administering active substances.

Seen on the whole, the solid lipid nanospheres combine the advantages of polymer nanoparticles (solid core, controllable liberation over a longer period of time, possibility of incorporating hydrophili'c. edh with the advantages of parenteral fatty emulsions (relatively fast degradation, low or no toxicity, producibility on an industrial scale by methods established for the emulsion products, no difficulties with sterilization by autoclaving) by avoiding the disadvantages of nanoparticles (too slow degradation in vivo or toxic degradation products, lack of scaling-up possibility in the production) and the disadvantages of fatty emulsions very quick metabolization, very fast liberation of the medicine).

i c

I

1

Claims (30)

1. A process for the manufacture of a drug carrier which comprises tenside-containing or tenside-free particles of lipid or lipid-like (lipoid) material or mixtures thereof and having a diameter range of 10nm to whereby the particles have an average diameter of between 40 and 1000 nm and are solid at room temperature characterised in that the particles when in a melted or softened state are homogenised under high pressure in a dispersion medium being water, aqueous solution o' i liquid miscible with water, or the particles when in a solid state are d.'persed under high pressure in the dispersion medium, whereby the particles are finely dispersed.

2. The process as in claim 1, characterised in that the particles have an average diameter of 100 to 500 nm.

3. The process as in claim 2 characterised in that the particles have an average diameter of 40 to

4. The process as in claim 1, 2 or 3 characterised in that the proportion of particles in relation to the total preparation is 0.1 to 30% by weight.

The process as in claim 4, characterised in that the proportion of the particles in relation to the total preparation is 1 to 10% by weight. 20

6. The process as in one of the claims 1 to 5, characterised in that the "lipid particle material comprises monoglyceride, diglyceride, triglyceride, fatty alcohols and the esters or ethers thereof, waxes and lipid peptides or S*mixtures thereof.

7. The process as in claim 6, characterised in that the triglyceride comprises glycerine trilaurate, glycerine myristate, glycerine palmitate, glycerine stearate and glycerine behenate; the fatty alcohol comprises cetyl and stearyl alcohol; and the wax comprises cetyl palmitate and bleached beeswax.

8. The process as in one of the claims 1 to 7, characterised in that the 30 drug carrier further includes one or more dispersion-stabilising substances, whereby the dispersion-stabilising substances are included in a quantity of 0.1 to 20% by weight in relation to the total preparation.

9. The process as in claim 8 wherein the dispersion-stabilising substances are included in a quantity of 0.5 to 5% by weight.

10. The process as in claim 8 or 9 characterised in that the dispersion stabilising substances comprise compounds selected from the group consisting of poloxamers, poloxamins, ethoxylated monoglycerides and diglycerides, ethoxylated lipids and lipoids, ethoxylated fatty alcohols and alkyl phenols, ethoxylated fatty acid esters, polyglycerine ethers and esters, lecithins, esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols, phospholipid and sphingolipids, sterols and the esters and ethers thereof, and mixtures thereof.

11. The process as in claim 8, 9 or 10 characterised in that the dispersion-stabilising substances comprise egg-lecithin, soya-lecithin or hydrogenated lecithin, mixtures thereof, or mixtures of one or both lecithins with one or more phospholipid components, cholesterin, cholesterin palmitate, stigmaterin or other sterols.

12. The process as in one of the preceding claims characterised in that the drug carrier further includes charge-enhancing sterically stabilising compounds in a quantity of 0.01 to 10% by weight in relation to the total preparation.

13. The process as in claim 12 wherein the charge enhancing sterically stabilising compounds are in a quantity of 0.05 to 2% by weight.

14. The process as in claim 13 or 14, characterised in that the charge- enhancing storically stabilising compounds comprise dicetyl phosphate, 20 phosphatidylglycerol, saturated or unsaturated fatty acids, sodium cholate, sodium glycholate, sodium taurocholate or mixtures thereof, antiflocculants or amino acids.

15. The process as in claim 8, characterised in that the drug carrier further comprises one or more viscosity-increasing substances, whereby the viscosity-increasing substances in a quantity of 0.1 to 10% by weight in relation to the total preparation.

16. The process as in claim 15, wherein the one or more viscosity increasing substances in a quantity of 0.5 to 15% by weight.

17. The process as in claim 15 or 16, characterised in that the viscosity- 30 increasing substances comprise cellulose ethers and esters, polyvinyl derivatives, alginates, polyacrylates, xanthanes and pectins.

