Oral medicinal product with modified release of at least one active principle in multimicrocapsular form

Abstract

The field of the invention is that of oral pharmaceutical medicinal products or compositions, more particularly of the type of those comprising one or more active principles. The aim of the invention is to provide an improved oral medicinal product that can be administered in one or more daily doses, with modified release of active principle (in particular an active principle), for improving the prophylactic and therapeutic efficacy of such a medicinal product. This aim is achieved by means of the multimicrocapsular oral pharmaceutical form according to the invention in which the release of the AP is controlled by means of a double mechanism of triggering the release: time triggering and pH triggering. This medicinal product comprises microcapsules with modified release of active principle, each containing a core comprising the active principle and one or more swelling agents, and at least one coating making possible the modified release of the active principle.

Claims

1. An oral medicinal product comprising a plurality of microcapsules with modified release of active principle(s), wherein at least one .[.of said microcapsules.]. .Iadd.microcapsule .Iaddend.individually comprises: a microparticle comprising at least one active principle having a solubility of less than 20 g/L .[.(with the exclusion of carvedilol).]. and a swelling agent; and one coating on said microparticle making possible the modified release of the at least one active principle, said release being controlled by means of two distinct triggering mechanisms, wherein a first triggering mechanism is based on a variation in pH and wherein a second triggering mechanism is based on release of the at least one active principle after a predetermined period of residence in the stomach, wherein said coating confers on the microcapsules an in vitro dissolution behavior such that: at constant pH 1.4, the dissolution profile comprises a lag phase of less than or equal to 7 hours, and a change from pH 1.4 to pH 7.0 results in a release phase that begins without any lag time; wherein said swelling agent is capable of increasing the permeability of the coating for modified release of the .Iadd.at least one .Iaddend.active principle; wherein said swelling agent is selected from the group consisting of crosslinked polyvinylpyrrolidones, crosslinked carboxyalkylcelluloses, polacrilin potassium and mixtures thereof; .Iadd.and .Iaddend. .[.and.]. wherein the fraction by weight of the at least one active .[.principle(s).]. .Iadd.principle .Iaddend.released during the lag phase is less than or equal to 15% by weight per hour.

2. The medicinal product according to claim 1, wherein the swelling agent is chosen from those that allow the microcapsules to release in vitro at least 50% by weight of the .Iadd.at least one .Iaddend.active principle after 16 hours at pH 1.4.

3. The medicinal product according to claim 1, wherein the swelling agent is in the form of microparticles with a mean diameter of between 5 and 200 m.

4. The medicinal product according to claim 1, wherein the swelling agent is present in an amount of between 3 and 40% by weight relative to the total mass of the microcapsules.

5. The medicinal product according to claim 1, further comprising at least one wetting agent, contained in the microparticle, selected from the group consisting of anionic surfactants, nonionic surfactants, and mixtures thereof.

6. The medicinal product according to claim 1, wherein the microcapsules are capable of releasing in vitro at least 80% by weight of the .Iadd.at least one .Iaddend.active .[.principle(s).]. .Iadd.principle .Iaddend.after 12 hours at pH=7.0.

7. The medicinal product according to claim 1, wherein at least one .[.of said modified-release microcapsules.]. .Iadd.microcapsule .Iaddend.comprises a microparticle comprising a neutral core, and at least one active layer comprising at least one active principle.

8. The medicinal product according to claim 1, wherein .[.at least one of.]. the coating making possible .Iadd.the .Iaddend.modified release of the .Iadd.at least one .Iaddend.active .[.principle(s).]. .Iadd.principle .Iaddend.comprises a composite material comprising: at least one hydrophilic polymer A carrying groups that are ionized at neutral pH and at least one hydrophobic compound B; representing a mass fraction of 40% weight relative to the total mass of the microcapsules; and wherein the microcapsules have a mean diameter of less than 2000 m.

9. The medicinal product according to claim 8, wherein the weight ratio of B/A is between 0.2 and 1.5; and the hydrophobic compound B is selected from products that are crystalline in the solid state and that have a melting point T.sub.mB40 C.

10. The medicinal product according to either of claims 8 and 9, wherein the hydrophilic polymer A is selected from the group consisting of copolymers of (meth)acrylic acid, copolymers of (meth)acrylic acid alkyl ester, cellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetates succinate; and mixtures thereof.

11. The medicinal product according to one of claims 8 and 9, wherein the compound B is selected from the group consisting of vegetable waxes, mixtures of vegetable waxes, hydrogenated vegetable oils, mixtures of hydrogenated vegetable oils, diesters of glycerol and fatty acid, triesters of glycerol and fatty acid, yellow wax, lanolin, cetyl alcohol, and mixtures thereof.

12. The medicinal product according to claim 11, wherein compound B is selected from the group consisting of: hydrogenated cottonseed oil, hydrogenated soybean seed oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearin, tripalmitin, trimyristin, yellow wax, hard fat, fat that is useful as suppository bases, anhydrous dairy fats, lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogolglycerides, cetyl alcohol, polyglyceryl diisostearate, and mixtures thereof.

13. The medicinal product according to claim 8 wherein the coating making possible the .Iadd.modified .Iaddend.release of the at least one active .[.principle(s) of the microcapsules with modified release of active.]. principle comprises a single coating film comprising the composite material AB.

14. The medicinal product according to claim 1, said product comprising a mixture of more than one population of microunits, .[.each microunit containing at least one.]. .Iadd.the populations of microunits comprising .Iaddend.active principle(s), .[.(with the exclusion of carvedilol),.]. and wherein the populations differ from one another in that they have different in vitro dissolution profiles for at least one pH value of between 1.4 and 7.4.

15. The medicinal product according to claim 14, wherein each population of microunits comprises a population of microcapsules with modified release of active principle(s), and wherein at least one population of microcapsules with modified release of active principle(s) differs from at least one other population of microcapsules with modified release of active principle(s) through their respective triggering pHs.

