You’re using a public version of DrugPatentWatch with 5 free searches available | Register to unlock more free searches. CREATE FREE ACCOUNT

Last Updated: March 29, 2024

Claims for Patent: 6,117,455


✉ Email this page to a colleague

« Back to Dashboard


Summary for Patent: 6,117,455
Title: Sustained-release microcapsule of amorphous water-soluble pharmaceutical active agent
Abstract:A sustained-release microcapsule contains an amorphous water-soluble pharmaceutical agent having a particle size of from 1 nm-10 .mu.m and a polymer. The microcapsule is produced by dispersing, in an aqueous phase, a dispersion of from 0.001-90% (w/w) of an amorphous water-soluble pharmaceutical agent in a solution of a polymer having a wt. avg. molecular weight of 2,000-800,000 in an organic solvent to prepare an s/o/w emulsion and subjecting the emulsion to in-water drying.
Inventor(s): Takada; Shigeyuki (Kobe, JP), Kurokawa; Tomofumi (Hyogo-ken, JP), Iwasa; Susumu (Tsuzuki-gun, JP)
Assignee: Takeda Chemical Industries, Ltd. (Osaka, JP)
Application Number:08/535,386
Patent Claims:1. A sustained-release microcapsule which is obtained by the steps comprising:

selecting a dispersion of an amorphous water-soluble pharmaceutical agent having a particle size of from 1 nm-10 .mu.m in a solution of a polymer in an organic solvent, wherein said pharmaceutical agent is dispersed in an amount of from 0.001-90% (w/w) and said polymer has a wt. avg. molecular weight of from 2,000-800,000;

dispersing said dispersion of amorphous water-soluble pharmaceutical agent in an aqueous phase to prepare an s/o/w emulsion; and

subjecting the s/o/w emulsion to in-water drying.

2. The microcapsule according to claim 1, wherein the concentration of the pharmaceutical agent in the solution of a polymer in an organic solvent is from about 0.01% to about 70% (W/W).

3. The microcapsule according to claim 1, wherein the solution of a polymer in an organic solvent additionally contains a basic substance.

4. The microcapsule according to claim 3, wherein the basic substance is a basic amino acid.

5. The microcapsule according to claim 3, wherein the basic substance is L-arginine.

6. The microcapsule according to claim 3, wherein the basic substance is N-methylglucamine.

7. The microcapsule according to claim 3, wherein the concentration of the basic substance in the solution of a polymer in an organic solvent is about 0.1% to about 3% (W/W).

8. The microcapsule according to claim 1, wherein the aqueous phase additionally contains an osmotic pressure adjustor.

9. The microcapsule according to claim 8, wherein the osmotic pressure adjustor is a salt.

10. The microcapsule according to claim 9, wherein the salt is sodium chloride.

11. The microcapsule according to claim 1, wherein the pharmaceutical agent is dispersed in the polymer.

12. The microcapsule according to claim 1, wherein the amorphous water-soluble pharmaceutical agent is obtained from an aqueous solution of a water-soluble pharmaceutical agent by a drying process.

13. The microcapsule according to claim 12, wherein the drying process is freeze drying or spray drying.

14. The microcapsule according to claim 1, wherein the pharmaceutical agent is readily soluble in water.

15. The microcapsule according to claim 1, wherein the water-solubility of the pharmaceutical agent is not less than about 1 g/100 ml at 20.degree. C.

16. The microcapsule according to claim 1, wherein the water-solubility of the pharmaceutical agent is not less than about 5 g/100 ml at 20.degree. C.

17. The microcapsule according to claim 1, wherein the average particle size of the pharmaceutical agent is not more than about 1 .mu.m.

18. The microcapsule according to claim 1, wherein the pharmaceutical agent is an acidic or neutral substance.

19. The microcapsule according to claim 14, wherein the pharmaceutical agent is a peptide or its derivative.

20. The microcapsule according to claim 19, wherein the peptide or its derivative is selected from the group consisting of a compound having LH-RH activity, an LH-RH antagonist, a GPIIb/IIIa antagonist, a compound having similar activity to GPIIb/IIIa antagonism, insulin, somatostatin, a somatostatin derivative, growth hormone, prolactin, adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), thyrotropin-releasing hormone (TRH) or a salt or derivative thereof, thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), parathyroid hormone (PTH) or a derivative thereof, an N-terminal peptide fragment (1-34 position) of human PTH, vasopressin, a vasopressin derivative, oxytocin, calcitonin, a calcitonin derivative having similar activity to calcitonin, glucagon, gastrin, secretin, pancreozymin, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin, an enkephalin derivative, endorphin, kyotorphin, interferon, interleukin, tuftsin, thymopoietin, thymosthymlin, thymic humoral factor (THF), serum thymic factor (FTS), an FTS derivative, thymosin, thymic factor X, tumor necrosis factor (TNF), colony stimulating factor (CSF), motilin, dynorphin, bombesin, neurotensin, caerulein, bradykinin, urokinase, asparaginase, kallikrein, substance P, nerve growth factor, a blood coagulation factor, lysozyme hydrochloride, polymyxin B, colistin, gramicidin, bacitracin, protein synthesis-stimulating peptide, gastric inhibitory polypeptide (GIP), vasoactive intestinal polypeptide (VIP), platelet-derived growth factor (PDGF), growth hormone-releasing factor (GRF), bone morphogenetic protein (BMP), epidermal growth factor (EGF), erythropoietin (EPO), and an endothelin antagonist or a salt or derivative thereof.

