CA2191773C - Stable gel formulation for topical treatment of skin conditions - Google Patents

Stable gel formulation for topical treatment of skin conditions Download PDF

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CA2191773C
CA2191773C CA002191773A CA2191773A CA2191773C CA 2191773 C CA2191773 C CA 2191773C CA 002191773 A CA002191773 A CA 002191773A CA 2191773 A CA2191773 A CA 2191773A CA 2191773 C CA2191773 C CA 2191773C
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gel
polysorbate
drug
poloxamer
active agent
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CA2191773A1 (en
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Prakash M. Charu
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Allergan Inc
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Allergan Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

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Abstract

The present invention provides a stable gel formulation for topical treatment of skin conditions in humans. The stable gel formulation includes an active agent, having activity for treatment of acne and psoriasis, which is insoluble in water and a plurality of nonaqueous vehicles for both sotubilizing said active agent and forming a gel therewith enabling topical application of the gel to a skin condition. The plurality of vehicles am each present in amounts, and in combination, m control release of the active agent from the gel to the skin condition.

Description

STABLE GEL FORMOLATION FOR TOPICAL TREATMENT OF ERIN
' CONDITIONS
The present invention generally relates to pharmaceutical preparations and more specifically relates to stable gels for topical treatment of both acne and psoriasis in humans.
Acne is a relatively common inflammatory disease afflicting the skin. The severity of the disease ranges from a more or less superficial disorder to inflammatory conditions in which bacterial invasions occur causing inflamed and infected sacs to appear.
Most activity occurs where sebaceous glands are the largest, most numerous and of course most active.
Left untreated, the acne lesions may become extensive and leave permanent disfiguring scars.
The cause of acne is increased activity of the sebaceous glands and the epithelial tissue lining the infundibulum. The increased activity of the sebaceous glands produces more sebum which consists of free and esterified fatty acids as well as unsaponifiable lipid components which results in increased skin oiliness.
In inflammatory acne, the initial inflammation of hair follicle walls results from the presence of free fatty acids derived from the sebum. In the presence of bacterial lipolytic enzymes, triglycerides of the sebum are split, releasing the fatty acids. The ~ normal bacterial flora in the sebaceous duct produce the enzymes responsible for splitting the triglycer-ides.

WO 95133489 ~ ~ PCT/US95/07338 Current treatments for acne include cymedolytics, exfoliants, oral and topical bacteriostatics, as well as systemic antibiotics: Ideally, topical formula-tions for the treatment of acne should be compounded with little or no oil in the formulation and should not leave any oil film on the skin to compound the condition.
Psoriasis, on the other hand, is a chronic, hereditary, recurrent papulosquamous dermatosis typically involving the scalp and extensor surfaces of the limbs, especially the elbows, knees and shins.
The distinctive lesion of psoriasis is a vivid red macule, papule or plaque covered almost to its edge by silvery lamellated scales. Psoriasis is further characterized by accelerated epidermal proliferation, leading to excessive scaling of the skin due to the fact that psoriatic skin loses water eight to ten times faster than normal skin. For this reason, topical treatment thereto typically contains oils which are best suited for moisturizing the skin.
The present invention is directed to a formula-tion and a method of producing a formulation in gel form that does not contain any oil and therefore meets the requirements of treatment and also offers a high moisturizing factor for psoriatic treatment. Effec-tiveness of an active agent for treatment of acne and psoriasis is, of course, dependent upon the availabil-ity of the agent for affected areas when applied in a topical manner. That is, the formulation must not only incorporate sufficient active agent to properly treat the condition but also the release of the active agent from the formulation is an absolute necessity.
In accordance with the present invention, a gel formulation has been developed which is suitable for treatment of both acne and psoriasis which incorpo-rates vehicles for both solubilizing the active agent and for controlling release of the active agent from the gel to the skin condition.
SUMMARY OF THE INVENTION
In accordance with the present invention, a stable gel formulation for topical treatment of skin conditions in humans is used as an active agent having activity for treatment of acne and psoriasis and is insoluble in water. In cambination therewith is a plurality of nonaqueous vehicles for both solubilizing the active agent and forming a gel therewith. The nonaqueous vehicles enable topical application of the gel to a skin condition with the vehicles each being present in amounts, in combination, to control the release of the active agent from the gel to the skin condition.
Other combinations of the vehicles provide a means to maximize the solubility of the active agent in the gel.
More particularly, the formulation comprises three vehicles and the active agents comprises a synthetic retinoid, preferably Ethyl-6-[2-(4,4-dimethyl.thiochroman-6-yl]nicotinate or any of the other synthetic retinoids disclosed in U.S. Patents 4,739,098; 4,923,884; 4,810,804; 5,013,744; 4,895,868 5,006,550; 4,992,458; 5,149,705; 5,202,471; 5,130,335 and 5,134,159.