16. The medicinal product according to claim 14, comprising at least two populations of microunits, wherein each population of microunits comprises a population of microcapsules with modified release of active principle(s), and wherein at least one population of microcapsules with modified release of active principle(s) differs from at least one other population of microcapsules with modified release of active principle(s) through their respective triggering times.

17. The medicinal product according to claim 14, wherein said product comprises: i. at least one population of microunits containing active principle(s) that allows immediate release of the active principle(s); ii. at least one population P1 of microcapsules with modified release of active principle(s); and iii. at least one population P2 of microcapsules with modified release of active principle(s); and wherein the respective triggering pHs of P1 and of P2 differ by at least 0.5 of a pH unit.

18. The medicinal product according to claim 14, wherein the respective triggering pH of each of the more than one population of .[.microcapsules with modified release of active principle(s).]. .Iadd.microunits .Iaddend.is between 5 and 7.

19. The medicinal product according to claim 14, wherein said product comprises: i. at least one population of microunits containing active principle(s) and allowing immediate release of the active principle(s); ii. at least one population P1 of microunits containing active principle(s), wherein the P1 population of microunits comprises microcapsules with modified release of the active principle(s) having a triggering pH .[.is.]. equal to 5.5; and iii. at least one population P2 of microunits containing active principle(s), wherein the P2 population of microunits comprises microcapsules with modified release of the active principle(s) having a triggering pH equal to 6.0 or 6.5.

20. The medicinal product according to claim 14, wherein said product has the following in vitro release profile: less than 20% of the active principle(s) is released after 2 hours at pH=1.4; .Iadd.and .Iaddend.at least 50% of the active principle(s) is released after 16 hours at pH=1.4.

21. The medicinal product according to claim 14, wherein said product comprises at least one population of microunits containing active principle(s) with immediate release, the behavior of which in an in vitro dissolution test is such that at least 80% of the active principle(s) is released in 1 hour at any pH of between 1.4 and 7.4.

22. The medicinal product according to claim 14, wherein the microunits containing active principle(s) contain active principle(s) in an amount that is between 5 and 80% by weight on a dry basis relative to the total mass of the microunits.

23. The medicinal product according to claim 1, wherein the product is provided in the form of a single daily oral dose comprising from 5,000 to 500,000 microcapsules with modified release of active principle(s).

24. The medicinal product according to claim 1, wherein at least one of the at least one active .[.principle(s).]. .Iadd.principle .Iaddend.is selected from the group consisting of: antiulcer agents, antidiabetic agents, anticoagulants, antithrombics, blood lipid-lowering agents, .[.antiarythmics.]. .Iadd.antiarrhythmics.Iaddend., vasodilators, anti-angina 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, antidepressants, antitussives, antihistamines or antiallergic agents, agents for combating congestive heart failure, angina pectoris, left ventricular hypertrophy, cardiac .[.arythmias.]. .Iadd.arrhythmias.Iaddend., myocardial infarctions, reflex tachycardia, ischaemic heart disease, atheromatosis, hypertension related to diabetes mellitus, portal hypertension, dizziness, bradycardia, arterial hypotension, hydrosodic retention, acute kidney failure, orthostatic hypotension, cerebral congestion, and mixtures thereof.

25. The medicinal product according to claim 1, wherein at least one of the at least one active .[.principle(s).]. .Iadd.principle .Iaddend.is selected from the group of products consisting of: acetylsalicylic acid, carbamazepine, pentoxifylline, prazosine, acyclovir, nifedipine, diltiazem, naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, fentiazac, oestradiol valerate, metoprolol, sulpiride, captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenolol, salbutamol, carbamazepine, ranitidine, enalapril, simvastatin, fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir, spironolactone, 5-asa, quinidine, perindopril, morphine, pentazocine, paracetamol, omeprazole, lansoprazole, metoclopramide, aminosalicylic acid, nalidixic acid, amoxicillin, amoxicillin and potassium clavulanate, ampicillin, ampicillin and sulbactam, azithromycin, bacampicillin, carbenicillin indanyl sodium .[.(and other carbenicillin salts).]., .Iadd.other carbenicillin salts, .Iaddend.capreomycin, cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephacelor, cefprozil, cephadrine, cefamandole, cefonicide, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefinetazole, cefotetan, cefoxitin, ciprofloxacine, clarithromycin, clindamycin, clofazimine, cloxacillin, cotriamoxazole, cycloserine, dicloxacillin, dirithromycin, erythromycin .[.(and erythromycin salts such as estolate, ethylsuccinate, gluceptate, lactobionate, stearate).]., .Iadd.erythromycin estolate, erythromycin ethylsuccinate, erythromycin gluceptate, erythromycin lactobionate, erythromycin stearate, .Iaddend.ethambutol-HCl .[.and.]..Iadd., .Iaddend.other .Iadd.ethambutol .Iaddend.salts, ethionamide, fosfomycin, imipenem, isoniazide, levofloxacine, lomefloxacine, loracarbef, methicillin, methenamine, metronidazole, metoclopramide, mezlocillin, nafcillin, nitrofurantoin, norfloxacin, novobiocin, ofloxacin, oxacillin, penicillin V, penicillin salts, penicillin complexes, pentamidine, piperacillin, piperacillin and tazobactam, sparfloxacin, sulphacytine, sulphamerazine, sulphamethazine, sulphamethixole, sulphasalazine, sulphisoxazole, sulphapyrizine, sulphadiazine, sulphmethoxazole, sulphapyridine, ticarcillin, ticarcillin and potassium clavulanate, trimethoprime, trimetrexate, troleanomycin, vancomycin, verapamil and mixtures thereof.

26. A method of therapeutic treatment, wherein the treatment comprises oral administration, according to a given dosage, of a medicinal product of claim 1.

