Solubility of hydrophobic drugs with a compound having a carboxylic acid moiety

• US 7,939,104 B2
• Filed: 02/15/2008
• Issued: 05/10/2011
• Est. Priority Date: 05/06/2004
• Status: Expired due to Fees

• Current Assignee: Basel Secure, LLC
• Original Assignee: Sandoz Ag (Novartis Ag)
• Inventors: Doshi, Chetan Chhabildas, Barbera, Gary, Davila, Pablo, Patel, Satishkumar Ambalal, Patel, Mahendra R
• Primary Examiner(s): Sheikh; Humera N
• Application Number:
  US12/070,071
• Publication Number:
  US 20080146581A1
• Time in Patent Office: 1,180 Days
• Field of Search: None
• US Class Current: 424/489
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/205 Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Abstract

A pharmaceutical composition having improved solubility comprising a hydrophobic drug or pharmaceutically acceptable salt thereof and a compound having at least one carboxylic acid moiety, wherein the molar ratio of the compound having at least one carboxylic acid moiety to the hydrophobic drug or pharmaceutically acceptable salt thereof is from about 0.1:1 to about 25:1. The pharmaceutical composition exhibits rapid dissolution upon contact with physiological solvents, such as water, saliva or gastrointestinal fluids.

Claims

1. A wet granulation method of preparing a pharmaceutical composition having improved solubility comprising a hydrophobic drug or pharmaceutically acceptable salt thereof and a compound having at least one carboxylic acid moiety, wherein the molar ratio of the compound having at least one carboxylic acid moiety to the hydrophobic drug or pharmaceutically acceptable salt thereof is from about 2:

1 to about 10;

1, said method comprising;

(a) combining a compound having at least one carboxylic acid moiety with a solid hydrophobic drug or pharmaceutically acceptable salt thereof, and optionally one or more excipients, to form a premix;

(b) adding a solvent, and optionally a surfactant, to the premix formed in step (a) to form a wet granulation; and

(c) drying the wet granulation to form a pharmaceutical composition;

wherein the hydrophobic drug or pharmaceutically acceptable salt thereof is selected from the group consisting of ziprasidone, raloxifene, paroxetine, glimepiride, anagrelide, modafinil, cabergoline, replaginide, glipizide, benzodiazepines, clofibrate, chlorpheniramine, dinitirate, digoxin, digitoxin, ergotamin tartate, estradiol, fenofibrate, griseofulvin, hydrochlorothiazide, hydrocortisone, isosorbide, medrogeston, oxyphenbutazone, prednisolone, prednisone, polythiazide, progensterone, spironolactone, tolbutamide, 10,11-dihydro-5H-dibenzo[a,d]cyclo-heptene-5-carboxamide, 5H-dibenzo[a,d]cycloheptene-5-carboxamide and mixtures thereof and wherein the hydrophobic drug or pharmaceutically acceptable salt thereof in the pharmaceutical composition exhibits a dissolution rate in a buffered aqueous medium at a pH of 7.5 and a temperature of 37°

C. of at least about 35% over about 30 minutes after being combined therewith.

2. The wet granulation method according to claim 1, wherein the compound having at least one carboxylic acid moiety is selected from the group consisting of a monocarboxylic acid, dicarboxylic acid, tricarboxylic acid, tetracarboxylic acid, polycarboxylic acid and mixtures thereof.

3. The wet granulation method according to claim 1, wherein the compound having at least one carboxylic acid moiety is selected from the group consisting of ascorbic acid, maleic acid, citric acid succinic acid, glutaric acid, adipic acid, azelaic acid, sebacic acid, fumaric acid, itaconic acid, 1,3-cyclohexane dicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, diglycolic acid, 2,5-norbornanedicarboxylic acid, phthalic acid, terephthalic acid, 1,4 naphthalenedicarboxylic acid, 2,5-naphthalenedicarboxylic acid, diphenic acid, 4,4′

oxydibenzoic acid, 4,4′

-sulfonyldibenzoic acid and isophthalic acid and mixtures thereof.

4. The wet granulation method according to claim 3, wherein the compound having at least one carboxylic acid moiety is selected from the group consisting of ascorbic acid, maleic acid and citric acid.

5. The wet granulation method according to claim 4, wherein the compound having at least one carboxylic acid moiety is citric acid.

11. The wet granulation method according to claim 1, wherein the molar ratio of the compound having at least one carboxylic acid moiety to the hydrophobic drug or pharmaceutically acceptable salt thereof is from about 3.5:

1 to about 4;

1.

6. A method of preparing a pharmaceutical composition having improved solubility comprising a hydrophobic drug or pharmaceutically acceptable salt thereof and a compound having at least one carboxylic acid moiety, wherein the molar ratio of the compound having at least one carboxylic acid moiety to the hydrophobic drug or pharmaceutically acceptable salt thereof is from about 1:

1 to about 15;

1, said method comprising;

(a)′

combining a hydrophobic drug or pharmaceutically acceptable salt thereof, in the form of particles having a mean particle size from about 100 microns to about 150 microns, and one or more excipients to form a premix;

(b)′

adding a mixture comprising a solvent and a compound having at least one carboxylic acid moiety to the premix formed in step (a)′

to form a wet granulation; and

(c)′

drying the wet granulation to form a pharmaceutical composition

wherein the hydrophobic drug or pharmaceutically acceptable salt thereof is selected from the group consisting of ziprasidone, raloxifene, paroxetine, glimepiride, anagrelide, modafinil, cabergoline, replaginide, glipizide, benzodiazepines, clofibrate, chlorpheniramine, dinitirate, digoxin, digitoxin, ergotamin tartate, estradiol, fenofibrate, griseofulvin, hydrochlorothiazide, hydrocortisone, isosorbide, medrogeston, oxyphenbutazone, prednisolone, prednisone, polythiazide, progensterone, spironolactone, tolbutamide, 10,11-dihydro-5H-dibenzo[a, d]cyclo-heptene-5-carboxamide, 5H-dibenzo[a,d]cycloheptene-5-carboxamide and mixtures thereof.

7. The method according to claim 6, wherein the compound having at least one carboxylic acid moiety is selected from the group consisting of a monocarboxylic acid, dicarboxylic acid, tricarboxylic acid, tetracarboxylic acid, polycarboxylic acid and mixtures thereof.

8. The method according to claim 6, wherein the compound having at least one carboxylic acid moiety is selected from the group consisting of ascorbic acid, maleic acid, citric acid succinic acid, glutaric acid, adipic acid, azelaic acid, sebacic acid, fumaric acid, itaconic acid, 1,3-cyclohexane dicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, diglycolic acid, 2,5-norbornanedicarboxylic acid, phthalic acid, terephthalic acid, 1,4 naphthalenedicarboxylic acid, 2,5-naphthalenedicarboxylic acid, diphenic acid, 4,4′

oxydibenzoic acid, 4,4′

-sulfonyldibenzoic acid and isophthalic acid and mixtures thereof.

9. The method according to claim 8, wherein the compound having at least one carboxylic acid moiety is selected from the group consisting of ascorbic acid, maleic acid and citric acid.

10. The method according to claim 9, wherein the compound having at least one carboxylic acid moiety is citric acid.

12. The method according to claim 6, wherein the wherein the molar ratio of the compound having at least one carboxylic acid moiety to the hydrophobic drug or pharmaceutically acceptable salt thereof is from about 2:

1 to about 10;

1.

13. The method according to claim 6, wherein the wherein the molar ratio of the compound having at least one carboxylic acid moiety to the hydrophobic drug or pharmaceutically acceptable salt thereof is from about 3.5:

1 to about 4;

1.