21. The microcapsule according to claim 20, wherein the compound having LH-RH activity is a compound represented by the formula (I):

wherein R.sub.1 is His, Tyr, Trp or p-NH.sub.2 -Phe; R.sub.2 is Tyr or Phe; R.sub.3 is Gly or a D-amino acid residue; R.sub.4 is Leu, Ile or Nle; R.sub.5 is Gly-NH-R.sub.6 or NH-R.sub.6 in which R.sub.6 is H or lower alkyl optionally substituted with hydroxy, or a salts thereof.

22. The microcapsule according to claim 21, wherein R.sub.1 is His, R.sub.2 is Tyr, R.sub.3 is D-Leu, R.sub.4 is Leu, and R.sub.5 is NHCH.sub.2 --CH.sub.3.

23. The microcapsule according to claim 20, wherein the LH-RH antagonist is N-(2S-tetrahydrofuroryl)Gly-3-(2-naphthyl)-D-alanyl-(4-chloro)-D-Phe-3-(3- pyridyl)-D-Ala-L-Ser-N-methyl-L-Tyr-(N-.epsilon.-nicotinyl)-D-Lys-L-Leu-(N- .epsilon.-isopropyl)-L-Lys-L-Pro-D-Ala.multidot.NH.sub.2.

24. The microcapsule according to claim 20, wherein the GPIIb/IIIa antagonist is barbourin, a peptide having the sequence Arg-Gly-Asp.

25. The microcapsule according to claim 24, wherein the peptide having the sequence Arg-Gly-Asp is a peptide selected from the group consisting of Arg-Gly-Asp-Ser, (Arg-Gly-Asp-Ser)tetramer, Gly-Arg-Gly-Asp-Ser-Pro, and cyclo-S,S-[Ac-Cys(N.sup..alpha. -methyl)Arg-Gly-D-Asn-penicillamine]-NH.sub.2).

26. The microcapsule according to claim 20, wherein the compound having similar activity to GPIIb/IIIa antagonism is selected from the group consisting of (S)-4-[(4-amidinobenzoyl)glycyl]-3-methoxy-carbonylmethyl-2-oxopiperazine- 1-acetic acid, 4-(4-amidinobenzoylglycyl)-2-oxopiperazine-1,3-diacetic acid hydrochloride, 2-S-(n-butylsulfonyl-amino)-3-[4-(N-piperidin-4-yl)butyloxyphenyl]-propion ic acid hydrochloride, L-Tyr-N-(butylsulfonyl)-O-[4-(4-piperidinyl)butyl] monohydrochloride, ethyl[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxybutyl]amino-4-pentyno ate, [1-[N-(p-amidinophenyl)-L-Tyr]-4-piperidinyl]acetic acid, and cyclic[D-2-aminobutyryl-N-2-methyl-L-Arg-Gly-L-Asp-3-aminomethyl-benzoic acid] methanesulfonate.

27. The microcapsule according to claim 20, wherein the endothelin antagonist is cyclo-[D-.alpha.-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-L-alanyl-L- .alpha.-aspartyl-D-2-(2-thienyl)glycyl-L-leucyl-D-tryptophyl] sodium salt.

28. The microcapsule according to claim 12, wherein the peptide or its derivative is (S)-4-[(4-amidinobenzoyl)glycyl]-3-methoxy-carbonylmethyl-2-oxopiperazine- 1-acetic acid].

29. The microcapsule according to claim 1, wherein the polymer is a biodegradable polymer.

30. The microcapsule according to claim 29, wherein the biodegradable polymer is a polyester.

31. The microcapsule according to claim 30, wherein the polyester is lactic acid/glycolic acid copolymer.

32. The microcapsule according to claim 31, wherein the molar ratio of lactic acid/glycolic acid is 100/0 to 25/75.

33. The microcapsule according to claim 32, wherein the molar ratio of lactic acid/glycolic acid is 100/0 to 50/50.

34. The microcapsule according to claim 31, wherein the weight-average molecular weight of lactic acid/glycolic acid copolymer is about 5,000 to about 30,000.

35. The microcapsule according to claim 31, wherein the weight-average molecular weight of lactic acid/glycolic acid copolymer is about 5,000 to about 20,000.

36. The microcapsule according to claim 30, wherein the polyester is hydroxybutyric acid/glycolic acid copolymer.

37. The microcapsule according to claim 36, wherein the molar ratio of hydroxybutyric acid/glycolic acid is 100/0 to 25/75.

38. The microcapsule according to claim 37, wherein the molar ratio of hydroxybutyric acid/glycolic acid is 100/0 to 50/50.

39. The microcapsule according to claim 36, wherein the weight-average molecular weight of hydroxybutyric acid/glycolic acid copolymer is about 5,000 to about 25,000.

40. The microcapsule according to claim 39, wherein the weight-average molecular weight of hydroxybutyric acid/glycolic acid copolymer is about 5,000 to about 20,000.

41. The microcapsule according to claim 1, which is for treating a disease in the circulatory system.

42. The microcapsule according to claim 1, which is for treating thrombosis.

Details for Patent 6,117,455

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 01/15/1974 ⤷  Try a Trial 2014-09-30
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 12/27/1984 ⤷  Try a Trial 2014-09-30
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 02/15/1985 ⤷  Try a Trial 2014-09-30
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

Make Better Decisions: Try a trial or see plans & pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.