HYDROPHILIC, NON-AQUEOUS PHARMACEUTICAL CARRIERS AND COMPOSITIONS AND USES

• US 20080299220A1
• Filed: 01/14/2008
• Published: 12/04/2008
• Est. Priority Date: 08/04/2003
• Status: Active Grant

• Current Assignee: VYNE Therapeutics, Inc.
• Original Assignee: Foamix Ltd. (VYNE Therapeutics, Inc.)
• Inventors: Danziger, Jorge, Besonov, Alex, Keynan, Rita, Schuz, David, Berman, Tal, Friedman, Doron, Tamarkin, Dov, Eini, Meir, Zlatkis, Ella
• Granted Patent: US 8,486,374 B2
• Time in Patent Office: Days
• US Class Current: 424/600
• CPC Class Codes: A01N 25/02 containing liquids as carriers, diluents or solvents
• CPC Class Codes: A01N 25/16 Foams
• CPC Class Codes: A61K 31/047 having two or more hydroxy groups, e.g. sorbitol
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 31/375 Ascorbic acid, i.e. vitamin C; Salts thereof
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 47/38 Cellulose; Derivatives 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 9/12 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

Abstract

A waterless composition suitable for delivery of an active agent to a body surface or cavity includes a vehicle having about 70% to about 99% by weight of a hydrophilic polar solvent, said hydrophilic solvent selected from the group consisting of (i) a mixture of two or more different polyethylene glycols (PEGs), wherein at least one PEG is a high molecular weight PEG having a melting point greater than 25° C.; and (ii) propylene glycol (PG); about 0% to about 10% of at least one surface active agent; about 0% to about 5% of a polymeric agent; about 0% to about 30% of a secondary hydrophilic solvent; and about 0% to about 5% of a silicone oil; and about 3% to about 25% hydrophobic propellant. The composition is otherwise substantially free of a hydrophobic solvent and includes at least one of a surface active agent and a polymeric agent. The vehicle and the propellant are sufficiently miscible that the components may be homogeneously distributed with mild shaking.

Claims

1. A waterless composition suitable for delivery of an active agent to a body surface or cavity comprising:

a vehicle comprising;

a) about 70% to about 99% by weight of a hydrophilic polar solvent, said hydrophilic solvent selected from the group consisting of;

i) a mixture of two or more different polyethylene glycols (PEGs), wherein at least one PEG is a high molecular weight PEG having a melting point greater than 25°

C.; and

ii) propylene glycol (PG);

b) about 0% to about 10% of at least one surface active agent;

c) about 0% to about 5% of a polymeric agent;

d) about 0% to about 30% of a secondary hydrophilic solvent; and

e) about 0% to about 5% of a silicone oil; and

about 3% to about 25% hydrophobic propellant;

wherein the composition is otherwise substantially free of a hydrophobic solvent;

wherein the composition includes at least one of a surface active agent and a polymeric agent; and

wherein the vehicle and the propellant are sufficiently miscible that the components may be homogeneously distributed with mild shaking.

2. The composition of claim 1, wherein the hydrophilic solvent is PEG and the high molecular weight PEG is selected from the group consisting of PEG 1000, PEG 1500, PEG 4000, PEG 6000 and PEG 8000.

3. The composition of claim 2, wherein the balance of the PEG is selected from the group consisting of PEG 200, PEG 300, PEG 400, and PEG 600.

4. The composition of claim 1, wherein the hydrophilic solvent is PEG and the high molecular weight PEG comprises about 1% to about 15% of the composition.

5. The composition of claim 1, wherein mixture of two or more different PEGs are selected to provide viscosity of the vehicle of less than 52,000 CPs, as measured at room temperature at 10 rmp spindle speed.

6. The composition of claim 1, wherein the hydrophilic polar solvent is PG and the components of the composition are sufficiently miscible that the vehicle and the propellant do not phase separate upon centrifugation at 1000 rpm.

7. The composition of claim 6, wherein the hydrophilic solvent is PG, the composition includes a steareth surface active agent and a hydroxypropylcellulose polymeric agent, and is substantially free of silicone and a secondary hydrophilic solvent.

8. The composition of claim 1, wherein one or both of the surface active agent and the polymeric agent are selected to increase the solubility of the propellant in the vehicle.

9. The composition of claim 1 wherein the a polymeric agent is present in the composition and is selected from the group consisting of locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum, starch, an amine-bearing polymer, chitosan, alginic acid, hyaluronic acid, a chemically modified starch, a carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, a polyacrylic acid polymer, a polymethacrylic acid polymer, polyvinyl acetate, a polyvinyl chloride polymer, a polyvinylidene chloride polymer, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose, carboxymethylcellulose carboxymethylhydroxyethylcellulose, a cationic cellulose PEG 1000, PEG 4000, PEG 6000 and PEG 8000, polycarbophil, carbomer, ASOS, klucel and permulen.

