Coated particles with prolonged release and tablets containing same

• US 7,718,194 B2
• Filed: 04/23/2003
• Issued: 05/18/2010
• Est. Priority Date: 04/23/2002
• Status: Active Grant

• Current Assignee: ETHYPHARM
• Original Assignee: ETHYPHARM
• Inventors: Chenevier, Phillippe, Marechal, Dominique
• Primary Examiner(s): Tran; S.
• Application Number:
  US10/512,220
• Publication Number:
  US 20050152976A1
• Time in Patent Office: 2,582 Days
• Field of Search: None
• US Class Current: 424/490
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50

Abstract

The invention concerns coated particles with prolonged release, a method for preparing same and multiparticulate tablets comprising said coated particles.

Claims

1. A multiparticulate tablet comprising sustained-release coated particles and a mixture of excipients, wherein said mixture of excipients comprises:

a disintegrant and/or swelling agent,

at least one diluent, and

a lubricant,

and said sustained-release coated particles comprise;

a core comprising at least one active principle and at least one binder,

a coating film consisting of ethylcellulose which ensures sustained release of the active principle and none, one or more of a pore-forming agent, a surfactant, an antistatic agent and a lubricant, and

at least one thermoplastic agent which is applied as a protective coating onto the coating film, wherein said thermoplastic agent is selected from the group consisting of partially hydrogenated oils, beeswax, carnauba wax, paraffin waxes, silicone waxes, fatty alcohols, C₁₂-C₁₈ fatty acids, solid semisynthetic glycerides, glyceryl monoesters, diesters or triesters, polyoxyethylene glycols, polyoxyethylenated glycosyl glycerides, and mixtures thereof, and wherein said thermoplastic agent has a melting point of from about 25°

C. to about 100°

C.,

and wherein a proportion of the mixture of excipients relative to the coated particles is from 1 to 5 parts by weight.

2. The multiparticulate tablet of claim 1, wherein said thermoplastic agent has a hydrophilic/lipophilic balance (HLB) greater than 10.

3. The multiparticulate tablet of claim 1, wherein the mixture of excipients further comprises an additional excipient selected from the group consisting of a binder, a permeabilizer, sweeteners, flavorings, colorants and mixtures thereof, and wherein the protective coating further comprises an antistatic agent and a lubricant.

4. The multiparticulate tablet of claim 1, wherein the tablet is adapted to disintegrate in a mouth on contact with saliva in less than 60 seconds, forming a suspension that is easy to swallow.

7. The multiparticulate tablet of claim 1, wherein the at least one active principle is selected from the group consisting of gastrointestinal sedatives, antacids, analgesics, antiinflammatories, coronary vasodilators, peripheral and cerebral vasodilators, antiinfectives, antibiotics, antiviral agents, antiparasitic agents, anticancer agents, anxiolytics, neuroleptics, central nervous system stimulants, antidepressants, antihistamines, antidiarrheal agents, laxatives, dietary supplements, immunodepressants, hypocholesterolemiants, hormones, enzymes, antispasmodics, antianginal agents, medicinal products that decrease the heart rate, medicinal products that regulate the heart rate, medicinal products used in the treatment of arterial hypertension, antimigraine agents, medicinal products that decrease blood clotting, medicinal products that increase blood clotting, antiepileptics, muscle relaxants, medicinal products used in the treatment of diabetes, medicinal products used in the treatment of thyroid dysfunctions, diuretics, anorexigenic agents, antiasthmatics, expectorants, antitussive agents, mucoregulators, decongestants, hypnotics, antinausea agents, hematopoietic agents, uricosuric agents, plant extracts and contrast agents.

8. The multiparticulate tablet of claim 1, wherein the binder of the sustained-release coated particles is a member selected from the group consisting of cellulosic polymers, acrylic polymers, povidones, copovidones, polyvinyl alcohols, alginic acid, sodium alginate, starch, pregelatinized starch, sugars and derivatives thereof, guar gum and polyethylene glycols, and mixtures thereof.

