Microcapsules with modified release of active principles with low solubility for oral delivery

• US 20070160678A1
• Filed: 10/20/2006
• Published: 07/12/2007
• Est. Priority Date: 07/26/2002
• Status: Active Grant

• Current Assignee: Flamel Ireland, Ltd.
• Original Assignee: Flamel Ireland, Ltd.
• Inventors: Guimberteau, Florence, Soula, Gerard, Castan, Catherine, Meyruiex, Remi
• Granted Patent: US 8,821,935 B2
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Abstract

The present invention is directed to microcapsules for reliably modified release and adapted to industrial reproduction of an active principle hardly water-soluble, other than anti-hyperglycemia agents. Each of said microcapsules comprises a core of hardly soluble active principle and a coating film applied on the core. Their mean diameter is less than 1000 microns. The coating film contains a film-forming polymer (PI) insoluble in gastrointestinal tract fluids, a water-soluble polymer (P2), a plasticizer (PL), and optionally a lubricating surfactant (TA). Said coating film represents at least 4% p/p of dry matter of their total weight, and its components P1, P2, PL satisfy the following characteristics: dry weight mass fraction of PI relative to the total coating weight ranging between 40 and 90%; dry matter weight fraction of PL/P1 +P2 ranging between 15 and 60%; dry matter weight fraction of PL/P1+P2 ranging between 1 and 30%. The present invention is also directed to the uses of said microcapsules in galenic formulation.

Claims

1-13. -13. (canceled)

14. A microcapsule for the modified release of at least one active principle with low water solubility,

wherein the microcapsule comprises a core, at least one active principle and a coating film applied onto the core, wherein the mean diameter of the microcapsule is less than 1000 microns,

wherein the coating film is at least 3% dry weight to total weight and comprises:

I. at least one film-forming polymer insoluble in gastrointestinal tract fluid;

II. at least one water-soluble polymer; and

III. at least one plasticizer,

wherein the at least one film-forming polymer insoluble in gastrointestinal tract fluid is between 40 and 90% dry weight relative to the total mass of the coating;

wherein the mass fraction of the at least one water-soluble polymer dry weight, relative to the total dry weight of the at least one film-forming polymer insoluble in gastrointestinal tract fluids and at least one water-soluble polymer, is between 15 and 60%; and

wherein the mass fraction of the at least one plasticizer dry weight, relative to the total dry weight of the at least one film-forming polymer insoluble in gastrointestinal tract fluids and the at least one plasticizer, is between 1 and 30%.

15. The microcapsule of claim 14, wherein

I. the at least one film-forming polymer insoluble in gastrointestinal tract fluid is not present in a proportion of 50 to 90% by dry weight relative to the total mass of the coating composition and does not comprise a water-insoluble derivative of cellulose;

II. the at least one water-soluble polymer is not present in the proportion of 2 to 25% by dry weight relative to the total mass of the coating composition and does not consist of polyacrylamide, one poly-N-vinyl-amide or one poly(N-vinyl lactam); and

III. the at least one plasticizer is not present in a proportion of 2 to 20% by dry weight relative to the total mass of the coating composition and does not consist of glyceryl esters, phthalates, citrates, sebacates, cetyl alcohol esters, castor oil, salicylic acid and cutin.

16. The microcapsule of claim 14, wherein the at least one film-forming polymer insoluble in gastrointestinal tract fluid is selected from the group comprising:

water-insoluble derivatives of cellulose, acrylic derivatives, poly (vinyl acetates), and mixtures thereof.

17. The microcapsule of claim 14, wherein the at least one water-soluble polymer is selected from the group comprising:

water-soluble derivatives of cellulose, polyacrylamides, poly-N-vinylamides, poly(N-vinyl lactams), polyvinyl alcohols (PVAs), polyoxyethylenes (POEs), polyvinylpyrrolidones (PVPs), and mixtures thereof.

18. The microcapsule of claim 14, wherein the at least one plasticizer is selected from the group comprising:

glycerol and esters thereof, acetylated glycerides, glyceryl monostearate, glyceryl triacetate, glyceryl tributyrate, phthalates, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, citrates, acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate, sebacates, diethyl sebacate, dibutyl sebacate, adipates, azelates, benzoates, plant oils, fumarates, diethyl fumarate, malates, diethyl malate, oxalates, diethyl oxalate, succinates, dibutyl succinate, butyrates, acetyl alcohol esters, salicylic acid, triacetin, malonates, diethyl malonate, cutin castor oil, and mixtures thereof.

19. The microcapsule of claim 14, wherein the coating film also comprises

IV. at least one lubricating surfactant.

20. The microcapsule of claim 19, wherein the at least one lubricating surfactant is not present in a proportion of 2 to 20% by dry weight relative to the total mass of the coating composition and is not chosen from alkali metal salts, alkaline-earth metal salts of fatty acids, polyoxyethylenated sorbitan esters, polyoxyethylenated castor oil derivatives, calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, sodium stearyl fumarate and glyceryl behenate.

