DK175849B1 - Process for the preparation of microparticles comprising a drug substance, sustained release formulation, octreotide pamoate and process for the preparation thereof - Google Patents

Process for the preparation of microparticles comprising a drug substance, sustained release formulation, octreotide pamoate and process for the preparation thereof Download PDF

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DK175849B1
DK175849B1 DK199001625A DK162590A DK175849B1 DK 175849 B1 DK175849 B1 DK 175849B1 DK 199001625 A DK199001625 A DK 199001625A DK 162590 A DK162590 A DK 162590A DK 175849 B1 DK175849 B1 DK 175849B1
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drug
microparticles
emulsion
water
polymer
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DK199001625A
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DK162590D0 (en
DK162590A (en
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Thomas Kissel
David Bodmer
Jones Wing Fong
Hawkins Valliant Maulding
Oskar Nagele
Jane Edna Pearson
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Novartis Ag
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08Peptides having 5 to 11 amino acids
    • A61K38/095Oxytocins; Vasopressins; Related peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/23Calcitonins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/31Somatostatins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1641Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647Polyesters, e.g. poly(lactide-co-glycolide)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/02Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin

Description

DK 175849 B1 iDK 175849 B1 i

Den foreliggende opfindelse angår lægemiddelformuleringer med forlænget afgivelse (depotformuleringer), især vandopløselige peptider, fx somatostatin eller somatostatina-naloger såsom octreotid, i et bionedbrydeligt og biokompa-5 tibelt polymert bærestof, fx en matrix eller et overtræk, fx i form af en implanterbar indretning eller fortrinsvis i form af mikropartikler (også kendt som mikrokapsler eller mikromikrosfærer).The present invention relates to sustained-release drug formulations (depot formulations), especially water-soluble peptides, e.g., somatostatin or somatostatin analogs such as octreotide, in a biodegradable and biocompatible polymeric carrier, e.g., a matrix or coating, e.g., in the form of an implant. or preferably in the form of microparticles (also known as microcapsules or micromicrospheres).

10 Opfindelsen angår også sådanne formuleringer, der udviser tilfredsstillende peptidafgivelsesprofiler hen over et specifikt tidsrum.The invention also relates to such formulations which exhibit satisfactory peptide release profiles over a specific period of time.

Nærmere betegnet angår opfindelsen en fremgangsmåde til 15 fremstilling af mikropartikler omfattende et lægemiddelstof, jf. krav 1-15, en formulering med forlænget afgivelse, jf. krav 16-34 og krav 37, samt octreotidpamoat som angivet i krav 35 og en fremgangsmåde til fremstiling deraf som angivet i krav 36.More particularly, the invention relates to a process for the preparation of microparticles comprising a drug substance according to claims 1-15, an extended release formulation, according to claims 16-34 and claim 37, and octreotide pamoate as claimed in claim 35 and a method of preparation. thereof as claimed in claim 36.

2020

Efter oral eller parenteral administration udviser peptidlægemiddelstoffer ofte en lav biotilgængelighed i blodet, fx på grund af deres korte biologiske halveringstid forårsaget af deres metaboliske instabilitet. Såfremt de 25 administreres oralt eller nasalt, udviser de ydermere ofte en lav resorption gennem slimhinderne. Det er vanskeligt at opnå et terapeutisk relevant blodniveau i et længere tidsrum.Following oral or parenteral administration, peptide drug substances often exhibit low bioavailability in the blood, for example due to their short biological half-life caused by their metabolic instability. Furthermore, if administered orally or nasally, they often exhibit low resorption through the mucous membranes. It is difficult to achieve a therapeutically relevant blood level for an extended period of time.

30 Parenteral administration af peptidlægemiddelstoffer i form af en depotformulering i en bionedbrydelig polymer, fx som mikropartikler eller implantater, har været foreslået til muliggørelse af forlænget afgivelse efter en nogen tids ophold i polymeren, som beskytter peptidet mod de biologi-35 ske mediers enzymatiske og hydrolytiske påvirkninger.Parenteral administration of peptide drug substances in the form of a depot formulation in a biodegradable polymer, e.g., as microparticles or implants, has been proposed to allow prolonged release after a period of residence in the polymer which protects the peptide from the enzymatic and hydrolytic media of the biological media. influences.

I DK 175849 B1 II DK 175849 B1 I

22

I Skønt visse parenterale depotformuleringer af peptidlæge- IAlthough certain parenteral depot formulations of peptide physician I

I middelstoffer i en polymer i form af mikropartikler eller IIn agents in a polymer in the form of microparticles or I

I en implanterbar indretning er kendte, er tilfredsstillende IIn an implantable device known, satisfactory I

I peptidafgivelsesprofiler i praksis kun opnået i meget fåIn peptide release profiles, in practice, only obtained in very few

I 5 tilfælde. Der må træffes særlige foranstaltninger for at IIn 5 cases. Special measures must be taken to:

I opnå en kontinuerlig peptidafgivelse med henblik på et IYou obtain a continuous peptide release for an I

terapeutisk virksomt serumniveau af lægemiddelstoffet og, Itherapeutically effective serum level of the drug and, I

om ønsket, for at undgå for høje lægemiddelstofserumkon- Iif desired, to avoid excessive drug serum con- I

centrationer, der forårsager uønskede farmakologiske bi- Icenters that cause undesirable pharmacological bi-I

10 virkninger. I10 effects. IN

I Afgivelsesmønsteret for peptidlægemiddelstof afhænger afIn the peptide drug substance delivery pattern depends on

I talrige faktorer, fx peptidets art, og fx om det er til IIn numerous factors, for example, the nature of the peptide and, for example, whether it is for I

I stede i fri form eller i anden form, fx i saltform, hvilketPresent in free form or other form, eg in salt form, which

I 15 kan påvirke dets vandopløselighed. En anden vigtig faktor II15 can affect its water solubility. Another important factor I

er valg af polymer blandt den omfattende række af mulig- Iis the choice of polymer among the wide range of possible I

I heder, som er beskrevet i litteraturen.In the honors described in the literature.

I Hver polymertype har sin karakteristiske biologiske ned- IEach polymer type has its own distinct biological downstream

I 20 brydningshastighed. Der kan dannes frie carboxylgrupper, IAt 20 breaking speed. Free carboxyl groups, I, can be formed

I hvilket bidrager til pH-værdien i polymeren og således IIn which contributes to the pH of the polymer and thus I

I yderligere påvirker peptidets vandopløselighed og dermed IIn addition, the water solubility of the peptide and thus I

I afgivelsesmønsteret deraf. IIn the release pattern thereof. IN

I 25 Andre faktorer, som kan påvirke depotformuleringens af- II 25 Other factors that may affect the depot formulation I

I givelsesmønster, er, den mængde af lægemiddelstof, der IIn the pattern of giving, is the amount of drug that I

I fyldes i det polymere bærestof, fordelingsmåden af lægemid- IYou fill in the polymeric carrier, the mode of distribution of drug I

I delstof i polymeren, partikelstørrelsen og yderligere, når IIn partial substance in the polymer, particle size and further, when I

I det drejer sig om en implanterbar indretning, dets form. IIn the case of an implantable device, its shape. IN

I 30 Endvidere har formuleringens placering i kroppen betyd- IFurthermore, the position of the formulation in the body has been important

ning. Iequipment. IN

I Hidtil er der ikke markedsført noget somatostatinpræparat ISo far, no somatostatin preparation has been marketed

I med forlænget afgivelse til parenteral administration, IWith extended release for parenteral administration,

I 35 måske fordi der ikke har kunnet opnås et præparat, der IYou might because you have not been able to obtain a preparation that you

I udviser en tilfredsstillende serumniveauprofil. IYou have a satisfactory serum level profile. IN

3 DK 175849 B13 DK 175849 B1

Polymerformuleringer med lægemiddelstoffer, .hvilke formuleringer er udformet til forlænget eller forsinket afgivelse af lægemiddelstoffet, er kendte inden for området.Polymer formulations with drug substances, which formulations are designed for prolonged or delayed delivery of the drug substance, are known in the art.

5 I US patentskrift nr. 3.773.919 beskrives formuleringer med styret lægemiddelstofafgivelse, hvor lægemiddelstoffet, fx et vandopløseligt peptidlægemiddelstof, dispergeres i en bionedbrydelig og biokompatibel lineær polylactid- eller polylactid-co-glycolidpolymer. Der er imidlertid ikke blevet 10 beskrevet lægemiddelstofafgivelsesmønstre, og der findes ingen henvisning til somatostatin. I US patentskrift nr. 4.293.539 beskrives antibakterielle formuleringer i mikro-partikelform.U.S. Patent No. 3,773,919 discloses controlled drug delivery formulations wherein the drug substance, e.g., a water-soluble peptide drug substance, is dispersed in a biodegradable and biocompatible linear polylactide or polylactide co-glycolide polymer. However, no drug delivery patterns have been described and no reference to somatostatin is found. U.S. Patent No. 4,293,539 discloses antibacterial formulations in micro-particle form.

15 I US patentskrift nr. 4.675.189 beskrives formuleringer med forlænget afgivelse af det LHRH-analoge decapeptid-nafarelin og beslægtede LHRH-analoger i polylactid-co-glycolidpolyme-rer. Der er ikke beskrevet afgivelsesmønstre.U.S. Patent No. 4,675,189 describes extended release formulations of the LHRH analog decapeptide nafarelin and related LHRH analogs in polylactide co-glycolide polymers. No release patterns are described.

20 T. Chana har i J. Bioeng. 1, s. 25-32, 1976 beskrevet forlænget afgivelse af biologiske substanser, enzymer og vacciner fra mikropartikler.20 T. Chana has in J. Bioeng. 1, pp. 25-32, 1976 disclosed prolonged delivery of biological substances, enzymes and vaccines from microparticles.

Polymerer/co-polymerer af mælkesyre og lactid-/glycolid-co-25 polymerer og beslægtede præparater til kirurgisk anvendelse og til forlænget afgivelse og bionedbrydning er beskrevet i US patentskrift nr. 3.991.776, 4.076.798 og 4.118.470.Polymers / copolymers of lactic acid and lactide / glycolide copolymers and related preparations for surgical use and for extended release and biodegradation are disclosed in U.S. Patent Nos. 3,991,776, 4,076,798 and 4,118,470.

I EP patentskrift nr. 0.203.031 beskrives en række somato-30 statin-octapeptidanaloger, fx forbindelse RC-160 med formlen: * * D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 med en bro mellem -Cys-grupperne i spalte 15-16.EP patent specification No. 0.203,031 discloses a number of somatostatin statin octapeptide analogs, for example compound RC-160 of the formula: * * D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH a bridge between the -Cys groups in columns 15-16.

3535

DK 175849 B1 IDK 175849 B1 I

Muligheden for, at somatostatinerne kan være mikroindkapslet IThe possibility that the somatostatin may be microencapsulated I

med polylactid-co-glycolidpolymer er nævnt i EP-skriftets Iwith polylactide co-glycolide polymer is mentioned in EP I

krav 18, men der er ingen anvisninger på, hvorledes et kon- Iclaim 18, but there is no indication as to how a con

tinuerligt terapeutisk virksomt serumniveau kan opnås. Itinuously therapeutically effective serum level can be achieved. IN

I US patentskrift nr. 4.011.312 beskrives, at der kan opnås IU.S. Patent No. 4,011,312 discloses that I can be obtained

en kontinuerlig afgivelse af et antimikrobielt lægemiddel- Ia continuous delivery of an antimicrobial drug I

stof, fx det vandopløselige polymyxin B fra en polylactid- Isubstance, e.g., the water-soluble polymyxin B from a polylactide I

co-glycolidmatrix med en lav molekylvægt (under 2000) og et Ilow molecular weight co-glycolide matrix (below 2000) and an I

10 relativt højt glycol idindhold i form af en implanterbar I10 relatively high glycol content in the form of an implantable I

indretning, når den implanterbare indretning er indlagt i Idevice when the implantable device is inserted into I

en kopatte. Lægemiddelstoffet afgives inden for et kort Iand copate. The drug is dispensed within a card I

tidsrum på grund af polymerens høje glycolidindhold og lave Itime due to the high glycolide content of the polymer and low I

molekylvægt, hvilke begge stimulerer en hurtig bionedbrydningmolecular weight, both of which stimulate a rapid biodegradation

15 af polymeren og dermed en tilsvarende hurtig afgivelse af I15 of the polymer and thus a correspondingly rapid release of I

lægemiddelstof. Et relativt højt indhold af lægemiddelstof Idrug substance. A relatively high content of drug substance I

bidrager yderligere til en hurtig lægemiddelstofafgivelse. Ifurther contributes to rapid drug delivery. IN

Der er ikke beskrevet somatostatiner eller lægemiddelstof-No somatostatin or drug substances have been described.

afgivelsesmønstre. Irelease patterns. IN

20 I20 I

I EP-patentskrift nr. 58.481 beskrives, at en kontinuerlig IEP Patent No. 58,481 discloses that a continuous I

afgivelse af et vandopløseligt peptid fra en polylactid- Idelivery of a water-soluble peptide from a polylactide-I

polymerholdig implanterbar indretning stimuleres ved nedsæt- Ipolymer-containing implantable device is stimulated by immersion I

telse af molekylvægten af i det mindste en del af polymer- Iincreasing the molecular weight of at least a portion of polymer I

25 molekylerne ved indføring af glycolidenheder i polymermole- I25 molecules by introducing glycolide units into polymer molecules

kylet, ved forøgelse af polymerens blokpolymerkarakter, når Icooled, by increasing the block polymer character of the polymer, when I

der anvendes polylactid-co-glycolidmolekyler, ved forøgelse Ipolylactide-co-glycolide molecules are used in Increase I

af lægemiddelstof indholdet i polymermatricen og ved forøgelse Iof the drug substance in the polymer matrix and by increase I

af implantatets overflade. Iof the surface of the implant. IN

30 I30 I

Selv om somatostatiner er omtalt som vandopløselige pepti- IAlthough somatostatin is referred to as water-soluble peptide I

der, er der ikke beskrevet afgivelsesprofiler for soma- Ithere, no release profiles for soma- I are described

tostatin, og der er ingen angivelse af, hvordan alle disse Itostatin, and there is no indication of how all of these I

parametre skal kombineres for fx at opnå et kontinuerligt Iparameters must be combined to obtain, for example, a continuous I

35 somatostatinserumniveau i et tidsrum på mindst én uge, fx I35 somatostatin serum levels for a period of at least one week, e.g.

en måned. Ione month. IN

5 DK 175849 B1 s ί i I EP patentskrift nr. 92.918 beskrives, at der kan opnås en kontinuerlig afgivelse af peptider, fortrinsvis af hydrofile peptider, i et længere tidsrum, når pepidet inkorporeres i en konventionel hydrofob polymermatrix, fx af polylactid, 5 der er gjort mere tilgængelig for vand ved i polymermolekylet at indføre en hydrofil enhed, fx af polyethylenglycol, poly-vinylalkohol, dextran, polymethacrylamid. Det hydrofile bidrag til den amfipatiske polymer kommer fra alle ethylen-oxidgrupper, når det drejer sig om polyethylenglycolen-10 heder, fra de frie hydroxylgrupper, når det drejer sig om en polyvinylalkoholenhed eller en dextranenhed; og fra amidgrupper, når det drejer sig om en polymethyacrylamiden-hed. På grund af den hdyrofile enheds tilstedeværelse i polymermolekylerne opnår implantaterbar indretning hydro- .In EP Patent No. 92,918, it is disclosed that a continuous release of peptides, preferably of hydrophilic peptides, can be obtained for a prolonged period of time when the pepid is incorporated into a conventional hydrophobic polymer matrix, e.g. is made more accessible to water by introducing into the polymer molecule a hydrophilic moiety, for example of polyethylene glycol, polyvinyl alcohol, dextran, polymethacrylamide. The hydrophilic contribution to the amphipathic polymer comes from all ethylene oxide groups in the case of polyethylene glycol units, from the free hydroxyl groups in the case of a polyvinyl alcohol unit or a dextran unit; and from amide groups in the case of a polymethyacrylamide moiety. Due to the presence of the hydrophilic unit in the polymer molecules, the implantable device achieves hydro-.

15 gelagtige egenskaber efter absorption af vand. Somatostatin omtales som et hydrofilt peptid, men ingen afgivelsesprofiler er beskrevet, og der er ingen angivelser af hvilken type polymer, der foretrækkes til dette peptid, og hvilken molekylvægt og hvor mange hydrofile grupper, polymeren bør 2 0 have.15 gel-like properties after absorption of water. Somatostatin is referred to as a hydrophilic peptide, but no release profiles are disclosed, and there are no indications of the type of polymer preferred for this peptide and the molecular weight and how many hydrophilic groups the polymer should have.

i I GB patentskrift nr. 2.145.422 B beskrives, at der kan opnås en forlænget afgivelse af forskellige slags lægemiddelstoffer, fx af vitaminer, enzymer, antibiotika, antigener, 25 over en længere periode, når lægemiddelstoffet inkorporeres i en implanterbar indretning, fx af mikropartikelstørrelse, fremstillet af en polyolpolymer, fx af glucose eller mannitol, der har én eller flere, fortrinsvis mindst 3, poly-lactidestergrupper. Polylactidestergrupperne indeholder 30 fortrinsvis fx glycolidenheder.GB Patent No. 2,144,422 B discloses that a prolonged release of various kinds of drugs, e.g., of vitamins, enzymes, antibiotics, antigens, can be obtained over a prolonged period when the drug is incorporated into an implantable device, e.g. microparticle size, made of a polyol polymer, e.g., of glucose or mannitol having one or more, preferably at least 3, polyactide ester groups. The polylactide ester groups contain 30 preferably, for example, glycolide units.

