Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof

• US 9,161,916 B2
• Filed: 12/31/2012
• Issued: 10/20/2015
• Est. Priority Date: 12/07/2007
• Status: Active Grant

• Current Assignee: Journey Medical Corp. (Fortress Biotech, Inc.)
• Original Assignee: Foamix Pharmaceuticals, Ltd. (VYNE Therapeutics, Inc.)
• Inventors: Tamarkin, Dov, Friedman, Doron, Eini, Meir, Besonov, Alex, Shifrin, Helena
• Primary Examiner(s): Oswecki, Jane C
• Application Number:
  US13/732,024
• Publication Number:
  US 20130189191A1
• Time in Patent Office: 1,023 Days
• Field of Search: 424/43, 424/45, 424/59, 424/78.02, 424/78.03, 424/78.05, 424/78.07, 424/405, 424/725, 514/18.6, 514/18.7, 514/20.8, 514/152, 514/154, 514/613, 514/778, 514/783, 514/945
• US Class Current: 1/1
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 31/65 Tetracyclines
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/06 Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• 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 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 8/046 Aerosols; Foams
• 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 9/12 Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015
• CPC Class Codes: A61K 9/122 Foams; Dry foams edible foams A61K9/0056
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Abstract

The present disclosure teaches unique formulations for topical administration of tetracycline antibiotics, in which the tetracycline antibiotics remain stable.

Claims

1. A topical composition comprising a foamable pharmaceutical composition and a propellant, the foamable pharmaceutical composition comprising:

a) an unstable active agent;

b) at least one emollient;

or

at least one liquid oil;

or

a combination of at least one emollient and at least one liquid oil;

c) at least one surfactant, wherein the surfactant comprises a fatty acid ester having a C8-C24 hydrocarbon chain; and

d) optionally at least one foam adjuvant;

wherein each component is compatible with the unstable active agent present in the composition;

wherein the composition is free of one or more of PPG-15 stearyl ether, octyldodecanol, ethanol propylene glycol, glycerol, PEG 200, PEG 400, MCT oil, isostearic acid, polyoxyl 20 stearyl ether, polyoxyl 2 stearyl ether, methyl glycose sesquistearate, PEG 40 stearate, cocoglycerides, hexylene glycol, butylene glycol, sorbitan monolaurate, and dimethyl isosorbide,

wherein the composition comprises less than about 2% by weight of the foamable pharmaceutical composition of water; and

wherein at least 90% by mass of the unstable active agent is present in the foamable pharmaceutical composition when stored for 72 hours at 25°

C. after mixing with the pharmaceutical composition.

2. The topical composition of claim 1, wherein the unstable active agent is a tetracycline antibiotic;

wherein at least 90% by mass of the tetracycline antibiotic is present in the foamable pharmaceutical composition when stored for 72 hours at 25°

C. after mixing with the pharmaceutical composition.

3. The composition of claim 2, wherein the weight ratio of the foamable pharmaceutical composition to the propellant is about 100:

3 to about 100;

35.

4. The topical composition of claim 2, wherein the emollient is selected from the group consisting of PPG-15 stearyl ether, octyldodecanol, diisopropyl adipate isostearic acid, cetearyl octanoate, and mixtures of any two or more thereof.

5. The topical composition of claim 2, wherein the liquid oil is selected from the group consisting of a plant-based oil, a mineral oil, a triglyceride, an essential oil, a light mineral oil, a MCT oil, a jojoba oil, a peppermint oil, and mixtures of any two or more thereof.

6. The topical composition of claim 2, wherein the fatty acid ester having a C8-C24 hydrocarbon chain is selected from the group consisting of a stearic acid ester, a monoglyceride, a diglyceride, glycerol monostearate, sorbitan monostearate, PEG 40 stearate, PEG 100 stearate, and mixtures of any two or more thereof.

