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

• US 8,343,945 B2
• Filed: 06/07/2010
• Issued: 01/01/2013
• Est. Priority Date: 12/07/2007
• Status: Active Grant

• Current Assignee: Journey Medical Corp. (Fortress Biotech, Inc.)
• Original Assignee: Foamix Ltd. (VYNE Therapeutics, Inc.)
• Inventors: Tamarkin, Dov, Friedman, Doron, Eini, Meir, Besonov, Alex, Shifrin, Helena
• Primary Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US12/795,164
• Publication Number:
  US 20100310476A1
• Time in Patent Office: 939 Days
• Field of Search: 514/152, 514/613, 424/45
• US Class Current: 514/152
• 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 tetracycline antibiotic composition comprising a foamable pharmaceutical composition and a propellant, the foamable pharmaceutical composition comprising:

a) about 0.1% to about 10% by weight of the foamable pharmaceutical composition of a tetracycline antibiotic;

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

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

at least one oil, wherein the oil is a liquid hydrocarbon-based oil;

or

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

c) about 0.01% to about 15% by weight of the foamable pharmaceutical composition of at least one surfactant, wherein the surfactant is a fatty acid ester, having a C8-C24 saturated hydrocarbon chain;

d) optionally 0.01% to about 10% by weight of the foamable pharmaceutical composition of at least one foam adjuvant, wherein the foam adjuvant is a fatty alcohol or a cocoglyceride; and

wherein each component is tetracycline-compatible;

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

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; and

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

5 to about 100;

35.

2. The topical tetracycline antibiotic composition of claim 1, wherein the oil is selected from the group consisting of a plant-based oil, a mineral oil, a triglyceride, an essential oil, and an animal-based oil.

3. The topical tetracycline antibiotic composition of claim 2, wherein the oil is selected from the group consisting of light mineral oil, MCT oil, hydrogenated castor oil, jojoba oil, and peppermint oil.

4. The topical tetracycline antibiotic composition of claim 1, wherein the surfactant is a stearic acid derived ester;

or

wherein the surfactant is a monoglyceride or diglyceride;

or

wherein the surfactant is selected from the group consisting of glycerol monostearate, sorbitan monostearate, PEG 40 stearate, and PEG 100 stearate.

5. The topical tetracycline antibiotic composition of claim 1, wherein the foam adjuvant is selected from the group consisting of oleyl alcohol, stearyl alcohol, myristyl alcohol, and cocoglycerides.

6. The topical tetracycline antibiotic composition of claim 1, wherein the tetracycline antibiotic is selected from the group consisting of a minocycline, a doxycycline, minocycline hydrochloride, doxycycline hyclate, and doxycycline monohydrate.

7. The topical tetracycline antibiotic composition of claim 1, further comprising at least one of ethanol, aluminum starch octenyl succinate, titanium dioxide, coconut alcohol, and hexylene glycol.

8. The topical tetracycline antibiotic composition of claim 1, wherein chemical stability is determined by observing a color change in the foamable pharmaceutical composition.

9. The topical tetracycline antibiotic composition of claim 1, further comprising at about 0.1% to about 5% by weight of the foamable pharmaceutical composition of a silicone oil.

10. The topical tetracycline antibiotic composition of claim 9, wherein the silicone oil is cyclomethicone.

11. The topical tetracycline antibiotic composition of claim 1, further comprising at least one tetracycline-compatible additional active agent.

12. The topical tetracycline antibiotic composition of claim 1, wherein the tetracycline antibiotic is chemically stable in the foamable pharmaceutical composition when stored for about 3 weeks, wherein chemical stability is determined by measuring at least about 90% by mass of the tetracycline antibiotic at three weeks compared to time 0.

13. The topical tetracycline antibiotic composition of claim 1, wherein the foam adjuvant is a C14-C18 fatty alcohol.

14. The topical tetracycline antibiotic composition of claim 1, 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 at least about 90% by mass of the tetracycline antibiotic at 72 hours compared to time 0.

15. A method of treating a bacterial infection, the method comprising topically administering the topical tetracycline antibiotic composition of claim 1 to a subject in need of treatment, wherein the topical antibiotic 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, and the rectum.

16. A method of treating post-surgical adhesions, the method comprising topically administering the topical tetracycline antibiotic composition of claim 1 to a surgical site of a subject.

17. A topical tetracycline antibiotic composition comprising a foamable pharmaceutical composition and a propellant, the foamable pharmaceutical composition comprising:

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

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[;

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

or

a combination of at least one emollient and 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 monoglyceride, a diglyceride, glycerol monostearate, sorbitan monostearate, PEG 40 stearate and PEG 100 stearate;

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

wherein each component is minocycline-compatible;

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

wherein at least 90% by mass of the minocycline or salt thereof is present in the foamable pharmaceutical composition when stored for 72 hours at 25°

C. after mixing with the pharmaceutical composition; and

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

5 to about 100;

35.

18. The topical tetracycline antibiotic composition of claim 17, wherein less than about 1% by mass of a 4-epiminocylcine is measured when the foamable pharmaceutical composition is stored for 72 hours at 25°

C. compared to time 0.

19. The topical tetracycline antibiotic composition of claim 17 comprising minocycline hydrochloride.

20. A method of treating a bacterial infection, the method comprising topically administering the topical tetracycline antibiotic composition of claim 17 to a subject in need of treatment, wherein the topical antibiotic composition is administered to skin, a mucosal membrane, or a body cavity.

21. A method of treating post-surgical adhesions, the method comprising topically administering the topical tetracycline antibiotic composition of claim 17 to a surgical site of a subject.

22. A topical tetracycline antibiotic composition comprising a foamable pharmaceutical composition and a propellant, the foamable pharmaceutical composition comprising either A):

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

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;

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

or

a combination of at least one emollient and 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 monoglyceride, a diglyceride, monostearate, sorbitan monostearate, hydrogenated castor oil, PEG 40 stearate and PEG 100 stearate;

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

or B);

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

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, octyldodecanol, diisopropyl adipate, and isostearic acid;

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

or a combination of at least one emollient and 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 monoglyceride, a diglyceride, glycerol monostearate, sorbitan monostearate, PEG 40 stearate, and PEG 100 stearate;

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

wherein each component is doxycycline-compatible;

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

wherein at least 90% by mass of the doxycycline or salt thereof is present in the foamable pharmaceutical composition when stored for 72 hours at 25°

C. after mixing with the foamable pharmaceutical composition; and

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

5 to about 100;

35.

23. The topical tetracycline antibiotic composition of claim 22 comprising doxycycline hyclate or doxycycline monohydrate.

24. A method of treating a bacterial infection, the method comprising topically administering the topical tetracycline antibiotic composition of claim 22 to a subject in need of treatment, wherein the topical antibiotic composition is administered to skin, a mucosal membrane, or a body cavity.

25. A method of treating post-surgical adhesions, the method comprising topically administering the topical tetracycline antibiotic composition of claim 22 to a surgical site of a subject.