Orally administrable immediate-release and prolonged-release galenic form comprising an absorption-promoting agent and use of this absorption-promoting agent

• US 6,426,087 B1
• Filed: 08/22/2000
• Issued: 07/30/2002
• Est. Priority Date: 02/23/1998
• Status: Expired due to Term

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Michel, Dominique, Saslawski, Olivier, Holot, Thierry, Giet, Philippe
• Primary Examiner(s): Carr, Deborah D
• Application Number:
  US09/622,663
• Time in Patent Office: 707 Days
• Field of Search: 424/400, 424/464, 424/450, 424/456, 424/489, 424/490, 424/448, 424/449, 424/488
• US Class Current: 424/450
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 9/0007 Effervescent A61K9/0065 takes precedence
• CPC Class Codes: A61K 9/0065 Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4858 Organic compounds
• 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 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention relates to an orally administrable galenic form allowing improved absorption by the transmembrane or paracellular route in the gastrointestinal tract of active ingredients which are hydrophilic or ionizable in physiol. media, comprising at least one such active ingredient, an absorption-promoting agent having an HLB>8, the the absorption-promoting agent consisting of one or more lipid substances chosen from: polysorbates; polyoxyethylene ethers; esters of polyoxyethylene and fatty acids; fatty acids; fatty alcs.; bile acids and their salts with pharmaceutically acceptable cations; esters of C1-C6 alkanol with fatty acids; esters of polyol with fatty acids, the polyol comprising from 2 to 6 hydroxyl functional groups; and polyglycolyzed glycerides; in combination with one or more pharmaceutically acceptable excipients, the pharmaceutical forms comprising captopril being excluded. A controlled-release tablet contained (1) cores contg. calcium acamprosate 50, Gelucire 44/14 10, Compritol 10, microcryst. cellulose 19, Povidone 10, and Mg stearate 1% and (2) a film-coating compn. contg. HPMC 64, PEG-4000 15, and talc 21%.

Claims

1. An orally administerable galenic formulation allowing improved absorption by the transmembrane or paracellular route in the gastrointestinal tract, comprising

at least one active ingredient which is a guanidine or a guanylguanidine,

an absorption-promoting agent having an HLB greater than 8 which is one or more lipid substances selected from polysorbates, ethers of polyoxyethylene and alkyl, esters of polyoxyethylene and fatty acids, fatty acids, fatty alcohols, bile acids and their salts with pharmaceutically acceptable cations, esters of C₁-C₆ alkanols with fatty acids, esters of polyol with fatty acids, wherein said polyol comprises 2 to 6 hydroxyl functional groups, and polyglycolysed glycerides, and

one or more pharmaceutically acceptable excipients.

2. The galenic formulation according to claim 1, further comprising an active ingredient which is hydrophilic or ionizable in physiological media which comprises at least one functional group chosen from carboxylic acid, sulphonic acid, phosphonic acid, phosphoric acid, phosphinic acid and phenol functional groups in free form or ionized form with pharmacologically acceptable cations.

3. The galenic formulation according to claim 2, wherein the active ingredient which is hydrophilic or ionizable in physiological media comprises at least one functional group chosen from sulphonic acid, phosphoric acid, phosphinic acid and phosphinic acid functional groups in free form or ionized form with pharmacologically acceptable cations.

4. The galenic formulation according to claim 1, comprising an active ingredient in the form of a calcium salt.

5. The galenic formulation according to claim 1, wherein the active ingredient, free or in ionized form with the cations or the anions present, has a solubility greater than 100 g/l.

6. The galenic formulation according to claim 5, wherein said active ingredient free or in its ionized form with the cations or the anions present has a partition coefficient D (octanol/water) corresponding to the relationship log₁₀D<

−

0.5.