27. The medicinal product according to claim 14, wherein one population of microunits consists of microunits that allow immediate release of the active principle(s).

28. The medicinal product according to claim 5, wherein the at least one wetting agent is selected from the group consisting of alkali metal salts of fatty acids, alkaline-earth metal salts of fatty acids, polyoxyethylenated oils, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenated esters of sorbitan, polyoxyethylenated derivatives of castor oil, calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, sodium stearylfumarate, glyceryl behenate, and mixtures thereof.

.Iadd.29. A composition comprising a plurality of microcapsules, wherein at least one microcapsule individually comprises: a microparticle comprising at least one active principle having a solubility of less than 20 g/L and a swelling agent; and one coating on said microparticle making possible modified release of the at least one active principle, wherein said coating confers on the microcapsules an in vitro dissolution behavior such that: at constant pH 1.4, the dissolution profile comprises a lag phase of less than or equal to 7 hours, and a change from pH 1.4 to pH 7.0 results in a release phase that begins without any lag time; wherein said swelling agent is capable of increasing the permeability of the coating for modified release of the at least one active principle; wherein said swelling agent is selected from the group consisting of crosslinked polyvinylpyrrolidones, crosslinked carboxyalkylcelluloses, polacrilin potassium and mixtures thereof; and wherein the fraction by weight of the at least one active principle released during the lag phase is less than or equal to 15% by weight per hour..Iaddend.

.Iadd.30. The composition of claim 29, wherein the composition is an oral pharmaceutical form in the form of a tablet, powder, sachet, liquid suspension, or capsule..Iaddend.

.Iadd.31. The composition of claim 29, wherein said swelling agent is selected from the group consisting of crosslinked carboxymethylcelluloses..Iaddend.

.Iadd.32. The composition of claim 31, wherein said swelling agent is sodium croscarmellose..Iaddend.

.Iadd.33. The composition of claim 29, wherein said swelling agent allows the microcapsules to release in vitro at least 50% by weight of the at least one active principle after 16 hours at pH 1.4..Iaddend.

.Iadd.34. The composition of claim 29, wherein the swelling agent is in the form of microparticles with a mean diameter of between 5 and 200 m..Iaddend.

.Iadd.35. The composition of claim 29, wherein the swelling agent is in the form of microparticles with a mean diameter of between 10 and 50 m..Iaddend.

.Iadd.36. The composition of claim 29, wherein said swelling agent is present in an amount of 4 to 30% by weight relative to the total mass of the microcapsules..Iaddend.

.Iadd.37. The composition of claim 29, wherein said swelling agent is present in an amount of 4 to 30% by weight relative to the total mass of the microcapsules..Iaddend.

.Iadd.38. The composition of claim 29, wherein said swelling agent is present in an amount of 5 to 25% by weight relative to the total mass of the microcapsules..Iaddend.

.Iadd.39. The composition of claim 29, further comprising at least one wetting agent, contained in the microparticle, said at least one wetting agent selected from the group consisting of anionic surfactants, nonionic surfactants, and mixtures thereof..Iaddend.

.Iadd.40. The composition of claim 39, wherein said at least one wetting agent is selected from the group consisting of: alkali metal salts of fatty acids, alkaline-earth metal salts of fatty acids, and combinations thereof..Iaddend.

.Iadd.41. The composition of claim 40, wherein said at least one wetting agent is selected from the group consisting of: alkali metal salts of stearic acid, alkali metal salts of oleic acid alkaline-earth metal salts of stearic acid, alkaline-earth metal salts of oleic acid and combinations thereof..Iaddend.

.Iadd.42. The composition of claim 40, wherein said at least one wetting agent is selected from the group consisting of: polyoxyethylenated oils, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenated esters of sorbitan, polyoxyethylenated derivatives of castor oil, stearates, calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, stearyl fumarates, sodium stearyl fumarate, glyceryl behenate, and combinations thereof..Iaddend.

.Iadd.43. The composition of claim 42, wherein said at least one wetting agent is polyoxyethylenated hydrogenated castor oil..Iaddend.

.Iadd.44. The composition of claim 29, wherein said at least one microcapsule releases in vitro at least 80% by weight of the at least one active principle after 12 hours at pH=7.0..Iaddend.

.Iadd.45. The composition of claim 29, wherein at least one microcapsule comprises a microparticle comprising a neutral core, and at least one active layer comprising at least one active principle..Iaddend.

.Iadd.46. The composition of claim 45, wherein said neutral core comprises sucrose, dextrose, lactose, or combinations thereof..Iaddend.

.Iadd.47. The composition of claim 45, wherein said neutral core comprises a cellulose microsphere..Iaddend.

.Iadd.48. The composition of claim 45, wherein said neutral core has a mean diameter of between 1 and 800 m..Iaddend.

.Iadd.49. The composition of claim 45, wherein said neutral core has a mean diameter of between 20 and 500 m..Iaddend.

.Iadd.50. The composition of claim 45, wherein said swelling agent is contained in said at least one active layer..Iaddend.

.Iadd.51. The composition of claim 45, wherein said at least one active layer comprises the at least one active principle, at least one swelling agent, at least one binder, and at least one surfactant..Iaddend.

.Iadd.52. The composition of claim 29, wherein said coating represents a mass fraction of less than or equal to 30% by weight relative to the total mass of the microcapsules..Iaddend.

.Iadd.53. The composition of claim 29, wherein said coating comprises a composite material, wherein the composite material comprises: at least one hydrophilic polymer A carrying groups that are ionized at neutral pH and at least one hydrophobic compound B; and wherein said coating represents a mass fraction of less than or equal to 40% by weight relative to the total mass of the microcapsules; and wherein the microcapsules have a mean diameter of less than 2000 m..Iaddend.