7. The topical composition of claim 2, wherein the foam adjuvant is selected from the group consisting of a fatty alcohol, a C14-C18 fatty alcohol, oleyl alcohol, stearyl alcohol, myristyl alcohol, a fatty acid, cocoglycerides, and mixtures of any two or more thereof.

8. The topical composition of claim 2, wherein the tetracycline antibiotic is selected from the group consisting of a minocycline, a doxycycline, minocycline hydrochloride, doxycycline hyclate, doxycycline monohydrate, and mixtures of any two or more thereof.

9. The topical composition of claim 2 further comprising at least one of aluminum starch octenyl succinate, titanium dioxide, coconut alcohol, and hexylene glycol.

10. The topical composition of claim 2, wherein chemical stability is determined by observing a color change in the foamable pharmaceutical composition.

11. The topical composition of claim 2 comprising:

a) about 0.1% to about 10% by weight of the foamable pharmaceutical composition of minocycline hydrochloride;

b) about 60% to about 95% by weight of the foamable pharmaceutical composition of;

at least one emollient selected from the group consisting of PPG-15 stearyl ether, octyldodecanol, diisopropyl adipate, and cetearyl octanoate;

or

at least one oil selected from the group consisting of a light mineral oil, a MCT oil, a jojoba oil, and a peppermint oil;

or

a combination of said at least one emollient and said at least one oil;

c) about 0.01% to about 15% by weight of the foamable pharmaceutical composition of at least one surfactant selected from the group consisting of a stearic acid ester, a monoglyceride, a diglyceride, glycerol monostearate, sorbitan monostearate, PEG 40 stearate and PEG 100 stearate; and

d) optionally 0% to about 10% by weight of the foamable pharmaceutical composition of at least one foam adjuvant comprising a fatty alcohol and or cocoglycerides, wherein the fatty alcohol is selected from the group consisting of oleyl alcohol, stearyl alcohol and myristyl alcohol;

wherein each component is compatible with minocycline hydrochloride;

wherein the composition is free of propylene glycol, glycerol, PEG 200, PEG 400, ethanol, isostearic acid, polyoxyl 20 stearyl ether, polyoxyl 2 stearyl ether, methyl glucose sesquistearate, hexylene glycol, butylene glycol, sorbitan monolaurate, and dimethyl isosorbide; and

wherein the weight ratio of the foamable pharmaceutical composition to the propellant is about 100;

3 to about 100;

35.

12. The topical composition of claim 11, wherein less than about 1% by mass of a 4-epiminocycline is measured when the foamable pharmaceutical composition is stored for 72 hours at 25°

C. compared to time 0.

13. The topical composition of claim 2 comprising either A):

a) about 0.1% to about 10% by weight of the foamable pharmaceutical composition of doxycycline hyclate or doxycycline monohydrate;

b) about 60% to about 95% by weight of the foamable pharmaceutical composition of;

at least one emollient selected from the group consisting of PPG-15 stearyl ether, diisopropyl adipate, and cetearyl octanoate;

or

at least one oil selected from the group consisting of a mineral oil and a MCT oil;

or

a combination of said at least one emollient and said at least one oil;

c) about 0.01% to about 15% by weight of the foamable pharmaceutical composition of at least one surfactant selected from the group consisting of a stearic acid ester, a monoglyceride, a diglyceride, glycerol monostearate, sorbitan monostearate, hydrogenated castor oil, and PEG 100 stearate; and

d) optionally 0% to about 10% by weight of the foamable pharmaceutical composition of at least one foam adjuvant comprising a fatty alcohol and or a fatty acid selected from the group consisting of stearyl alcohol, oleyl alcohol, isostearic acid and myristyl alcohol;

or B);

a) about 0.1% to about 10% by weight of the foamable pharmaceutical composition of doxycycline hyclate or doxycycline monohydrate;

b) about 60% to about 95% by weight of the foamable pharmaceutical composition of;