Der er ikke omtalt peptider, fx somatostatiner, som lægemiddelstoffer, og ingen serumniveauer for lægemiddelstof er beskrevet.No peptides are mentioned, e.g., somatostatin, as drug substances, and no serum drug levels are described.

3535

DK 175849 B1 IDK 175849 B1 I

Den foreliggende opfindelse angår formuleringer, fx mikro- HThe present invention relates to formulations, e.g., micro-H

partikelformuleringer, med forlænget afgivelse af et læge- Hparticulate formulations, with extended delivery by a physician- H

middelstof, især af et hormonalt aktivt, vandopløseligt Hagent, especially of a hormonally active, water-soluble H

somatostatin eller en hormonalt aktiv, vandopløselig soma- Isomatostatin or a hormonally active, water-soluble soma- I

5 tostatinanalog såsom octreotid, hvilke formuleringer til- H5 tostatin analog such as octreotide which formulations for H

vejebringer et tilfredsstillende plasmaniveau for lægemid- Iprovides a satisfactory plasma level for drug I

delstof, og, fx i en bionedbrydelig, biokompatibel polymer, Hpart substance, and, for example, in a biodegradable, biocompatible polymer, H

fx i en indkapslende polymermatrix. Polymermatricen kanfor example, in an encapsulating polymer matrix. The polymer matrix can

være en syntetisk eller naturlig polymer. Hbe a synthetic or natural polymer. H

Mikropartiklerne ifølge den foreliggende opfindelse kan IThe microparticles of the present invention can

fremstilles ifølge en hvilken som helst konventionel tek- Hprepared according to any conventional text H

nik, fx en organisk faseadskillelsesteknik, en spraytør- Inick, for example, an organic phase separation technique, a spray-drying agent

ringsteknik eller en tripelemulsionsteknik, hvor polymeren Iring technique or a triple emulsion technique in which the polymer I

15 udfældes sammen med lægemiddelstoffet, og hvor det resul- I15 precipitates with the drug substance and where it results

terende produkt derefter hærdes, når der anvendes fasead- IThe adherent product is then cured when using phase adder

skillelses- eller tripelemulsionsteknik. Iseparation or triple emulsion technique. IN

Formuleringerne med forlænget afgivelse kan, om ønsket, IThe sustained release formulations may, if desired, I

20 foreligge i form af en implanterbar indretning. I20 in the form of an implantable device. IN

Der er nu fundet en særlig nyttig modificering af fasead- IA particularly useful modification of phase I has now been found

skillelsesteknikken til fremstilling af mikropartikler med Ithe separation technique for the preparation of microparticles with I

et hvilket som helst lægemiddelstof. Iany drug substance. IN

I overensstemmelse hermed tilvejebringer den foreliggende HAccordingly, the present H provides

opfindelse også en fremgangsmåde til fremstilling af mi- Iinvention also provides a method for the preparation of mi-I

kropartikler, der omfatter lægemiddelstof i bionedbryde- Ibody articles comprising biodegradable drug substance I

ligt, biokompatibelt bærestof, hvilken fremgangsmåde om- Ibiocompatible carrier, which method comprises I

30 fatter følgende trin: I30 takes the following steps:

a) opløsning af det polymere bærestofmateriale i et Ia) dissolving the polymeric carrier material in an I

hensigtsmæssigt opløsningsmiddel, i hvilket lægemid- Iappropriate solvent in which drug I

delstoffet ikke er opløselig, Ithe substance is not soluble;

7 DK 175849 B1 b) tilsætning til og dispersion i oplosningen fra trin a) af en oplosning af lægemiddelstof i et hensigtsmæssigt oplosningsmiddel, fx en alkohol, i hvilket polymeren ikke er opløselig, 5 c) tilsætning af et faseinduceringsmiddel til dispersionen fra trin b) for at fremkalde mikropartikeldannel- i se, 10 d) tilsætning af en olie-i-vand emulsion til blandingen fra trin c) til hærdning af mikropartiklen, og e) isolering af mikropartiklen.7 DK 175849 B1 b) adding to and dispersing in the solution from step a) a solution of drug substance in a suitable solvent, eg an alcohol in which the polymer is not soluble, 5 c) adding a phase inducing agent to the dispersion from step b) to induce microparticle formation, d) adding an oil-in-water emulsion to the mixture of step c) for curing the microparticle, and e) isolating the microparticle.

15 Der er yderligere fundet en særlig nyttig modificering af tripelemulsionsteknikken til fremstilling af mikropartikler med et hvilket som helst lægemiddelstof.A particularly useful modification of the triple emulsion technique has been found for the preparation of microparticles with any drug substance.

I overensstemmelse hermed tilvejebringer den foreliggende 20 opfindelse:Accordingly, the present invention provides:

En fremgangsmåde til fremstilling af mikropartikler, hvilken fremgangsmåde omfatter 25 (i) kraftig blanding af en vand-i-olie-emulsion dannet af et vandigt medium og et organisk opløsningsmiddel, der ikke er blandbart med vand, indeholder lægemiddelstoffet i én fase og en bionedbrydelig, biokompatibel polymer i den anden fase, med et overskud af et vandigt medium, der 30 indeholder en emulgerende substans eller et beskyttelses-kolloid til dannelse af en vand-i-olie-i-vand-emulsion uden tilsætning af lægemiddelstoftilbageholdende substans til vand-i-olie-emulsionen eller anvendelse af mellemliggende viskositetsforøgende trin, 35 (ii) desorbering af det organiske opløsningsmiddel derfra, (iii) isolering og tørring af de fremkomne mikropartikler.A process for the preparation of microparticles which comprises (i) vigorously mixing a water-in-oil emulsion formed from an aqueous medium and an water-immiscible organic solvent, contains the one-phase drug and a biodegradable , a second phase biocompatible polymer, with an excess of an aqueous medium containing an emulsifying substance or a protective colloid to form a water-in-oil-in-water emulsion without the addition of drug-retaining substance to water. (i) desorbing the organic solvent therefrom; (iii) isolating and drying the resulting microparticles.

DK 175849 B1 IDK 175849 B1 I

HH

Den foreliggende opfindelse tilvejebringer også: IThe present invention also provides:

a) en formulering med forlænget afgivelse, der omfatter I(a) a prolonged-release formulation comprising:

et peptidlægemiddelstof i en fra 40/60 til 60/40 Ia peptide drug substance in one from 40/60 to 60/40 I

5 polylactid-co-glycolidester af en polyol, idet polyol- I5 polylactide co-glycol ester of a polyol, with polyol I

enheden er valgt fra gruppen bestående af en alkoholthe device is selected from the group consisting of an alcohol

indeholdende (C3_6)-carbonkæde med 3-6 hydroxylgrupper Icontaining (C3_6) carbon chain having 3-6 hydroxyl groups I

og et mono- eller disaccharid, og idet den esteri- Iand a mono- or disaccharide, and the ester I

ficerede polyol har mindst 3 polylactid-co-glycolid- Ifused polyol has at least 3 polylactide-co-glycolide-I

10 kæder. I10 chains. IN

b) en formulering med forlænget afgivelse, der omfatter I(b) a prolonged-release formulation comprising:

et peptidlægemiddelstof valgt fra gruppen bestående af Ia peptide drug selected from the group consisting of I

en calcitonin, en lypressin eller et somatostatin i en Ia calcitonin, a lypressin or a somatostatin in an I

fra 40/60 til 60/40 polylactid-co-glycolidpolymer, der Ifrom 40/60 to 60/40 polylactide co-glycolide polymer which I

har lineære kæder med en molekylvægt Mw på mellem Ihas linear chains having a molecular weight Mw of between I

25.000 og 100.000, en polydispersitet Mw/Mn på mellem I25,000 to 100,000, a polydispersity Mw / Mn of between I

1,2 og 2 og med en peptidlægemiddelstofkoncentration I1,2 and 2 and with a peptide drug concentration I

på fra 0,2 vægtprocent, fortrinsvis fra 2 til 10 Iof from 0.2% by weight, preferably from 2 to 10 l

20 vægtprocent. I20% by weight. IN

c) en formulering med forlænget afgivelse, der omfatter I(c) a prolonged-release formulation comprising:

octreotid eller et salt eller derivat deraf i et Ioctreotide or a salt or derivative thereof in an I

bionedbrydeligt, biokompatibelt, polymert bærestof.biodegradable, biocompatible polymeric carrier.

25 I25 I

Det har vist sig, at et hidtil ukendt octreotidsalt er IIt has been found that a novel octreotide salt is I

pamoatet, som er meget stabilt i sådanne formuleringer. Ithe pamoate, which is very stable in such formulations. IN

Den foreliggende opfindelse tilvejebringer i overensstem- IThe present invention provides in accordance with I

30 melse hermed (i) octreotidpamoat og (ii) en fremgangsmåde IAnd (ii) a method I

til fremstilling af octreotidpamoat, hvilken fremgangsmåde Ifor the preparation of octreotide pamoate, which method I

omfatter omsætning af octreotid med embonsyre (eller et Iincludes reacting octreotide with embonic acid (or an I

reaktivt derivat deraf) .reactive derivative thereof).

3 5 En fremgangsmåde til administration af et peptid til et IA method for administering a peptide to an I

individ omfatter parenteral administration af en depotfor- Isubject includes parenteral administration of a custodian

9 DK 175849 B1 mulering som defineret ovenfor til et individ, der har behov for en sådan behandling, især til behandling af akromegali eller brystkræft.9 DK 175849 B1 as defined above for an individual in need of such treatment, especially for the treatment of acromegaly or breast cancer.

5 Lægemiddelstofferne, der anvendes ifølge opfindelsen, er fortrinsvis vandopløselige lægemiddelstoffer, fx peptider.The drug substances used according to the invention are preferably water-soluble drug substances, for example peptides.

Peptiderne, der anvendes ved fremgangsmåderne og i formuleringerne ifølge den foreliggende opfindelse, kan være en 10 calcitonin, fx laksecalcitonin, en lypressin og det naturligt forekommende somatostatin og syntetiske analoger deraf.The peptides used in the methods and in the formulations of the present invention may be a calcitonin, e.g., salmon calcitonin, a lypressin and the naturally occurring somatostatin and synthetic analogs thereof.

Det naturligt forekommende somatostatin er ét af de foretrukne forbindelser og er et tetradecapeptid, der har 15 strukturen:The naturally occurring somatostatin is one of the preferred compounds and is a tetradecapeptide having the structure:

Ala-Gly-Cys-Lys-Asn-Phe-Phe-TrpAla-Gly-Cys-Lys-Asn-Phe-Phe-Trp

Cys-Ser-Thr-Phe-Thr-Lys* 20 Dette hormon frembringes af hypothalamuskirtlen samt andre organer, fx mave-tarmkanalen og medierer sammen med GRF, q.v. neuroreguleringen af hypofysens afgivelse af væksthormon. Ud over inhibering af hypofysens afgivelse af væksthormon er somatostatin en potent inhibitor af et antal 25 systemer, herunder det centrale og perifere nervesystem, mave-tarmsystemet og vaskulær, glat muskulatur. Den hæmmer også afgivelsen af insulin og glucagon.Cys-Ser-Thr-Phe-Thr-Lys * 20 This hormone is produced by the hypothalamic gland as well as other organs, for example the gastrointestinal tract and mediates with GRF, q.v. the neuroregulation of the pituitary release of growth hormone. In addition to inhibiting the pituitary release of growth hormone, somatostatin is a potent inhibitor of a number of 25 systems, including the central and peripheral nervous system, gastrointestinal tract, and vascular smooth muscle. It also inhibits the release of insulin and glucagon.

Udtrykket "somatostatin" omfatter analoger eller derivater 30 deraf. Ved derivater og analoger forstås ligekædede, broforbundne eller cykliske polypeptider, hvor én eller flere aminosyreenheder er udeladt og/eller erstattet med ét eller flere andre aminoradikal(er), og/eller hvor én eller flere funktionelle grupper er erstattet med én eller flere andre 35 funktionelle grupper, og/eller én eller flere grupper er ; erstattet med én eller flere andre isosteriske grupper.The term "somatostatin" includes analogues or derivatives thereof. Derivatives and analogs are understood to be straight-chain, bridged or cyclic polypeptides in which one or more amino acid moieties are omitted and / or replaced by one or more other amino radical (s) and / or where one or more functional groups are replaced by one or more others. functional groups, and / or one or more groups; replaced with one or more other isosteric groups.

Udtrykket dækker generelt alle modificerede derivater af etThe term generally covers all modified derivatives of one

I DK 175849 B1 II DK 175849 B1 I

I 10 II 10 I

I biologisk aktivt peptid, der udviser den kvalitativt sanune IIn biologically active peptide exhibiting the qualitatively sanune I

I virkning som det umodificerede somatostatinpeptid. IIn effect as the unmodified somatostatin peptide. IN

Somatostatinagonistanaloger er således nyttige til erstat- IThus, somatostatin agonist analogs are useful for replacement I

I 5 ning af naturligt somatostatin med hensyn til virkningen IIn addition of natural somatostatin to the effect I

I deraf på regulering af fysiologiske funktioner. IIn that, on the regulation of physiological functions. IN

I Foretrukne kendte somatostatiner er: IPreferred known somatostatin is:

ίο * * Iίο * * I

I a) (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol II a) (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol I

(Generisk navn Octreotid) I(Generic name Octreotide) I

I II I

I 15 b) (D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-ThrNH2 IB) (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-ThrNH2 I

I II I

I c) (D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-TrpNH2 II c) (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-TrpNH2 I

I 20 * II 20 * I

I d) (D)Trp-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH2 II d) (D) Trp-Cys-Phe- (D) Trp-Lys-Thr-Cys-ThrNH2 I

I II I

I e) (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH2 IIn e) (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-ThrNH2 I

IIN

I iI i

f) 3-(2-(Naphthyl)-(D)Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys- If) 3- (2- (Naphthyl) - (D) Ala-Cys-Tyr- (D) Trp-Lys-Val-Cys-I

I ThrNH2 IIn ThrNH2 I

I 30 II 30 I

I g) (D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-0-Nal-NH2 IIn g) (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-O-Nal-NH 2 I

I II I

h) 3-(2-naphtyl)-Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys-ø-Nal-NH2 Ih) 3- (2-Naphthyl) -Ala-Cys-Tyr- (D) Trp-Lys-Val-Cys-N-Nal-NH 2

I 35 II 35 I

i ii i

I i) (D) Phe-Cys-/3-Nal-(D)Trp-Lys-Val-Cys-Thr-NH2 II i) (D) Phe-Cys- / 3-Nal- (D) Trp-Lys-Val-Cys-Thr-NH2 I

11 DK 175849 B1 hvor der i hver af forbindelserne a)-i) er en bro mellem aminosyrerne markeret med * som vist i nedenstående formel.In each of compounds a) -i) there is a bridge between the amino acids marked with * as shown in the formula below.

Andre foretrukne somatostatiner er: 5 ★--------—-----------—-------—— *Other preferred somatostatin is: 5 ★ --------—-----------—-------—

H-Cys-Phe-Phe-(D)Trp-Lys-Thr-Phe-Cys-OHH-Cys-Phe-Phe- (D) Trp-Lys-Thr-Phe-Cys-OH

(jf. Vale et al., Metabolism, 27, supp.l, 139 (1978)).(cf. Vale et al., Metabolism, 27, Suppl., 139 (1978)).

10 * *10 * *

Asn-Phe-Phe-(D)Trp-Lys-Thr-Phe-Gaba (jf. EP 1295 og EP patent nr. 78100994.9).Asn-Phe-Phe- (D) Trp-Lys-Thr-Phe-Gaba (cf. EP 1295 and EP Patent No. 78100994.9).

* * 15 MeAla-Tyr-(D)Trp-Lys-Val-Phe (jf. Verber et al., Life Sciences, 34, 1371-1378 (1984) og EP patent nr. 82106205.6 (offentliggjort som EP 70021)) også kendt som cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe).* * 15 MeAla-Tyr- (D) Trp-Lys-Val-Phe (cf. Verber et al., Life Sciences, 34, 1371-1378 (1984) and EP Patent No. 82106205.6 (published as EP 70021)) also known as cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe).

