NL8802323A - Farmaceutisch preparaat met vertraagde werking en werkwijze voor de bereiding daarvan. - Google Patents
Farmaceutisch preparaat met vertraagde werking en werkwijze voor de bereiding daarvan. Download PDFInfo
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- NL8802323A NL8802323A NL8802323A NL8802323A NL8802323A NL 8802323 A NL8802323 A NL 8802323A NL 8802323 A NL8802323 A NL 8802323A NL 8802323 A NL8802323 A NL 8802323A NL 8802323 A NL8802323 A NL 8802323A
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- Netherlands
- Prior art keywords
- water
- composition according
- peptide
- pharmaceutical composition
- insoluble
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- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Neurosurgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Description
* - 1 - ï
Farmaceutisch preparaat met vertraagde werking en werkwijze voor de bereiding daarvan.
Deze uitvinding betreft farmaceutische preparaten van therapeutisch werkzame maar in water onoplosbare polypeptiden, die een continue, beheerste en lang aanhoudende afgifte van zulke peptiden geven indien ze door implantatie of 5 injectie onder de huid of in de spieren van mens of dier in een omgeving van het fysiologische type geplaatst worden.
Deze uitvinding wordt verder gekenmerkt doot het gebruik van biologisch afbreekbare en biologisch verdragen polymeren en copolymeren als matrix waarin de in water onoplosbare 10 polypeptiden gedispergeerd of ingekapseld worden.
De behoefte aan een vertraagde afgifte van peptiden voor parenterale toediening wordt reeds lang onderkend. (Zie T.M.S. Chang "Biodegradable Semipermeable Microcapsules containing enzymes, hormones, vaccines and other biologicals" 15 in J. Bioengineering 1, 25 (1976); R. Langer "Controlled
Release of Macromolecules" in Chemtech, februari 1982, biz.
98-105; F.G. Hutchinson en B.J.A. Furr "Biodegradable carriers for the sustained release of polypeptides" in TIBTECH, april 1987 (vol. 5) biz. 102-106).
20 Een aantal van zulke formuleringen, maar toegepast op in water oplosbare polypeptiden is beschreven in het op 27 augustus 1986 gepubliceerde Europese octrooischrift 0.052.510 "Microencapsulation of water soluble polypeptides" en in het op 1 oktober 1986 gepubliceerde Europese octrooi-25 schrift 0.058.481 "Continuous release pharmaceutical compos itions".
Het nieuwe, verrassende en totaal en onverwachte aspect van deze uitvinding ligt hierin dat therapeutisch nuttige preparaten met lang aanhoudende en beheerste afgifte met 30 voordeel verkregen kunnen worden door in wezen in water onoplos bare peptiden te gebruiken welke bij kamer- of lichaamstemperatuur een onmeetbare lage oplosbaarheid in waterige oplossingen hebben en die toch een werkzame en beheerste afgifte van zulke peptiden geven wanneer hun preparaten parenteraal in een fysio- ,8802323 \ - 2 - i -"4 logische, in wezen waterige omgeving toegediend worden.
Deze uitvinding verschaft de verrassende en nieuwe mogelijkheid polypeptiden, die van nature of na synthese normaliter in water oplosbaar zijn, met voordeel in water onoplosbaar 5 worden door er in water onoplosbare additiezouten van te maken, zoals met pamoëzuur, tannienzuur, stearinezuur en andere niet-toxische, in water onoplosbare zuren, hetgeen men doet voordat men ze in een biologisch afbreekbare polymere matrix inkapselt of dispergeert.
10 Het gebruik van in water weinig of niet oplosbare derivaten bij behoefte aan een depot met lange afgifte is natuurlijk goed bekend, ook op het gebied van peptiden (zie het Amerikaanse octrooischrift 4.010.125 van Schally c.s., kolom 7, regel 25).