18. The process as in claim 15, 16 or 17 characterised in that the drug carrier further comprises sugar or sugar alcohols.

19. The process as in claim 18 wherein the sugar is glucose.

20. The process as in one of the claims 15 to 19 characterised in that the drug carrier further comprises Mcompounds.

21. The process as in one of the preceding claims, characterised in that the particles are dispersed in distilled water, in an aqueous solution with additives of electrolytes, monosaccharides and disaccharides, polyols or mixtures thereof or a liquid miscible with water, whereby the additives comprise sodium chloride, mannose, glucose, fructose, xylose, Lrehalose, mannitol, sorbitol, xylitol and glycerol in a quantity of 0.1 to 50% by weight in relation to the total preparation.

22. The process as in claim 21 wherein the further additives are in a quantity of 1 to 30% by weight.

23. The process as in one of the preceding claims, characterised in that the particles are lyophilised or spray-dried.

24. The process as in claim 1, characterised in that the drug carrier is manufactured without the use of halogenated organic solvents.

The process as in one of the preceding claims, characterised in that the drug carrier further includes one or more active substances.

26. The process as in claim 25 wherein the one or more active substances are pharmaceutically active substances,

27. The process as in claim 25 or 26, characterised in that the one or more active substances are dissolved or dispersed in the particles, adsorbed 20 on the surface of the particles or dispersed in the particles as an aqueous solution.

28. The process as in claim 25 or 26 characterised in that the drug carrier contains one or more active substances and is suitable for intravenous administration, intramuscular administration, intra-arthricular administration, intracavital administration, subcutaneous administration, intradermal administration, enteral administration, pulmonary application and topical and ophthalmclogical application.