20 * * NMePhe-His-(D)Trp-Lys-Val-Ala (jf. R. F. Nutt et al., Klin. Wochenschr. (1986) 64 (suppl. VII) 25 * *20 * * NMePhe-His- (D) Trp-Lys-Val-Ala (cf. R. F. Nutt et al., Clinical Weekly (1986) 64 (Suppl. VII) 25 * *)

H-Cys-His-His-Phe-Phe-(D)Trp-Lys-Thr-Phe-Thr-Ser-Cys-°HH-Cys-His-His-Phe-Phe- (D) Trp-Lys-Thr-Phe-Thr-Ser-Cys- ° H

(jf. EP-A-200,188) 30 * ’ * X-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 og 35 * * X-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol hvor X er et kationisk "anker",(cf. EP-A-200,188) 30 * * X-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 and 35 * X-Cys-Phe-D-Trp-Lys-Thr Cys-Thr-ol where X is a cationic "anchor",

DK 175849 B1 IDK 175849 B1 I

især Iespecially I

Ac-hArg(Et2)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-NH2 IAc-hArg (Et2) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-NH2 I

5 (jf. EP 0363589A2) I5 (cf. EP 0363589A2) I

hvor der i de ovennævnte aminosyrer er en bro mellem amino- Iwherein in the above amino acids there is a bridge between amino-I

syrerne markeret med *. Ithe acids marked with *. IN

I nærværende beskrivelse og krav henvises der specifikt til IIn this specification and claims, reference is made specifically to I

indholdet af alle de ovennævnte publikationer, herunder de Ithe contents of all the above publications, including those of I

10 særlige forbindelser. I10 special compounds. IN

Udtrykket "derivat" omfatter også de tilsvarende derivater IThe term "derivative" also includes the corresponding derivatives I

med en sukkerrest. Iwith a sugar residue. IN

Når somatostatiner har en sukkerrest, er denne fortrinsvis IWhen somatostatin has a sugar residue, it is preferably I

forbundet med én N-terminal aminogruppe og/eller med mindst Ilinked to one N-terminal amino group and / or at least I

15 én aminogruppe, der er til stede i pept ids idekæden, især I15 is one amino group present in the peptide id chain, especially I

til en N-terminal aminogruppe. Sådanne forbindelser og Ito an N-terminal amino group. Such compounds and I

fremstillingen deraf er beskrevet fx i WO 88/02756. Ithe preparation thereof is described, for example, in WO 88/02756. IN

I Udtrykket "octreotidderivater" omfatter sådanne, der har en IThe term "octreotide derivatives" includes those having an I

gruppe Igroup I

I 20 II 20 I

-D-Phe-Cys-Phe-DTrp-Lys-Thr-Cys- med en bro mellem Cys- I-D-Phe-Cys-Phe-DTrp-Lys-Thr-Cys- with a bridge between Cys-I

resterne. Iresidues. IN

Særligt foretrukne derivater er N“-[a-glucosyl-{l-4-deoxy- ι IParticularly preferred derivatives are N “- [α-glucosyl- (1-4-deoxy-ι I)

fructosyl]-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol og NQ-[/9- Ifructosyl] -DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol and NQ - [/ 9- I

25 deoxyfructosyl]-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol, der I(Deoxyfructosyl] -DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol, which I

H hver har en bro mellem -Cys-grupperne, især i form af IH each has a bridge between the -Cys groups, especially in the form of I

H acetatsaltet, og som er beskrevet i henholdsvis eksempel 2 IH acetate salt and described in Example 2 I, respectively

og 1 i ovennævnte ansøgning. Iand 1 in the above application. IN

Somatostatinerne kan foreligge fx i fri form, saltform IThe somatostatin may be present, for example, in free form, salt form I

30 eller i form af komplekser deraf. Syreadditionssalte kan I30 or in the form of complexes thereof. Acid addition salts can be

13 DK 175849 B1 være dannet med fx organiske syrer, polymere syrer og uorganiske syrer. Syreadditionssalte omfatter fx hydro-chloridet og acetater. Komplekser er fx dannet ved fra somatostatiner efter tilsætning af uorganiske stoffer, fx 5 uorganiske salte eller hydroxider såsom Ca- og Zn-salte, og/eller tilsætning af polymere organiske stoffer.13 DK 175849 B1 may be formed with, for example, organic acids, polymeric acids and inorganic acids. Acid addition salts include, for example, the hydrochloride and acetates. Complexes are formed, for example, from somatostatin after addition of inorganic substances, for example 5 inorganic salts or hydroxides such as Ca and Zn salts, and / or addition of polymeric organics.

Acetatsaltet er et foretrukket salt til sådanne formuleringer, især til mikropartikler, idet det medfører en reduktion af indledende pludselig afgivelse af lægemiddelstof.The acetate salt is a preferred salt for such formulations, especially for microparticles, in that it results in a reduction of initial sudden release of drug substance.

10 Den foreliggende opfindelse angår også pamoatsaltet, der er nyttigt, især til implanterbare indretninger, og fremgangsmåde til fremstilling deraf.The present invention also relates to the pamoate salt which is useful, especially for implantable devices, and to the method of preparation thereof.

Pamoatet kan vindes på konventionel måde, fx ved omsætning af embonsyre (2,2'-dihydroxy-l,l'-dinaphthylmethan-3,3'-15 dicarboxylsyre) med octreotid fx i fri baseform. Omsætningen kan udføres i et polært opløsningsmiddel, fx ved stuetemperatur.The pamoate can be obtained in conventional manner, for example, by reacting embonic acid (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylic acid) with octreotide, for example, in free base form. The reaction may be carried out in a polar solvent, for example at room temperature.

Somatostatinerne er indikeret til anvendelse i behandlingen af sygdomme, hvor der forudses langvarig anvendelse af 20 lægemiddelstoffet, fx sygdomme med en ætiologi, der omfatter eller er forbundet med for stor væksthormonsekretion, fx i behandlingen af akromegali, til anvendelse i behandlingen af gastrointestinale sygdomme, fx i behandlingen eller profylaksen af peptisk ulcus, enterokutane og 25 pankreatikokutane fistler, irritabelt tarmsyndrom, dumpingsyndrom, vanddiarrésyndrom, akut pankreatitis og ga-stroenteropatiske endokrine tumorer (fx vipomer, GRFomer, glucagonomer, insulinomer, gastrinomer og karcinoide tumorer) samt gastrointestinale blødninger, brystkræft og 30 komplikationer relateret til diabetes.The somatostatin is indicated for use in the treatment of diseases wherein long-term use of the drug is envisaged, e.g. in the treatment or prophylaxis of peptic ulcer, enterocutaneous and 25 pancreaticocutaneous fistulas, irritable bowel syndrome, dumping syndrome, water diarrhea syndrome, acute pancreatitis and gastroenteropathic endocrine tumors (e.g. 30 complications related to diabetes.

Det polymere bærestof kan være fremstillet ud fra biokompatible og bionedbrydelige polymerer, fx lineære polyestre, forgrenede polyestre, som er lineære kæder, der stråler ud fra en polyolgruppe, fx glucose; andre estre er estre afThe polymeric carrier may be made from biocompatible and biodegradable polymers, e.g., linear polyesters, branched polyesters, which are linear chains radiating from a polyol group, e.g., glucose; other esters are esters of

I DK 175849 B1 II DK 175849 B1 I

I 14 II 14 I

I polymælkesyre, polyglycolsyre, polyhydroxysmørsyre, polyca- IIn polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polyca- I

I prolactone, polyalkylenoxalat, polyalkylenglycolestre af IIn prolactone, polyalkylene oxalate, polyalkylene glycol esters of I

I syrer fra Krebs' cyklus, fx citronsyre og lignende, og IIn acids from the Krebs cycle, eg citric acid and the like, and I

I copolymerer deraf. IIn copolymers thereof. IN

I 5 De foretrukne polymerer er de lineære polyestere og de for- IThe preferred polymers are the linear polyesters and the preferred ones

I grenede polyestre. IIn branched polyesters. IN

I De lineære polyestere kan fremstilles ud fra a-hydroxy- II The linear polyesters can be prepared from α-hydroxy-I

I carboxylsyrer, fx mælkesyre og glycolsyre, ved kondensering IIn carboxylic acids, eg lactic acid and glycolic acid, by condensation I

I af lactondimererne, jf. fx US 3,773,919. II of the lactone dimers, cf., for example, US 3,773,919. IN

I 1 II 1 I

I 10 Lineære polylactid-co-glycolider, som fortrinsvis anvendes IIn 10 Linear polylactide co-glycolides which are preferably used

ifølge opfindelsen, har hensigtsmæssigt en molekylvægt på Iaccording to the invention suitably has a molecular weight of 1

I mellem 25.000 og 100.000 og en polydispersibilitet Mw/Mn IIn between 25,000 and 100,000 and a polydispersibility Mw / Mn I

I fx på mellem 1,2 og 2. IFor example, between 1.2 and 2. I

De forgrenede estere, der fortrinsvis anvendes ifølge op- IThe branched esters preferably used according to op

I 15 findelsen, kan fremstilles under anvendelse af polyhydroxy- IIn the finding, can be prepared using polyhydroxy-I

I forbindelser, fx polyol, fx glucose eller mannitol, som IIn compounds, e.g., polyol, e.g., glucose or mannitol, such as I

I initiator. Disse polyolestre er kendte og beskrevet i IIn the initiator. These polyol esters are known and described in I

I GB 2.145.422 B. Polyolen indeholder mindst 3 hydroxygrupper IIn GB 2.145.422 B. The polyol contains at least 3 hydroxy groups I

og har en molekylvægt på op til 20.000, idet mindst 1, Iand has a molecular weight of up to 20,000, with at least 1, 1

20 fortrinsvis mindst 2, fx gennemsnitligt 3 af polyolens IPreferably at least 2, e.g., an average of 3 of polyol I

I hydroxygrupper foreligger i form af estergrupper, som IIn hydroxy groups are in the form of ester groups which I

indeholder polylactid- eller co-polylactidkæder. Der an- Icontains polylactide or co-polylactide chains. There- I

vendes typisk 0,2% glucose til initiering af polymerise- Itypically 0.2% glucose is inverted to initiate polymerization

ring. De forgrenede polyesteres struktur er stjerneformede. Iring. The structure of the branched polyesters is star-shaped. IN

I 25 De foretrukne polyesterkæder i de lineære og stjerneformede ; II 25 The preferred polyester chains in the linear and star-shaped; IN

I polymerforbindelser, der fortrinsvis anvendes ifølge opfin- I IIn polymer compounds preferably used according to the invention

delsen, er copolymerer af a-carboxylsyregrupper, mælkesyre Ithe copolymers of α-carboxylic acid groups, lactic acid I

og glycolsyre, eller af lactondimerer. Molforholdet lac- Iand glycolic acid, or of lactone dimers. The molar ratio lac- I

H tid:glycolid ligger på fra ca. 75:25 til 25:75, fx fra IH time: glycolide ranges from approx. 75:25 to 25:75, e.g.

I 30 60:40 til 40:60, hvor de mest foretrukne er fra 55:45 til IIn 30 60:40 to 40:60, the most preferred being from 55:45 to 1

45:55, fx fra 55:45 til 50:50. I45:55, for example, from 55:45 to 50:50. IN

De stjerneformede polymerer kan fremstilles ved omsætning IThe star-shaped polymers can be prepared by reaction I

af en polyol med et lactid og fortrinsvis også et glycolid Iof a polyol with a lactide and preferably also a glycolide I

^— - -1 DK 175849 B1 15 ved forhøjet temperatur i nærværelse af en katalysator, hvilket muliggør en ringåbningspolymerisation.At elevated temperature in the presence of a catalyst, which allows a ring opening polymerization.

I Det har vist sig, at én fordel ved den stjerneformede poly- | mertype i formuleringerne ifølge den foreliggende opfindelse I ' 5 er, at dens molekylvægt kan være relativt høj, hvilket giver fysisk stabilitet, fx en vis hårdhed, til implanter-bare indretninger og mikropartikler, hvilket hindrer, at de klæber sammen, selv om der er relativt korte polylactid-; kæder til stede, hvilket medfører en regulerbar bioned- 10 brydningshastighed af polymeren i området fra flere uger til 1 til 2 måneder og en tilsvarende forlænget afgivelse af peptidet, hvilket gør en depotformulering, der er fremstillet deraf, egnet til fx én måneds afgivelse.It has been found that one advantage of the star-shaped poly | The mercury type of the formulations of the present invention I '5 is that its molecular weight can be relatively high, providing physical stability, e.g., some hardness, to implantable devices and microparticles, preventing them from sticking together even though there is relatively short polylactide; chains, which result in an adjustable biodegradation rate of the polymer in the range of several weeks to 1 to 2 months and a correspondingly prolonged release of the peptide, making a depot formulation made thereof suitable for, for example, one month's release.

De stjerneformede polymerer har fortrinsvis hovedsageligt 15 en molekylvægt Mw i området på fra ca. 10.000 til 200.000, fortrinsvis fra 25.000 til 100.000, især fra 35.000 til 60.000 og en polydispersitet fx på fra 1,7 til 3,0, fx fra 2.0 til 2,5. Grænseviskositeten af de stjerneformede polymerer Mw 35.000 og Mw 60.000 er henholdsvis 0,36 og 0,51 20 dl/g i chloroform. En stjerneformet polymer med Mw 52.000 har en viskositet på 0,475 dl/g i chloroform.The star-shaped polymers preferably have substantially a molecular weight Mw in the range of from about. 10,000 to 200,000, preferably from 25,000 to 100,000, especially from 35,000 to 60,000 and a polydispersity, for example, of from 1.7 to 3.0, for example from 2.0 to 2.5. The intrinsic viscosity of the star-shaped polymers Mw 35,000 and Mw 60,000 is 0.36 and 0.51 20 dl / g in chloroform, respectively. A star-shaped polymer with Mw 52,000 has a viscosity of 0.475 dl / g in chloroform.

I forbindelse med den foreliggende opfindelse anses udtrykkene "mikrosfære, mikrokapsel og mikropartikel" for at være ækvivalente eller indbyrdes udskiftelige og betegner 25 peptidernes indkapsling ved hjælp af polymeren, fortrinsvis med peptidet fordelt i polymeren, som derved er en matrix for peptidet. I det tilfælde anvendes fortrinsvis udtrykkene mikrosfære eller mere generelt mikropartikel.For purposes of the present invention, the terms "microsphere, microcapsule, and microparticle" are considered to be equivalent or interchangeable, and denote the encapsulation of the peptides by the polymer, preferably with the peptide distributed in the polymer, which is thereby a matrix for the peptide. In that case, the terms microsphere or, more generally, microparticle are preferably used.

Ved at anvende faseadskillelsesteknikken ifølge den fore-30 liggende opfindelse kan formuleringerne ifølge opfindelsen fremstilles fx ved opløsning af det polymere bærestofmateriale i et opløsningsmiddel, som ikke er opløsningsmiddel for peptidet, efterfulgt af tilsætning af en opløsning af peptidet og dispersion deraf i det polymere solventpræ-By using the phase separation technique of the present invention, the formulations of the invention can be prepared, for example, by dissolving the polymeric carrier material in a non-solvent solvent for the peptide, followed by adding a solution of the peptide and dispersing thereof in the polymeric solvent preparation.

I DK 175849 B1 II DK 175849 B1 I

I 16 II 16 I

I parat. Et faseinduceringsmiddel, fx et siliconepræparat, IReady. A phase inducing agent, e.g., a silicone composition, I

I tilsættes derefter for at fremkalde peptidindkapsling ved II is then added to induce peptide encapsulation at I

I hjælp af polymeren. IWith the help of the polymer. IN

I Den pludselige afgivelse af lægemiddelstof ("burst") kan IIn the sudden release of drug ("burst") you can

I 5 være væsentligt nedsat ved in situ udfældning af ultrafine II 5 be substantially reduced by in situ precipitation of ultrafine I

I lægemiddelstofpartikler ved tilsætning af en lægemiddel- IIn drug particles by the addition of a drug I

I stofopløsning til polymeropløsningen før faseadskillelse. IIn substance solution to the polymer solution before phase separation. IN

I Den tidligere kendte fremgangsmåde omfatter tilsætning af IIn the prior art method, the addition of I

I tørre partikler direkte til polymeropløsningen. IIn dry particles directly to the polymer solution. IN

I 10 Den terapeutiske varighed af peptidafgivelsen kan øges ved, IThe therapeutic duration of the peptide release may be increased by, I

I at mikropartiklerne hærdes/vaskes med en buffer/heptan- IIn that the microparticles are cured / washed with a buffer / heptane I

I emulsion. Den tidligere kendte fremgangsmåde omfatter et IIn emulsion. The prior art method comprises an I

I hærdningstrin efterfulgt af enten ingen efterfølgende vask IIn curing steps followed by either no subsequent washing I

I eller et særskilt vandbaseret vasketrin. IIn or a separate water-based washing step. IN

I 15 En emulsion af typen olie-i-vand (= o/v) kan anvendes til II An oil-in-water emulsion (= o / v) can be used for I

vask og hærdning af mikrosfærerne og til at fjerne ikke- Iwashing and curing the microspheres and removing non-I

indkapslet peptid. Vaskningen bidrager til fjernelse af Iencapsulated peptide. The wash contributes to the removal of I

I ikke-indkapslet peptid fra mikrosfærernes overflade. Fjer- IIn non-encapsulated peptide from the surface of the microspheres. Removes I

I nelse af overskydende peptid fra mikrosfærerne nedsætter IIn the formation of excess peptide from the microspheres, I decrease

20 den indledende pludselige afgivelse af lægemiddelstof, I20 the initial sudden release of drug substance, I

hvilket er karakteristisk for mange konventionelle ind- Iwhich is characteristic of many conventional ind

I kapslingsformuleringer. Således muliggør de foreliggendeIn capsule formulations. Thus, they enable the present

I mikrosfæreformuleringer en mere ensartet lægemiddelstofaf- IIn microsphere formulations, a more uniform drug substance I

givelse over et tidsrum. Igiving over a period of time. IN

I 25 Emulsionen bidrager også til fjernelsen af tilbageværende IThe emulsion also contributes to the removal of residual I

polymeropløsningsmiddel og siliconevæske. Emulsionen kan Ipolymer solvent and silicone fluid. The emulsion can be

I sættes til polymerpeptidblandingen, eller blandingen kan IYou are added to the polymer peptide mixture or the mixture can be I

I sættes til emulsionen. Det foretrækkes, at polymerpeptid- IYou are added to the emulsion. It is preferred that polymer peptide I

blandingen sættes til emulsionen. Ithe mixture is added to the emulsion. IN

I 30 O/w-emulsionen kan fremstilles under anvendelse af en IThe 30 o / w emulsion can be prepared using an I

emulgator såsom sorbitanmonooleat (Span SO ICI Corp.) og Iemulsifier such as sorbitan monooleate (Span SO ICI Corp.) and I

I lignende til dannelse af en stabil emulsion. Emulsionen kan IIn the like to form a stable emulsion. The emulsion can be

I ' buf res med en buffer, der ikke er skadelig for peptidet og II am buffered with a buffer which is not deleterious to the peptide and I

17 DK 175849 B1 polymermatrixmaterialet. Bufferen kan have en pH-værdi på fra 2 til 8, især foretrækkes pH 4. Bufferen kan fremstilles af sure buffere såsom phosphatbuffer, acetatbuffer og lignende. Kun vand kan erstatte bufferen.17 DK 175849 B1 polymer matrix material. The buffer may have a pH value of from 2 to 8, especially preferably pH 4. The buffer may be made of acidic buffers such as phosphate buffer, acetate buffer and the like. Only water can replace the buffer.