Vehicles are used to both solubilize the active agent and form a gel and preferably comprise Polysor-bate 40 (a polyhydroxy organic compound), Poloxamer 407 and Hexylene glycol.
More specifically, the present invention provides a stable gel formulation having an effective amount of a compound having the formula: Ethyl-6-[2-(4,4-dimethylthiochroman-6-yl)nicotinate, (sometimes hereinafter referered to as AGN, see U.S. 4,810,804) for treating acne in a pharmaceutical carrier compris ing water, edetate disodium, ascorbic acid, Carbomer 934P, Poloxamer 407, polyethylene glycol, Polysorbate 40, hexylene glycol, butylated hydroxytoluene, butylated hydroxyanisole, benzyl alcohol, and tromethamine.
A method in accordance with the present invention for preparing a formulation for topical treatment of both acne and psoriasis includes the steps of mixing purified water, edetate disodium, ascorbic acid and Carbomer 934P (a polyacrylic acid) until the carbomer is dispersed to form a part I, mixing purified water, Poloxamer 407 to form a part II and adding part II to part I while homogenizing same.
The method further includes mixing polyethylene glycol, Polysorbate 40, hexylene glycol, butylated hydroxytoluene and butylated hydroxyanisole and heating to dissolve same. Thereafter, the heated mixture is cooled to room temperature and benzyl alcohol and Ethyl-6-[2-(4,4-dimethylthiochroman-6-yl]nicotinate are added thereto to form a part III.
Purified water is mixed with tromethamine to form part IV and part III is added to parts I and II while stirring before part IV with mixing until homogeneous.
AMENDED SHEET

WO 95/33489 ~ ~ PCT/US95/07338 i BRIEF DESCRIPTION OF THE DRAWINGS
The advantages and features of the present invention will be better understood by the following description when considered in conjunction with the accompanying drawings indicated as follows:
Figure 1: Plot of residuals vs. fitted values for the solubility data;
Figure 2: Normal plot of residuals for the solubility data;
Figure 3: Effect of transformation of the response (solubility data);
Figure 4: Response surface fitting the solubil-ity data (with hexylene glycol);
Figure 5: Effect of square root of time on %
drug released from gels 1 through 6;
Figure 6: Effect of square root of time on %
drug released from gels 7 through 10;
Figure 7: Effect of square root of time on %
drug released from gels 11 through 14:
Figure 8: Effect of square root of time on drug released from gels 15 through 18;
Figure 9: Plot of residuals vs. fitted values for the release data;
Figure 10: Normal plot of residuals for the release data;
Figure 11: Effect of transformation of the response (release data);
Figure 12: Response surface fitting the release data (with hexylene glycol);
Figure 13: Correlation between release rate of ' drug from gels and the square root of drug solubil ity;
Figure 14: Release profiles comparing drug release from the prototype gel (H) to drug release from a saturated solution; and WO 95133489 ~ PCT/US95107338 Figure 15: Release profiles showing the effect of increasing the concentration of drug in the gel vehicle on the release rate, 0.025%, 0.05%, and 0.1%.
DETAILED DESCRIPTION
The following factors must be taken into consid eration in the formulation of a suitable pharmaceuti cal preparation for the treatment of acne and psoria sis:
Formulation and Patient Compliance Issues ~ Nonirritating and nonstaining ~ Odor-free ~ Nonoily and nondrying ~ Water washable ~ Easy application and storage ~ Ingredient labeling Formulation Issues ~ Development of only one formula for both acne and psoriasis ~ Local drug delivery and little systemic effect ~ Ease of scaleup ~ Stability for a minimum of two years ~ Use of safe and compendial excipients ~ Paraben-free formulation ~ Propylene glycol-free formulation ~ Drug having minimal affinity for the base ~ Alcohol-free formulation ~ Oil-free formulation ~ Formula showing minimal placebo effect ~ Some portion of drug in solution for immedi-ate release WO 95/33489 ~ ~ PCT/US95/07338 -~ Irritation levels comparable to other mar-keted retinoids It has been found that the compound Ethyl-6-[2-(4,4-dimethylthiochroman-6-yl]nicotinate is active in the treatment of acne and psoriasis. However, the solubility of AGN 190168 in water is extremely low.
The solubility of Ethyl-6-[2-(4,4-dimethylthiochroman 6-yl]nicotinate in various solutions at 35° ~ 0.5°C is shown in Table I.