7. The galenic formulation according to claim 1, wherein an active ingredient is contained of the formula:

in which

X is

R is a C₁-C₇ alkyl radical,

R₁, R₂, R₃ are hydrogen or a C₁-C₇ alkyl radical,

A is a group of the formula;

v and w=0, 1, 2, independently,

or A is a group of formula

R₅, R₆, independently of each other, are hydrogen, C₁-C₇ alkyl, an aryl radical having from 6 to 14 carbon atoms, or a heteroaryl radical which furyl, thienyl or thiazolyl, it being possible for the aryl and heteroaryl radicals to carry 1 to 3 substituents which are C₁-C₇ alkyl, halogen or trifluoromethyl, and

t=1-3,

R₄ is hydrogen, C₁-C₇ alkyl, CF₃, aryl having from 6 to 14 carbon atoms, heteroaryl which is furyl, thienyl, or thiazolyl, it being possible for the aryl and heteroaryl radicals to carry 1 to 3 substituents which are C₁-C₇ alkyl, halogen or trifluoromethyl,

M represents a monovalent metal (Na, K, Li) or a divalent metal (Ca, Mg, Sr, Zn),

m=1 or 2,

p=1-2 and q=1-2, p and q being such that the electrical neutrality of the salt is ensured.

8. The galenic formulation according to claim 7, wherein an active ingredient has the formula (I) in which

9. The galenic formulation according to claim 7, wherein an active ingredient has the formula (I) in which

10. The galenic formulation according to claim 7, wherein an active ingredient which is hydrophilic or ionizable in physiological media of Formula I is calcium acamprosate.

11. The galenic formulation according to claim 1, wherein the active ingredient which is a guanidine or a guanylguanidine is metformin or one of its pharmaceutically acceptable salts.

12. The galenic formulation according to claim 1, wherein the absorption-promoting agent has an HLB greater than 10.

13. The galenic formulation according to claim 1, wherein the polyol esters with fatty acids are esters of glycols, esters of polyglycerols, esters or anhydrides of sorbitol.

14. The galenic formulation according to claim 1, wherein the absorption-promoting agent comprises at least one polyglycolyzed glyceride having an HLB of between 12 and 16.

15. The galenic formulation according to claim 1, wherein the absorption-promoting agent comprises at least one polyglycolyzed glyceride and a sorbitan ester with one or more fatty acids.

16. The galenic formulation according to claim 15, wherein the absorption-promoting agent comprises a mixture of one or more polyglycolyzed glycerides and a sorbitan ester with a saturated or unsaturated C₈-C₂₂ fatty acid.

17. The galenic formulation according to claim 1, wherein the weight ratio of the active ingredient to the absorption-promoting agent is between 0.001 and 10.

18. The galenic formulation according to claim 17, which is a tablet wherein the weight ratio of the active ingredient to the absorption-promoting agent is between 1 and 10.

19. The galenic formulation according to claim 17, which is a gelatin capsule wherein the weight ratio of the active ingredient to the absorption-promoting agent is between 0.1 and 2.

20. The galenic formulation according to claim 1, further comprising an agent allowing the control of the kinetics of release of the active ingredient chosen from glycerol palmitostearates, glycerol behenates, hydrogenated castor oils and mixtures thereof.

21. A method for improving the absorption by the transmembrane or paracellular route in the gastrointestinal tract of active ingredients which are hydrophilic or ionizable in physiological media, comprising administering an absorption-promoting agent in the form of an orally administerable pharmaceutical formulation according to claim 1.

22. The method according to claim 21, wherein the active ingredient which is hydrophilic or ionizable in physiological media comprises at least one functional group which is carboxylic acid, sulphonic acid, phosphinic acid, phosphoric acid, phosphinic acid or phenol functional groups in free form or ionized with pharmaceutically acceptable cations.

23. The method according to claim 21, wherein the weight ratio of the active ingredient to the absorption-promoting agent is between 0.01 and 10.

24. The method of preparing a galenic formulation according to claim 1 in the form of a tablet, comprising (i) preparing by the wet route, a granule of an active substance form a pulverulent mixture of the active substance and various excipients, and (ii) compressing, wherein the absorption-promoting agent used in (i) acts as a wetting liquid.

25. The galenic form according to claim 5, wherein the active ingredient has a solubility greater than 250 g/l.

26. The galenic form according to claim 6, wherein the active ingredient, free or in its ionized form with a cation or anion present, has a partition coefficient D (octanol/water) corresponding to the relationship log₁₀D<

−

20.

27. The galenic form according to claim 12, wherein the absorption-promoting agent has an HLB between 12 and 16.

28. The galenic form according to claim 16, wherein the absorption-promoting agent comprises a mixture of one or more polyglycolyzed glycerides and a sorbitan ester with a saturated or unsaturated C₁₀-C₁₄ fatty acid.