15 Maar als voor het afgeven van geneesmiddelen bio logisch afbreekbare polymeren zoals polymelkzuur, polyglycol-zuur, polyhydroxyboterzuur, polyorthoësters, polyacetalen e.d. gebruikt worden vereist het op continue wijze afgeven der peptiden altijd een aanmerkelijke oplosbaarheid in water. Beschre- 20 ven experimenten hebben laten zien dat de biologische afbraak van polymeren (zoals bijvoorbeeld polylactide en polylactide-co-glycolide) tot de opname van water en het ontstaan van waterige kanalen of poriën leidt waaruit de peptiden weglekken doordat zij in water oplosbaar zijn.
25 Onze ontdekking dat peptiden uit matrixen en micro- capsules in een zeer wenselijk patroon vrij kunnen komen als hun oplosbaarheid in water tot praktisch nul verlaagd wordt is totaal verrassend en in tegenspraak met wat de wetenschap leerde. In het bijzonder hebben we gevonden dat de afgifte van g 30 bepaalde peptiden zoals D-Trp -LHRH uit polymere matrixen in termen van uniformiteit en duur beter is naarmate het additie-zout van het peptide minder in water oplosbaar is.
"Oplosbaarheid in water" wordt hier gedefinieerd als de hoeveelheid peptide die in oplossing gevonden wordt wan- 35 neer het zout 4 uur in gedestilleerd water van 40°C of lager gedispergeerd of geroerd wordt; een stof heet "in water onoplosbaar" als de hoeveelheid dan 25 mg/1 of lager (0 tot 25 dpm) is.
Het is zeer wenselijk biologisch werkzame peptiden continu en gedurende lange tijd te verstrekken, zo van ëën week 40 tot meerdere maanden. Het is ook zeer wenselijk dat het afgifte- * 8802323 i - 3 - patroon beheerst wordt, om ongelijkmatige afgifte van peptiden bij het begin, in het midden of het einde van de therapeutische cyclus te voorkomen. Men vindt vaak dat peptiden in stoten uit biologisch afbreekbare matrixen vrijkomen (het "stooteffect"), 5 'of bij het begin van de cyclus of bij het einde daarvan, wanneer het polymere matrix door hydrolyse geërodeerd is.
Een belangrijk aspect van deze uitvinding is een beheersing van het afgiftepatroon, en in het algemeen een sterke vermindering van het stooteffect in het begin. Het in water 10 onoplosbare peptide wordt in mindere mate afgegeven dan de in water oplosbare derivaten daarvan, wat een langduriger afgifte mogelijk maakt en een overdosering voorkomt. Door een normaliter in water oplosbaar peptide in een onoplosbaar produkt om te zetten is men nu in staat het stooteffect van het begin (d.i. de 15 hoeveelheid peptide die in de eerste 24 uur vrijkomt) tot minder dan 30 % van de totale dosis te beperken.
Voorbeeld I
In 950 g methyleenchloride werd 50 g 50:50 copoly- meer van D,L-melkzuur en glycolzuur en een gemiddeld molecuul- 20 gewicht van 50.000 opgelost. Deze oplossing ging door een milli- pore-filter om eventuele fijne deeltjes en pyrogenen te verwij- 6 deren. Aan deze oplossing werd 1 g D-Trp -LHRH-pamoaat toegevoegd en dat werd met een menger met hoge afschuifkrachten ge-dispergeerd.
25 Dit mengsel werd in een draaiverdamper geplaatst en het grootste deel van het methyleenchloride werd er onder vacuum uit verwijderd. De overgehouden dikke suspensie werd op een glazen plaat uitgeschonken en de laag werd met een regelbare schraper op een dikte van 0,7 mm gebracht. Na drogen aan 30 de lucht werd de verkregen foelie 48 uur onder vacuum uitge droogd en daarna bij 70°C onder druk door een mondstuk van 0,8 mm geëxtrudeerd. De verkregen staafjes werden kryogeen bij -40°C vermalen.
Het verkregen korrelvormige materiaal werd door een 35 zeef van 180 jm gezeefd en de fijne fractie werd opgevangen en gesteriliseerd door het aan γ-straling tussen 2,5 en 2,8 Mrad bloot te stellen.
Voorbeeld II
De werkwijze van voorbeeld I werd herhaald, maar nu 40 met het stearaat van D-Trp^-LHRH in plaats van het pamoaat.