29. A drug carrier consisting of tenside-free particles of lipid or lipid-like (lipoid) material or mixtures thereof and having a diameter of lOnm to 30 manufactured by means of a high-pressure homogenisation process in accordance with one of the claims 1 to 28, whereby the majority of the particles have an average diameter of between 40 and lO0Onm and are solid at room temperature. The drug carrier as in claim 29 when used for the manufacture of drugs which are suitable for intravenous administration, intramuscular administration, intra-arthricular administration, intracavital administration, subcutaneous administration, intradermnal administration, en teral administration, pulmonary application and topical and ophithalmological application. DATED this 12th day of July 1996 MIEDAC GESELLSCHAFT FUR KLINISCHE SPEZIALPRAPARATE MIB I Patent Attorneys for the Applicant: F.B. RICE CO. 31 ABSTRACT The invention relates to a drug carrier which comprises particles of lipid or lipid-like (lipoid) material or mixtures thereof which have a diameter of 10 nm to 10 im and which are solid at room temperature. On account of its solid core, the drug carrier allows a controllable liberation of active substances over a longer period of time and the incorporation of hydrophilous medicinal agents into the solid core. Furthermore, the drug carrier makes a relatively quick degrading possible at which no toxic by-products are produced. INTERNATIONAL SEARCH REPORT International application No. PCT/EP 92/02132 A. CLASSIFICATION OF SUBJECT MATTER Int. Cl. 5 A61K9/16; A61K9/51 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int. Cl. 5 A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X EP, A, 0 167 825 (DR. RENTSCHLER ARZNEIMITTEL 1-14, GMBH CO) 24-27 JanuL-y 1986 Y see page 1, line 1 line 4 15-19 see page 4, line 6 line see page 4, line 17- page 5, line 23 see page 16 page 17; examples 1,2 see page 18 page 19; example 4 see page 20; example 9 see claims X EP, A, 0 418 153 (MEDGENIX GROUP SA) March 1991 20-23 Y see page 2, line 1 line 44 18 see page 3, line 6 line see pages 8,9 9"" see claims 1,8,9,11 Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: later document published after heinternational filing dateorpriority document defining the general stateof the art which is not considered date and not in conict with the application but citd to understand to be of particular relevance the principle or theory underlying the invention earlier document but published on or after the international filing date document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance; the claimed invention cannot be document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the document is means combined with oneor more other such documents, such combination being obvious to a person skilled in the art document published prior to the international filing date but later than being obvious to a person skilled in the art the priority date claimed document member of the same patent family Date of the actual'completion of the international search Date of mailing of the international search report 24 November 1992 (24.11.92) 07 December 1992 (07.12.92) Name and mailing address of the ISA/ Authorized officer European Patent Office Facsimile No. Telephone No. Form PCT/ISA/210 (second sheet) (July 1992) INTERNATIONAL SEARCH REPORT International application No. PCT/EP 92/02132 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X EP, A, 0 375 520 (CENTRE INTERNATIONAL DE 1-3,6-9 RECHERCHES DERMATOLOGIQUES CIRD) 27 June 1990 see page 2, line 28 line 32 see page 3, line 41 line 46 see page 11; example 8 see page 12; example 11 Y EP, A, 0 438 359 (RHONE POULENC RORER SA) 15-17,19 24 July 1991 see page 2, line 30 page 3, line 51 Y JOURNAL OF PHARMACEUTICAL SCIENCES 15-17 Vol. 55, No. 4, April 1966, pages 376-380 DRAPER E.V. ET AL'SOME WAX FORMULATIONS OF SULFAETHYLTHIADIAZOLE PRODUCED BY AQUEOUS DISPERSION FOR PROLONGED RELEASE MEDICATION' see page 377 page 378 Form FCT/ISA/210 (continuation of second sheet) (July 1992) INTERNATIONALER RECHERCHENBERICHT Internatonajs Akt ezae PCT/EP 92/02132 Klassder ateaionye aetisiiain(PQoe ahdrntoa Klaflkaion nboder Int.K1. 