5 Heptan, hexan og lignende kan anvendes som den organiske fase i bufferen.Heptane, hexane and the like can be used as the organic phase in the buffer.

Emulsionen kan indeholde dispersionsmidler såsom silico-neolie.The emulsion may contain dispersing agents such as silicone oil.

En foretrukken emulsion kan omfatte heptan, phosphatbuffer 10 på pH 4, siliconeolie og sorbitanmonooleat. Når en indledende lægemiddelstofafgivelse er ønskelig, kan et enkelt hærdningstrin med ikke-opløsningsmiddel erstatte emulsionshærdningen. Heptan, hexan og lignende kan anvendes som opløsningsmiddel .A preferred emulsion may include heptane, pH 4 phosphate buffer 10, silicone oil and sorbitan monooleate. When an initial drug release is desired, a single non-solvent curing step can replace the emulsion cure. Heptane, hexane and the like can be used as a solvent.

15 Andre alternativer til o/w-emulsionen kan anvendes til hærdning af mikrokapsler, fx:Other alternatives to the o / w emulsion can be used to cure microcapsules, for example:

Opløsningsmiddel plus emulgator til hærdning af mikrokaps-lerne uden vask; og opløsningsmiddel plus emulgator til hærdning efterfulgt af et særskilt vasketrin.Solvent plus emulsifier for curing the microcapsules without washing; and solvent plus emulsifier for curing followed by a separate washing step.

20 O/w-emulsionen kan anvendes uden dispersionsmiddel. Dispersionsmidlet forhindrer dog den aggregering af de tørre mikrokapselpartikler, der skyldes statisk elektricitet, og det bidrager til at nedsætte niveauet af tilbageblivende opløsningsmiddel.The 20 w / w emulsion can be used without dispersant. However, the dispersant prevents the aggregation of the dry microcapsule particles caused by static electricity, and it helps to reduce the level of residual solvent.

25 Eksempler på opløsningsmiddel for polymermatrixmaterialet omfatter methylenchlorid, chloroform, benzen, ethylacetat og lignende. Peptidet opløses fortrinsvis i et alkoholisk opløsningsmiddel, fx methanol, som er blandbart med polymeropløsningsmidlet .Examples of solvent for the polymer matrix material include methylene chloride, chloroform, benzene, ethyl acetate and the like. The peptide is preferably dissolved in an alcoholic solvent, e.g., methanol, which is miscible with the polymer solvent.

I DK 175849 B1 II DK 175849 B1 I

I 18 II 18 I

I II I

i Ii

Faseinducermgsmidlerne (koacervationsmidler) er opløs- IThe phase inducers (coacervatives) are soluble

I ningsmidler, som er blandbare med polymer-lægemiddelstof- IIn admixtures which are miscible with polymer-drug substance I

I , blandingen, og som forårsager, at de embryoniske mikro- II, the mixture, which causes the embryonic micro- I

I i kapsler dannes før hærdning; siliconeolier er foretrukne II in capsules are formed before curing; silicone oils are preferred

I I 5 faseinduceringsmidler. II In 5 phase inducers. IN

I O/w-emulsionen kan fremstilles på konventionel måde under IThe O / w emulsion can be prepared in a conventional manner under I

I anvendelse af heptan, hexan og lignende til de organiske IUsing heptane, hexane and the like for the organic I

I faser. IIn stages. IN

10 I10 I

I Mikropartiklerne kan også fremstilles ifølge den almindeligt IThe microparticles may also be prepared according to the usual I

I kendte spraytørrings fremgangsmåde . Ifølge denne fremgangsmåde IIn known spray drying method. According to this method

I blandes somatostatin eller en opløsning af peptidet i et IYou mix somatostatin or a solution of the peptide in an I

I organisk opløsningsmiddel, fx methanol, i vand eller i en IIn organic solvent, eg methanol, in water or in an I

I 15 buffer, fx med en pH-værdi på 3-8, og en opløsning af poly- IIn buffer, eg with a pH of 3-8, and a solution of poly-I

I meren i et organisk opløsningsmiddel, der ikke er bland- IIn the lake in an organic solvent which is not mixed I

I bart med ovennævnte, fx methylenchlorid. IIn the case of the above, for example methylene chloride. IN

I Den dannede opløsning, suspension eller emulsion sprayes IThe resulting solution, suspension or emulsion is sprayed

I ; 20 derefter i en luftstrøm, fortrinsvis i varm luft. De frem- II; 20 then in an air stream, preferably in hot air. They forward

I komne mikropartikler opsamles, fx ved hjælp af en cyklon, IIn microparticles are collected, for example, by means of a cyclone, I

og vaskes om ønsket, fx i en bufferopløsning med fx en pH- Iand, if desired, washed, for example, in a buffer solution having, for example, a pH-I

H værdi på 3,0-8,0, fortrinsvis pH 4,0, eller i destilleret IH value of 3.0-8.0, preferably pH 4.0, or in distilled I

vand og tørres i vakuum, fx ved en temperatur på 20-40eC. Iwater and dried in vacuo, for example at a temperature of 20-40 ° C. IN

I 25 Vasketrinet kan anvendes, hvis partiklerne udviser en IThe washing step can be used if the particles exhibit an I

pludselig afgivelse af lægemiddelstof in vivo. og omfanget Isudden release of drug substance in vivo. and the scope I

I af denne pludselige afgivelse af lægemiddelstof er uønsket. IIn this sudden release of drug substance is undesirable. IN

Som buffer kan der anvendes en acetatbuffer. IAs an buffer, an acetate buffer can be used. IN

30 Der kan i overensstemmelse hermed vindes mikropartikler, IAccordingly, microparticles, I

der in vivo udviser en forbedret somatostatinafgivelsespro- Ishowing in vivo an improved somatostatin delivery process

I fil- IIn file I

I Opfindelsen tilvejebringer således yderligere en formu- IThus, the invention further provides a formulation

I 35 lering med forlænget afgivelse, hvilken formulering er IIn prolonged release gelation, which formulation is I

DK 175849 Bl * 19 fremstillet ved at blande somatostatin eller en opløsning af somatostatin i methanol eller vand eller en buffer med en pH-værdi på 3-8 med en opløsning af polylactid-co-glyco-lid i methylenchlorid og spraye den dannede somatostatin-5 opløsning, -emulsion eller -suspension i polymeropløsningen i en varm luftstrøm, opsamle mikros faer erne og vaske dem i en bufferopløsning med en pH-vaerdi på 3,0-8,0 eller i destilleret vand og tørre dem i vakuum ved en temperatur i området fra 20eC til 40°C. I sammenligning med mikropartik-10 ler, der er fremstillet ifølge faseadskillelsesteknikken, indeholder de ikke siliconeolie, end ikke spor deraf, da siliconeolie ikke anvendes ved spraytørringsteknikken.Prepared by mixing somatostatin or a solution of somatostatin in methanol or water or a buffer having a pH of 3-8 with a solution of polylactide-co-glyco-lid in methylene chloride and spraying the resulting somatostatin. 5 solution, emulsion or suspension in the polymer solution in a hot air stream, collect the microspheres and wash them in a buffer solution with a pH of 3.0-8.0 or in distilled water and dry them in vacuo at a temperature in the range of 20 ° C to 40 ° C. Compared to microparticles made according to the phase separation technique, they do not contain any silicone oil, nor traces thereof, since silicone oil is not used in the spray drying technique.

Formuleringerne ifølge opfindelsen kan også fremstilles under anvendelse af en tripelemulsionsfremgangsmåde. Ved en 15 typisk teknik opløses peptid, fx octreotid, i et hensigtsmæssigt opløsningsmiddel, fx vand, og emulgeres grundigt i en opløsning af polymeren, fx 50/50 poly(D,L-lactid-co-glycolid)glucose i et opløsningsmiddel, som ikke er et opløsningsmiddel for peptidet, fx i methylenchlorid. Eksemp-20 ler på opløsningsmidler for polymermatrixmaterialet omfatter methylenchlorid, chloroform, benzen, ethylacetat og lignende. Den resulterende vand/olie-emulsion (w/o) emulgeres yderligere i et overskud af vand, der indeholder en emulgerende substans, fx et anionisk eller ikke-ionisk 25 overfladeaktivt middel eller lecithin eller et beskyttel-seskolloid, fx gelatine, dextrin, carboxymethylcellulose, polyvinylpyrrolidon, polyvinylalkohol, hvilken substans giver kontinuerlig dannelse af tripel-emulsionen (w/o/w). Mikropartiklerne dannes ved spontan udfældning af polymeren 30 og hærdes ved afdampning af det organiske opløsningsmiddel. Gelatine medvirker til at forhindre agglomeration af mi-krosfærerne. Efter sedimentation af mikropartiklerne dekanteres supernatanten, og mikropartiklerne vaskes med vand og derefter med acetatbuffer. Mikropartiklerne filtreres og 35 tørres derefter.The formulations of the invention can also be prepared using a triple emulsion method. In a typical technique, peptide, e.g., octreotide, is dissolved in a suitable solvent, e.g., water, and thoroughly emulsified in a solution of the polymer, e.g., 50/50 poly (D, L-lactide-co-glycolide) glucose in a solvent which is not a solvent for the peptide, for example in methylene chloride. Examples of solvents for the polymer matrix material include methylene chloride, chloroform, benzene, ethyl acetate and the like. The resulting water / oil emulsion (w / o) is further emulsified in an excess of water containing an emulsifying substance, e.g. an anionic or nonionic surfactant or lecithin or a protective colloid, e.g., gelatin, dextrin, carboxymethyl cellulose , polyvinylpyrrolidone, polyvinyl alcohol which provides continuous formation of the triple emulsion (w / o / w). The microparticles are formed by spontaneous precipitation of the polymer 30 and cured by evaporation of the organic solvent. Gelatin helps prevent agglomeration of the microspheres. After sedimentation of the microparticles, the supernatant is decanted and the microparticles washed with water and then with acetate buffer. The microparticles are filtered and then dried.

DK 175849 B1 IDK 175849 B1 I

20 I20 I

Peptidet kan også dispergeres direkte i polymeropløsningen, IThe peptide can also be directly dispersed in the polymer solution, I

hvorefter den resulterende suspension blandes med den Iafter which the resulting suspension is mixed with the I

gelatineholdige vandfase. Igelatinous aqueous phase. IN

Tripelemulsionsfremgangsmåden er kendt fra US 4,652,441. IThe triple emulsion method is known from US 4,652,441. IN

5 Ifølge dette patentskrift blandes i et første trin enAccording to this patent, in a first step one is mixed

lægemiddelstofopløsning (1) i et opløsningsmiddel, fx Idrug solution (1) in a solvent, e.g.

somatostatin i vand (spalte 2, 1. 31-32), grundigt med et Isomatostatin in water (column 2, 1. 31-32), thoroughly with an I

overskud af en polylactid-co-glycolidopløsning (2) i et Iexcess of a polylactide co-glycolide solution (2) in an I

andet opløsningsmiddel, i hvilket det første opløsnings- Isecond solvent in which the first solvent I

10 middel ikke er opløseligt, fx methylenchlorid, hvilket I10 is not soluble, for example methylene chloride, which I

giver en vand-i-olie-emulsion (w/o) (3) af fine lægemiddel- Iprovides a water-in-oil emulsion (w / o) (3) of fine drug I

stofholdige dråber af (1) i opløsning (2). I opløsning (1) Idrug-containing drops of (1) in solution (2). In solution (1) I

opløses yderligere en såkaldt lægemiddelstoftilbageholdende Ianother so-called drug retention I is dissolved

substans (spalte 1, 1. 31), fx gelatine, albumin, pectin Isubstance (column 1, 1. 31), e.g., gelatin, albumin, pectin I

15 eller agar. IOr agar. IN

I et andet trin øges viskositeten af den indre fase (l) på IIn another step, the viscosity of the inner phase (1) is increased to 1

hensigtsmæssig måde såsom ved opvarmning, afkøling, ændringappropriate way such as by heating, cooling, changing

af pH-værdien, tilsætning af metalioner eller tværbinding Iof the pH, addition of metal ions or cross-linking I

af fx gelatine med en aldehyd. Iof, for example, gelatin with an aldehyde. IN

20 I et tredje trin blandes et overskud af vand grundigt med IIn a third step, an excess of water is thoroughly mixed with I

w/o-emulsionen (3), (spalte 7, 1. 52-54), hvilket giver en Iw / o emulsion (3), (column 7, 1. 52-54), giving an I

tredobbeltemulsion af w/o/w-typen. I overskuddet af vand kan der, om ønsket, findes et såkaldt emulgerende middeltriple emulsion of the w / o / w type. In the excess of water, a so-called emulsifying agent can be found, if desired

(spalte 7, 1. 56) valgt fra gruppen bestående af fx et I(column 7, 1. 56) selected from the group consisting of, for example, an I

25 anionisk eller ikke-ionisk overfladeaktivt middel eller fx I25 anionic or nonionic surfactant or e.g.

polyvinylpyrrolidon, polyvinylalkol eller gelatine.polyvinylpyrrolidone, polyvinyl alcohol or gelatin.

I et fjerde trin udsættes w/o/w-emulsionen for "i-vand- IIn a fourth step, the w / o / w emulsion is exposed to "i-water-I

I tørring” (1. 52). Dette betyder, at det organiske opløs- IIn drying ”(1.52). This means that the organic solution

I ningsmiddel i olielaget desorberes til dannelse af mikro- IDesiccant in the oil layer is desorbed to form micro-I

30 partikler. Desorptionen udføres på en måde, der er kendt I30 particles. The desorption is carried out in a manner known in the art

I per se. (spalte 8, 1. 3-5), fx ved sænkning af trykket II per se. (column 8, 1. 3-5), for example by lowering the pressure I

I under omrøring (spalte 8, 1. 5-7) eller fx ved at blæse IIn stirring (column 8, 1, 5-7) or eg by blowing I

I nitrogengas gennem olielaget (fx methylenchlorid) (1. 19). IIn nitrogen gas through the oil layer (e.g. methylene chloride) (1. 19). IN

I De dannede mikropartikler isoleres ved centrifugering eller IThe microparticles formed are isolated by centrifugation or I

21 DK 175849 B1 filtrering (1. 26-27), og de komponenter, der ikke er inkorporeret i polymeren, fjernes ved vask med vand (1.Filtration (1.26-27) and the components not incorporated in the polymer are removed by washing with water (1.

29). Om ønsket opvarmes mikropartiklerne under reduceret tryk for at opnå bedre fjernelse af vand og opløsnings-5 middel (fx methylenchlorid fra mikropartikelvæggen (1.29). If desired, the microparticles are heated under reduced pressure to achieve better removal of water and solvent (e.g., methylene chloride from the microparticle wall (1).

30-32)).30-32)).

Selv om ovennævnte fremgangsmåde er tilfredsstillende til fremstillingen af formuleringerne ifølge opfindelsen, er den ovennævnte såkaldte lægemiddelstoftilbageholdende 10 substans, fx gelatine, albumin, pectin eller agar, dog stadig indeholdt i de resulterende mikropartikler.Although the above process is satisfactory for the preparation of the formulations of the invention, the aforementioned so-called drug-retaining substance, e.g., gelatin, albumin, pectin or agar, is still contained in the resulting microparticles.

Det har nu vist sig, at der endog kan opnås tilfredstillende mikropartikler, når tilsætningen af lægemiddelstoftilba- i geholdende substans undgås (= i opløsning (1), og der 15 undgås det trin, der bevirker forøgelse af den indre fases viskositet ved overskud af vand i den tredobbelte w/o/w-emulsion, og der bibeholdes foranstaltningen med tilsætning ; af en emulgerende substans eller et beskyttelseskolloid, fx gelatine. Desuden indeholder mikropartiklerne ingen læge-20 middelstoftilbageholdende substans og kun en meget lille mængde methylenchlorid.It has now been found that satisfactory microparticles can be obtained even when the addition of drug additive in containing substance is avoided (= in solution (1) and the step of increasing the viscosity of the internal phase is avoided by excess water). in the triple w / o / w emulsion, and the measure is maintained with the addition of an emulsifying substance or a protective colloid, e.g., gelatin, In addition, the microparticles contain no drug retaining substance and only a very small amount of methylene chloride.