.Iadd.54. The composition of claim 53, wherein the weight ratio of B to A is between 0.2 and 1.5; and the hydrophobic compound B is selected from products that are crystalline in the solid state and that have a melting point T.sub.mB more than or equal to 40 C..Iaddend.

.Iadd.55. The composition of claim 53, wherein the hydrophilic polymer A is selected from the group consisting of: copolymers of (meth)acrylic acid, copolymers of (meth)acrylic acid alkyl ester, cellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and mixtures thereof..Iaddend.

.Iadd.56. The composition of claim 53, wherein the compound B is selected from the group consisting of vegetable waxes, mixtures of vegetable waxes, hydrogenated vegetable oils, mixtures of hydrogenated vegetable oils, diesters of glycerol and fatty acid, triesters of glycerol and fatty acid, yellow wax, lanolin, cetyl alcohol and mixtures thereof..Iaddend.

.Iadd.57. The composition of claim 56, wherein the compound B is selected from the group consisting of: hydrogenated cottonseed oil, hydrogenated soybean seed oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearin, tripalmitin, trimyristin, yellow wax, hard fat, fat that is useful as suppository bases, anhydrous dairy fats, lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogolglycerides, cetyl alcohol, polyglyceryl diisostearate, and mixtures thereof..Iaddend.

.Iadd.58. The composition of claim 53, wherein said coating comprises a single coating film comprising the composite material AB..Iaddend.

.Iadd.59. The composition of claim 29, said composition comprising a mixture of more than one population of microcapsules, each population of microcapsules containing at least one active principle, and wherein the populations differ from one another in that they have different in vitro dissolution profiles for at least one pH value of between 1.4 and 7.4..Iaddend.

.Iadd.60. The composition of claim 59, wherein at least one population of microcapsules differs from at least one other population of microcapsules through their respective triggering pHs..Iaddend.

.Iadd.61. The composition of claim 60, wherein the respective triggering pH of each of the more than one population of microcapsules is between 5 and 7..Iaddend.

.Iadd.62. The composition of claim 59, comprising at least two populations of microcapsules, and wherein at least one population of microcapsules differs from at least one other population of microcapsules through their respective triggering times..Iaddend.

.Iadd.63. The composition of claim 59, said composition comprising: i. at least one immediate release active principle; ii. at least one population P1 of microcapsules with modified release of the at least one active principle; and iii. at least one population P2 of microcapsules with modified release of the at least one active principle; and wherein the respective triggering pHs of P1 and of P2 differ by at least 0.5 of a pH unit..Iaddend.

.Iadd.64. The composition of claim 59, said composition comprising: i. at least one immediate release active principle; ii. at least one population of microcapsules with modified release of the at least one active principle and having a triggering pH equal to 5.5; and iii. at least one population of microcapsules with modified release of the at least one active principle and having a triggering pH equal to 6.0 or 6.5..Iaddend.

.Iadd.65. The composition of claim 59, said composition having the following in vitro release profile: less than 20% of the at least one active principle is released after 2 hours at pH=1.4; and at least 50% of the at least one active principle is released after 16 hours at pH=1.4..Iaddend.

.Iadd.66. The composition of claim 59, wherein the populations of microcapsules contain the at least one active principle in an amount that is between 5 and 80% by weight on a dry basis relative to the total mass of the microcapsules..Iaddend.

.Iadd.67. The composition of claim 59, wherein the populations of microcapsules contain the at least one active principle in an amount that is between 10 and 70% by weight on a dry basis relative to the total mass of the microcapsules..Iaddend.

.Iadd.68. The composition of claim 59, wherein the populations of microcapsules contain the at least one active principle in an amount that is between 15 and 60% by weight on a dry basis relative to the total mass of the microcapsules..Iaddend.

.Iadd.69. The composition of claim 29, said composition comprising at least one active principle with immediate release, the behavior of which in an in vitro dissolution test is such that at least 80% of the at least one active principle is released in 1 hour at any pH of between 1.4 and 7.4..Iaddend.

.Iadd.70. The composition of claim 29, wherein said composition is provided in the form of a single daily oral dose..Iaddend.

.Iadd.71. The composition of claim 29, comprising from 5,000 to 500,000 microcapsules with modified release of the at least one active principle..Iaddend.

.Iadd.72. The composition of claim 29, wherein at least one of the at least one active principle is selected from the group consisting of: antiulcer agents, antidiabetic agents, anticoagulants, antithrombics, blood lipid-lowering agents, antiarrhythmics, vasodilators, anti-angina 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, antidepressants, antitussives, antihistamines or antiallergic agents, agents for combating congestive heart failure, angina pectoris, left ventricular hypertrophy, cardiac arythmias, myocardial infarctions, reflex tachycardia, ischaemic heart disease, atheromatosis, hypertension related to diabetes mellitus, portal hypertension, dizziness, bradycardia, arterial hypotension, hydrosodic retention, acute kidney failure, orthostatic hypotension, cerebral congestion, and mixtures thereof..Iaddend.