-g-Table I.
Solubility of AGN in Various Aqueous Solutions at 35° _+0.5°C
Aqueous Mixtures (v/v) Avg. Solubilit y ( mg/ml ) 100% Water Not Detected 20% Ethanol/Water Not Detected 40% Ethanol/Water 0.1472 0.0209 60% Ethanol/Water 2:2235 0.000780%

40% Ethanol/Water 0.1472 + 0.0209 80% Ethanol/Water 8.2248 + 0.2206 20% PEG-400/Water Not Detected 40% PEG-400/Water 0.0044 0.0005 60% PEG-400/Water 0.0896 0.0011 80% PEG-400/Water 2.1628 0.0899 1% Oleth-20/Water 0.0733 0.0030 2% Oleth-20/Water 0.1492 0.0006 4% Oleth-20/Water 0.3112 0.007 96% Oleth-20/Water 0.4352 0.0011 0.07% Polysorbate 40 0.0037 0.0006 0.15% Polysorbate 40 0.0092 0.0014 0.30% Polysorbate 40 0.0183 0.0018 0.50% Polysorbate 40 0.0332 0.0003 As hereinabove noted, a solution dosage form con-taining AGN is not desirable in view of the aqueous content, the difficulty in handling the solution, and application to skin. A cream formulation is feasible but the oil utilized therein is also not suitable for acne treatment as hereinabove noted.
The formulation in accordance with the present invention includes a number of ingredients as set forth in Table II.

_g-Table II
Ingredients Used in Formulation of an AGN Gel INGREDIENT FUNCTION

AGN Drug Purified water Excipient Edetate Disodium Stabilizer Ascorbic acid Stabilizer Carbomer 934P Thickening agent Poloxamer 407 Surfactant PEG-400 Co-solvent Polysorbate 40 Surfactant Hexylene glycol Co-solvent Butylated hydroxytoluene Stabilizer Butylated hydroxyanisole Stabilizer Benzyl alcohol Preservative Triethanolamine/
Tromethamine Neutralizer Rationale For Selection of Excipients The rationale for selecting the excipients used in the AGN topical gel is outlined below.
PEG 400: Polyethylene glycol 400 is used in AGN
topical gel formulation as a solvent to solubilize the active drug, AGN. Solubility of AGN in PEG 400 is 2.2 mg/mL. At ambient conditions PEG 400 is a liquid which is completely miscible with water, and the . topical formulations can be compounded easily. PEG
400 is chemically stable and does not support microbial growth. PEG 400 is hygroscopic and topical formulations prepared with PEG 400 do not dry on skin readily after application. The following marketed Rx products in USA contain PEG 400 as excipient: Retin A

