Oil and liquid silicone foamable carriers and formulations

• US 8,900,553 B2
• Filed: 06/07/2010
• Issued: 12/02/2014
• Est. Priority Date: 12/07/2007
• Status: Expired due to Fees

• Current Assignee: Journey Medical Corp. (Fortress Biotech, Inc.)
• Original Assignee: Foamix Pharmaceuticals, Ltd. (VYNE Therapeutics, Inc.)
• Inventors: Tamarkin, Dov, Shifrin, Helena, Keynan, Rita, Ziv, Enbal, Berman, Tal, Schuz, David, Gazal, Elana
• Primary Examiner(s): Haghighatian, Mina
• Application Number:
  US12/795,213
• Publication Number:
  US 20110212033A1
• Time in Patent Office: 1,639 Days
• Field of Search: 424/43, 424/78.07, 514/871, 514/945
• US Class Current: 424/43
• 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

A waterless foamable pharmaceutical composition suitable for external administration is disclosed. The composition includes a foamable carrier least one liquefied or compressed gas propellant. The foamable carrier includes at least one liquid oil; at least one silicone and at least one least one stabilizing agent; wherein the stabilizing agent selected from the group consisting of about 0.01% to about 25% by weight of at least one surface-active agent alone or on combination with a foam adjuvant; and about 0% to about 5% by weight of at least one polymeric agent alone or on combination with a foam adjuvant; and mixtures thereof. Pharmaceutical compositions comprising active agents, methods for their preparation, propellants suitable for use with the carriers and uses thereof are further described.

Claims

1. A waterless foamable pharmaceutical composition, comprising a foamable carrier and at least one liquefied or compressed gas propellant, wherein the foamable carrier comprises:

a) about 60% to about 95% by weight of the foamable carrier of at least one liquid oil selected from the group comprising a mineral oil, a MCT oil, a liquid paraffin, a vegetable oil, an essential oil, an organic oil, a lipid, or a mixture of two or more thereof comprising about 60-90% mineral oil;

b) about 0.5% to about 15% by weight of the foamable carrier of a silicone; and

c) about 0.01% to about 25% by weight of the foamable carrier of at least one foam stabilizing agent comprising glyceryl monostearate;

wherein the foamable carrier is a single phase;

wherein the foam stabilizing agent optionally comprises at least one foam adjuvant;

wherein the silicone is selected from the group consisting of a siloxane compound having 4-6 Si—

O groups in its backbone, a cyclomethicone, a cyclotetrasiloxane, a cyclopentasiloxane, a cyclohexasiloxane, a phenyl trimethicone, a stearyl dimethicone, a cetyl dimethicone, a caprylyl methicone, a PEG/PPG 18/18 dimethicone, a dimethiconol, and a mixture of any two or more thereof;

wherein the composition is essentially free of water;

wherein the ratio of the foamable carrier to the propellant is 100;

3 to 100;

35;

wherein the resultant foam does not collapse immediately upon release and is breakable on mechanical shear;

wherein the waterless foamable pharmaceutical composition comprises a minocycline or a doxycycline or both; and

wherein the minocycline or the doxycycline is stable for at least 3 weeks at 25°

C. in the waterless foamable pharmaceutical composition.

2. The waterless foamable pharmaceutical composition of claim 1, wherein the oil is a mixture of heavy mineral oil and light mineral oil having a weight ratio from about 1:

5 to about 25;

1.

3. The waterless foamable pharmaceutical composition of claim 1, further comprising an emollient selected from the group consisting of cocoglycerides, PPG 15 stearyl alcohol, octyldodecanol, isopropyl myristate, diisopropyl adipate, cetearyl octanoate isohexadecanol, diisopropyl adipate, and a mixture of any two or more thereof.

4. The waterless foamable pharmaceutical composition of claim 1, further comprising a solid wax or solid oil selected from the group consisting of a solid paraffin, a hydrogenated oil, a hydrogenated emollient, palmitic acid, stearic acid, arachidic acid, behenic acid, and a mixture of any two or more thereof.

5. The waterless foamable pharmaceutical composition of claim 1, wherein the foam adjuvant comprises a fatty alcohol and a fatty acid.

6. The waterless foamable pharmaceutical composition of claim 1, wherein the foam stabilizing agent is in combination with a foam adjuvant selected from the group consisting of stearyl alcohol, cetyl alcohol, cetostearyl alcohol, myristyl alcohol, palmitoleyl alcohol, arachidyl alcohol, benhyl alcohol, and a mixture of any two or more thereof.

7. The waterless foamable pharmaceutical composition of claim 1, wherein the foam stabilizing agent is in combination with a foam adjuvant, wherein said foam adjuvant comprises oleyl alcohol.

8. The waterless foamable pharmaceutical composition of claim 1, wherein the weight ratio of foam stabilizing agent to silicone ranges from about 1:

1 to about 1;

4.

9. The waterless foamable pharmaceutical composition of claim 1, comprising by weight of the foamable carrier:

a) about 60-90% mineral oil;

b) about 1-15% of a silicone, where the silicone is selected from the group consisting of a cyclomethicone, a cyclohexasiloxane, a cyclopentasiloxane, a cyclytetrasiloxane, a dimethiconol, a phenyl trimethicone, a stearyl dimethicone and a mixture of any two or more thereof;

c) about 1-8% glycerol monostearate; and

d) about 1-8% myristyl alcohol or cetostearyl alcohol.