Opfindelsen tilvejebringer derfor en fremgangsmåde til fremstilling af mikropartikler, der er fremstillet ved grunding blanding af:The invention therefore provides a process for preparing microparticles prepared by priming blend of:

25 a) en opløsning af et lægemiddelstof, fortrinsvis somatostatin, især octreotid, i et vandigt medium, for- IA) a solution of a drug substance, preferably somatostatin, especially octreotide, in an aqueous medium,

trinsvis vand eller en buffer, fortrinsvis i et vægt/- j volumenforhold på 0,8-4,0 g/1-120 ml, især 2,5/10 og i ! en buffer med en pH-værdi på 3-8, især en acetatbuf-30 fer, og b) en opløsning af en polymer, fortrinsvis et polylactid-co-glycolid som nævnt ovenfor, i et organisk opløsningsmiddel, der ikke er blandbart med det vandigestepwise water or a buffer, preferably in a weight / volume ratio of 0.8-4.0 g / 1-120 ml, especially 2.5 / 10 and i. a buffer having a pH of 3-8, especially an acetate buffer, and b) a solution of a polymer, preferably a polylactide co-glycolide as mentioned above, in an organic solvent which is not miscible with it. aqueous

DK 175849 B1 IDK 175849 B1 I

medium, fx methylenchlorid, fortrinsvis i et vægt/- Hmedium, eg methylene chloride, preferably in a weight / - H

volumenforhold på 40 g/90-400 ml, især 40/100, for- Ivolume ratio of 40 g / 90-400 ml, especially 40/100, for I

trinsvis på en sådan måde, at vægt/vægtforholdet Hstepwise in such a way that the weight / weight ratio H

mellem lægemiddelstoffet og polymeren ligger på fra Hbetween the drug substance and the polymer is from H

5 1/10 til 50, især 1/16, og volumen/volumenforholdet af H5 1/10 to 50, especially 1/16, and the volume / volume ratio of H

vandigt medium/organisk opløsningsmiddel er 1/1,5-30, Iaqueous medium / organic solvent is 1 / 1.5-30, 1

især 1/10, og grundig blanding af w/o-emulsionen fra Hespecially 1/10, and thorough mixing of the w / o emulsion from H

a) i b) sammen meda) in b) together with

10 c) et overskud af et vandigt medium, fortrinsvis vand HC) an excess of an aqueous medium, preferably water H

eller en buffer, fx en acetat- eller phosphatbuffer, Hor a buffer, e.g., an acetate or phosphate buffer, H

fortrinsvis med en pH-værdi på 3-8, indeholdende en Hpreferably with a pH of 3-8 containing an H

emulgerende substans eller et beskyttelseskolloid, Hemulsifying substance or a protective colloid, H

fortrinsvis i en koncentration på 0,01-15,0 vægtpro- Hpreferably at a concentration of 0.01-15.0% by weight of H

15 cent, især gelatine, fortrinsvis i en koncentration på15 cents, especially gelatin, preferably at a concentration of

0,1-3 vægtprocent, især 0,5 vægtprocent, fortrinsvis i H0.1-3% by weight, especially 0.5% by weight, preferably in H

et forhold mellem volumen og volumenblandingshastighed Ha ratio of volume to volume mixing rate H

for ab) og c) på fra 1/10 til 100, især 1/40, Ifor ab) and c) of from 1/10 to 100, especially 1/40, I

20 uden tilsætning af nogen lægemiddelstoftilbageholdende H20 without the addition of any drug withholding H

substans til vand-i-olie-emulsionen eller anvendelse af Hsubstance for the water-in-oil emulsion or the use of H

mellemtrin til viskositetsforøgelse, hærdning af de em- bryoniske mikropartikler i den dannede w/o/w-emulsion ved desorption, fortrinsvis ved afdampning, af det organiskeintermediate steps for viscosity enhancement, curing of the embryonic microparticles in the resulting w / o / w emulsion by desorption, preferably by evaporation, of the organic

25 opløsningsmiddel, fortrinsvis methylenchlorid, og H25, preferably methylene chloride, and H

ved isolering, eventuelt vask og tørring af de dannede Hby isolating, optionally washing and drying the formed H

mikropartikler. Hmicroparticles. H

20 Opfindelsen tilvejebringer også en fremgangsmådevariant, HThe invention also provides a process variant, H

hvor lægemiddelstoffet dispergeres direkte i polymeropløs- Hwherein the drug substance is directly dispersed in polymer solution- H

ningen, hvorefter den resulterende dispersion blandes medThe resulting dispersion is mixed with

den gelatineholdige vandfase. Ithe gelatinous aqueous phase. IN

35 Mikropartikler, der er fremstillet ifølge ovennævnte frem- H35 Microparticles prepared according to the above-mentioned H

gangsmåder, indeholder ligesom mikropartiklerne fremstillet Hprocedures, just like the microparticles containing H

DK 175849 B1 23 ifølge spraytørringsteknikken ikke siliconeolie. I sammenligning med mikropartikierne fremstillet ifølge den kendte tripelemulsionsfremgangsmådetype indeholder de ikke et beskyt tel seskol loid.DK 175849 B1 23 according to the spray drying technique does not contain silicone oil. Compared to the microparticles prepared according to the known triple emulsion method type, they do not contain a protected telescopic loid.

55

Formuleringerne med forlænget afgivelse kan også fremstilles ifølge fremgangsmåder, der er kendt per se. fx - hvis peptidet er tilstrækkeligt stabilt til fremstilling 10 af en implanterbar indretning, ved opvarmning af mikropar-tiklerne indeholdende peptidet, fx et somatostatin i et polylactid-co-glycolid, især et sådant som beskrevet ovenfor eller en blanding deraf opnået ved blanding af peptidet og polymeren ved en temperatur på fx fra 70*C til 100®C og 15 ekstrudering og afkøling af den kompakte masse, hvorefter ekstrudatet skæres og eventuelt vaskes og tørres.The sustained release formulations can also be prepared according to methods known per se. for example - if the peptide is sufficiently stable to produce an implantable device, by heating the microparticles containing the peptide, e.g., a somatostatin in a polylactide co-glycolide, especially one as described above or a mixture thereof obtained by mixing the peptide and the polymer at a temperature of, for example, from 70 ° C to 100 ° C and extrusion and cooling of the compact mass, after which the extrudate is cut and optionally washed and dried.

Formuleringerne ifølge opfindelsen fremstilles hensigtsmæssigt under aseptiske betingelser.The formulations of the invention are conveniently prepared under aseptic conditions.

2020

Formuleringerne ifølge opfindelsen kan anvendes i depotform, fx i form af injicerbare mikrosfærer eller implanterbar e indretninger.The formulations of the invention can be used in depot form, for example in the form of injectable microspheres or implantable devices.

25 De kan administreres på konventionel måde, fx ved subkutan eller intramuskulær injektion, fx til indikationer kendte for det deri indeholdte lægemiddelstof.They can be administered in a conventional manner, for example, by subcutaneous or intramuscular injection, for example, for indications known to the drug substance contained therein.

Formuleringerne roed forlænget afgivelse indeholdende oc-30 treotid kan administreres til alle kendte indikationer for octreotidet eller derivater deraf, fx sådanne som er beskrevet i GB 2,199,829 A, s. 89-96, samt for akromegali og brystkræft.The formulations of prolonged release containing octreotide may be administered to all known indications for the octreotide or derivatives thereof, for example those described in GB 2,199,829 A, pp. 89-96, as well as for acromegaly and breast cancer.

3535

I DK 175849 B1 II DK 175849 B1 I

I 24 II 24 I

Mikropartiklerne kan have en diameter i et størrelsesområde IThe microparticles may have a diameter in a size range I

I på fra ca. 1 til 250 /zm, fortrinsvis fra 10 til 200 μπ\, IIn from approx. 1 to 250 µm, preferably from 10 to 200 µm

I især fra 10 til 130 /zm, fx fra 10 til 90 /zm. Implantater IIn particular, from 10 to 130 µm, for example from 10 to 90 µm. Implants I

I kan være fx fra ca. 1 til 10 mm3. Mængden af lægemiddelstof, IYou can be, for example, from approx. 1 to 10 mm3. The amount of drug, I

I 5 dvs. peptid, der er til stede i formuleringen, afhænger af IIn 5 i.e. peptide present in the formulation depends on I

den ønskede dosis, der dagligt afgives, og således at den Ithe desired dose given daily and so that it is administered

I indkapslende polymers bionedbrydningshastighed. Den nøjagtige IIn the biodegradation rate of encapsulating polymers. The exact I

I peptidmængde kan betemmes ved biotilgængelighedsforsøg. IIn amount of peptide can be determined by bioavailability experiments. IN

I Formuleringerne kan indeholde peptid i en mængde på fra IThe formulations may contain peptide in an amount of from I

10 mindst 0,2, fortrinsvis fra 0,5 til 20 vægtprocent i forhold I10 at least 0.2, preferably from 0.5 to 20% by weight in ratio I

til polymermatricen, fortrinsvis fra 2,0 til 10, især fra Ito the polymer matrix, preferably from 2.0 to 10, especially from I

I 3,0 til 6 vægtprocent. IIn 3.0 to 6 weight percent. IN

I Afgivelsestiden for peptidet fra mikropartiklen kan være IThe delivery time of the peptide from the microparticle may be I

I 15 fra 1 eller 2 uger til ca. 2 måneder. IFor 15 from 1 or 2 weeks to approx. Two months. IN

Formuleringen med forlænget afgivelse indeholder hensigts- IThe prolonged release formulation contains expedient I

I mæssigt et somatostatin, fx octreotid, i et bionedbryde- IIn terms of a somatostatin, e.g., octreotide, in a biodegradable I

I ligt, biokompatibelt polymerbærestof, som, når det admini- IA corrugated, biocompatible polymer carrier which, when administered

2 0 streres subkutant til en rotte med en dosis på 10 mg soma- I20 is subcutaneously administered to a rat at a dose of 10 mg soma- I

I tostat in pr. kg dyre legemss vægt, udviser en somatostatin- II tostat in pr. kg of animal body weight, exhibits a somatostatin I

koncentration i blodplasmaet på mindst 0,3 ng/ml og for- Iblood plasma concentration of at least 0.3 ng / ml and pre-I

I trinsvis mindre end 20 ng/ml i et tidsrum på 30 dage eller IFor less than 20 ng / ml for a period of 30 days or I

I hensigtsmæssigt i et tidsrum på 60 dage. IConveniently for a period of 60 days. IN

I 25 II 25 I

I Formuleringen med forlænget afgivelse omfatter alternativt IIn the extended release formulation, alternatively, I

hensigtsmæssigt et somatostatin, fx octreotid, i et bioned- Iconveniently a somatostatin, e.g., octreotide, in a biodegradable I

brydeligt, biokompatibelt polymer bærestof, som, når det Ifragile, biocompatible polymeric carrier, which, when applied

I administreres intramuskulært til en kanin i en dosis på IYou are administered intramuscularly to a rabbit at a dose of I

30 5 mg pr. kg legemsvægt, udviser en somatostatinkoncentra- I5 mg per kg body weight, exhibits a somatostatin concentration

tion på mindst 0,3 ng/ml i et tidsrum på 50 dage og hen- Iat a rate of at least 0.3 ng / ml for a period of 50 days and adhered to

sigtsmæssigt en koncentration på højst 20 ng/ml. Ipreferably a concentration not exceeding 20 ng / ml. IN

Yderlige foretrukne egenskaber hos de opnåede depotfor- IFurther preferred properties of the obtained repository form

35 muleringer, fx somatostatiner indeholdende octreotid, er, I35 formulations, e.g., somatostatins containing octreotide, are, I

afhængigt af den anvendte fremgangsmåde: Idepending on the procedure used:

25 DK 175849 B1DK 175849 B1

FaseadskillelsesteknikPhase Separation Technique

Kanin 5 mg somatostatin/kg, intramuskulært retardering (0-42 dage) 76% gennemsnitligt plasmaniveau 5 (cp, ideal) (0-42 dage) 4 ng/ml AUC (0-42 dage) 170 ng/ml x dageRabbit 5 mg somatostatin / kg, intramuscular retardation (0-42 days) 76% average plasma level 5 (cp, ideal) (0-42 days) 4 ng / ml AUC (0-42 days) 170 ng / ml x days

SpravtørringsteknikSpravtørringsteknik

Rotte 10 mg somatostatin/kg, subkutant retardering (0-42 dage) > 75% 10 gennemsnitligt plasmaniveu (cp, ideal) (0-42 dage) 4-6 ng/ml AUC (0-42 dage) 170-210 ng/ml x dageRat 10 mg somatostatin / kg, subcutaneous retardation (0-42 days)> 75% 10 average plasma levels (cp, ideal) (0-42 days) 4-6 ng / ml AUC (0-42 days) 170-210 ng / ml x days

Kanin 5 mg somatostatin/kg, intramuskulært retardering (0-43 dage) > 75% 15 gennemsnitligt plasmaniveu (cp, ideal) (0-43 dage) 4-6 ng/ml AUC (0-43 dage) 200-240 ng/ml x dageRabbit 5 mg somatostatin / kg, intramuscular retardation (0-43 days)> 75% average plasma level (cp, ideal) (0-43 days) 4-6 ng / ml AUC (0-43 days) 200-240 ng / ml x days

TripelemulsionsteknikTripelemulsionsteknik

Rotte 10 mg somatostatin/kg, subkutant 20 retardering (0-42 dage) > 75% gennemsnitligt plasmaniveu (cp, ideal) (0-42 dage) 4-6,5 ng/ml AUC (0-42 dage) 170-230 ng/ml x dageRat 10 mg somatostatin / kg, subcutaneous retardation (0-42 days)> 75% mean plasma level (cp, ideal) (0-42 days) 4-6.5 ng / ml AUC (0-42 days) 170-230 ng / ml x days

Kanin 5 mg somatostatin/kg, intramuskulært · 25 retardering (0-42/43 dage) > 74% gennemsnitligt plasmaniveu (cp, ideal) (0-42/43 dage) 3,5-6,5 ng/ml AUC (0-42/43 dage)160-270 ng/ml x dage iRabbit 5 mg somatostatin / kg, intramuscular · 25 retardation (0-42 / 43 days)> 74% mean plasma level (cp, ideal) (0-42 / 43 days) 3.5-6.5 ng / ml AUC (0 -42/43 days) 160-270 ng / ml x days i

DK 175849 B1 IDK 175849 B1 I

Opfindelsen tilvejebringer således også somatostatinpræ- IThus, the invention also provides somatostatin pre-I

parater, fortrinsvis octreotid- og octreotidanalogpræpara- Ipreparations, preferably octreotide and octreotide analogue preparations

ter, med følgende egenskaber: Hter, having the following properties: H

1. en retardering på mindst 70%, fortrinsvis mindst 74%, H1. a retardation of at least 70%, preferably at least 74%, H

5 fx mindst 75%, 80%, 88% eller mindst 89%, i en periode H5 for example at least 75%, 80%, 88% or at least 89%, for a period H

på fra 0 til 42 eller 43 dage, og/eller Ifrom 0 to 42 or 43 days, and / or I

2. et gennemsnitligt plasmaniveau (Cp, ideal) på H2. an average plasma level (Cp, ideal) of H

2,5-6,5 ng/ml, fortrinsvis 4-6,5 ng/ml, i en periode H2.5-6.5 ng / ml, preferably 4-6.5 ng / ml, for a period H

på fra 0 til 42 dage i rotte, når 10 mg somatostatin Hfrom 0 to 42 days in the rat, when 10 mg somatostatin H

10 administreres subkutant, og/eller et gennemsnitligt H10 is administered subcutaneously, and / or an average H

plasmaniveau på 3,5-6,5 ng/ml, fx 4-6,5 ng/ml, i en Iplasma levels of 3.5-6.5 ng / ml, eg 4-6.5 ng / ml, in an I

periode på fra 0 til 42 eller 43 dage i kanin, når Iperiod of 0 to 42 or 43 days in rabbits when I

5 mg somatostatin administreres intramuskulært, og/el- H5 mg somatostatin is administered intramuscularly and / or H

ler Iyou laugh

15 3. et AUC i en periode på fra 0 til 42 dage på mindst I3. an AUC for a period of from 0 to 42 days of at least I

160, fortrinsvis 170-230, ng/ml x dage for rotte, når I160, preferably 170-230, ng / ml x days for rat when I

10 mg somatostatin administreres subkutant, og/eller I10 mg somatostatin is administered subcutaneously, and / or I

et AUC i en periode på fra 0 til 42 eller 43 dage på Ian AUC for a period of 0 to 42 or 43 days on I

mindst 160, fortrinsvis fra 180 til 275, fx fra 200 Iat least 160, preferably from 180 to 275, e.g., from 200 l

20 til 275, ng/ml x dage for kanin, når 5 mg somatostatin I20 to 275, ng / ml x days for rabbit when 5 mg somatostatin I

administreres intramuskulært. Iadministered intramuscularly. IN

Til kvantitativ karakterisering af ovenfor beskrevne for- IFor the quantitative characterization of the above described I-

muleringer med forlænget afgivelse anvendes den metode for Iextended release moldings use the method for I

områdeafvigelse "area deviation" (AD), der er offentlig- Harea deviation "area deviation" (AD) that is public- H

25 gjort af F. Nimmerfall og J. Rosenthaier,· Intern. J. Phar- I25 by F. Nimmerfall and J. Rosenthaier, · Intern. J. Phar- I

maceut. 32, 1-6 (1986). I korthed går AD-metoden ud på, at Ichemist. 32, 1-6 (1986). In short, the AD method assumes that you

den eksperimentelle plasmaprofils områdeafvigelse udregnesthe area deviation of the experimental plasma profile is calculated

ud fra en idealprofil, som er et konstant gennemsnitligt Ibased on an ideal profile which is a constant average I

plasmaniveau (= cp,ideal), der er fremkommet ved omdannelse Hplasma level (= cp, ideal) produced by conversion H

30 af det eksperimentelle areal under plasmaniveau-tidskurven I30 of the experimental area under the plasma level time curve I

(AUC) til et rektangel med lige stort areal. Ud fra den I(AUC) for a rectangle of equal area. From the I

procentuelle områdeafvigelse (med henvisning til AUC)percent area deviation (citing AUC)

beregnes den procentuelle retardering på følgende måde: Hthe percentage deceleration is calculated as follows: H

27 DK 175849 B1 procentuel retardering = 100 x (l - AD/AUC)27 DK 175849 B1 percent deceleration = 100 x (l - AD / AUC)

Ved denne fremgangsmåde karakteriseres hele plasmaprofilen målt i et forudbestemt tidsrum, ved hjælp af et enkelt numerisk indeks.In this method, the entire plasma profile measured over a predetermined period of time is characterized by a single numerical index.