Liquid~, Lotrimin~ solution~, Cleocin T~ gel, Halotex~
1% Cream, Halog~ 0.1% ointment, and Mycelex~ solution.
PEG 400 is a component of "Polyethylene glycol ointment NF".
Carbomer 934P is used as a viscosity builder in AGN topical gel formulations. Carbomer 934P has the ability to produce high viscosities at low concentration after neutralization, with much greater lot to lot consistency than the natural gums and does not support microbial growth. Carbomer 934P gels show good plastic flow properties, having a significant yield value (commonly defined as initial resistance to flow under applied stress). AGN topical gel, prepared with carbomer 934P, shows acceptable thickness and spreads evenly on application to the skin.
Edetate disodium is used in AGN topical gels as a chelating agent for the stabilization of the overall formulation. Trace amounts of iron and other transition metals are known to degrade carbopol resins (used as a thickener) and PEG 400 (used as solvent) in AGN gel. Edetate disodium is used to sequester traces of metal ions which would catalyze oxidation of AGN and ascorbic acid used in the formulation. Aqueous solutions of Polysorbate 40 are known to undergo autoxidation as well.
Polysorbate 40 is used as surfactant to solu-bilize the AGN. Polysorbate 40 is liquid at ambient conditions and miscible with PEG 400-water mixtures and does not cloud the solution. Polysorbate 40 has an HLB value of 15.6 and this high HLB value surfactant is selected to solubilize AGN in PEG 400.

Poloxamer 407 is used as a surfactant in the water phase of the AGN gel formulation. Poloxamer 407 is water soluble and has an HLB value of 20.
Hexylene glycol is miscible with water-PEG 400 mixtures and is used as a cosolvent to solubilize AGN
along with PEG 400.
Tromethamine is used to neutralize Carbomer 934P
and as a pH adjuster while manufacturing AGN topical gel.
Ascorbic acid is used as an antioxidant and is added to the water phase while manufacturing AGN
topical gel. Laboratory formulation of AGN prepared without ascorbic acid shows poor stability.
Benzyl alcohol is used along with PEG 400 and Polysorbate 40 to solubilize the active AGN. Benzyl alcohol is also used as preservative.
Butylated hydroxytoluene, butylated hydroxyani-sole are used in the AGN topical gel formulation as antioxidants protecting the overall product from residual peroxides found in excipients. These antiox-idants are not water soluble and are added to the PEG
400 phase while manufacturing. Alcoholic solutions containing AGN are stabilized by BHT (preformulation report).
Nitrogen, as inert gas, is used while manufactur-ing AGN topical gel to reduce any potential for autoxidation of the active ingredient and other excipients.

'~.'~ '~
WO 95133489 PCTlUS95/07338 Purified Water is used as the vehicle in the AGN
topical gel formulation.
Typical concentration of each ingredient in the gel is shown in Table III.
Table III.
Concentration (% w/w) of ingredients in the 0.1% AGN
Topical Gel (Formula 8606X) INGREDIENT FUNCTION CONCENTRATION
% W/W

AGN Drug 0.1 Purified water Excipient 49.25 Edetate Disodium Stabilizer 0.05 Ascorbic acid Stabilizer 0.05 Carbomer 934P Thickening 1.25 agent Poloxamer 407 Surfactant 0.2 PEG-400 Co-solvent 45.0 Polysorbate 40 Surfactant 0.2 Hexylene glycol Co-solvent 2.0 Butylated hydroxytoluene Stabilizer 0.05 Butylated hydroxyanisole Stabilizer 0.05 Benzyl alcohol Preservative1.0 Triethanolamine/ Neutralizer 0.8 Tromethamine The ingredients are combined together to make the following four parts:

Part I:
INGREDIENT FUNCTION
Purified water Excipient Edetate Disodium Stabilizer Ascorbic acid Stabilizer Carbomer 934P Thickening agent Part II:
Purified water Excipient Poloxamer 407 Surfactant Part III:
PEG-400 Co-solvent Polysorbate 40 Surfactant Hexylene glycol Co-solvent Butylated hydroxytoluene Stabilizer Butylated hydroxyanisole Stabilizer Benzyl alcohol Preservative AGN Drug Part IV:
Purified water Excipient Tromethamine Neutralizer Procedure for Preparing the Gel The procedure for preparation of the gel is as follows:
1. The ingredients in part I are mixed with low speed homogenization until the carbomer is dispersed.
2. The ingredients in part II are mixed.
3. Part II is added to part I and the mixture is homogenized.
4. The first four ingredients in part III are combined and heated to 65 degrees Centegrade until all compounds are dissolved.