.Iadd.73. The composition of claim 29, wherein at least one of the at least one active principle is selected from the group of products consisting of: acetylsalicylic acid, carbamazepine, pentoxifylline, prazosine, acyclovir, nifedipine, diltiazem, naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, fentiazac, oestradiol valerate, metoprolol, sulpiride, captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenolol, salbutamol, carbamazepine, ranitidine, enalapril, simvastatin, fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir, spironolactone, 5-asa, quinidine, perindopril, morphine, pentazocine, paracetamol, omeprazole, lansoprazole, metoclopramide, aminosalicylic acid, nalidixic acid, amoxicillin, amoxicillin and potassium clavulanate, ampicillin, ampicillin and sulbactam, azithromycin, bacampicillin, carbenicillin indanyl sodium, and other carbenicillin salts, capreomycin, cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephacelor, cefprozil, cephadrine, cefamandole, cefonicide, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefinetazole, cefotetan, cefoxitin, ciprofloxacine, clarithromycin, clindamycin, clofazimine, cloxacillin, cotriamoxazole, cycloserine, dicloxacillin, dirithromycin, erythromycin, erythromycin estolate, erythromycin ethylsuccinate, erythromycin gluceptate, erythromycin lactobionate, erythromycin stearate, ethambutol-HCl, other ethambutol salts, ethionamide, fosfomycin, imipenem, isoniazide, levofloxacine, lomefloxacine, loracarbef, methicillin, methenamine, metronidazole, metoclopramide, mezlocillin, nafcillin, nitrofurantoin, norfloxacin, novobiocin, ofloxacin, oxacillin, penicillin V, penicillin salts, penicillin complexes, pentamidine, piperacillin, piperacillin and tazobactam, sparfloxacin, sulphacytine, sulphamerazine, sulphamethazine, sulphamethixole, sulphasalazine, sulphisoxazole, sulphapyrizine, sulphadiazine, sulphmethoxazole, sulphapyridine, ticarcillin, ticarcillin and potassium clavulanate, trimethoprime, trimetrexate, troleanomycin, vancomycin, verapamil and mixtures thereof..Iaddend.

.Iadd.74. A method of therapeutic treatment, wherein the treatment comprises oral administration, according to a given dosage, of a composition of claim 29..Iaddend.

Description

EXAMPLES

Description of the Figures

(1) FIG. 1: In vitro release profiles for the microcapsules prepared according to Comparative Example 1.

(2) FIG. 2: In vitro release profiles for the microcapsules prepared according to Comparative Example 2.

(3) FIG. 3: In vitro release profiles for the microcapsules prepared according to Comparative Example 3.

(4) FIG. 4: In vitro release profiles for the microcapsules prepared according to Comparative Example 4.

(5) FIG. 5: In vitro release profiles for the microcapsules prepared according to Example 5 and comparison with the release profiles for the microcapsules prepared according to Comparative 1.

(6) FIG. 6: In vitro release profiles for the microcapsules prepared according to Example 6 and comparison with the release profiles for the microcapsules prepared according to Comparative 2.

(7) FIG. 7: In vitro release profiles for the microcapsules prepared according to Example 7 and comparison with the release profiles for the microcapsules prepared according to Comparative 3.

(8) FIG. 8: Release profiles for the microcapsules prepared according to Examples 8, 9 and 10 at pH 1.4.

(9) FIG. 9: Release profiles for the microcapsules prepared according to Examples 8, 9 and 10, measured for 2 h at pH 1.4 and then at pH 6.8.

(10) FIG. 10: Release profiles for the microcapsules prepared according to Examples 10, 11, 12 and 13 at pH 1.4.

(11) FIG. 11: Release profiles for the microcapsules prepared according to Example 14.

(12) FIG. 12: Release profiles for the microcapsules prepared according to Example 15.

(13) FIG. 13: Release profiles for the microcapsules prepared according to Example 16.

(14) FIG. 14: Release profiles for the microcapsules prepared according to Example 17.

(15) The examples below relate to the following active principles:

(16) TABLE-US-00001 Active principle Solubility (g/l) Spironolactone 0.02 Lansoprazole 0.05 Nitrofurantoin 0.3 Amoxicillin trihydrate 3.0 Acyclovir 10.0

(17) Comparative Example 1 (spironolactone), Comparative Example 2 (amoxicillin trihydrate), Comparative Example 3 (nitrofurantoin) and Comparative Example 4 (carvedilol) illustrate formulations with delayed and controlled release of the active principle, obtained according to WO-A-03/03878. However, it would be advantageous to retain the lag phase while at the same time increasing the rate of release after the lag phase, in order to optimize the bioavailability and the efficacy of the active principle. The microcapsules of Comparative Examples 1 to 4 do not comprise any swelling agent.

(18) Examples 5 (spironolactone), 6 (amoxicillin trihydrate) and 7 (nitrofurantoin) illustrate formulas according to the invention.

(19) Examples 8, 9 and 10 (acyclovir) show the influence of the amount of swelling agent present in the formulas on the release kinetics at pH 1.4.

(20) Examples 11, 12 and 13 (acyclovir) illustrate a nonexhaustive selection of swelling agents which may be used in the formulas according to the invention.

(21) Example 14 (acyclovir) illustrates the preparation of microcapsules combining a wet granulation step and a coating step in a fluidized air bed.

(22) Example 15 (acyclovir) illustrates the preparation of microcapsules combining an extrusion/spheronization step and a coating step in a fluidized air bed.

(23) Example 16 (acyclovir) illustrates the preparation of microcapsules combining a compacting step and a coating step in a fluidized air bed.

(24) Example 17 (acyclovir) illustrates the preparation of a medicinal product composed of the mixture of various types of microunits.

Comparative Example 1

Preparation of Microcapsules of Spironolactone Containing No Swelling Agent

(25) Step 1:

(26) 432 g of spironolactone and 48 g of low molar mass hydroxypropylcellulose (Klucel EF/Hercules) are dispersed in 1120 g of purified water. The suspension is sprayed onto 720 g of neutral microspheres (Asahi-Kasei) in a Glatt GPCG1 spray coater.

(27) Step 2:

(28) 43.2 g of hydrogenated cottonseed oil (Penwest) and 64.8 g of poly(methacrylicacid)(ethyl acrylate) Eudragit L100-55 (Rhm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 492 g of microparticles prepared above.

(29) The microcapsules obtained at the end of the second step were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media: HCl at pH 1.4 HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8 the dissolution profiles are given in FIG. 1.

(30) It is noted that: at pH 1.4, the release of the active principle is slow after the lag period of approximately 2 hours; when the pH changes from 1.4 to 6.8, the release kinetics accelerate but remain slow (approximately 8 hours are required in order to release 80% of the active principle).