10. The composition of claim 1, wherein a surface active agent is present in the composition and is selected from the group consisting of a

a. polysorbate, including polysorbate 80 and Twin 80, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, a polyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59;

a polyoxyethylene alkyl ether, including polyoxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, Brij 10, Brij, 21, Brij 38, Brij 52, Brij 56, Brij 72, Brij 721 and Brij W1, a sucrose ester, including Span 20, Span 60 and Span 80, a partial ester of sorbitol, including sorbitan monolaurate, sorbitan monolaurate, and Surphope 1811, a monoglyceride, a diglyceride, isoceteth-20, a mono, di or tri fatty acid sucrose ester, laureth-4, glyceryl stearate, polyoxyl-100 stearate, glyceryl monostearate, PEG-100 stearate, PEG-40 stearate, ceteareth-6, ceteareth-16, ceteareth-20, stearyl alcohol, myrj 52, steareth-2, steareth-20, isosteareth-20, polyglyceryl 10 laurate, POE (2) cetyl ether, cetearyl glucoside, cetyryl alcohol, methyl glucose sesquistearate, span 60, sucrose stearic acid esters, sorbitan stearate, sucrose cocoate, sucrose stearate, Peg 40 stearate, isosteareth 20, methyl glucose sesquistearate, polyoxyl 100 stearate, macrogel cetostearyl ether, a polymeric emulsifier, including Permulen (TR1 or TR2); and

liquid crystal systems, including Arlatone (2121), Stepan (Mild RM1), Nikomulese (41) and Montanov (68); and

b. a combination of surfactants selected from the group consisting of a Brij surfactant and a Twin surfactant, wherein the Brij surfactant is the major component of the combination, combinations of polyoxyethylene alkyl ethers, including Brij 59/Brij 10;

Brij 52/Brij 10;

Steareth 2/Steareth 20;

Steareth 2/Steareth 21 (Brij 72/BRIJ

     721);

Myrj 52/Myrj 59, Steareth 2/Laureth 4;

combinations of sucrose esters, including Surphope 1816/Surphope 1807;

combinations of sorbitan esters, including Span 20/Span 80;

Span 20/Span 60;

combinations of sucrose esters and sorbitan esters, including Surphope 1811 and Span 60; and

combinations of liquid polysorbate detergents and PEG compounds, particularly Twin 80/PEG-40 stearate/methyl glucose sequestrate, glyceryl stearate/PEG-100 stearate;

ceteareth-6/stearyl alcohol;

cetearyl glucoside/cetyryl alcohol;

sorbitan stearate/sucrose cocoate; and

polysorbate 80/PEG-40 stearate.

11. The composition of claim 1, wherein silicone oil is present in the composition and is selected from the group consisting of dimethicone, cyclomethicone and mixtures thereof.

12. The composition of claim 1 wherein the second hydrophilic solvent is present in the composition and is a polyol selected from the group consisting of a diol, a triol and a saccharide, wherein the triol is selected from the group consisting of glycerin, butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol, and wherein the diol is selected from the group consisting of propylene glycol, butanediol, butenediol, butynediol, pentanediol, hexanediol, octanediol, neopentyl glycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol and dibutylene glycol.

13. The composition of claim 1, wherein the ratio between the polyethylene glycol and the secondary hydrophilic solvent is between about 9:

1 and about 1;

1.

14. The composition of claim 1 wherein the composition further comprises one or more modulating agents.

15. The composition of claim 14, wherein the modulating agent is selected from the group of triethanol amine, sodium citrate and citric acid.

16. The composition of claim 1, further comprising an active agent.

17. The composition of claim 16, wherein the active agent is selected from the group consisting of antiinfectives, antifungals, antivirals, anesthetic analgesic, corticosteroids, non steroid anti inflammatory, retinoids, lubricating agents anti warts, antiproliferative, vasoactive, keratolytic, insecticide and repellants, dicarboxylic acids and esters;

calcium channel blockers, cholinergic, N-oxide doners, photodynamic, anti acne, anti wrinkle, antioxidants, self tanning active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotics, 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, antiyeast 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, sanatives, scabicides, self tanning agents, skin whitening agents, asoconstrictors, vasodilators, vitamins, vitamins A, B, C, D, E, K and derivatives, wound healing agents and wart removers.

18. The composition of claim 16, wherein the active agent is selected from the group consisting of:

Acyclovir, Azelaic acid, Benzoyl peroxide, Betamethasone 17 valerate micronized, Caffeine, Calcipotriol hydrate, Ciclopiroxolamine, Diclofenac sodium, Ketoconazole, Miconazole nitrate, Minoxidil, Mupirocin, Nifedipine regular, Permethrin BPC (cis;

trans 25;

75), Piroxicam, Salicylic acid, Terbinafine HCl, estradiol hemihydrate and progesterone or combinations thereof.

19. The composition of claim 16, wherein the active agent includes progesterone, estrogen, a derivative thereof or mixtures thereof.

20. The composition of claim 16, wherein the active agent includes a vitamin.

21. The composition of claim 20, wherein the vitamin selected from the group consisting of a Vitamin D, retinol, retinoic acid, tocopherol, Vitamin K Vitamin C or Vitamin B or a derivatives thereof.