at least one emollient selected from the group consisting of cetearyl octanoate, PPG-15 stearyl ether, propylene glycol, diisopropyl adipate, and isostearic acid;

or

at least one oil selected from the group consisting of light mineral oil, MCT oil, and hydrogenated castor oil;

or a combination of said at least one emollient and said at least one oil;

c) about 0.01% to about 15% by weight of the foamable pharmaceutical composition of at least one surfactant selected from the group consisting of a stearic acid ester, a monoglyceride, a diglyceride, glycerol monostearate, sorbitan monostearate, PEG 40 stearate, and PEG 100 stearate; and

d) about 1% to about 10% by weight of the foamable pharmaceutical composition of at least one foam adjuvant comprising a fatty alcohol and or fatty acid selected from the group consisting of oleyl alcohol, stearyl alcohol, myristyl alcohol and stearic acid;

wherein each component is compatible with doxycycline hyclate or doxycycline monohydrate;

wherein the composition is free of octyldodecanol, propylene glycol, glycerol, PEG 200, PEG 400, butylene glycol, sorbitan monolaurate, and dimethyl isosorbide; and

wherein the weight ratio of the foamable pharmaceutical composition to the propellant is about 100;

3 to about 100;

35.

14. The topical composition of claim 2 further comprising about 0.1% to about 5% by weight of the foamable pharmaceutical composition of a silicone oil or a cyclomethicone.

15. The topical composition of claim 2, wherein the tetracycline antibiotic is chemically stable in the foamable pharmaceutical composition, wherein at least 90% by mass of the tetracycline antibiotic is present in the foamable pharmaceutical composition when stored for about 3 weeks, wherein chemical stability is determined by measuring mass of the tetracycline antibiotic at three weeks compared to time 0.

16. The topical tetracycline antibiotic composition of claim 2 further comprising at least one tetracycline-compatible additional active agent.

17. A method of treating a bacterial infection or post-surgical adhesions, the method comprising topically administering the topical composition of claim 2 to a subject in need of treatment, wherein the topical composition is administered to one or more of skin, face, a mucosal membrane, a body cavity, the nose, the mouth, the eye, the ear canal, the respiratory system, the vagina, the rectum or a surgical site of the subject.

18. A method of treating a bacterial infection, the method comprising administering the topical composition of claim 11 to a subject in need of treatment, wherein the topical composition is administered topically to one or more of skin, a mucosal membrane, or a body cavity of the subject.

19. A method of treating a bacterial infection, the method comprising administering the topical composition of claim 13 to a subject in need of treatment, wherein the topical composition is administered topically to one or more of skin, a mucosal membrane, or a body cavity of the subject.

20. The topical composition of claim 2, wherein at least 90% by mass of the tetracycline antibiotic is present in the foamable pharmaceutical composition when stored for 72 hours at 40°

C. after mixing with the pharmaceutical composition, wherein chemical stability is determined by measuring mass of the tetracycline antibiotic at 72 hours compared to time 0.

21. The topical composition of claim 1, wherein said unstable active agent is a water sensitive agent, an ester or amide prone to hydrolysis by water, an agent sensitive to free radical attack or oxidation, or sensitive to a specific pH level.

22. The topical composition of claim 1, wherein the composition is free of PPG-15 stearyl ether, octyldodecanol, MCT oil, isostearic acid, PEG 40 stearate, and cocoglycerides.

23. The topical composition of claim 1, wherein the composition is free of PPG-15 stearyl ether, MCT oil, isostearic acid, PEG 40 stearate, cocoglycerides and hexylene glycol.

24. The topical composition of claim 2, wherein the emollient is selected from the group consisting of diisopropyl adipate, cetearyl octanoate, and mixtures thereof.

25. The topical composition of claim 2, wherein the liquid oil is selected from the group consisting of a plant-based oil, a mineral oil, a triglyceride, an essential oil, a light mineral oil, jojoba oil, a peppermint oil, and mixtures of any two or more thereof.