10. A waterless foamable pharmaceutical composition according to claim 1, further comprising an active agent in addition to a minocycline and or a doxycycline.

11. The waterless foamable pharmaceutical composition according to claim 10, wherein the active agent is selected from the group consisting of active herbal extracts, acaricides, age spot removing agents, keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotic agents, antiburn agents, anticancer agents, antidandruff agents, antidepressants, antidermatitis agents, antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents, antiseborrheic agents, antiseptic, antiswelling agents, antiviral agents, anti-yeast agents, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, dicarboxylic acids, disinfectants, fungicides, hair growth regulators, hormones, hydroxy acids, immunosuppressants, immunoregulating agents, insecticides, insect repellents, keratolytic agents, lactams, metals, metal oxides, mitocides, neuropeptides, non-steroidal anti-inflammatory agents, oxidizing agents, pediculicides, photodynamic therapy agents, retinoids, scabicides, self tanning agents, skin whitening agents, vasoconstrictors, vasodilators, vitamin A, vitamin A derivatives, vitamin B, vitamin B derivatives, vitamin C, vitamin C derivatives, vitamin D, vitamin D derivatives, vitamin E, vitamin E derivatives, vitamin K, vitamin K derivatives wound healing agents, wart removers, and a mixture of any two or more thereof.

12. The waterless foamable pharmaceutical composition according to claim 10, wherein the additional active agent is selected from the group consisting of acyclovir, azaleic acid, clindamycin phosphate, pimicrolimus, diclofenac potassium, calcipotriol, calcitriol, vitamin A acetate, betamethasone 17-valerate, alpha tocopherol, imiquimod, ciclopiroxolamine, and a mixture of any two or more thereof.

13. A method for treating or ameliorating a disorder comprising administering to a target site a pharmaceutically effective amount of the waterless foamable pharmaceutical composition according to claim 1, wherein the target site is selected from the group consisting of the skin, a body cavity, a mucosal surface, the nose, the mouth, the eye, the ear canal, the respiratory system, the vagina, and the rectum.

14. A method according to claim 13, wherein the waterless foamable pharmaceutical composition comprises at least one additional active agent.

15. The waterless foamable pharmaceutical composition according to claim 1, wherein the resultant foam displays all of the following characteristics:

a. does not collapse immediately upon release;

b. is breakable on mechanical shear;

c. has a viscosity below about 13,000 cps;

d. has an average bubble size below 200 microns;

e. has a hardness between about 5 to about 35;

f has a collapse time in excess of about 180 seconds; and

g. has a density below about 0.2g/ml.

16. The waterless foamable pharmaceutical composition according to claim 1, further comprising up to 5% or about 5% by weight of at least one polymeric agent alone or in combination with a foam adjuvant.

17. The waterless foamable pharmaceutical composition according to claim 10, wherein the foamable carrier including the active agent is a homogenous suspension.

18. A method for preparing a single phase waterless foamable pharmaceutical composition according to claim 1, the method comprising the steps of either:

(a) combining the at least one liquid oil with the at least one foam stabilizing agent at a temperature of at least 50°

C. or about 50°

C.;

(b) rapidly cooling the combination of one liquid oil and at least one foam stabilizing agent to less than 40°

C.;

(c) adding the silicone and the minocycline or the doxycycline or both to the cooled combination to make a prefoam formulation; and

(d) combining the prefoam formulation with a compressed gas propellant in a weight ratio of 100;

3 to 100;

35 to form the waterless foamable pharmaceutical composition;

or

(i) preparing a prefoam formulation by combining at a temperature of at least 50°

C. or about 50°

C.;

the at least one liquid oil;

the silicone; and

the at least one foam stabilizing agent;

(ii) rapidly cooling the prefoam formulation to less than 40°

C.;

(iii) adding the minocycline or the doxycycline or both to the prefoam formulation; and

(iv) combining the prefoam formulation with a compressed gas propellant in a weight ratio of 100;

3 to 100;

35 to form the waterless foamble pharmaceutical composition.

19. The method of claim 18, wherein the cooling step is carried out by placing the combination of one liquid oil and at least one foam stabilizing agent in an ice bath, or in an alcohol water bath, or in a water bath or jacket.

20. The method of claim 18, wherein the combination of one liquid oil and at least one foam stabilizing agent is cooled at a rate of at least 5 degrees/minute or about 5 degrees/minute.

21. The method of claim 18, wherein the combination of one liquid oil and at least one foam stabilizing agent is cooled to a temperature of at least 25°

C. or about 25°

C.

22. The method of claim 18, wherein the foam stabilizing agent is a monoglyceride, diglyceride, or triglyceride, or a mixture of any two or more thereof, wherein the side chain of the monoglyceride, diglyceride, or triglyceride is a saturated hydrocarbon.

23. The method of claim 18, wherein the foam stabilizing agent is glycerol monostearate and glycerol palmitostearate.