5 A61K Recherchierte nichzu m MindestprtIfstaff gdxiirende Verdiffentliidungen, soweit diese uiter die redierchierten Sachgebiete fWien M. EINSCHLAGIGE VEROFFENTLICHUNGEN 9 Art.- Kennzeichoung der VertlffeatlikhUng~ t soweit eforderici ante: Angabe der mlgabiichen Tciie 1 2 Betr. Ansruch Nr.13 X EP,A,C:' 167 825 (DR. RENTSCHLER 1-14, ARZNEIMITTEL GMBH CO) 24-27 Januar 1986 Y siehe Seite 1, Zeile 1 Zeile 4 15-19 siehe Sei... 4, Zeile 6 Zeile siehe Seite 4, Zeile 17 Seite 5, Zefle 23 siehe Seite 16 Seite 17; Beispiele 1,2 siehe Seite 18 Seite 19; Beispiel 4 siehe Seite 20; Beispiel 9 siehe AnsprUche X EP,A,0 418 153 (MEDGENIX GROUP SA) Mdrz 1991 20-23 Y siehe Seite 2, Zeile 1 Zeile 44 18 siehe Seite 3, Zeile 6 Zeile siehe Seite 8,9 9""1 siehe AnsprUche 1,8,9,11__ 0 Besondere Kategorica von angegebenexi Veriffatlicbunen 10 Verliffentlichung, die den aliganeinen Stand der Tedinik 'T Sp~tere Verttffentlichung, die nibh dem internationalen An- definiert, aber nicht als besonders badeutsam amrseben In? meldedatum ode: dem fvroritltsdatum veftlffentlidxt warden ilteres Dokument, das jedocki ema am oder nacb dan interOa- Is and mit der Anmeidung~ nicht kollidiert, sondern our zum tionalen Anmeldedatum ve~fntiI, wan s Verst~ndals des der Erfnlung zugrnddeggnien Plps 'V Vrtifentichag, ie e4 e Is, eizn riont~fsan uchexder der list zugrundeilegenden Theore angegeben ist zw eitfefticbn die reeine r ub i ists esna- Vcrttffcntidxng von besonderer Bed eutungi die b ans :tu± iweieibat asbeinn zaassx~ oer dtch ie ds e Erfindang kano nlcbt us neu Dder aid erldesber T~t fcntlicbangsdatum einer anderen Im Recdzadebeicht go kdl beIbt btdte ere nanoten Veroffentlicbung bciegt werden soil oder die axs elnern ki euedbrcttwre anderen besonderen Grand angegben ist (wie aaasgefubhrt) Veroffentlicliang von besonderer Bedeutung; die beansprucb- 0' Verofifnttichung, die sich aid emin ilndlie Ofebrvng, te Erfindung kano nktbt a1s auf erfindeisther T~tlgkeit be- elneBenanio, ae Asstdungoderand~ ~rubend betracistet werden, wen die Veroffentidsung mit tie ic gtn Astist de ner ainhe aine oder menreren anderen Vertiffentlichangen dieser Kate- bezietgone in Verbindung gebracst wird and diese Verbindung fur 'I Veiiffentichung, die vor dem Internationaien Anmeldeda- onen Facbmann nabeflegend 1st turn, aber ouch den beinspruchten Priorit~zsatum verbffeit- W Vertiffatlicbung, die Ntfltgiied derseiben Patentfimilie Lst lids? worden ist MV FESCHEINIGUNG Datum des Absuciasses der internationalen Recbserbe Absededatum des internationslen Recercbasbericbts 24.NOVEMBER 1992 0 7. 12. 92 loternatinuie Rechercbenbebbrde Unterscbnift des beviimIcbt 0 Beienstten EUROPAISCHES PATENTAMT BOULOIS D. ?aaa~lea PCTIISA/210 (BI 21 (JaWW I"S PCT/EP 92/02132 Inniamiwes Aktemelca 11L EINSCHIAGIGE VEROFFENUJCHUNGEN (Forsetng von Blaft 2) Ar Unzdchoung der Veraffewfchung, zowdt afocrt~cb unter Axgabe der wa~peilcbm Thice Bear. Anlpnich Nr. X EP,A,0 375 520 (CENTRE INTERNATIONAL DE 1-3,6-9 RECHERCHES DERMATOLOGIQUES CIRD) 27. Juni 1990 siehe Seite 2, Zeile 28 Zeile 32 siehe Seite 3, Zeile 41 Zeile 46 siehe Seite 11; Beispiel 8 siehe Seite 12; Beispiel 11 Y EP,A,0 438 359 (RHONE POULENC RORER SA) 15-17,19 24. Juli 1991 siehe Seite 2, Zeile