-8802323 - 4 - *
Voorbeeld III
Voorbeeld I werd herhaald, maar nu met het pamoaat I-:-1 van D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-N^ als in water onoplosbaar peptide.
5 Voorbeeld IV
Voorbeeld I werd herhaald met elk der volgende in water onoplosbare pamoëzuur-zouten: C.
D-Nal(2) -LHRH-pamoaat D-Sêr (0-tBu) ^-desGly ^-Azgly ^-LHRH-pamoaat 10 D-Ser(But)^-LHRH(l-9)-ethylamide-pamoaat 6 10
D-Leu -desGly -LHRH-ethylamide-pamoaat Voorbeeld V
De werkwijze van voorbeelden I t/m IV werd uitgevoerd met copolymeren van D,L-melkzuur en glycolzuur waarin de 15 molverhouding 67 % melkzuur/33 % glycolzuur, 75 % D,L-melkzuur en 25 % glycolzuur of 100 % D,L-melkzuur was.
Voorbeeld VI
De werkwijze van voorbeelden I t/m V werd toegepast met de in water onoplosbare pamoaten, tannaten en stea-20 raten van de volgende peptiden: oxytocine, vasopressine, ACTH, calcitonine, epidermale groeifactor, prolactine, inhibine, interferon, LHRH, somatostatine, insuline, glucagon, natriureti-sche factor van de hartboezem, endorphine, een renine-remmer, GHRH, peptide-T en synthetische analoga en modificaties daarvan. 25 Afgiftepatroon in dieren (ratten)
Een representatief afgiftepatroon van een geïmplanteerde formulering van D-Trp^-LHRH-pamoaat in ratten is als 6 volgt: ng/ml radioactief gemeten D-Trp -LHRH in plasma (gemiddelde van zes ratten): t 0,04; 1 uur: 7,74; 6 uur: 0,80; o 30 2e dag: 0,85; 4® dag: 0,77; 7® dag: 0,25; 11® dag: 0,12; 14® dag: 0,11; 18® dag: 0,11; 21® dag: 0,14; 25® dag: 0,18.
Zoals een vakman in zal zien is de uitvinding niet tot de bovenstaande voorbeelden beperkt.
35 * 8802323
Claims (11)
1. Farmaceutisch preparaat voor vertraagde en beheerste afgifte van een geneesmiddel over langere tijd, be- 5 staande uit een polylactide, een copolymeer van melkzuur en glycolzuur of een mengsel van zulke polymeren en uit een in water onoplosbaar peptide, dat geplaatst in een waterige omgeving van het fysiologische type het peptide gedurende ten minste één week continu afgeeft en dat in de eerste 24 uur 10 niet meer dan 30 % van de totale dosis afgeeft.
2. Farmaceutisch preparaat volgens conclusie 1 waarvan het in water onoplosbare peptide een farmaceutisch aanvaardbaar zout van LHRH of een synthetisch bereid analogon daarvan is.
3. Farmaceutisch preparaat volgens conclusie 1 of 2 waarvan het farmaceutisch aanvaardbare zout een zout van pamoë-zuur, tannienzuur of stearinezuur is.
4. Farmaceutisch preparaat volgens een der voorafgaande conclusies, waarvan het in water onoplosbare peptide een 20 farmaceutisch aanvaardbaar zout van oxytocine, vasopressine, ACTH, calcitonine, epidermale groeifactor, prolactine, inhibine, interferon, somatostatine, insuline, glucagon, natriuretische factor van de hartboezem, endorphine, een renine-remmer, groeihormoon vrijmakend hormoon, peptide T of een synthetisch analo-25 gon of modificatie daarvan is.
5. Farmaceutisch preparaat volgens een der conclusies 1, 2 of 3, waarvan het in water onoplosbare peptide het g pamoaat van D-Trp -LHRH is.
6. Farmaceutisch preparaat volgens een der conclu- 30 sies 1, 2 of 4 waarvan het in water onoplosbare peptide het pamoaat van D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-N^ is.
