Medicinal and/or nutritional microcapsules for oral administration

• US 6,022,562 A
• Filed: 10/17/1995
• Issued: 02/08/2000
• Est. Priority Date: 10/18/1994
• Status: Expired due to Term

• Current Assignee: Flamel Technologies SA (Avadel Pharmaceuticals Plc)
• Original Assignee: Flamel Technologies SA (Avadel Pharmaceuticals Plc)
• Inventors: Selles, Jean-Philippe, Soula, Gerard, Autant, Pierre
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/544,208
• Time in Patent Office: 1,575 Days
• Field of Search: 424/489, 424/490, 424/488
• US Class Current: 424/489
• 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 relates to microcapsules for the oral administration of medicinal and/or nutritional active principles (AP), which are smaller than or equal to 1000 μm in size. These microcapsules consist of particles which are coated with a coating material consisting of a mixture of a film-forming polymer derivative, a hydrophobic plasticizer, a functional agent and a nitrogen-containing polymer. These microcapsules are also characterized by their ability to remain in the small intestine for a long time (at least 5 hours) and to allow, during the residence, release and absorption of the AP. The invention also relates to a process for the production of the said microcapsules.

Claims

1. Microcapsules of reservoir kind containing at least one medicinal nd nutritional active principle (AP), with the exclusion of acetylsalicylic acid (ASA), which are intended for oral administration, characterized:

in that they consist of particles of AP each coated with at least one coating film of specific following composition;

1- at least one film-forming polymer (P1) which is insoluble in the liquids of the digestive tract, present in a quantity of 50 to 90%, preferably 50 to 80% by weight of dry matter of the whole coating composition, and consisting of at least one non-hydrosoluble cellulose derivate, ethylcellulose and/or cellulose acetate being prefered;

2- at least one nitrogen-containing polymer (P2), present in a quantity of 2 to 25, preferably 5 to 15% by weight of dry matter of the whole coating composition, and consisting of at least one polyacrylarnide and/or one poly-N-vinylamide and/or one poly-N-vinyl-lactame, the polyacrylamide and/or the polyvinylpyrrolidone being prefered;

3- at least one plasticizer present in a quantity of 2 to 20%, preferably 4 to 15% by weight of dry matter of the whole coating composition, and consisting of at least one of the following compounds;

glycerol esters, phtalates, citrates, sebacates, cetylalcohol esters, castor oil and cutin, castor oil being particularly prefered;

4- at least one surface-active and/or lubricating agent, present in a quantity of 2 to 20%, preferably 4 to 15% by weight of dry matter of the whole coating composition, and chosen from anionic surfactants, preferably the alkali metal or alkakine-earth metal salts of fatty acids, stearic acid and/or oleic acid being preferred, and/or from nonionic surfactants, preferably polyoxyethylenated esters of sorbitan and/or polyoxyethylenated esters of sorbitan and/or polyoxyethylenated derivatives of castor oil, and/or from lubricants such as stearates, preferably calcium, magnesium, aluminium or zinc stearate, or such as stearylfumarate, preferably sodium stearylfimarate, and/or glyceryl behenate, said agent comprising only one or a mixture of the above products;

in that they have a particle size of between 50 and 1000 microns, preferably of between 100 and 750 microns and, more preferably, of between 100 and 500 microns;

in that they are designed so as to be able to remain in the small intestine for a period of at least about 5 hours, preferably of at least about 7 hours and, even more preferably, for a period of between about 8 hours and about 24 hours, and permitting so the absorption of the AP during at least part of their residence in the small intestine.

2. Microcapsules according to claim 1, characterized in that they comprise an amount of AP of between 55 and 95% by weight, and preferably of between 70 and 85% by weight.

3. Microcapsules according to claim 1, characterized in that the coating composition comprises from 60 to 80% of ethylcellulose, from 5 to 10% of polyvinylpyrrolidone, from 5 to 10% of castor oil and from 2 to 8% of magnesium stearate.