21. The microcapsule of claim 19, wherein the at least one lubricating surfactant is in a proportion of 2 to 20% of the total mass of the dry coating.

22. The microcapsule of claim 19, wherein the at least one lubricating surfactant is selected from the group comprising:

anionic surfactants, alkali metal salts of fatty acids, alkaline-earth metal salts of fatty acids, stearic acid, oleic acid, polyoxyethylene oils, polyoxyethylenated hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenated sorbitan esters, polyoxyethylenated castor oil derivatives, stearates, calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, stearyl fumarates, sodium stearyl fumarate, glyceryl behenate, and mixtures thereof.

23. The microcapsule of claim 14, wherein the microcapsule mean diameter is between 800 and 50 microns.

24. The microcapsule of claim 23, wherein the microcapsule mean diameter is between 600 and 100 microns.

25. The microcapsule of claim 14, wherein the active principle is not an orally administered blood glucose-lowering agent.

26. The microcapsule of claim 14, wherein the active principle is selected from the group comprising:

antiulcer agents, antidiabetic agents, anticoagulants, antithrombics, blood lipid-lowering agents, antiarrhythmics, vasodilators, antiangina agents, antihypertensives, vasoprotective agents, fertility promoters, inducers and inhibitors of uterine labor, contraceptives, antibiotics, antifungal agents, antiviral agents, anticancer agents, anti-inflammatories, analgesics, antiepileptics, antiparkinsonian agents, neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigraine agents, antidepressives, antitussives, antihistamines and antiallergic agents.

27. The microcapsule of claim 14, wherein the active principle is selected from the group comprising:

prazosine, acyclovir, nifedipine, naproxen, ibuprofen, ketoprofen, fenoprofen, indomethacine, diclofenac, sulpiride, terfenadine, carbamazepine, fluoxetine, alprazolam, famotidine, ganciclovir, spironolactone, acetylsalicyclic acid, quinidine, morphine, amioxicillin, paracetamol, metoclopramide, verapamil and mixtures thereof.

28. A medicinal product comprising the microcapsules of claim 14.

29. The medicinal product of claim 28, wherein the form of the medicinal product is selected from the group comprising:

tablet, gelatin capsule, powder, liquid, and an aqueous suspension.

30. A method of controlling the in vivo release of at least one active principle with a low water solubility by use of orally administered microcapsules, wherein the microcapsules comprise a core, at least one active principle and a coating film applied onto the core, wherein the mean diameter of the microcapsule is less than 1000 microns, and

wherein the coating film is at least 4% dry weight to total weight and comprises:

I. at least one film-forming polymer insoluble in gastrointestinal tract fluid;

II. at least one water-soluble polymer; and

III. at least one plasticizer,

wherein the at least one film-forming polymer insoluble in gastrointestinal tract fluid is between 40 and 90% dry weight relative to the total mass of the coating;

wherein the mass fraction of the at least one water-soluble polymer dry weight, relative to the total dry weight of the at least one film-forming polymer insoluble in gastrointestinal tract fluids and at least one water-soluble polymer, is between 15 and 60%; and

wherein the mass fraction of the at least one plasticizer dry weight, relative to the total dry weight of the at least one film-forming polymer insoluble in gastrointestinal tract fluids and the at least one plasticizer, is between 1 and 30%.

31. The method of claim 30, wherein:

I. the at least one film-forming polymer insoluble in gastrointestinal tract fluid is not present in a proportion of 50 to 90% by dry weight relative to the total mass of the coating composition and does not comprise a water-insoluble derivative of cellulose;

II. the at least one water-soluble polymer is not present in the proportion of 2 to 25% by dry weight relative to the total mass of the coating composition and does not consist of polyacrylamide, one poly-N-vinyl-amide or one poly(N-vinyl lactam); and

III. the at least one plasticizer is not present in a proportion of 2 to 20% by dry weight relative to the total mass of the coating composition and does not consist of glyceryl esters, phthalates, citrates, sebacates, cetyl alcohol esters, castor oil, salicylic acid and cutin.

32. The method of claim 30, wherein the coating film also comprises

IV. at least one lubricating surfactant.

33. The method of claim 32, wherein the at least one lubricating surfactant is not present in a proportion of 2 to 20% by dry weight relative to the total mass of the coating composition and is not chosen from alkali metal salts, alkaline-earth metal salts of fatty acids, polyoxyethylenated sorbitan esters, polyoxyethylenated castor oil derivatives, calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, sodium stearyl fumarate and glyceryl behenate.

34. The method of claim 30, wherein the at least one active principle is not an orally administered blood glucose-lowering agent.