7. Farmaceutisch preparaat volgens een der conclusies 1 t/m 6 in de vorm van injiceerbare deeltjes met afmetingen van 1 tot 500 jm.
8. Farmaceutisch preparaat volgens een der conclu sies 1 t/m 6 in de vorm van een voor subcutane implantatie geschikte vaste stof die door γ-straling gesteriliseerd is.
9. Farmaceutisch preparaat volgens een der conclusies 1 t/m 7, gesteriliseerd door γ-straling en gesuspendeerd 40 in een farmaceutisch aanvaardbare drager die voor parenterale ‘8802323 $ . -6- f' toediening geschikt is.
10. Werkwijze voor het bereiden van een preparaat volgens een der conclusies 1 t/m 6, hieruit bestaande dat men een in water onoplosbaar zout van een peptide suspendeert in 5 een oplossing van een polylactide, een polyglycolide, een copoly- meer van melkzuur en glycolzuur of een mengsel van dergelijke polymeren, met het oplosmiddel verdampt en men het ontstane mengsel tot vaste deeltjes vormt die geschikt zijn voor paren-terale injectie of voor subcutaan implanteren.
11. Werkwijze voor het bereiden van een preparaat volgens een der conclusies 1 t/m 7, hieruit bestaande dat men een in water onoplosbare peptide dispèrgeert in een oplossing van een polylactide, polyglycolide, een copolymeer van melkzuur en glycolzuur of een mengsel van dergelijke polymeren, dat men 15 een coacerveringsmiddel toevoegt en de nu gevormde microcapsules in een farmaceutisch aanvaardbare uithardingsvloeistof uitschenkt en men uit deze suspensie de microcapsules afscheidt. -o-o-o-o-o- . 880232.3
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8722134A GB2209937B (en) | 1987-09-21 | 1987-09-21 | Water insoluble polypeptides |
| GB8722134 | 1987-09-21 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NL8802323A true NL8802323A (nl) | 1989-04-17 |
| NL193818B NL193818B (nl) | 2000-08-01 |
| NL193818C NL193818C (nl) | 2000-12-04 |
Family
ID=10624108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8802323A NL193818C (nl) | 1987-09-21 | 1988-09-20 | Farmaceutisch vast preparaat voor vertraagde en beheerste afgifte van een therapeutisch werkzame polypeptide verbinding. |
Country Status (23)
| Country | Link |
|---|---|
| US (2) | US5192741A (nl) |
| JP (1) | JPH0713023B2 (nl) |
| AT (1) | AT397035B (nl) |
| AU (1) | AU611944B2 (nl) |
| BE (1) | BE1001685A5 (nl) |
| CA (1) | CA1326438C (nl) |
| CH (1) | CH675968A5 (nl) |
| DE (2) | DE122004000023I2 (nl) |
| DK (1) | DK175311B1 (nl) |
| ES (1) | ES2009346A6 (nl) |
| FI (1) | FI96919C (nl) |
| FR (1) | FR2620621B1 (nl) |
| GB (1) | GB2209937B (nl) |
| GR (1) | GR1002244B (nl) |
| IE (1) | IE60608B1 (nl) |
| IL (1) | IL87790A (nl) |
| IT (1) | IT1225148B (nl) |
| LU (1) | LU87340A1 (nl) |
| NL (1) | NL193818C (nl) |
| NO (2) | NO178604C (nl) |
| PT (1) | PT88557B (nl) |
| SE (1) | SE503406C2 (nl) |
| ZA (1) | ZA886827B (nl) |
Families Citing this family (193)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4997815A (en) * | 1988-11-01 | 1991-03-05 | Children's Hospital Medical Center Of Northern California | Method for augmenting fetal hemoglobin by treatment with activin and/or inhibin |
| US5538739A (en) * | 1989-07-07 | 1996-07-23 | Sandoz Ltd. | Sustained release formulations of water soluble peptides |
| HU221294B1 (en) * | 1989-07-07 | 2002-09-28 | Novartis Ag | Process for producing retarde compositions containing the active ingredient in a polymeric carrier |