30 Seite 3, Zeile 51 Y JOURNAL OF PHARMACEUTICAL SCIENCES 15-17 Bd. 55, Nr. 4, April 1966, Seiten 376 380 DRAPER E.V. ET AL 'SOME WAX FORMULATIONS OF SULFAETHYLTHIADIAZOLE PRODUCED BY AQUEOUS DISPERSION FOR PROLONGED RELEASE MEDICATION' siehe Seite 377 Seite 378 =ggt PCTIISAJ2I l1mam"In U~mw Ils) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. EP SA 9202132 64480 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on The European Patent Office is in no 'ray liable for these particulars which are merely given for the purpose of information. 24/ 11/92 Patent document Publication Patent family Publication cited in search report I date Imember(s) Idate EP-A-0167825 15-01-86 DE-A- JP-A- US-A- 3421468 61056122 4880634 19-12-85 20-03-86 14-11-89 EP-A-0418153 20-03-91 FR-A- 2651680 15-03-91 CA-A- 2025298 15-03-91 J P-A- 3169808 23-07-9 1 US-A- 5100591 31-03-92 EP-A-0375520 27-06-90 LU-A- 87410 10-07-90 AU-B- 626619 06-08-92 AU-A- 4709989 28-06-90 CA-A- 2006028 20-06-90 JP-A- 3135913 10-06-91 EP-A-0438359 24-07-91 FR-A- 2657257 26-07-91 AU-A- 6948191 25-07-91 CN-A- 1054189 04-09-9 1 JP-A- 4212359 03-08-92 ta For more details about this annx ee Official Jownual of the European Patent Office, No. 12182 ANHANG ZUM INTERN ATIONALEN RECHERCHENBERICHT OJBER DIE INTERNATIONALE PATENTANMELDUNG NR. EP 9202132 SA 64480 Ini diesem Anhang sind die Mitglieder der Patentfamilien der im ohengenumten i ternationnlea Rechehbcht angefdirten Ptm uite angegeben. ic Ae.:0en uhber die Faiiienmitgliedcr eiitaprecben demi Staiid der Datei des Europaiiscien Patentamt M Die Angaben dienen nur zur Unterrichtung and crfolgen ohnc Gewihr. 24/11/92 lIi Recherchenberit Datum der Mitgliod(cr r Datum der angefillites Patentdokuint Verdffentiicbung Patentfamii Verdfftiichung EP-A-0167825 150-6DE-A- 3421468 19-12-85 JP-A- 61056122 20-03-86 US-A- 4880634 14-11-89 EP-A-0418153 20-03-91 FR-A- 2651680 15-03-91 CA-A- 2025298 15-03-91 ~JP-A- 3169808 23-07-91 US-A- 5100591 31-03-92 EP-A-0375520 27-06-90 LU-A- 87410 10-07-90 AU-B- 626619 06-08-92 AU-A- 4709989 28-06-90 CA-A- 2006028 20-06-90 JP-A- 3135913 10-06-91 EP-A-0438359 24-07-91 FR-A- 2657257 26-07-91 AU-A- 6948191 25-07-91 CN-A- 1054189 04-09-91 JP-A- 4212359 03-08-92 U- 0 ok FOr niAber Uiwdbcitu zu Aim Anhang siebe Azmts~at des Europiscben Patnteat~s, Wr12182 INTERNATIONAL SEARCH REPORT International application No. PCT/EP 92/02132 A. CLASSIFICATION OF SUBJECT MATTER Int. Cl. 5 A61K9/16; A61K9/51 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int. Cl. 5 A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X EP, A, 0 167 825 (DR. RENTSCHLER ARZNEIMITTEL 1-14, GMBH CO) 24-27 Janua-y 1986 Y see page 1, line 1 line 4 15-19 see page 4, line 6 line see page 4, line 17- page 5, line 23 see page 16 page 17; examples 1,2 see page 18 page 19; example 4 see page 20; example 9 see claims X EP, A, 0 418 153 (MEDGENIX GROUP SA) March 1991 20-23 Y see page 2, line 1 line 44 18 see page 3, line 6 line see pages 8,9 9"" see claims 1,8,9,11 Further documents are listed in the continuation of Box C. O See patent family annex. S Special categories of cited documents: later document published after the international filing dateorpriority document defining the general state of the art whie is not considered dte p ninconflict applition ut cited to understand to be of particular relevance the principle or theory underlying the ivention earlier document but published on or after the international filing date document of particular relevance: the claimed invention can;ot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance; the claimed invention cannot be document referring to an oral disclosure, use, exhibition or other conside.ed to involve an inventive step when the document is means combined with one or more othersuch documents,such combination document published prior to the international filing date but later than being obvious to a person skilled in the art the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 24 November 1992 (24.11.92) 07 December 1992 (07.12.92) Name and mailing address of the ISA/ Authorized officer European Patent Office Facsimile No. Telephone No. Form PCT/ISA/210 (second sheet) (July 1992) INTERNATIONALER RECHFRCHENBERICHT Internatlonales Alitenzeicben PCT/EP 92/02132 I. KlASSIFIICATION DES ANMELDUNGSGEGENSTANDS (bel Inebreren EiassiflkatUonssymbolen sind aile anzugebea) 6 Nacb der Iiitemationaien Patentkhssiflkalioo [PC) odes nach der flationalen KI-sifikation arnd der [PC Int.K1. 