WO 95/33489 2, PCT/US95107338 5. The mixture is allowed to cool to room temper-ature. Then benzyl alcohol and the drug are slowly combined while mixing (in the yellow room).
6. Part III is added to Part I/II while stirred using a low speed homogenizer.
7. The ingredients in part IV are combined and added to the above mixture and mixed until homoge-neous.
It has been found that three vehicles influenced drug solubility and release; namely, polysorbate 40, poloxamer 407, and hexylene glycol. Using experi-mental design, variations of the gel were formulated which contained polysorbate 40 and poloxamer 407, each at three levels, and hexylene glycol at two levels.
Based on this 2x32 factorial design, eighteen varia-tions of the gel were formulated and the effect of surfactant and co-solvent concentration on drug solubility and in vitro release were evaluated.
Materials Ethyl-6-[2-(4,4-dimethylthiochroman-6-yl]nicotinate (available from SK&F, Cambridge), Ascorbic acid, USP (Hoffman-La Roche), Benzyl alcohol, NF (Akzo), Butylated hydroxyanisole, NF (Penta), Butylated hydroxytoluene, NF (Penta), Carbomer 934P, NF (Carbopol 974P, B.F. Goodrich), Edetate Disodium, USP (Akzo), Ethyl alcohol (Quantum Chemical Corp.), Hexylene glycol, NF (Union Carbide), Poloxamer 407, NF
(BASF), Polyethylene glycol 400, NF (Union Carbide), Polysorbate 40, NF (ICI), Purified water, USP, Silastic~ medical grade sheeting (Dow Corning Wright), Tromethamine, USP, (American Biorganic).

Ecruipment Brookfield counter rotating mixer (Brookfield Engineering laboratories Inc.), Nova II Hot plate/
stirrer, (Baxter).
Diffusion Apparatus Cassette~ pump drive unit (Manostat), Posi Bloc' Diffusion cell heater (Crown glass company, Inc.), Retriever IV fraction collector (ISCO, Inc.), Teflon~
flow-thru diffusion cells (Crown Glass Company, Inc.).
Chromatography Instrumentation 116 programmable solvent module (Beckman), 166 Detector (Beckman), Beckman Ultrasphere XL HPLC
column, 4.6 mm x 7.0 cm (Beckman) , Auto-injector WISP'"
model 712 (Waters).
~cVAX~ Software Access Chrom~ data collection system (Perkin-Elmer Nelson), RS/Discover~ (BBN software).
Methods Preparation of Experimental Gels The ingredients used in the prototype gel (form-ula 8606X) are shown in Table III. Based on experi-mental design, variations of the prototype gel were prepared which contained different concentrations of three ingredients present in the gel; polysorbate 40 (PS), poloxamer 407 (PX), and hexylene glycol (HG).
The purpose was to study the effect of these factors on the release rate and solubility of AGN in the WO 95/33489 ~ ~ ~~ ~ ~ ~ v PCT/LTS95107338 vehicle of the gels. The procedure for the prepara-tion of the gels is described in the formulation record.
Experimental Design Experimental design was used to determine the number of formulations necessary to provide the desired information in the most efficient way. The variables studied were the concentrations of hexylene glycol, poloxamer 407, and poTysorbate 40. Hexylene glycol was studied at 2 levels and each of the sur-factants was studied at 3 levels. Therefore, a 2x32 factorial design was produced which required the prep-aration of 18 formulations. Table IV shows the actual concentrations used for each of these ingredients.
For all ingredients, the concentration of 0 indicates that the ingredient is not present.
Table IV.