| PH30995A (en) * | 1989-07-07 | 1997-12-23 | Novartis Inc | Sustained release formulations of water soluble peptides. |
| US5225205A (en) * | 1989-07-28 | 1993-07-06 | Debiopharm S.A. | Pharmaceutical composition in the form of microparticles |
| US5439688A (en) * | 1989-07-28 | 1995-08-08 | Debio Recherche Pharmaceutique S.A. | Process for preparing a pharmaceutical composition |
| CH679207A5 (nl) * | 1989-07-28 | 1992-01-15 | Debiopharm Sa | |
| CH681425A5 (nl) * | 1990-11-14 | 1993-03-31 | Debio Rech Pharma Sa | |
| EP0423484B1 (de) * | 1989-10-16 | 1993-11-03 | PCD-Polymere Gesellschaft m.b.H. | Pressling mit retardierter Wirkstofffreisetzung |
| DE3935736A1 (de) * | 1989-10-27 | 1991-05-02 | Chemie Linz Deutschland | Pressling mit retardierter wirkstofffreisetzung |
| CA2046830C (en) * | 1990-07-19 | 1999-12-14 | Patrick P. Deluca | Drug delivery system involving inter-action between protein or polypeptide and hydrophobic biodegradable polymer |
| IE912365A1 (en) * | 1990-07-23 | 1992-01-29 | Zeneca Ltd | Continuous release pharmaceutical compositions |
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- 1987-09-21 GB GB8722134A patent/GB2209937B/en not_active Expired - Lifetime
-
1988
- 1988-07-04 DE DE122004000023C patent/DE122004000023I2/de active Active
- 1988-07-04 DE DE3822459A patent/DE3822459C2/de not_active Expired - Lifetime
- 1988-09-08 IE IE272788A patent/IE60608B1/en not_active IP Right Cessation
- 1988-09-12 AT AT0223488A patent/AT397035B/de not_active IP Right Cessation
- 1988-09-13 ZA ZA886827A patent/ZA886827B/xx unknown
- 1988-09-13 CA CA000577205A patent/CA1326438C/en not_active Expired - Lifetime
- 1988-09-14 FR FR8811991A patent/FR2620621B1/fr not_active Expired - Lifetime
- 1988-09-16 ES ES8802838A patent/ES2009346A6/es not_active Expired
- 1988-09-16 GR GR880100619A patent/GR1002244B/el not_active IP Right Cessation
- 1988-09-16 DK DK198805189A patent/DK175311B1/da active Protection Beyond IP Right Term
- 1988-09-16 AU AU22326/88A patent/AU611944B2/en not_active Expired
- 1988-09-19 IL IL87790A patent/IL87790A/xx active Protection Beyond IP Right Term
- 1988-09-19 FI FI884297A patent/FI96919C/fi not_active IP Right Cessation
- 1988-09-19 NO NO884154A patent/NO178604C/no not_active IP Right Cessation
- 1988-09-20 BE BE8801079A patent/BE1001685A5/fr not_active IP Right Cessation
- 1988-09-20 SE SE8803321A patent/SE503406C2/sv not_active IP Right Cessation
- 1988-09-20 PT PT88557A patent/PT88557B/pt not_active IP Right Cessation
- 1988-09-20 US US07/247,060 patent/US5192741A/en not_active Expired - Lifetime
- 1988-09-20 CH CH3494/88A patent/CH675968A5/fr not_active IP Right Cessation
- 1988-09-20 IT IT8805213A patent/IT1225148B/it active
- 1988-09-20 NL NL8802323A patent/NL193818C/nl not_active IP Right Cessation
- 1988-09-21 JP JP63238626A patent/JPH0713023B2/ja not_active Expired - Lifetime
- 1988-09-21 LU LU87340A patent/LU87340A1/fr unknown
-
1994
- 1994-02-10 US US08/196,872 patent/US5776885A/en not_active Expired - Lifetime
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2005
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Free format text: DEBIOPHARM S.A. |
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Owner name: DEBIO RECHERCHE PHARMACEUTIQUE S.A. |
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Effective date: 20080920 |