SELF-PRESERVED EMULSIONS

• US 20090298956A1
• Filed: 05/27/2009
• Published: 12/03/2009
• Est. Priority Date: 05/28/2008
• Status: Abandoned Application

• Current Assignee: Alcon Research Limited (Nestle SA)
• Original Assignee: Alcon Research Limited (Nestle SA)
• Inventors: Chowhan, Masood A., Ghosh, Malay
• Application Number:
  US12/472,880
• Publication Number:
  US 20090298956A1
• Time in Patent Office: Days
• US Class Current: 514/785
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0046 Ear
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses

Abstract

The use of multifunctional synthetic compounds to both stabilize and preserve therapeutic emulsions is described. The multifunctional synthetic compounds have unique molecular arrangement wherein a phosphate group is linked to one, two or three quaternary ammonium functionalities via a substituted propenyl group, and each quaternary ammonium functionality is further linked to at least one hydrocarbon chain. The pharmaceutical emulsions which include these multifunctional compounds may be prepared without heating or homogenization, and may not require the use of any additional stabilizing or preserving agents.

Claims

1. An emulsion suitable for ocular, nasal or otic administration comprising

water,

a buffering agent,

an oil,

an emulsifier,

a pH adjuster,

a multifunctional synthetic compound of formula I,

wherein:

x is 1 to 3 or mixtures thereof,

x+y is equal to 3;

a is 0 to 2;

z is equal to x;

B is O—

or OM;

A is an anion;

M is a cation;

Y is selected from the group consisting of OH, O—

C₁-C₁₀ alkyl and O—

C₁-C₁₀ alkenyl;

and

R1, R2 and R3 are the same or different and are alkyl, substituted alkyl, alkyl aryl or alkenyl groups, optionally interrupted by —

NHC(═

O)—

, of up to 16 carbon atoms with the proviso that the total carbon atoms in R1+R1+R3 is between 10 and 24,

and optionally a therapeutic agent.

2. An emulsion according to claim 1, wherein:

R1 and R2 are independently C₁-C₆ alkyl;

R3 is C₆-C₁₆ alkyl, optionally interrupted by —

NHC(═

O)—

;

x is 2;

a is 1;

B is O⁻

;

A is halo;

Y is selected from the group consisting of OH, O—

C₁-C₁₀ alkyl and O—

C₁-C₁₀ alkenyl; and

M is selected from the group consisting of sodium and potassium.

3. An emulsion according to claim 2, wherein:

R1 is methyl;

R2 is methyl;

R3 is —

(CH₂)₁₁CH₃;

A is Cl⁻

;

Y is OH;

and

M is Na⁺.

4. An emulsion according to claim 1, wherein the emulsion is free of a biocidal agent other than a compound of Formula I.

5. An emulsion according to claim 1, wherein the emulsion is substantially free of a biocidal agent other than a compound of Formula I.

6. An emulsion according to claim 1, wherein the amount of the multifunctional compound of formula I is from about 0.001% to about 1% (w/v).

7. An emulsion according to claim 1, wherein the emulsion does not require heating, homogenization or thickening agents for emulsion stabilization.

8. An emulsion according to claim 1, wherein the emulsion further comprises a demulcent selected from the group consisting of HPMC, HEC, CMC, Guar gum and Xanthan gum.

9. An emulsion according to claim 1, wherein the optional therapeutic agent, when present, is selected from the group consisting of ophthalmic, otic and nasal agents.

10. An emulsion according to claim 1, wherein the emulsion is non-irritating to ocular tissues.

11. A method of both preserving and stabilizing an emulsion for pharmaceutical use, comprising adding to the emulsion a stabilizing and preserving amount of a multifunctional compound of formula (I),

wherein:

x is 1 to 3 or mixtures thereof;

x+y is equal to 3;

a is 0 to 2;

z is equal to x;

B is O—

or OM;

A is an anion;

M is a cation;

Y is selected from the group consisting of OH, O—

C₁-C₁₀ alkyl and O—

C₁-C₁₀ alkenyl; and

R1, R2 and R3 are the same or different and are alkyl, substituted alkyl, alkyl aryl or alkenyl groups, optionally interrupted by —

NHC(═

O)—

, of up to 16 carbon atoms with the proviso that the total carbon atoms in R1+R1+R3 is between 10 and 24.

12. A method according to claim 11, wherein:

R1 and R2 are independently C₁-C₆ alkyl;

R3 is C₆-C₁₆ alkyl, optionally interrupted by —

NHC(═

O)—

;

x is 2;

a is 1;

B is O—

;

A is halo;

Y is selected from the group consisting of OH, O—

C₁-C₁₀ alkyl and O—

C₁-C₁₀ alkenyl; and

M is selected from the group consisting of sodium and potassium.

13. A method according to claim 12, wherein:

R1 is methyl;

R2 is methyl;

R3 is —

(CH₂)₁₁CH₃;

A is Cl⁻

;

Y is OH;

and

M is Na⁺.

14. A method according to claim 11, wherein the emulsion further comprises a therapeutic agent.

15. A method according to claim 11, wherein the emulsion further comprises a demulcent selected from the group consisting of HPMC, HEC, CMC, Guar gum and Xanthan gum.

16. A method of preparing an emulsion suitable for ophthalmic, otic or nasal administration, wherein to a composition comprising a buffering agent, an oil, an emulsifier, a pH adjuster and optionally a therapeutic agent is added, in an amount sufficient to both preserve and stabilize said composition, a multifunctional synthetic compound of formula (I)

wherein:

x is 1 to 3 or mixtures thereof;

x+y is equal to 3;

a is 0 to 2;

z is equal to x;

B is O—

or OM;

A is an anion;

M is a cation;

Y is selected from the group consisting of OH, O—

C₁-C₁₀ alkyl and O—

C₁-C₁₀ alkenyl;

and

R1, R2 and R3 are the same or different and are alkyl, substituted alkyl, alkyl aryl or alkenyl groups, optionally interrupted by —

NHC(═

O)—

, of up to 16 carbon atoms with the proviso that the total carbon atoms in R1+R2+R3 is between 10 and 24.

17. A method according to claim 16, wherein:

R1 and R2 are methyl

R3 is selected from the group consisting of (CH₂)₁₁CH₃, (CH₂)₃—

NHC(═

O)—

(CH₂)₁₀CH₃, and —

(CH₂)₃—

NHC(═

O)—

(CH₂)₁₂CH₃;

x is 2;

a is 1;

B is O—

;

A is chloro;

Y is OH; and

M is an alkali metal ion.

18. A method according to claim 17, wherein:

R1 is methyl;

R2 is methyl;

R3 is —

(CH₂)₁₁CH₃;

Y is OH;

and

M is Na⁺.

19. A method according to claim 16, wherein the emulsion further comprises a demulcent selected from the group consisting of HPMC, HEC, CMC, Guar gum and Xanthan gum.

20. A method according to claim 16, wherein the optional therapeutic agent, when present, is selected from the group consisting of ophthalmic, otic and nasal agents.