5 I Proc. natl. Acad. Sci. USA 85 (1988) 5688-5692 er der i fig. 4 beskrevet en plasmaniveauprofil for octapeptidanalo-gen af somatostatin med formlen * * D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 10 i rotte.5 In Proc. Natl. Acad. Sci. US 85 (1988) 5688-5692 shows in FIG. 4 discloses a plasma level profile of the octapeptide analogue of somatostatin of the formula * * D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 10 in rat.

Imidlertid kan der ikke foretages en klar sammenligning med de ovennævnte plasmaniveaudata for præparatet ifølge opfindelsen i rotte nævnt ovenfor, da den beskrevne plasmaniveauprof il er baseret på en anden administrationsmåde 15 (intramuskulær injektion) og - hvad der er vigtigere - mikrokapslernes fyldning (mellem 2% og 6%) og doseringsmængde til administration (25-50 mg portioner af mikro-kapsler i 30 dage, selv om der blev foretaget bestemmelser i mindst 45 dage) ikke er nøjagtigt angivet. Desuden er den 20 anvendte slags poly(D,L-lactid-co-glycolid) ikke nøjagtigt beskrevet.However, no clear comparison can be made with the above plasma level data for the composition of the invention in rat mentioned above, as the described plasma level profile is based on a different mode of administration 15 (intramuscular injection) and - more importantly - filling the microcapsules (between 2% and 6%) and dosage amount for administration (25-50 mg aliquots of microcapsules for 30 days, although determinations were made for at least 45 days) are not exactly indicated. Furthermore, the kind of poly (D, L-lactide-co-glycolide) used is not exactly described.

Værdien af det i publikationen beskrevne er således for lav til, at publikationen kan anses for at være en forudgående offentliggørelse, der kolliderer med den foreliggende op-25 findelse.Thus, the value of the publication disclosed is too low for the publication to be considered a prior publication which conflicts with the present invention.

Følgende eksempler illustrerer opfindelsen.The following examples illustrate the invention.

Mw af polymerer er den gennemsnitlige molekylvægt bestemt ved GLPC under anvendelse af polystyren som standard.Mw of polymers is the average molecular weight determined by GLPC using polystyrene as standard.

iin

DK 175849 B1 IDK 175849 B1 I

EKSEMPEL 1 IEXAMPLE 1 I

1 g poly(D,L,-lactid-co-glycolid)(50/50 molær, Mw = 45.000; I1 g of poly (D, L, -lactide-co-glycolide) (50/50 molar, Mw = 45,000; I

polydispersitet ca. 1,7) blev under magnetisk omroring Ipolydispersity approx. 1.7) was under magnetic stirring I

opløst i 15 ml methylenchlorid efterfulgt af tilsætning af Idissolved in 15 ml of methylene chloride followed by addition of I

5 75 mg octreotidacetat opløst i 0,5 ml methanol. 15 ml I5 75 mg of octreotide acetate dissolved in 0.5 ml of methanol. 15 ml I

siliconeolie (af mærket Dow 360 Medical Fluid, 1000 cs) Hsilicone oil (Dow 360 Medical Fluid brand, 1000 cs) H

siliconevæske) blev sat til polymerpeptid-blandingen. Den Isilicone liquid) was added to the polymer peptide mixture. The I

resulterende blanding blev sat til en omrørt emulsion, der Iresulting mixture was added to a stirred emulsion which I

indeholdt 400 ml n-heptan, 100 ml phosphatbuffer pH 4, Icontained 400 ml of n-heptane, 100 ml of phosphate buffer pH 4, I

10 40 ml Dow 360 Medical Fluid, 350 cs og 2 ml Span 80 (emul- I10 40 ml Dow 360 Medical Fluid, 350 cs and 2 ml Span 80 (emulsion)

gator). Omrøring fortsattes i mindst 10 minutter. De resul- HGator). Stirring was continued for at least 10 minutes. The result- H

terende mikropartikler blev isoleret ved filtrering og Hcorrosive microparticles were isolated by filtration and H

tørret natten over i en vakuumovn. Udbyttet blev ca. 90% Hdried overnight in a vacuum oven. The yield was approx. 90% H

mikropartikler størrelsesområdet 10-40 μτη. Imicroparticles the size range 10-40 μτη. IN

15 Mikropartiklerne blev suspenderet i et vehikel og admini- IThe microparticles were suspended in a vehicle and administered

streret intramuskulært i en 4 mg octreotiddosis til hvide HStretched intramuscularly in a 4 mg octreotide dose for white H

New Zealand-kaniner. Der blev periodisk taget blodprøver, HNew Zealand rabbits. Blood samples were taken periodically, H

der viste plasmaniveauer på fra 0,5 til 1,0 ng/ml i 30 Hshowing plasma levels of 0.5 to 1.0 ng / ml for 30 H

dage målt ved radioimmunoanalyse (RIA).days measured by radioimmunoassay (RIA).

i Ii

29 DK 175849 B1 EKSEMPEL 2 i i 1 g poly(D,L,-lactid-co-glycolid)glucose (Mw = 45.000 (55/45 molær fremstillet ifølge fremgangsmåden beskrevet i GB 2,145,422 B; polydispersitet ca. 1,7; fremstillet ud fra 5 0,2% glucose) blev under magnetisk omrøring opløst i 25 ml ethylacetat efterfulgt af tilsætning af 75 mg octreotid opløst i 3 ml methanol. 25 ml siliconeolie (af mærket Dow 360 Medical Fluid, 1000 cs) blev sat til polymer-peptidblandingen. Den resulterende blanding blev sat til emulsio-10 nen, der er beskrevet i eksempel 1. Omrøring fortsattes i mindst 10 minutter. De resulterende mikropartikler blev isoleret ved vakuumfiltrering og tørret natten over i en vakuumovn. Udbyttet var mere end 80% af mikropartiklerne i størrelsesområdet 10-40 μΐπ.EXAMPLE 2 ii 1 g of poly (D, L, -lactide-co-glycolide) glucose (Mw = 45,000 (55/45 molar prepared according to the method described in GB 2,145,422 B; polydispersity about 1.7; prepared from from 5 0.2% glucose) was dissolved under magnetic stirring in 25 ml of ethyl acetate followed by the addition of 75 mg of octreotide dissolved in 3 ml of methanol. 25 ml of silicone oil (of the Dow 360 Medical Fluid brand, 1000 cs) was added to the polymer-peptide mixture The resulting mixture was added to the emulsion described in Example 1. Stirring was continued for at least 10 minutes. The resulting microparticles were isolated by vacuum filtration and dried overnight in a vacuum oven. The yield was more than 80% of the microparticles in the size range 10-40 μΐπ.

15 Mikropartiklerne blev suspenderet’i et vehikel og administreret intramuskulært i en 4 mg octreotiddosis til hvide New Zealand-kaniner. Der blev periodisk taget blodprøver, der målt ved RIA viste plasmaniveauer på 0,5-2 ng/ml i 21 dage.The microparticles were suspended in a vehicle and administered intramuscularly in a 4 mg octreotide dose to white New Zealand rabbits. Blood samples periodically measured at RIA showed plasma levels of 0.5-2 ng / ml for 21 days.

20 EKSEMPEL 3EXAMPLE 3

En opløsning på 1,5 g octreotidacetat i 20 ml methanol blev under omrøring sat til en opløsning af 18,5 g poly(D,L,-lactid-co-glycolid)glucose (50:50 molær, Mw 45.000) i 500 ml methylenchlorid. Faseadskillelse blev udført ved 25 tilsætning af 500 ml Dow 360 Medical Fluid (1000 cs) og 800 ml Dow 360 Medical Fluid (350 cs) til peptid-polymer-suspensionen. Den resulterende blanding blev sat til en omrørt emulsion bestående af 1800 ml n-heptan, 2000 ml sterilt vand og 40 ml Span 80. Efter omrøring i 10 minutter 30 blev mikrosfærerne opsamlet ved vakuumfiltrering.A solution of 1.5 g of octreotide acetate in 20 ml of methanol was added with stirring to a solution of 18.5 g of poly (D, L, -lactide-co-glycolide) glucose (50:50 molar, Mw 45,000) in 500 ml. methylene chloride. Phase separation was performed by adding 500 ml of Dow 360 Medical Fluid (1000 cs) and 800 ml of Dow 360 Medical Fluid (350 cs) to the peptide-polymer suspension. The resulting mixture was added to a stirred emulsion consisting of 1800 ml of n-heptane, 2000 ml of sterile water and 40 ml of Span 80. After stirring for 10 minutes, the microspheres were collected by vacuum filtration.

I DK 175849 B1 II DK 175849 B1 I

I 30 II 30 I

I Halvdelen af produktet blev tørret natten over i en vakuum- IHalf of the product was dried overnight in a vacuum I

I ovn ved 37*C. Niveauet af det tilbageblevne methylenchlorid IIn oven at 37 ° C. The level of methylene chloride remaining I

I var 1,2%. II was 1.2%. IN

I Den anden halvdel af produktet blev vasket ved omrøring med IThe other half of the product was washed by stirring with I

I 5 1000 ml ethanol indeholdende 1 ml Span 80. Efter omrøring i IIn 5 ml of ethanol containing 1 ml of Span 80. After stirring in I

I 1 time blev ethanolet dekanteret, og mikropartiklerne blev IFor 1 hour, the ethanol was decanted and the microparticles became 1

I omrørt med 1000 ml n-heptan indeholdende 1 ml Span 80. IStir with 1000 ml of n-heptane containing 1 ml of Span 80. I

I Efter omrøring i 1 time blev mikropartiklerne opsamlet ved IAfter stirring for 1 hour, the microparticles were collected at 1

I vakuumfiltrering og tørret natten over i en vakuumovn ved IIn vacuum filtration and dried overnight in a vacuum oven at 1

I 10 37‘C. Niveauet af det tilbageblevne methylenchlorid i IAt 37 ° C. The level of methylene chloride remaining in I

mikropartiklerne, der var vasket på denne måde, var redu- Ithe microparticles washed in this way were reduced

I ceret fra 1,2% til 0,12%. IIn the range from 1.2% to 0.12%. IN

Det samlede produktudbytte var 18,2 g (91%) af mikropar- IThe total product yield was 18.2 g (91%) of the microparticle

I tikler indeholdende 5,6% octreotid, gennemsnitligt diame- IIn females containing 5.6% octreotide, average diam

I 15 ter 24 μΐη, 1,5% tilbageværende heptan. IIn 15 ter 24 μΐη, 1.5% residual heptane. IN

Mikropartiklerne blev suspenderet i et vehikel og injiceret IThe microparticles were suspended in a vehicle and injected I

intramuskulært i 5 mg/kg octreotiddoser til hvide kaniner. Iintramuscularly in 5 mg / kg octreotide doses for white rabbits. IN

I Der blev periodisk taget blodprøver, der målt ved RIA viste IBlood tests periodically measured by RIA showed I

I plasmaniveauer på 0,3-7,7 ng/ml i 49 dage. IAt plasma levels of 0.3-7.7 ng / ml for 49 days. IN

I 20 EKSEMPEL 4 IEXAMPLE 4 I

I 1 g poly(D,L,-lactid-co-glycolid)glucose Mw 46.000 (50:50) IIn 1 g of poly (D, L, -lactide-co-glycolide) glucose Mw 46,000 (50:50) I

I molær fremstillet ifølge fremgangsmåden beskrevet i IIn molar prepared according to the method described in I

I GB 2,145,422 B, polydispersitet ca. 1,7, fremstillet ud fra IIn GB 2,145,422 B, polydispersity approx. 1.7, prepared from I

I 0,2% glucose) blev under magnetisk omrøring opløst i 10 ml IIn 0.2% glucose), under magnetic stirring, was dissolved in 10 ml of I

I 25 methylen-chlorid efterfulgt af tilsætning af 75 mg octreo- IIn 25 methylene chloride followed by the addition of 75 mg of octreo- I

I tid opløst i 0,133 ml methanol. Blandingen blev blandet ITime dissolved in 0.133 ml of methanol. The mixture was mixed I

I kraftigt, fx ved hjælp af en Ultra-Turax, i 1 minut ved IYou vigorously, for example, using an Ultra-Turax, for 1 minute at 1

20.000 omdrejninger/minut, hvilket gav en suspension af20,000 rpm, giving a suspension of

meget små octreotidkrystaller i polymeropløsningen. Ivery small octreotide crystals in the polymer solution. IN

31 DK 175849 B131 DK 175849 B1

Suspensionen blev sprayet ved hjælp af en "high speed"-turbine (Niro Atomizer), og de små dråber blev torret i en varm luftstrøm til dannelse af mikropartikler. Mikropartik-lerne blev opsamlet af en "zyklon" og tørret natten over 5 ved stuetemperatur i en vakuumovn.The suspension was sprayed using a high speed turbine (Niro Atomizer) and the small droplets were dried in a hot air stream to form microparticles. The microparticles were collected by a "cyclone" and dried overnight at room temperature in a vacuum oven.

Mikropartiklerne blev vasket med 1/15 molær acetatbuffer, pH 4,0, i 5 minutter og tørret igen ved stuetemperatur i en vakuumovn. Efter 72 timer blev mikropartiklerne sigtet (0,125 mm maskestørrelse), hvilket gav slutproduktet.The microparticles were washed with 1/15 molar acetate buffer, pH 4.0, for 5 minutes and dried again at room temperature in a vacuum oven. After 72 hours, the microparticles were screened (0.125 mm mesh size) to give the final product.

10 Mikropartiklerne blev suspenderet i et vehikel og administreret intramuskulært i 5 mg/kg octreotiddoser til hvide kaniner (chinchilla-bastarder) og subkutant i en 10 mg/kg dosis til hanrotter. Der blev periodisk taget blodprøver, der målt ved radioimmunoanalyse (RIA) viste plasmaniveauer 15 på 0,3-10,0 ng/ml (5 mg dosis) hos kaniner og 0,5-7,0 ng/ml hos rotter i 42 dage.The microparticles were suspended in a vehicle and administered intramuscularly in 5 mg / kg octreotide doses to white rabbits (chinchilla bastards) and subcutaneously in a 10 mg / kg dose to male rats. Blood samples were taken periodically as measured by radioimmunoassay (RIA) plasma levels of 0.3-10.0 ng / ml (5 mg dose) in rabbits and 0.5-7.0 ng / ml in rats for 42 days .

EKSEMPEL 5EXAMPLE 5

Mikropartikler blev fremstillet ved spraytørring på samme måde som beskrevet i eksempel 4 med den enkelte ændring, at 20 octreotid blev suspenderet direkte i polymeropløsningen uden anvendelse af methanol.Microparticles were prepared by spray drying in the same manner as described in Example 4 with the single change that 20 octreotide was suspended directly in the polymer solution without the use of methanol.

Mikropartiklerne blev suspenderet i et vehikel og administreret subkutant i en 10 mg/kg octreotiddosis til hanrotter. Der blev periodisk taget blodprøver, der målt ved 25 radioimmunoanalyse (RIA) viste plasmaniveauer på 0,5-10,0 ng/ml i rotter i 42 dage.The microparticles were suspended in a vehicle and administered subcutaneously in a 10 mg / kg octreotide dose to male rats. Blood samples were taken periodically, as measured by 25 radioimmunoassay (RIA), showing plasma levels of 0.5-10.0 ng / ml in rats for 42 days.