9. The multiparticulate tablet of claim 1, wherein:

the core of the sustained-release coated particles further comprises a diluent and an antistatic agent, and

a polymer layer is applied between the core and the coating film of the sustained-release coated particles.

10. The multiparticulate tablet of claim 1, wherein the diameter of the sustained-release coated particles is from 150 to 700 μ

m with at least 50% of the particles having a diameter from 150 to 500 μ

m, and less than 15% of the particles having a diameter of less than 150 μ

m.

11. A method for preparing the sustained-release coated particles of the multiparticulate tablet of claim 1, the method comprising:

(a) preparing by wet granulation or mounting on neutral supports, cores comprising at least one active principle,

(b) coating the cores thus obtained by spraying a coating composition consisting of ethylcellulose which ensures sustained release of the active principle and none, one or more of a pore-forming agent, a surfactant, an antistatic agent and a lubricant to obtain coated cores,

(c) coating the coated cores thus obtained by spraying with a protective coating composition comprising a thermoplastic agent, dissolved in an aqueous solvent devoid of organic solvent, and

(d) drying.

14. The multiparticulate tablet of claim 1, further comprising a binder, a permeabilizer, sweeteners, flavorings and colorants and wherein the protective coating of the sustained-release coated particles further comprises an antistatic agent and a lubricant.

18. The multiparticulate tablet of claim 14, wherein the binder of the sustained-release coated particles is selected from the group consisting of cellulosic polymers, acrylic polymers, povidones, copovidones, polyvinyl alcohols, alginic acid, sodium alginate, starch, pregelatinized starch, sugars and derivatives thereof, guar gum and polyethylene glycols, and mixtures thereof.

5. A multiparticulate tablet comprising sustained-release coated particles and a mixture of excipients, wherein said mixture of excipients comprises:

at least one disintegrant,

at least one diluent,

a lubricant, and optionally a swelling agent, a permeabilizer, sweeteners, and flavorings,

and said sustained-release coated particles comprise;

a core comprising at least one active principle and at least one binder,

a coating film consisting of ethylcellulose which ensures sustained release of the active principle and none, one or more of a pore-forming agent, a surfactant, an antistatic agent and a lubricant, and

at least one thermoplastic agent which is applied as a protective coating onto the coating film, wherein said thermoplastic agent is selected from the group consisting of partially hydrogenated oils, beeswax, carnauba wax, paraffin waxes, silicone waxes, fatty alcohols, C₁₂-C₁₈ fatty acids, solid semisynthetic glycerides, glyceryl monoesters, diesters or triesters, polyoxyethylene glycols and polyoxyethylenated glycosyl glycerides, and mixtures thereof, and wherein said thermoplastic agent has a melting point of from about 25°

C. to about 100°

C.,

wherein the multiparticulate tablet is adapted to disintegrate in a mouth on contact with saliva in less than 60 seconds, forming a suspension that is easy to swallow, and wherein a proportion of the mixture of excipients relative to the coated particles is from 1 to 5 parts by weight.

6. The multiparticulate tablet of claim 5, wherein the at least one diluent is chosen from soluble agents with binding properties, consisting of a polyol of less than 13 carbon atoms and being in the form of a directly compressible product with a mean particle diameter of from 100 to 500 μ

m, or in the form of a powder with a mean particle diameter of less than 100 μ

m, this polyol being a member selected from the group consisting of mannitol, xylitol, sorbital and maltitol.

22. The multiparticulate tablet of claim 6, wherein the mixture of excipients comprises two diluents, wherein one of the diluents is in a form of a directly compressible product with a mean particle diameter from 100 to 500 μ

m, the other diluent is in a form of a powder with a mean particle diameter of less than 100 μ

m, and proportions of directly compressible product and of powder are from 99/1 to 20/80.