5 A61K9/16; A61K9/51 MI RECIERCHIERTE SACHGEB[T Redchcicrter Mindestpriltstoff Ki~sifiatinsstemKiassiflicationssym bole Int.K1. 5 A61K Resberchierte nidnt zum Mindestpriffstoff gebbrende Vefl~ffenlicbunge,~ soweit die ntes die redierchlerten Sachgebiete Waien Ml. EINSCHLAGIGE VEROFFENMTCHUNGEN 9 Arv 0 Kentzeichnung der Vertlffentlicbung' t soweit erfordericb unte? Ang2be der mailgeblichen Tellel 2 Berr. Anspruch Nr.13 X EP,A,O 167 825 (DR. RENTSCHLER 1-14, ARZNEIMITTEL %'3MBH CO) 24-27 Januar 1986 Y siehe Seite 1, Zeile 1 Zeile 4 15-19 siehe Seitz 4, Zeile 6 Zeile siehe Seite 4, Zeile 17 Seite 5, Zeile 23 siehe Seite 16 Seite 17; Beispiele 1,2 siehe Seite 18 Seite 19; Beispiel 4 siehe Seite 20; Beispiel 9 siehe AnsprUche X EP,A,0 418 153 (MEDGENIX GROUP SA) Mdrz 1991 20-23 Y siehe Seite 2, Zeile 1 Zeile 44 18 siehe Seite 3, Zeile 6 Zeile siehe Seite 8,9 90111 siehe AnsprUche 1,8,9,11 Besondere Ktegorien von angegebenen VerdfezntlidagenlO 10 pt~fetlb~~ieheitstdoinn literts Dokument, das jedocb erst am oder tacdemdanterna- ist tand mit der Anmeldung nicbt kollidiert, sondrn nor zum tionalen Anmeidedatum itr~eiieich woe 61 Verst~ndais des der Erfladung zug ndeliegenden Pdinzips WU Veutifentlichung, die geej nej jet, eie Proi~sasrc oder der ihr zugrndeliegedeo Thenrie angepeben 1st miflhft rsheienzu a!'V Verliffentudiwing von besooderer Bedeutuag; de be runcb- swiflaf esk~inozuissen, oder dumbh die das V erf- teEfn~gknndtasnno er f tfidnde Thi feotlichuojadaturn einer anderen iso R eerchebicbt ge- ket bErlndgkn be t a ne oderaf nd ap ot nanoten Verfiffentlichung beiegt werden soil odes die aus cinemnki euedbercttwre anderto besondesen Gnind angegeben Ms (wie ausgefubri) Vertiffentlicliug von besonderer Bdaeutung; die beanspruch- Veslifentlichung, die sic), suf dnae molndlidie Ofebaug te Erfindung 1an aicht as aid crfioderischer Tgtdgkei I be- tineBentrug, tne usaeilug oes ndeeNI menrubeod betrachtet warden, wenn die Vertlffentlldsung mit tineBeatzun, tne ussillu& odr ader Miaihcn der odes menreren anderen Verlsiffastliungen dieser Kate- beziehtgone in Verbindung gebractit wird und diese Verbindung fuir Vadffentiichung, die vor demi Inte~wtionalen Anmeldeda- anen Factimann nabeliegaid Ws turn, aber naci, dem beanspruciiten P~nrit~tsdatum veeiffet W~ Verfffastlichung, die Mitglied derseiben Patentfamille ist iicbt worden ist IV. BESCHEINIGUING Datum des Abschlussgs der internationalen Rechserchie Absendedatum des internationallen Recderaiebaicbts 24.NOVEMBER 1992 07. 12.92 Intesnitonale Racerenbeiide Untersctifi des bevollmichtigtB eienseten EUROPAISCHES PATENTAMIT BOULOIS D 1uwwt)I PCTIISA/210 (BWI~ 2) (Joimw IWI) INTERNATIONAL SEARCH REPORT I intenational application No. PCT/EP 92/02132 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X EP, A, 0 375 520 (CENTRE INTERNATIONAL DE 1-3,6-9 RECHERCHES DERMATOLOGIQUES CIRD) 27 June 1990 see page 2, line 28 line 32 see page 3, line 41 line 46 see page 11: etample 8 see page 12: e:mple 11 Y EP, A, 0 438 359 (RHONE POULENC RORER SA) 15-17,19 24 July 1991 see page 2, line 30 page 3, line 51 Y JOURNAL OF PHARMACEUTICAL SCIENCES 15-17 Vol. 55, No. 4, April 1966, pages 376-380 DRAPER E.V. ET AL'SOME WAX FORMULATIONS OF SULFAETHYLTHIADIAZOLE PRODUCED BY AQUEOUS DISPERSION FOR PROLONGED RELEASE MEDICATION' see page 377 page 378 Form PCT/ISA/210 (continuation of second sheet) (July 1992) Intxtinais ~PCT/EP 92/02132 UL EINSCILAGIGE VElOFFENT11CHUNGEN (Forisewing von lanz 2) An K um2ZchOung der V enicbhn, sowdt erfotrdaicb Uuter AZ2Ibe der maiig idhe TelIe ler. Anprc Nr. X EP,A,0 375 520 (CENTRE INTERNATIONAL DE 1-3,6-9 RECHERCHES DERMATOLOGIQUES CIRD) 27. Juni 1990 siehe Seite 2, Zeile 28 Zeile 32 siehe Seite 3, Zeile 41 Zeile 46 siehe Seite 11; Beispiel 8 siehe Seite 12; Beispiel 11 Y EP,A,O 438 359 (RHONE POULENC RORER SA) 1517,19 24. Juli 1991 siehe Seite 2, Zeile 30 Seite 3, Zeile 51 Y JOURNAL OF PHARMACEUTICAL SCIENCES 15-17 Bd. 55, Nr. 4, April 1966, Seiten 376 380 DRAPER E.V. ET AL 'SOME WAX FORMULATIONS OF SULFAETHYLTHIADIAZOLE PRODUCED BY AQUEOUS DISPERSION FOR PROLONGED RELEASE MEDICATION' siehe Seite 377 Seite 378 Ywm~st 1?CTIISA4/2 IZxbini 4.~m tusi