(31) The novel compositions according to the invention make it possible to accelerate the release profiles at pH 1.4 and at pH 6.8, while at the same time conserving the lag phase at pH 1.4.

Comparative Example 2

Preparation of Microcapsules of Amoxicillin Trihydrate Containing No Swelling Agent

(32) Step 1:

(33) 1620 g of amoxicillin trihydrate and 180 g of low molar mass hydroxypropylcellulose (Klucel EF (Hercules)) are dispersed in 4200 g of purified water. The suspension is sprayed onto 200 g of neutral microspheres (Asahi-Kasei) in a Glatt GPCG1 spray coater.

(34) Step 2:

(35) 120 g of hydrogenated cottonseed oil (Penwest) and 180 g of poly(methacrylic acid)(ethyl acrylate) Acrycoat L100D (NP Pharm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 700 g of microparticles prepared above.

(36) The microcapsules obtained at the end of the second step were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media: HCl at pH 1.4 HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8 the dissolution profiles are given in FIG. 2.

(37) It is noted that: at pH 1.4, the release of the active principle is slow after the lag period of approximately 4 hours; when the pH changes from 1.4 to 6.8, the release kinetics are rapid as expected.

(38) The novel compositions according to the invention make it possible to optimize the release profiles at pH 1.4, while at the same time maintaining rapid release at pH 6.8 and conserving a lag phase at pH 1.4.

Comparative Example 3

Preparation of Microcapsules of Nitrofurantoin Containing No Swelling Agent

(39) Step 1:

(40) 640 g of amoxicillin trihydrate and 160 g of low molar mass hydroxypropylcellulose (Klucel EF/Hercules) are dispersed in 2400 g of purified water. The suspension is sprayed onto 200 g of neutral microspheres (Asahi-Kasei) in a Glatt GPCG1 spray coater.

(41) Step 2:

(42) 40 g of hydrogenated cottonseed oil (Penwest), 5 g of dibutyl sebacate (Morflex) and 55 g of poly(methacrylic acid) (methyl methacrylate) Eudragit L100 (Rhm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 900 g of microparticles prepared above.

(43) The microcapsules obtained at the end of the second step were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media: HCl at pH 1.4 HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8 the dissolution profiles are given in FIG. 3.

(44) It is noted that: at pH 1.4, the release of the active principle is slow after the lag period of approximately 2 hours; when the pH changes from 1.4 to 6.8, the release kinetics are rapid as expected.

(45) The novel compositions according to the invention make it possible to optimize the release profiles at pH 1.4, while at the same time maintaining rapid release at pH 6.8 and conserving a lag phase at pH 1.4.

Comparative Example 4

Preparation of Microcapsules of Carvedilol Phosphate Containing No Swelling Agent

(46) 1120 g of carvedilol phosphate and 280 g of Plasdone K29/32 (ISP) are dispersed in 1120 g of purified water. The suspension is sprayed onto 600 g of neutral microspheres (Asahi-Kasei) in a Glatt GPCG1 spray coater.

(47) 100 g of hydrogenated cottonseed oil (Penwest) and 150 g of Eudragit L100-55 (Rhm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 750 g of microparticles prepared above.

(48) The microcapsules obtained at the end of the second step were tested in a type II dissolutest in accordance with the Pharmacopoeia, at 37 C. and with agitation at 100 rpm, in the following media: HCl at pH 1.4 HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8

(49) The dissolution profiles are given in FIG. 4 in the appendix.

(50) It is noted that: at pH 1.4, the release of the active principle is slow after the lag period of approximately 2 hours; when the pH changes from 1.4 to 6.8, the release kinetics accelerate but remain slow (at 16 hours, only 40% of the active principle has been released).

Example 5

Preparation of Microcapsules of Spironolactone According to the Invention

(51) Step 1:

(52) 216 g of spironolactone, 72 g of low molar mass hydroxypropylcellulose (Klucel EF/Hercules), 72 g of PEG-40 hydrogenated castor oil (Cremophor RH 40/BASF) and 360 g of crospovidone (Kollidon CL/BASF) are dispersed in 1120 g of purified water. The suspension is sprayed onto 720 g of neutral microspheres (Asahi-Kasei) in a Glatt GPCG1 spray coater.

(53) Step 2:

(54) 43.2 g of hydrogenated cottonseed oil (Penwest) and 64.8 g of poly(methacrylic acid)(ethyl acrylate) Eudragit L100-55 (Rhm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 492 g of microparticles prepared above.

(55) The microcapsules obtained at the end of the second step were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media: HCl at pH 1.4 HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8 the dissolution profiles of Example 5 and of Comparative Example 1 are given in FIG. 4.

(56) It is noted that: at pH 1.4, approximately 60% of the active principle is released after a lag period of approximately 1 hour 30 min; when the pH changes from 1.4 to 6.8, the release kinetics are rapid.

Example 6

Preparation of Microcapsules of Amoxicillin Trihydrate According to the Invention

(57) Step 1:

(58) 630 g of amoxicillin trihydrate, 90 g of povidone (plasdone K29/32 (ISP)) and 180 g of crospovidone (Polyplasdone/ISP) are dispersed in 2100 g of isopropanol/water (70/30 m/m) mixture. The solution is sprayed onto 100 g of neutral microspheres (Asahi-Kasei) in a Glatt GPCG1 spray coater.

(59) Step 2:

(60) 120 g of hydrogenated cottonseed oil (Abitec) and 160 g of poly(methacrylic acid)(ethyl acrylate) Kollicoat MAE 100P (BASF) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 700 g of microparticles prepared above.

(61) The microcapsules obtained at the end of the second step were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media: HCl at pH 1.4 HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8 the dissolution profiles of Example 6 and of Comparative Example 2 are given in FIG. 6.