12. A multiparticulate tablet comprising sustained-release coated particles and a mixture of excipients, wherein said mixture of excipients comprises:

a disintegrant and/or swelling agent,

at least one diluent,

a lubricant, and

an antistatic agent, a permeabilizer, sweeteners, flavorings and colorants,

and said sustained-release coated particles comprise;

a core comprising at least one active principle and at least one binder,

a coating film consisting of ethylcellulose which ensures sustained release of the active principle and none, one or more of a pore-forming agent, a surfactant, an antistatic agent and a lubricant, and

at least one thermoplastic agent which is applied as a protective coating onto the coating film, wherein said thermoplastic agent is selected from the group consisting of partially hydrogenated oils, beeswax, carnauba wax, paraffin waxes, silicone waxes, fatty alcohols, C₁₂-C₁₈ fatty acids, solid semisynthetic glycerides, glyceryl monoesters, diesters or triesters, polyoxyethylene glycols and polyoxyethylenated glycosyl glycerides, and mixtures thereof, and wherein said thermoplastic agent has a melting point of from about 25°

C. to about 100°

C.,

and wherein a proportion of the mixture of excipients relative to the coated particles is from 1 to 5 parts by weight.

13. The multiparticulate tablet of claim 12, wherein said thermoplastic agent has a hydrophilic/lipophilic balance (HLB) greater than 10.

15. The multiparticulate tablet of claim 12, wherein the tablet is adapted to disintegrate in a mouth on contact with saliva in less than 60 seconds, forming a suspension that is easy to swallow.

16. The multiparticulate tablet of claim 12, wherein the at least one diluent is selected from soluble agents with binding properties, consisting of a polyol of less than 13 carbon atoms and being in the form of a directly compressible product with a mean particle diameter of from 100 to 500 μ

m, or in the form of a powder with a mean particle diameter of less than 100 μ

m, this polyol being selected from the group consisting of mannitol, xylitol, sorbitol and maltitol.

17. The multiparticulate tablet of claim 12, wherein the at least one active principle is selected from the group consisting of gastrointestinal sedatives, antacids, analgesics, antiinflammatories, coronary vasodilators, peripheral and cerebral vasodilators, antiinfectives, antibiotics, antiviral agents, antiparasitic agents, anticancer agents, anxiolytics, neuroleptics, central nervous system stimulants, antidepressants, antihistamines, antidiarrheal agents, laxatives, dietary supplements, immunodepressants, hypocholesteroleminats, hormones, enzymes, antispasmodics, antianginal agents, medicinal products that decrease the heart rate, medicinal products that regulate the heart rate, medicinal products used in the treatment of arterial hypertension, antimigraine agents, medicinal products that increase blood clotting, medicinal products that decrease blood clotting, antiepileptics, muscle relaxants, medicinal products used in the treatment of diabetes, medicinal products used in the treatment of thyroid dysfunctions, diuretics, anorexigenic agents, antiasthmatics, expectorants, antitussive agents, muco-regulators, decongestants, hypnotics, antinausea agents, hematopoietic agents, uricosuric agents, plant extracts and constrast agents.

19. The multiparticulate tablet of claim 12, wherein:

the core of the sustained-release coated particles further comprises a diluent and an antistatic agent, and

a polymer layer is applied between the core and the coating film of the sustained-release coated particles.

20. The multiparticulate tablet of claim 12, wherein the diameter of the coated particles is from 150 to 700 μ

m, with at least 50% of the particles having a diameter from 150 to 500 μ

m, and less than 15% of the particles having a diameter of less than 150 μ

m.

21. A method for preparing the sustained-release coated particles of the multiparticulate tablet of claim 12, the method comprising:

(a) preparing by wet granulation or mounting on neutral supports, cores comprising at least one active principle,

b) coating the cores thus obtained by spraying a coating composition consisting of ethylcellulose which ensures sustained release of the active principle and none, one or more of a pore-forming agent, a surfactant, an antistatic agent and a lubricant to obtain coated cores,

(c) coating the coated cores thus obtained by spraying with a protective coating composition consisting of a thermoplastic agent, dissolved in an aqueous solvent devoid of organic solvent, and

(d) drying.

23. The multiparticulate tablet of claim 16, wherein the mixture of excipients comprises two diluents, wherein one of the diluents is in a form of a directly compressible product with a mean particle diameter from 100 to 500 μ

m, the other diluent is in a form of a powder with a mean particle diameter of less than 100 μ

m, and proportions of directly compressible product and of powder are from 99/1 to 20/80.