4. Microcapsules according to claim 1, characterized in that they are mixed with 0,5 to 5% by weight, preferably 1,5 to 3% by weight, of at least one anti-agglomerating agent formed, preferably, of talc, colloidal silica or of a mixture of the two.

5. Microcapsules according to claim 1, characterized in that the AP used belongs to at least one of the following families of active substances:

antiulcer, antidiabetic, anticoagulant, antithrombic, hypolipaemic, antiarrhythmic, vasodilatory, antianginal, antihypertensive, and vasoprotective agents, fertility enhancers, labour inducers and inhibitors, and contraceptive, antibiotic, antifingal, antiviral, anticancer, anti-inflammatory, analgesic, antiepileptic, antiparkinsonian, neuroleptic, hypnotic, anxiolytic, psychostimulatory, antimigraine, antidepressant, antitussive, antihistamine or antiallergic agents.

6. Microcapsules according to claim 5, characterized in that AP is chosen from the following compounds pentoxifyllin, prazosin, acyclovir, nifedipin, diltiazem, naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, fentiazac, oestradiol valerate, metoprolol, sulpiride, captopril, cimetidin, zidovudin, nicardipine, terfenadine, atenolol, salbutamol, carbamazepin, ranitidine, enalapril, simvastatin, fluoxetin, alprazolam, famotidin, ganciclovir, famiciclovir, spironolacton, 5-asa, quinidin, perindopril, morphin, pentazocin, paracetamol, omeprazol, metoclopraniid and mixtures thereof.

7. Microcapsules according to claim 1, characterized in that the AP consists of at least one nutritional and/or dietary supplement, preferably chosen from vitamins, amino acids, trace elements, antioxidants and mixtures thereof.

8. Process for producing the microcapsules according to claim 1, characterized in that it consists essentially in:

a/ selecting, or in case of need making, microparticles of AP with a particle size of between 50 and 1000 microns, preferably of between 100 and 750 microns and, even more preferably, of between 100 and 500 microns,

b/ preparing the coating composition by mixing together a polymer P1, a polymer P2, the plasticizer and the surface active and/or lubricating agent in a solvent system

c/ applying the coating composition/solvent system mixture to particles of AP,

d/ drying the microcapsules thus obtained, and

e/ optionally, mixing these microcapsules with at least one anti-agglomerating agent.

9. Process according to claim 7, characterized in that the solvent system is formed by compounds selected from the following list:

ketones, esters, chlorinated solvents, alcohols, which are preferably aliphatic, alkanes and mixtures thereof;

the compounds containing from 1 to 6 carbons being preferred, and

acetone, methyl ethyl ketone, methanol, ethanol, isopropanol and methylene chloride being particularly preferred.

10. Process according to claim 7, characterized in that the coating composition/solvent system mixture is applied by spraying onto the articles of AP set in motion, preferably by mechanical stirring or by fluidization.

11. Method of preparation of pharmaceutical forms, preferably in the form of tablets that can advantageously be crumbled, or powders or gelatin capsules, wherein the improvement is the use of the microcapsules according to claim 1.

12. Galenical system containing the microcapsules according to claim 1.

13. Method for treating and/or preventing diseases and/or pains, consisting in using the microcapsules according claim 1.

14. A method for treating and/or preventing diseases and/or pains, which comprises using microcapsules as a vehicle for at least one medicinal, nutritional or combination thereof as Active Principle (AP) which is capable of remaining in the small intestine for a prolonged period, said microcapsules:

being designed for oral administration and so as;

to be able to remain in the small intestine for at least about 5 hours, preferably at least about 7 hours and, even more preferably, for a period of between 8 and 24 hours, and

to make it possible to release the AP in the small intestine during at least part of their residence, and

consisting of particles of AP each coated with at least one coating film of specific composition and having a particle size of between 50 and 1000 μ

m, preferably of between 100 and 750 μ

m and, even more preferably, of between 200 and 500 μ

m.