(62) It is noted that, with the composition according to the invention: the release of the active principle at pH 1.4 was accelerated (guaranteeing triggering of the system after a given amount of time and release of a sufficient amount of active agent, this release taking place over times compatible with the absorption times for the active principles in the organism); when the pH changes from 1.4 to 6.8, rapid release kinetics are maintained.

Example 7

Preparation of Microcapsules of Nitrofurantoin According to the Invention

(63) Step 1:

(64) 400 g of nitrofurantoin, 200 g of povidone (plasdone K29/32/ISP), 50 g of PEG-40 hydrogenated castor oil (BASF) and 350 g of crospovidone (Polyplasdone/ISP) are suspended in 2500 g of purified water. The solution is sprayed onto 1000 g of neutral microspheres (Asahi-Kasei) in a Glatt GPCG1 spray coater.

(65) Step 2:

(66) 120 g of hydrogenated cottonseed oil (Abitec) and 160 g of poly(methacrylic acid)(ethyl acrylate) Acrycoat L100D (NP Pharm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 700 g of microparticles prepared above.

(67) The microcapsules obtained at the end of the second step were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media: HCl at pH 1.4 HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8 the dissolution profiles of Example 7 and of Comparative Example 3 are given in FIG. 7.

(68) It is noted that, with the composition according to the invention: the release of the active principle at pH 1.4 was accelerated (guaranteeing triggering of the system after a given period of time and release of a sufficient amount of active agent, this release taking place over times compatible with the absorption times for the active principles in the organism); when the pH changes from 1.4 to 6.8, rapid release kinetics are maintained.

Comparative Example 8

Preparation of Microcapsules of Acyclovir Containing No Swelling Agent

(69) Step 1:

(70) 75 g of acyclovir and 75 g of povidone (Plasdone K29/32/ISP) are dissolved in 833 g of isopropanol. The solution is sprayed onto 850 g of neutral microspheres (NP Pharm) in a Glatt GPCG3 spray coater.

(71) Step 2:

(72) 93.3 g of hydrogenated soybean oil (Abitec) and 140 g of poly(methacrylic acid)(methyl methacrylate) Eudragit L100 (Rhm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 700 g of microparticles prepared above.

Example 9

Preparation of Microcapsules of Acyclovir Containing a Small Amount of Swelling Agent (Crospovidone)

(73) Step 1:

(74) 375 g of acyclovir, 50 g of low molar mass hydroxypropylcellulose (Klucel EF (Hercules)) and 75 g of crospovidone (Polyplasdone/ISP) are suspended in 1200 g of purified water. The solution is sprayed onto 500 g of neutral microspheres (NP Pharm) in a Glatt GPCG3 spray coater.

(75) Step 2:

(76) 100 g of hydrogenated cottonseed oil (Penwest) and 150 g of poly(methacrylic acid)(ethyl acrylate) Eudragit L100-55 (Rhm) are dissolved under hot conditions in ethanol. The solution is sprayed onto 750 g of microparticles prepared above.

Example 10

Preparation of Microcapsules of Acyclovir Containing a Larger Amount of Swelling Agent (Crospovidone)

(77) Step 1:

(78) 300 g of acyclovir, 50 g of low molar mass hydroxypropylcellulose, Klucel EF (Hercules), and 150 g of crospovidone (Polyplasdone/ISP) are suspended in 1200 g of purified water. The solution is sprayed onto 500 g of neutral microspheres (NP Pharm) in a Glatt GPCG3 spray coater.

(79) Step 2:

(80) 100 g of hydrogenated cottonseed oil (Penwest) and 150 g of poly(methacrylic acid)(ethyl acrylate) Eudragit L100-55 (Rhm) are dissolved under hot conditions in ethanol. The solution is sprayed onto 750 g of microparticles prepared above.

(81) The microcapsules obtained at the end of the second step in Comparative Examples 8, 9 and 10 were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media: HCl at pH 1.4 HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8 the dissolution profiles of Examples 8, 9 and 10 are given in FIGS. 8 and 9.

(82) It is noted that: a broad range of kinetics can be obtained at pH 1.4 according to the amount of swelling agent incorporated into the formulation; the release at pH 6.8 remains rapid whatever the composition under consideration.

Example 11

Preparation of Microcapsules of Acyclovir Containing a Swelling Agent (Sodium Croscarmellose)

(83) Step 1:

(84) 300 g of acyclovir, 50 g of low molar mass hydroxypropylcellulose, Klucel EF (Hercules), and 150 g of sodium croscarmellose (Ac-Di-Sol/FMC) are suspended in 1200 g of purified water. The solution is sprayed onto 500 g of neutral microspheres (NP Pharm) in a Glatt GPCG1 spray coater.

(85) Step 2:

(86) 100 g of hydrogenated cottonseed oil (Penwest) and 100 g of poly(methacrylic acid)(ethyl acrylate) Eudragit L100-55 (Rhm) are dissolved under hot conditions in ethanol. The solution is sprayed onto 750 g of microparticles prepared above.

Example 12

Preparation of Microcapsules of Acyclovir Containing a Swelling Agent (Hydroxypropylmethylcellulose)

(87) Step 1:

(88) 300 g of acyclovir, 50 g of low molar mass hydroxypropylcellulose, Klucel EF (Hercules), and 150 g of hydroxypropylmethylcellulose (Pharmacoat 615/Shin-Etsu) are suspended in 1200 g of purified water. The solution is sprayed onto 500 g of neutral microspheres (NP Pharm) in a Glatt GPCG1 spray coater.

(89) 100 g of hydrogenated cottonseed oil (Penwest), 100 g of poly(methacrylic acid)(ethyl acrylate) Eudragit L100-55 (Rhm) and 50 g of poly(methacrylic acid)(methyl methacrylate) Eudragit S100 (Rhm) are dissolved under hot conditions in ethanol. The solution is sprayed onto 750 g of microparticles prepared above.