22. The composition of claim 16 wherein the active agent includes a steroid.

23. The composition of claim 20, wherein the active agent includes a steroid.

24. The composition of claim 1, wherein the composition comprises a polymeric agent and the polymeric agent is selected from the group of bioadhesive polymers.

25. The composition of claim 24, wherein the composition has a bioadhesive force in the range of about −

3 g to about −

25 g.

26. The composition of claim 24 wherein the polymeric agent is selected from the group consisting of hydroxypropylcellulose and carbomer.

27. A waterless composition suitable for delivery of an active agent to a body surface or cavity comprising:

a vehicle, comprising;

a) about 70% to about 99% by weight of a hydrophilic polar solvent comprising butylene glycol (BG)

b) about 0% to about 10% of at least one surface active agent;

c) about 0% to about 5% of a polymeric agent;

d) about 0% to about 30% of a secondary hydrophilic solvent; and

e) about 0% to about 5% of an unmodified silicone; and

about 3% to about 25% hydrophobic propellant;

wherein the composition is otherwise substantially free of a hydrophobic solvent;

wherein the composition includes at least one of a surface active agent and a polymeric agent; and

wherein the components of the composition are sufficiently miscible that the vehicle and the propellant do not phase separate upon centrifugation at about 1000 rpm for about 10 mins.

28. The composition of claim 27, wherein the hydrophilic solvent further comprises a polyol selected from the group consisting of propylene glycol and hexylene glycol.

29. The composition of claim 28, wherein the ratio of butylene glycol to hexylene glycol is in the range of 1:

0.5 to about 1;

3.

30. The composition of claim 27, wherein the components of the composition are sufficiently miscible that the vehicle and the propellant do not phase separate upon centrifugation at about 3000 rpm for about 10 mins.

31. A waterless composition suitable for delivery of an active agent to a body surface or cavity comprising:

a vehicle, comprising;

a) about 70% to about 99% by weight of a hydrophilic polar solvent, said hydrophilic solvent selected from the group consisting of polyethylene glycols (PEGs) and propylene glycol (PG);

b) about 0.1% to about 10% of at least one surface active agent, a surface active agent is present in the composition and is a mixture of a Brij surfactant and a Twin surfactant, wherein the Brij surfactant is the major surface active agent component;

c) about 0% to about 5% of a polymeric agent;

d) about 0% to about 30% of a secondary hydrophilic solvent; and

e) about 0% to about 5% of an unmodified silicone; and

about 3% to about 25% hydrophobic propellant;

wherein the composition is otherwise substantially free of a hydrophobic solvent; and

wherein the components of the composition are sufficiently miscible that the propellant and vehicle may be homogeneously distributed with mild shaking.

32. A hygroscopic glycol composition comprising a polyethylene glycol or derivatives and mixtures thereof or comprising a propylene glycol or derivatives at a sufficient concentration alone as a component in the composition or with one or more other hygroscopic substances to provide

(a) at least one hygroscopic substance at a sufficient concentration to provide an Aw value of the hygroscopic therapeutic containing composition of less than 0.9;

and

(b) a therapeutic agent thereof or a combinations thereof.

33. The composition of claim 32, wherein the composition further comprises at least one component selected from the group consisting of

(a) about 0.01% to about 5% by weight of at least one polymeric agent selected from a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;

and

(b) a surface active agent,

wherein the polymeric agent is selected such that it has some surfactant properties if it is used in the absence of a surface active agent.

34. A waterless composition suitable for delivery of an active agent to a body surface or cavity comprising:

a) about 70% to about 99% by weight of a mixture of two or more different polyethylene glycols (PEGs), wherein at least one PEG is a high molecular weight PEG having a melting point greater than 25°

C., and wherein the mixture of two or more different PEGs is selected to provide an gel, ointment or cream; and

b) about 0% to about 10% of at least one surface active agent;

c) about 0% to about 5% of a polymeric agent; and

d) about 0% to about 30% of a secondary hydrophilic solvent;

wherein the composition includes at least one of a surface active agent and a polymeric agent.

35. The composition of claim 34, wherein the high molecular weight PEG is present in an amount greater than about 10% by weight of the composition.

36. The composition of claim 34, wherein the PEG is a combination of a high and low molecular weight PEG selected from the group consisting PEG6000/PEG200;

PEG400/PEG1500, PEG4000/PEG200;

PEG4000/PEG400, PEG 4000/PEG 600, PEG4000/PEG400/PEG200; and

the like.

37. A waterless composition suitable for delivery of an active agent to a body surface or cavity comprising:

a vehicle comprising;

a) about 70% to about 99% by weight of a hydrophilic polar solvent, said hydrophilic solvent comprising a mixture of PEG 200 and PEG 400;

b) about 0% to about 10% of at least one surface active agent;

c) about 0% to about 5% of a polymeric agent;

d) about 0% to about 30% of a secondary hydrophilic solvent; and

e) about 0% to about 5% of a silicone oil; and

about 3% to about 25% hydrophobic propellant;

wherein the composition is otherwise substantially free of a hydrophobic solvent;

wherein the composition includes at least one of a surface active agent and a polymeric agent; and

wherein the vehicle and the propellant are sufficiently miscible that the components may be homogeneously distributed with mild shaking.