DK 175849 B1 IDK 175849 B1 I

EKSEMPEL 6 IEXAMPLE 6 I

1 g poly(D,L,-lactid-co-glycolid)glucose, Mw 46.000 (50:50 I1 g of poly (D, L, -lactide-co-glycolide) glucose, Mw 46,000 (50:50 I

molær fremstillet ifølge fremgangsmåden beskrevet i Imolar prepared according to the method described in I

GB 2,145,422 B, polydispersitet ca. 1,7, fremstillet ud fraGB 2,145,422 B, polydispersity approx. 1.7, made from

5 0,2% glucose) blev opløst i 2,5 ml methylenchlorid efter- I(0.2% glucose) was dissolved in 2.5 ml of methylene chloride after I

fulgt af tilsætning af 75 mg octreotid opløst i 0,125 ml Ifollowed by addition of 75 mg octreotide dissolved in 0.125 ml I

deioniseret vand. Blandingen blandedes kraftigt, fx ved Hdeionized water. The mixture was mixed vigorously, for example at H

hjælp af en Ultra-Turax, i 1 minut ved 20.000 omdrejnin- Iusing an Ultra-Turax, for 1 minute at 20,000 rpm

ger/minut (indre w/o-fase). Iger / minute (internal w / o phase). IN

10 1 g Gelatine λ blev opløst i 200 ml deioniseret vand ved H10 l of Gelatin λ was dissolved in 200 ml of deionized water at H

50eC, og opløsningen blev afkølet til 20®C (ydre w-fase). H50 ° C and the solution was cooled to 20 ° C (outer w phase). H

W/o- og w-faserne blev blandet kraftigt. Derved blev den IThe w / o and w phases were mixed vigorously. Thereby, it became you

indre w/o-fase skilt fra i små dråber, som homogent blev Iinner w / o phase separated into small droplets that became homogeneous

dispergeret i den ydre w-fase. Den resulterende tripele- Hdispersed in the outer w phase. The resulting triple- H

15 mulsion blev omrørt langsomt i 1 time. Herved blev methy- H15 mulches were stirred slowly for 1 hour. Thereby, methyl H was obtained

lenchlorid afdampet, og mikrokapslerne blev hærdet ud fra Hlench chloride evaporated and the microcapsules were cured from H

smådråberne fra den indre fase. Efter sedimentering af Hthe droplets from the inner phase. After sedimentation of H

mikropartiklerne blev supernatanten suget fra, og mikropar- Ithe microparticles were suctioned off and the microparticle I

tiklerne blev isoleret ved vakuumfiltrering og renset med Hthe ticks were isolated by vacuum filtration and purified with H

20 vand for at fjerne gelatine. Tørring, sigtning, vask og H20 water to remove gelatin. Drying, sieving, washing and H

sekundær tørring af mikropartiklerne blev udført som be-secondary drying of the microparticles was performed as

skrevet i eksempel 4. Iwritten in Example 4. I

Mikropartiklerne blev suspenderet i et vehikel og admini- HThe microparticles were suspended in a vehicle and administered

streret intramuskulært i 5 mg/kg octreotiddosis til hvideintramuscularly stretched at 5 mg / kg octreotide dose to whites

25 kaniner (chinchillabastard) og subkutant i en 10 mg/kg I25 rabbits (chinchilla bastard) and subcutaneously in a 10 mg / kg I

dosis til hanrotter. Der blev periodisk taget blodprøver, Hdose for male rats. Blood samples were taken periodically, H

der målt ved radioimmunoanalyse (RIA) viste plasmaniveauer j Ithat measured by radioimmunoassay (RIA) plasma levels j I

på 0,3-15,0 ng/ml (5 mg dosis) hos kaniner og 0,5-8,0 ng/ml Iof 0.3-15.0 ng / ml (5 mg dose) in rabbits and 0.5-8.0 ng / ml I

hos rotter i 42 dage. Hin rats for 42 days. H

EKSEMPEL 7 DK 175849 B1 33EXAMPLE 7 DK 175849 B1 33

Mikropartikler blev fremstillet ved tripelemulsionsteknik på samme måde som beskrevet i éksempel 6 med følgende tre ændringer: 5 l. 0,25 ml acetatbuffer pH 4,0 blev anvendt i stedet for 0,125 ml vand til fremstilling af den indre w/o-fase.Microparticles were prepared by triple emulsion technique in the same manner as described in Example 6, with the following three changes: 5 l. 0.25 ml of acetate buffer pH 4.0 was used instead of 0.125 ml of water to prepare the internal w / o phase.

2. vask efter opsamling af mikropartiklerne blev udført med 1/45 molær acetatbuffer pH 4,0 i stedet for med vand.2. Washing after collecting the microparticles was performed with 1/45 molar acetate buffer pH 4.0 instead of with water.

10 3. yderligere vask af mikropartikler blév udeladt.10 3. further washing of microparticles was left out.

EKSEMPEL 8EXAMPLE 8

Mikropartikler blev fremstillet ved tripelemulsionsteknik på samme måde som beskrevet i eksempel 7 med den enkelte ændring, at den indre w/o-fase blev fremstillet under 15 anvendelse af vand indeholdende 0,7% (w/v) natriumchlorid i stedet for acetatbuffer.Microparticles were prepared by triple emulsion technique in the same manner as described in Example 7 with the single change that the inner w / o phase was prepared using water containing 0.7% (w / v) sodium chloride instead of acetate buffer.

EKSEMPEL 9EXAMPLE 9

Mikropartikler blev fremstillet på samme måde som beskrevet i eksempel 6 med den eneste forskel, at lægemiddelstoffet 20 direkte dispergeres i polymeropløsningen, hvorefter den resulterende dispersion blev blandet med den gelatineholdi-ge vandfase.Microparticles were prepared in the same manner as described in Example 6, with the only difference being that the drug 20 was directly dispersed in the polymer solution, after which the resulting dispersion was mixed with the gelatin-containing aqueous phase.

I DK 175849 B1 II DK 175849 B1 I

I 34 II 34 I

I EKSEMPEL 10 IIn Example 10 I

I Octreotidpamoat IIn Octreotide Pamoate I

I 10,19 g octreotid i form af fri base (10 mM) og 3,88 em- IIn 10.19 g of octreotide in the form of free base (10 mM) and 3.88 cm -1

I bonsyre (10 mM) opløses ill vand/dioxan (1:1). Reaktions- · IIn bonic acid (10 mM), dissolve 1 m water / dioxane (1: 1). Reaction · I

I 5 blandingen filtreres og lyofiliseres, hvilket giver et IIn the mixture, filter and lyophilize to give an I

I gult pulver [a]20D = + 7,5" (C = 0,35, i DMF), octreotid- IIn yellow powder [α] 20 D = + 7.5 "(C = 0.35, in DMF), octreotide I

I pamoathydrat. Faktor = 1,4, hvor faktor « lyofilisatvæg- IIn pamoate hydrate. Factor = 1.4, where factor «lyophilizate wall- I

I ten/vægten af det deri indeholdte octreotid. IIn the weight / weight of the octreotide contained therein. IN

I Pamoatet kan erstatte det octreotid, der er til stede i IIn Pamoate can replace the octreotide present in I

10 mikropartiklerne i eksempel 1-9, og har en fremragende I10 microparticles of Examples 1-9, and have an excellent I

stabilitet.stability.

I EKSEMPEL 11 IIn Example 11 I

I En opløsning af l g poly(D,L-lactid-co-glycolid) (50:50 IA solution of 1 g of poly (D, L-lactide-co-glycolide) (50:50 I)

I molær, Mw = 36.100) i 20 ml methylenchlorid blev under IIn molar, Mw = 36,100) in 20 ml of methylene chloride remained below I

15 omrøring sat til en opløsning af 100 mg calcitonin i 1,5 ml IStir was added to a solution of 100 mg calcitonin in 1.5 ml I

I methanol. Faseadskillelse blev udført ved tilsætning af IIn methanol. Phase separation was performed by the addition of I

I 20 ml siliconevæske (Dow 360 Medical Fluid, 1000 cs). Den IIn 20 ml of silicone liquid (Dow 360 Medical Fluid, 1000 cs). The I

I resulterende blanding blev sat til en omrørt emulsion be- IIn the resulting mixture, a stirred emulsion was added

I stående af 100 ml phosphatbuffer pH 4, 400 ml n-heptan, IIn standing 100 ml of phosphate buffer pH 4, 400 ml of n-heptane, I

I 20 4 ml Span 80 og 40 ml siliconevæske (Dow 360 Medical Fluid, IIn 20 ml of Span 80 and 40 ml of silicone fluid (Dow 360 Medical Fluid, I

1000 cs). Efter omrøring i 10 minutter blev mikrosfærerne1000 cs). After stirring for 10 minutes, the microspheres became

I opsamlet ved vakuumfiltrering og tørret i vakuumovn ved HI collected by vacuum filtration and dried in vacuum oven at H

I 37°C natten over. Udbyttet var 1,1 g mikrosfærer indehol- IAt 37 ° C overnight. The yield was 1.1 g microspheres

I dende 5,9% calcitonin.In the 5.9% calcitonin.

I 25 EKSEMPEL 12 IEXAMPLE 12 I

I En opløsning af 9,9 g poly(D,L-lactid-co-glycolid) (50/50 IA solution of 9.9 g of poly (D, L-lactide-co-glycolide) (50/50 I

I molær, Mw = 44.300) i 140 ml methylenchlorid blev sat til IIn molar, Mw = 44,300) in 140 ml of methylene chloride was added to I

I 100 mg lypressin. Dispersionen blev omrørt med magnetom- IIn 100 mg lypressin. The dispersion was stirred with magnetomol

I rører i 1 time før tilsætning af 140 ml siliconevæske (Dow IStir for 1 hour before adding 140 ml of silicone liquid (Dow I

35 DK 175849 B1 360 Medical Fluid, 1000 cs) og 2,5 ml Span 80. Blandingen ( blev sat til 2000 ml heptan og omrørt i 10 minutter. De resulterende mikrokapsler blev opsamlet ved vakuumfiltrering, vasket 3 gange med heptan og tørret i 10 minutter 5 under sugning. Halvdelen af prøven blev under omrøring vasket i vand i 10 minutter; den anden halvdel blev ikke vasket. Begge prøver blev tørret i vakuumovn ved 30°C natten over. Det samlede udbytte blev 10,65 g mikrokapsler.The mixture (was added to 2000 ml of heptane and stirred for 10 minutes. The resulting microcapsules were collected by vacuum filtration, washed 3 times with heptane and dried for 10 min.). Half of the sample was stirred in water for 10 minutes with stirring, the other half was not washed, both samples were dried in a vacuum oven at 30 ° C overnight, the total yield being 10.65 g of microcapsules.

Analyse af den vaskede prøve viste 0,5% lypressin og 0,6% 10 for den prøve, der ikke blev vasket med vand.Analysis of the washed sample showed 0.5% lypressin and 0.6% 10 for the sample not washed with water.

Claims (37)