Example 13

Preparation of Microcapsules of Acyclovir Containing a Swelling Agent (Povidone of Molar Mass Mw=1,000,000 g/mol)

(90) Step 1:

(91) 350 g of acyclovir, 50 g of low molar mass hydroxypropylcellulose (Klucel EF (Hercules)) and 100 g of high molar mass povidone (Kollidon 90 (BASF)) are suspended in 1200 g of purified water. The solution is sprayed onto 500 g of neutral microspheres (NP Pharm) in a Glatt GPCG1 spray coater.

(92) Step 2:

(93) 100 g of hydrogenated cottonseed oil (Penwest), 50 g of poly(methacrylic acid)(ethyl acrylate) Eudragit L100-55 (Rhm) and 100 g of poly(methacrylic acid)(methyl methacrylate) Eudragit S100 (Rhm) are dissolved under hot conditions in ethanol. The solution is sprayed onto 750 g of microparticles prepared above.

(94) The microcapsules obtained at the end of the second step of Examples 10, 11, 12 and 13 were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37 C. and with agitation of 100 rpm at pH 1.4.

(95) The dissolution profiles are given in FIG. 10.

Example 14

Preparation of Microcapsules of Acyclovir Containing a Swelling Agent (Granulation+Spray-Coating)

(96) Step 1:

(97) 700 g of acyclovir, 50 g of povidone (Plasdone/ISP) and 250 g of crospovidone (Polyplasdone/ISP) are dry-mixed beforehand in a laboratory granulator (Lodige) for 5 minutes. This pulverulent mixture is then granulated with water (200 g). The granules are dried at 40 C. in a ventilated oven, and then sized on a 500 m screen. The 200-500 m fraction is selected by sieving.

(98) Step 2:

(99) 100 g of hydrogenated palm oil (Huls), 100 g of poly (methacrylic acid)(ethyl acrylate) Acrycoat L100D and 50 g of poly(methacrylic acid)(methyl methacrylate) Acrycoat S100 (NP Pharm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 750 g of microparticles prepared above.

(100) The microcapsules obtained at the end of the second step of Example 13 were tested in a type II dissolutest in accordance with the European Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media:

(101) HCl at pH 1.4 HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4NaOH buffer medium at pH 6.8

(102) The dissolution profiles are given in FIG. 11.

Example 15

Preparation of Microcapsules of Acyclovir Containing a Swelling Agent (Extrusion/Spheronization+Spray Coating)

(103) Step 1:

(104) 700 g of acyclovir, 50 g of povidone (Plasdone/ISP) and 250 g of crospovidone (Kollidon CL/BASF) are premixed with 150 g of water in a laboratory mixer (Kitchen-Aid) for 5 minutes. This pasty mixture is extruded through a 0.5 mm screen using an Extruder 20 (Caleva). The filaments obtained are then spheronized using a Spheronizer 250 (Caleva). The particles obtained are dried at 40 C. in a fluidized air bed. The 300-700 m fraction is selected by sieving.

(105) Step 2:

(106) 100 g of hydrogenated palm oil (Huls), 100 g of poly(methacrylic acid)(ethyl acrylate) Acrycoat L100D and 50 g of poly(methacrylic acid)(methyl methacrylate) Acrycoat S100 (NP Pharm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 750 g of microparticles prepared above.

(107) The microcapsules obtained at the end of the second step of Example 14 were tested in a type II dissolutest in accordance with the Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media:

(108) HCl at pH 1.4

(109) HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8

(110) The dissolution profiles are given in FIG. 12.

Example 16

Preparation of Microcapsules of Acyclovir Containing a Swelling Agent (Compacting+Spray-Coating)

(111) Step 1:

(112) 590 g of acyclovir, 10 g of magnesium stearate and 400 g of crospovidone are mixed using a laboratory mixer (Kitchen-Aid type) for 5 minutes. This mixture is then compacted using an Alexenderwerk WP120 laboratory compactor. The product obtained is then granulated using an Erweka oscillating granulator equipped with a 500 m screen. The 100-500 m fraction of the product obtained is selected by sieving.

(113) Step 2:

(114) 100 g of hydrogenated palm oil (Huls), 100 g of poly(methacrylic acid)(ethyl acrylate) Acrycoat L100D and 50 g of poly(methacrylic acid)(methyl methacrylate) Acrycoat S100 (NP Pharm) are dissolved under hot conditions in isopropanol. The solution is sprayed onto 750 g of microparticles prepared above.

(115) The microcapsules obtained at the end of the second step of Example 14 were tested in a type II dissolutest in accordance with the Pharmacopoeia, 4th edition, at 37 C. and with agitation at 100 rpm, in the following media:

(116) HCl at pH 1.4

(117) HCl at pH 1.4 for 2 hours and then KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8

(118) The dissolution profiles are given in FIG. 13.

Example 17

Mixture of Microunits Having Various Release Profiles

(119) Various microunits of acyclovir are prepared, in which: 25% by weight of the acyclovir is in the form of immediate-release microunits as obtained at the end of the first step of Example 12, 25% of the acyclovir is in the form of delayed and prolonged-release microunits as obtained at the end of the second step of Example 10, and 50% of the acyclovir is in the form of delayed and prolonged-release microcapsules as obtained at the end of the second step of Example 12.

(120) The microcapsules of Example No. 10 begin to rapidly release their content beyond pH5.5 (use of Eudragit L100-55).

(121) The microcapsules of Example No. 12 begin to rapidly release their content beyond pH>6.5 (use of 67% Eudragit L100-55 and 33% Eudragit S100).

(122) The profiles are given in FIG. 14 and show that various release phases are obtained, which optimizes the release of an active principle in front of its window of absorption.