Chlorhexidine gluconate-containing, stabilized aqueous pharmaceutical preparations

• US 5,908,865 A
• Filed: 05/13/1997
• Issued: 06/01/1999
• Est. Priority Date: 05/13/1996
• Status: Expired due to Fees

• Current Assignee: Senju Pharmaceutical Company Limited
• Original Assignee: Senju Pharmaceutical Company Limited
• Inventors: Doi, Koji, Aki, Hiroshi
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): PRYOR, ALTON NATHANIEL
• Application Number:
  US08/855,586
• Time in Patent Office: 749 Days
• Field of Search: 424/433, 514/635
• US Class Current: 514/635
• 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 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals

Abstract

An aqueous pharmaceutical preparation is provided containing chloride ion and stably containing chlorhexidine gluconate, characterized in that said preparation further contains at least one pharmaceutically acceptable polycarboxylic acid of the formula I:

HOOC--(CR.sub.i 1 --CR.sub.i 2)n --COOH                    (I)

wherein n is an integer 1, 2 or 3; i is a positive integer not more than n; R¹¹ and R₁₂, when n=1, independently from each other, are H, --OH or --COOH; each of R₁₁, R₁₂, R₂₁ and R₂₂, when n=2, is H, --OH or --COOH, but not all of them are H simultaneously; and each of R₁₁, R₁₂, R₂₁, R₂₂, R₃₁ and R₃₂, when n=3, is H, --OH or --COOH, but two adjacent carbons in no case contain four hydrogen atoms in total; or a pharmaceutically acceptable salt thereof.

Claims

1. An aqueous pharmaceutical composition comprising an aqueous solution of stably maintained chlorhexidine gluconate, chloride ion and at least one pharmaceutically acceptable polycarboxylic acid of formula I:

space="preserve" listing-type="equation">HOOC--(CR.sub.i1 R.sub.i2)n--COOH (I)

wherein n denotes an integer of 1 to 3;

i denotes a positive integer not more than n;

R₁₁, and R₁₂, when n=1, independently from each other, denote H, --OH or --COOH;

each of R₁₁, R₁₂, R₂₁ and R₂₂, when n=2, denotes H, --OH or --COOH,

with the proviso that not all of them denote H simultaneously; and

each of R₁₁, R₁₂, R₂₁, R₂₂, R₃₁ and R₃₂, when n=3, denotes H, --OH or --COOH, with the proviso that two adjacent carbons in no case contain four hydrogen atoms in total;

or a pharmaceutically acceptable salt thereof.

2. The aqueous pharmaceutical composition of claim 1 which does not comprise a nonionic surface active agent.

3. The aqueous pharmaceutical composition of claim 1, wherein the concentration of said polycarboxylic acid is 0.01 to 5 W/V %.

4. The aqueous pharmaceutical composition of claim 3, wherein the concentration of chlorhexidine gluconate is 0.0001 to 0.05 W/V %.

5. The aqueous pharmaceutical composition of claim 4, wherein the concentration of chloride ion is 0.05 to 200 mEq/L.

6. The aqueous pharmaceutical composition of claim 1, wherein said polycarboxylic acid is selected from the group consisting of citric acid, oxalic acid, tartaric acid and malic acid.

12. The aqueous pharmaceutical composition of claim 2, wherein the concentration of said polycarboxylic acid is 0.01 to 5 W/V %.

13. The aqueous pharmaceutical composition of claim 2, wherein said polycarboxylic acid is selected from the group consisting of citric acid, oxalic acid, tartaric acid and malic acid.

16. The aqueous pharmaceutical composition of claim 1, wherein said polycarboxylic acid is in the form of a sodium, potassium, calcium or ammonium salt.

17. The aqueous pharmaceutical composition of claim 1, wherein the concentration of said polycarboxylic acid is 0.05-3 w/v %.

18. The aqueous pharmaceutical composition of claim 1, wherein the concentration of said chlorhexidine gluconate is 0.0001 to 0.025 w/v %.

19. The aqueous pharmaceutical composition of claim 2, wherein said polycarboxylic acid is in the form of a sodium, potassium, calcium or ammonium salt.

20. The aqueous pharmaceutical composition of claim 2, wherein the concentration of said chlorhexidine gluconate is 0.0001 to 0.025 w/v %.

21. The aqueous pharmaceutical composition of claim 2, wherein the concentration of said chlorhexidine gluconate is 0.0001 to 0.025 w/v %.

7. A method for prevention of precipitation of chlorhexidine gluconate in an aqueous solution containing chloride ion and chlorhexidine gluconate, comprising adding to said aqueous solution at least one polycarboxylic acid of the formula I:

space="preserve" listing-type="equation">HOOC--(CR.sub.i1 R.sub.i2)n--COOH (I)

wherein n denotes an integer of 1 to 3;

i denotes a positive integer not more than n;

R₁₁ and R₁₂, when n=1, independently from each other, denote H, --OH or --COOH;

each of R₁₁, R₁₂, R₂₁ and R₂₂, when n=2, denotes H, --OH or --COOH, with the proviso that not all of them denote H simultaneously; and

each of R₁₁, R₁₂, R₂₁, R₂₂, R₃₁ and R₃₂, when n=3, denotes H, --OH or --COOH, with the proviso that two adjacent carbons in no case contain four hydrogen atoms in total;

or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the concentration of said polycarboxylic acid is 0.01 to 5 W/V %.

9. The method of claim 7, wherein the concentration of chlorhexidine gluconate is 0.0001 to 0.05 W/V %.

10. The method of claim 7, wherein the concentration of chloride ion is 0.05 to 200 mEq/L.

11. The method of claim 7, wherein said polycarboxylic acid is selected from the group consisting of citric acid, oxalic acid, tartaric acid and malic acid.

14. The method of claim 8, wherein the concentration of chlorhexidine gluconate is 0.0001 to 0.05 W/V %.

15. The method of claim 8, wherein said polycarboxylic acid is selected from the group consisting of citric acid, oxalic acid, tartaric acid and malic acid.

22. The method of claim 7, wherein said polycarboxylic acid is in the form of a sodium, potassium, calcium or ammonium salt.

23. The method of claim 7, wherein the concentration of said polycarboxylic acid is 0.05-3 w/v %.

24. The method of claim 7, wherein the concentration of said chlorhexidine gluconate is 0.0001 to 0.025 w/v %.