1. Fremgangsmåde til fremstilling af mikropartikler om- I I fattende et lægemiddelstof i et bionedbrydeligt, biokompa- I I 5 tibelt polymert bærestof, I I kendetegnet ved, at den omfatter følgende trin: I I a) det polymere bærestofmateriale opløses i et hensigts- I I mæssigt opløsningsmiddel, i hvilket lægemiddelstoffet I I 10 ikke er opløseligt, I I b) en opløsning af lægemiddelstoffet sættes til og dis- I pergeres i et hensigtsmæssigt opløsningsmiddel, i I I hvilket polymeren i opløsningen fra trin a) ikke er I I 15 opløselig, I I c) et faseinduceringsmiddel sættes til dispergeringen fra I I trin b) for at fremkalde mikropartikeldannelse, I 20 d) en olie-i-vand-emulsion sættes til blandingen fra trin I I c) til hærdning af mikropartiklerne, og I I e) mikropartiklerne isoleres. I I 25 2. Fremgangsmåde til fremstilling af mikropartikler om- I I fattende et lægemiddelstof i et bionedbrydeligt, biokompa- I tibelt bærestof, kendetegnet ved, at den omfatter I I 30 i) kraftig blanding af en vand-i-olie-emulsion dannet af I I et vandigt medium og et organisk opløsningsmiddel, der I I ikke er blandbart med vand, hvilken emulsion inde- I I holder lægemiddelstoffet i én fase og en bionedbryde- I I lig/ biokompatibel polymer i den anden fase, med et I 35 overskud af vandigt medium, der indeholder en emul- I gerende substans eller et beskyttelseskolloid til I dannelse af en vand-i-olie-i-vand-emulsion uden til- I sætning af lægemiddelstoftilbageholdende substans til I --1 DK 175849 B1 vand-i-olie-emulsionen eller anvendelse af mellemliggende viskositetsforøgende trin, ii) desorbering af det organiske opløsningsmiddel derfra, 5 iii) isolering og tørring af de resulterende mikropartik-ler.A process for the preparation of microparticles comprising a drug substance in a biodegradable biocompatible polymeric carrier, II characterized in that it comprises the following steps: II a) the polymeric carrier material is dissolved in an appropriate solvent; in which the drug II 10 is not soluble, II b) a solution of the drug substance is added and dispersed in a suitable solvent, in II which the polymer in the solution of step a) is not soluble, II c) a phase inducing agent is added to the dispersion from II step b) to induce microparticle formation, I d) an oil-in-water emulsion is added to the mixture of step II c) to cure the microparticles, and II e) the microparticles are isolated. A process for the preparation of microparticles comprising a drug substance in a biodegradable biocompatible carrier, characterized in that it comprises II 30 i) vigorous mixing of a water-in-oil emulsion formed by II a aqueous medium and an organic solvent immiscible with water containing emulsion II in one phase and a biodegradable / biocompatible polymer in the second phase, with an excess of aqueous medium containing an emulsifying substance or a protective colloid for forming a water-in-oil-in-water emulsion without the addition of drug-retaining substance to the water-in-oil emulsion or use of intermediate viscosity-increasing steps, ii) desorbing the organic solvent therefrom, iii) isolating and drying the resulting microparticles. 3. Fremgangsmåde til fremstilling af mikropartikler inde-10 holdende et lægemiddelstof i en bionedbrydelig, biokompatibel polymer, kendetegnet ved, at den omfatter i) kraftig blanding af en lægemiddelstofsuspension 15 dannet af et lægemiddelstof og et organisk opløsnings middel, der ikke er blandbart med vand, og som indeholder en bionedbrydelig, biokompatibel polymer, med i i I overskud af vandigt medium indeholdende en emulgerende j substans eller et beskyttelseskolloid til dannelse af j 20 en olie-i-vand-emulsion, idet lægemiddelstoffet dis- i pergeres i oliekomponenten uden tilsætning af lægemid-delstoftilbageholdende substans eller anvendelse af mellemliggende viskositetsforøgende trin, 25 ii) desorbering af det organiske opløsningsmiddel derfra, iii) isolering og tørring af de resulterende mikropartikler.A process for preparing microparticles containing a drug substance in a biodegradable, biocompatible polymer, characterized in that it comprises i) vigorous mixing of a drug suspension 15 formed by a drug substance and an water-immiscible organic solvent. and containing a biodegradable, biocompatible polymer, with ii in excess of aqueous medium containing an emulsifying substance or protective colloid to form an oil-in-water emulsion, the drug being dispersed in the oil component without the addition of drug-retaining substance or the use of intermediate viscosity-increasing steps; ii) desorbing the organic solvent therefrom; iii) isolating and drying the resulting microparticles. 4. Fremgangsmåde til fremstilling af mikropartikler, kendetegnet ved, at den omfatter kraftig blanding af: a) en opløsning af et lægemiddelstof i et vandigt medium 35 og b) en opløsning af en polymer i et organisk opløsningsmiddel, der ikke er blandbart med det vandige medium, DK 175849 B1 IProcess for the preparation of microparticles, characterized in that it comprises vigorous mixing of: a) a solution of a drug substance in an aqueous medium and b) a solution of a polymer in an organic solvent which is not miscible with the aqueous medium, DK 175849 B1 I 38 I kraftig blanding af w/o/emulsionen fra a) og b) sammen med c) et overskud af et vandigt medium indeholdende et I 5 beskyttelseskolloid uden tilsætning af lægemiddelstof I tilbageholdende substans til vand-i-olie-emulsionen eller anvendelse af mellemliggende viskositetsfor- I øgende trin, hærdning af de embryoniske mikropartikler I i den dannede w/o/w/emulsion ved desorption og iso- I 10 lering af de resulterende mikropartikler. I38 In vigorous mixing of the w / o / emulsion from a) and b) together with c) an excess of an aqueous medium containing a protective colloid without the addition of drug substance retained substance to the water-in-oil emulsion or the use of intermediate increasing viscosity, curing the embryonic microparticles I in the resulting w / o / w / emulsion by desorption and isolating the resulting microparticles. IN 5. Fremgangsmåde ifølge krav 4, kendetegnet ved, at lægemiddelstoffet er et I somatostatin.Method according to claim 4, characterized in that the drug substance is a somatostatin. 15 I15 I 6. Fremgangsmåde ifølge krav 4, kendetegnet ved, I at lægemiddelstoffet er octreotid. IProcess according to claim 4, characterized in that the drug substance is octreotide. IN 7. Fremgangsmåde ifølge krav 4, kendetegnet ved, I 20 at lægemiddelstoffet er octreotid-pamoatsalt. IProcess according to claim 4, characterized in that the drug substance is octreotide pamoate salt. IN 8. Fremgangsmåde ifølge krav 4, kendetegnet ved, I at polymeren er et polylactid-coglycolid. IProcess according to claim 4, characterized in that the polymer is a polylactide coglycolide. IN 9. Fremgangsmåde ifølge krav 4, kendetegnet ved, I at det vandige medium er vand eller en buffer. IProcess according to claim 4, characterized in that the aqueous medium is water or a buffer. IN 10. Fremgangsmåde ifølge krav 4, kendetegnet I ved, at det vandige medium er en buffer med en pH-værdi på I 30 3-8. IProcess according to claim 4, characterized in that the aqueous medium is a buffer having a pH value of I 3-8. IN 11. Fremgangsmåde ifølge krav 4, kendetegnet I ved, at det organiske opløsningsmiddel er methylenchlorid. IProcess according to claim 4, characterized in that the organic solvent is methylene chloride. IN 35 I ^________π • I DK 175849 B135 I ^ ________ π • I DK 175849 B1 12. Fremgangsmåde til fremstilling af mikropartikler, kendetegnet ved, at den omfatter kraftig blanding af: 5 a) en somatostatinopløsning i vand eller en buffer i et vægt/volumenforhold på 0,8-4,0 g/1-120 ml og b) en opløsning af et polylactid-co-glycolid i et organisk opløsningsmiddel, der ikke er blandbart med det •10 vandige medium, i et vægt/volumenforhold på 40 g/- i 90-400 ml på en sådan måde, at vægt/vægtforholdet mellem lægemiddelstoffet og polymeren ligger på fra 1/10 til 50 og volumen/volumenforholdet af det vandige medium/organiske opløsningsmiddel er 1/1,5-30, og 15 kraftig blanding af w/o-emulsionen fra a) i b) sammen med c) et overskud af vand eller en buffer indeholdende et beskyttelseskolloid i et forhold mellem volumen og 20 volumenblandingshastighed for ab) og c) på fra 1/10 til 100, > uden tilsætning af lægemiddelstoftilbageholdende substans til vand-i-olie-emulsionen eller anvendelse af mellemtrin 25 til viskositetsforøgelse, hærdning af de embryoniske mikro-partikler i den dannede w/o/w-emulsion ved afdampning af det organiske opløsningsmiddel og isolering af de frembragte mikropartikler.Process for the preparation of microparticles, characterized in that it comprises vigorous mixing of: 5 a) a somatostatin solution in water or a buffer in a weight / volume ratio of 0.8-4.0 g / 1-120 ml and b) a solution of a polylactide co-glycolide in an organic solvent which is not miscible with the aqueous medium at a weight / volume ratio of 40 g / - in 90-400 ml in such a way that the weight / weight ratio of the drug substance and polymer range from 1/10 to 50 and the volume / volume ratio of the aqueous medium / organic solvent is 1 / 1.5-30 and vigorous mixing of the w / o emulsion from a) ib) with c) an excess of water or a buffer containing a protective colloid in a volume to 20 volume mixing rate for ab) and c) of 1/10 to 100, without the addition of drug-retaining substance to the water-in-oil emulsion or the use of intermediate steps 25 for viscosity enhancement, curing of the embryonic micro-particles in the formed w / o / w emulsion by evaporation of the organic solvent and isolation of the microparticles produced. 13. Fremgangsmåde ifølge krav 12, kendetegnet ved, at beskyttelseskolloidet er gelatine.Process according to claim 12, characterized in that the protective colloid is gelatin. 14. Fremgangsmåde til fremstilling af mikropartikler, kendetegnet ved, at den omfatter kraftig blanding af: a) en opløsning af somatostatin i et vandigt^medium i et 35 DK 175849 B1 I I 40 I vægt/volumenforhold på 2,5 mg/10 ml og B b) en opløsning af et polylactid-coglycolid i et organisk I opløsningsmiddel, der ikke er blandbart med det van- B I . 5 dige medium, i et vægt/volumenforhold på 40 g/100 ml ‘ B ' på en sådan måde, at vægt/volumenforholdet mellem læge- I middelstoffet og polymeren er 1/16, og volumen/volumen- B forholdet mellem det vandige medium og organisk opløs- B ningsmiddel er 1/10, kraftig blanding af w/o-emuisionen B 10 af a) i b) sammen med 1 B c) et overskud af et vandigt medium indeholdende et beskyt- B telseskolloid i en koncentration på 0,01 til 15,0% ved B et volumen/volumen-blandingshastighedsforhold mellem fl 15 ab) og c) på 1/40, I B uden tilsætning af lægemiddelstoftilbageholdende substans B til vand-i-olie-emulsionen eller anvendelse af mellemtrin B til viskositetsforøgelse, hærdning af de embryoniske mi- B kropartikler i den dannede w/o/w-emulsion ved afdampning B 20 af det organiske opløsningsmiddel og isolering af de frem- B bragte mikropartikler. BProcess for the preparation of microparticles, characterized in that it comprises vigorous mixing of: a) a solution of somatostatin in an aqueous medium in a 2.5 mg / 10 ml w / v ratio and 2.5 mg; B b) a solution of a polylactide coglycolide in an organic solvent which is not miscible with the water BI. 5 medium in a weight / volume ratio of 40 g / 100 ml 'B' in such a way that the weight / volume ratio of the drug to the polymer is 1/16 and the volume / volume B ratio of the aqueous medium and organic solvent is 1/10, vigorously mixing the w / o emulsion B 10 of a) ib) together with 1 B c) an excess of an aqueous medium containing a protective B colloid at a concentration of 0, 01 to 15.0% at B, a volume / volume mixing rate ratio between fl 15 ab) and c) of 1/40, 1B without the addition of drug retaining substance B to the water-in-oil emulsion or the use of intermediate stage B for viscosity increase, curing the embryonic micro-B particles in the resulting w / o / w emulsion by evaporation B 20 of the organic solvent and isolating the microparticles produced. B 15. Fremgangsmåde til fremstilling af mikropartikler, k e η- B detegnet ved, at den omfatter kraftig blanding af: BA process for the preparation of microparticles, characterized by the vigorous mixing of: B 25 I a) en opløsning af octreotid i et vægt/volumenforhold på B 2,5 g/10 ml i en buffer med en pH-værdi på 3-8 og B b) en opløsning af et polylactid-coglycolid i methylen i B 30 et vægt/volumenforhold på 40 g/100 ml på en sådan mde, B at vægt/vægtforholdet mellem lægemiddelstoffet og poly- B meren er 1/16, og volumen/volumenforholdet mellem det B vandige medium og organisk opløsningsmiddel er 1/10, B kraftig blanding af w/o-emulsionen af a) i b) sammen med B B c) et overskud af et buffer med en pH-værdi på 3-8, in- B . ., I DK 175849 B1 deholdende gelatine i en koncentration på 0,5 vægtprocent ved et volumen/volumenblandingshastighedsfor-hold mellem ab) og c) på 1/40, , uden tilsætning af lægemiddelstoftilbageholdende substans j 5 til vand-i-olie-emulsionen eller anvendelse af mellemtrin til viskositetsforøgelse, hærdning af de embryoniske mikro-j partikler i den dannede w/o/w-emulsion ved afdampning af I methylenchlorid og ! isolering, vask og tørring af de frembragte mikropartikler. : ioIn a) a solution of octreotide in a weight / volume ratio of B 2.5 g / 10 ml in a buffer having a pH of 3-8 and B b) a solution of a polylactide coglycolide in methylene in B 30 a weight / volume ratio of 40 g / 100 ml in such a manner, B that the weight / weight ratio of the drug substance to the polymer is 1/16, and the volume / volume ratio of the B aqueous medium to organic solvent is 1/10, B vigorous mixing of the w / o emulsion of a) ib) together with BB c) an excess of a buffer having a pH of 3-8, in- B. ., In DK 175849 B1 containing gelatin at a concentration of 0.5% by weight at a volume / volume mixing rate ratio of ab) to c) of 1/40, without the addition of drug retaining substance j5 to the water-in-oil emulsion or using intermediate steps to increase viscosity, cure the embryonic micro-particles in the resulting w / o / w emulsion by evaporation of 1 methylene chloride and! isolation, washing and drying of the microparticles produced. : in Island 16. Formulering med forlænget afgivelse, kendetegnet ved, at den omfatter octreotid eller et salt eller derivat deraf i et bionedbrydeligt, biokompatibelt polymert bærestof. 15A prolonged release formulation, characterized in that it comprises octreotide or a salt or derivative thereof in a biodegradable, biocompatible polymeric carrier. 15 17. Formulering ifølge krav 16, kendetegnet ved, at polymeren er poly-(DL-lactid-coglycolid)-glucose.Formulation according to claim 16, characterized in that the polymer is poly (DL-lactide-coglycolide) glucose. 18. Formulering ifølge krav 16 på mikropartikelform, k e n- 20 detegnet ved, at overfladen er i det væsentlige fri | for lægemiddelforbindelse. ’Formulation according to claim 16 in microparticle form, characterized in that the surface is substantially free | for drug connection. ' 19. Formulering med forlænget afgivelse ifølge krav 16, kendetegnet ved, at den er fremstillet ved at 25 blande lægemiddelforbindelsen eller en opløsning deraf i methanol eller vand eller en buffer med pH = 3-8 og en opløsning af et polylactid-coglycolid i methylenchlorid og spraying af den dannede suspensionsopløsning eller emulsion af lægemiddelforbindelse i polymeropløsningen i en strøm af 30 varm luft, opsamling af mikrosfærerne og vask deraf i en bufferopløsning ved pH = 3,0-8,0 eller destilleret vand og tørring deraf i vakuum ved en temperatur fra 20 til 40°C. I DK 175849 B1 I i 42 IAn extended release formulation according to claim 16, characterized in that it is prepared by mixing the drug compound or a solution thereof in methanol or water or a buffer of pH = 3-8 and a solution of a polylactide coglycolide in methylene chloride and spraying the resulting suspension solution or drug compound emulsion into the polymer solution in a stream of hot air, collecting the microspheres and washing them in a buffer solution at pH = 3.0-8.0 or distilling water and drying them in vacuo at a temperature of 20 to 40 ° C. I DK 175849 B1 I i 42 I 20. Formulering med forlænget afgivelse ifølge krav 16, H I kendetegnet ved, at octreotidkoncentrationen er H 2,0-10 vægtprocent. H I 5 21. Formulering med forlænget afgivelse ifølge krav 16, H I kendetegnet ved, at den har mikropartikelform H med en diameter fra 1 til 250 μτη. HThe sustained release formulation according to claim 16, H characterized in that the octreotide concentration is H 2.0-10% by weight. H I 5 An extended release formulation according to claim 16, H 1 characterized in that it has microparticle shape H having a diameter of 1 to 250 μτη. H 22. Formulering med forlænget afgivelse, H I 10 kendetegnet ved, at den omfatter en peptidlæge- H I middelforbindelse i en fra 40/60 til 60/40 polylactid-cogly- H I colidester af polyol, idet polyolenheden er valgt fra gruppen H I bestående af alkohol indeholdende en (C3_g)-carbonkæde med H I 3-6 hydroxylgrupper og et mono- eller disaccharid, idet den H I 15 esterificerede polyol har mindst 3 polylactid-coglycolid- : H kæder. HA prolonged release formulation, HI 10, characterized in that it comprises a peptide physician-HI agent compound in a 40/60 to 60/40 polylactide-cogly-HI polyester ester of polyol, the polyol unit being selected from the group HI consisting of alcohol containing a (C 3 -g) carbon chain having HI 3-6 hydroxyl groups and a mono- or disaccharide, the HI esterified polyol having at least 3 polylactide-coglycolide: H chains. H 23. Formulering med forlænget afgivelse, H I kendetegnet ved, at den omfatter et peptidlæge- H I 20 middelstof valgt fra gruppen bestående af calcitonin, lypres- H I sin og somatostatin i en lineær fra 40/60 til 60/40 polylac- H I tid-coglycolidpolymer med kæder med en molekylvægt Mw på I mellem 25.000 og 100.000, en polydispersitet Mw/Mn på mellem H I 1,2 og 2, i en peptidlægemiddelforbindelseskoncentration på H 25 fra 0,2 til 10 vægtprocent. HA sustained release formulation, HI, characterized in that it comprises a peptide physician HI agent selected from the group consisting of calcitonin, lypress HI sin and somatostatin in a linear from 40/60 to 60/40 polylac-HI time coglycolide polymer with chains having a molecular weight Mw of I between 25,000 and 100,000, a polydispersity Mw / Mn of between HI 1.2 and 2, in a peptide drug compound concentration of H 25 from 0.2 to 10% by weight. H 24. Formulering med forlænget afgivelse ifølge krav 22, H I kendetegnet ved, at den har en hovedmolekylvægt H I Mw på fra 10.000 til 200.000 og en polydispersitet Mw/Mn H I 30 på fra 1,7 til 3,0. H24. An extended release formulation according to claim 22, characterized in that it has a main molecular weight H I Mw of from 10,000 to 200,000 and a polydispersity Mw / Mn H I 30 of from 1.7 to 3.0. H 25. Formulering med forlænget afgivelse ifølge krav 22, H kendetegnet ved, at Mw er fra 35.000 til 60.000. H I 35 26. Formulering med forlænget afgivelse ifølge krav 22, H I kendetegnet ved, at Mw/Mn er fra 2,0 til 2,5. H DK 175849 B1An extended release formulation according to claim 22, H characterized in that Mw is from 35,000 to 60,000. H I 35 An extended release formulation according to claim 22, characterized in that Mw / Mn is from 2.0 to 2.5. H DK 175849 B1 27. Formulering med forlænget afgivelse ifølge krav 16, 22 eller 23, kendetegnet ved, at når formuleringen administreres subkutant til en rotte i en dosis på 10 mg lægemid-5 delstof pr. kg legemsvægt, udvises en lægemiddelstofkoncentration i blodplasmaet på mindst 0,3 ng/ml og mindre end 20 ng/ml i en 30 dages periode.The sustained-release formulation according to claim 16, 22 or 23, characterized in that when the formulation is administered subcutaneously to a rat at a dose of 10 mg drug per day. per kg body weight, a drug plasma concentration of at least 0.3 ng / ml and less than 20 ng / ml is exhibited over a 30 day period. 28. Formulering med forlænget afgivelse ifølge krav 16, 22 10 eller 23, kendetegnet ved, at når formuleringen administreres intramuskulært til en kanin i en dosis på 5 mg lægemiddelstof pr. kg legemsvægt, udvises en lægemiddelstofkoncentration på mindst 0,3 ng/ml og højst 20 ng/ml i 15 en 50 dages periode.The sustained release formulation according to claim 16, 22 or 23, characterized in that when the formulation is administered intramuscularly to a rabbit at a dose of 5 mg drug per per kg body weight, a drug concentration of at least 0.3 ng / ml and a maximum of 20 ng / ml is exhibited for a 50 day period. 29. Formulering med forlænget afgivelse ifølge krav 16, 22 eller 23, kendetegnet ved, at når formuleringen admini-20 streres intramuskulært til en kanin i en dosis på 5 mg lægemiddelstof pr. kg legemsvægt, udvises en retardering på mindst 70% i en periode på fra 0 til 42 eller 43 dage.The sustained release formulation according to claim 16, 22 or 23, characterized in that when the formulation is administered intramuscularly to a rabbit at a dose of 5 mg drug per day. per kg body weight, a retardation of at least 70% is exhibited for a period of 0 to 42 or 43 days. 30. Formulering med forlænget afgivelse ifølge krav 16, 22 25 eller 23, kendetegnet ved, at når formuleringen administreres subkutant til en rotte i en dosis på 10 mg lægemid-‘ delstof pr. kg legemsvægt, udvises et gennemsnitligt plas maniveau (cp-ideal) på fra 2,5 til 6,5 ng/ml i en tids-30 periode på fra o til 42 dage.The sustained-release formulation according to claim 16, 22 or 23, characterized in that when the formulation is administered subcutaneously to a rat at a dose of 10 mg of drug substance per day. per kg body weight, an average plasma level (cp ideal) of 2.5 to 6.5 ng / ml is exhibited over a time period of from 0 to 42 days. 31. Formulering med forlænget afgivelse ifølge krav 16, 22 eller 23, kendetegnet ved, at når formuleringen admini-35 streres intramuskulært til en kanin i en dosis på 5 mg· lægemiddelstof pr. kg legemsvægt, udvises et gennemsnitligt plasmaniveau (cp-ideal) på fra 3,5 til 6,5 ng/ml. — - - ------ . - - ---. H ^Β I DK 175849 B1 I I IAn extended-release formulation according to claim 16, 22 or 23, characterized in that when the formulation is administered intramuscularly to a rabbit at a dose of 5 mg of drug per dose. an average plasma level (cp ideal) of 3.5 to 6.5 ng / ml is exhibited. - - - ------. - - ---. H ^ Β I DK 175849 B1 I I I 32. Formulering med forlænget afgivelse ifølge krav 16, 22 I I eller 23, I I kendetegnet ved, at når formuleringen admini- I I streres subkutant til en rotte i en dosis på 10 mg lægemid- I 5 delstof pr. kg legemsvægt, udvises en AUC på fra 160 til B I 230 g/ml x dage i en periode på fra 0 til 42 eller 43 dage. BThe prolonged release formulation according to claims 16, 22 I or 23, I, characterized in that when the formulation is administered subcutaneously to a rat at a dose of 10 mg drug per 5 ml. kg body weight, an AUC of from 160 to B is exhibited at 230 g / ml x days for a period of from 0 to 42 or 43 days. B 33. Formulering med forlænget afgivelse ifølge krav 16, 22 B I eller 23, B I 10 kendetegnet ved, at når formuleringen admini- B ; streres intramuskulært til en kanin i en dosis på 5 mg B I 1 lægemiddelstof pr. kg legemsvægt, udvises en AUC på fra 160 B I til 275 ng/ml x dage i en periode på fra 0 til 42 eller 43 B dage. B I 15 IA sustained release formulation according to claims 16, 22 B I or 23, B I 10, characterized in that when the formulation is administered; is injected intramuscularly into a rabbit at a dose of 5 mg B in 1 drug per day. kg body weight, an AUC of 160 B I to 275 ng / ml x days is exhibited for a period of 0 to 42 or 43 B days. B I 15 I 34. Formulering med forlænget afgivelse ifølge krav 16 til B anvendelse ved behandling eller forebyggelse af akromegali B I eller brystcancer. B I 20 35. Octreotidpamoat. B I 1 IThe sustained release formulation of claim 16 of B for use in the treatment or prevention of acromegaly B I or breast cancer. B I 20 35. Octreotide pamoate. B I 1 I 36. Fremgangsmåde til fremstilling af octreotidpamoat, B I kendetegnet ved, at octreotid omsættes med embon- B I syre eller et reaktivt derivat deraf. B 1 25 IA process for the preparation of octreotide pamoate, B I, characterized in that octreotide is reacted with embonic B I acid or a reactive derivative thereof. B 1 25 I 37. Formulering med forlænget afgivelse, B I kendetegnet ved, at den omfatter et peptidlæge- B I middelstof valgt fra gruppen bestående af calcitonin og / B I lypressin og farmaceutisk acceptable salte deraf i en bio- B I 30 nedbrydelig, biokompatibel polymermatrix. . B37. Prolonged release formulation, B I, characterized in that it comprises a peptide drug B I agent selected from the group consisting of calcitonin and / B I lypressin and pharmaceutically acceptable salts thereof in a bio-B biodegradable biocompatible polymer matrix. . B
DK199001625A 1989-07-07 1990-07-05 Process for the preparation of microparticles comprising a drug substance, sustained release formulation, octreotide pamoate and process for the preparation thereof DK175849B1 (en)

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JPH0832624B2 (en) 1996-03-29
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HU211602A9 (en) 1995-12-28
AU5874690A (en) 1991-01-10
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