The Levels of Poloxamer 407, Polysorbate 40, and Hexylene Glycol Used in the Preparation of Various Experimental Gels INGREDIENT CONCENTRATION
(% W/W) Poloxamer 407 0 0.2 0.4 Polysorbate 40 0 0.2 0.4 Hexylene glycol 0 2 The experimental design is shown in Table V.
This design required the preparation of 18 gels con-taining all possible combinations of the surfactants and co-solvent at the desired levels. Since the pro-totype gel (gel B) represented one of the gels, it was necessary to formulate 17 other gels.

Table V.
The 2x32 Factorial Design Used to Prepare the Various Experimental Formulations of the Prototype Gel (Gel B) Gel Hexylene GlycolPolysorbate 40 Poloxamer 407 0.0 0.0 0.0 11 0.0 0.0 0.4 8 0.0 0.0 0.2 10 12 0.0 0.4 0.0 18 0.0 0.4 0.4 0.0 0.4 0.2 9 0.0 0.2 0.0 16 0.0 0.2 0.4 15 7 0.0 0.2 0.2 3 2.0 0.0 0.0 5 2.0 0.0 0.4 1 2.0 0.0 0.2 6 2.0 0.4 0.0 17 2.0 0.4 0.4 14 2.0 0.4 0.2 2 2.0 0.2 0.0 13 2.0 0.2 0.4 B 2.0 0.2 0.2 Solubility of AGN in the Gels To determine the saturated solubility of the drug in the vehicle of each of the 18 gel formulations, solvent systems containing the same ingredients as the gels were prepared. The saturated solubility was determined once in solutions of the vehicle without carbomer and base, and another time by substituting propionic acid for carbomer in order to ease filtra-tion of the solution while keeping the ionic strength WO 95/33489 t 8 3 PCT/US95/07338 of the solution as close to that of the gel as pos-sible. The solutions were filtered through a 0.45~m filter to remove any crystals which may have formed.
The resulting solutions were then diluted and their drug content was assayed using High Performance Liquid Chromatography (HPLC) as described in Method HL036.
Release of AGN from the Gels The release of AGN through each of the 0.1% gels was studied using a previously developed release method. The collected fractions were then assayed directly using HPLC Method HL036.
Slopes of the Release Profiles The data generated from the assay of the col-lected fractions for each gel were used to plot the release profile of the drug as the % drug released vs.
square root of time. For each release profile, the slope of the linear region containing at least 6 points was calculated using linear regression. The standard deviation and correlation coefficient of each slope was also calculated.
Analysis of Solubility and Release Data The saturated solubility values, and slopes of the line obtained from the plot of o drug released vs.
square root of time for each gel were analyzed statis-tically. The difference between the slopes and solubilities from gel to gel were studied using a two tailed t-test to find the gels which resulted in significantly different values. RS/Discover~ was used to calculate equations which fit the data and to construct response surfaces.

Maximizing Solubility and Release The resulting slope and solubility data were also analyzed using RS/Discover~ in order to maximize these S responses. Initially the slope was maximized to find the gel exhibiting maximum drug release, then solubil-ity was maximized in order to find the gel which had the highest drug solubility. Finally, both solubility and slope were simultaneously maximized to find the gel which provided optimum drug release and solubil-ity.
Effect of Drua Particle Solubility on Drua Release From the solubility data it is apparent that approximately 90% of the drug is present in the aqueous based gel in the form of solid particles. In order to determine if the rate of dissolution of the particles is limiting the rate of drug release, the data obtained form the in vitro release study was analyzed.
Effect of Membrane on Drua Release In order to investigate the possibility of the silicone membrane being rate limiting, the slope of the release profile for drug diffusion through the gel was compared to the slope of the release profile obtained from a saturated solution of the drug.
Effect of Drug' Concentration on Release Rate A release study showing the affect of drug concentration on the in vitro release of AGN from three gel formulations was conducted. The three gels were formula 8606X (0. 1%) , 8607X (0.05%) , and 8649X

1 ~ ~.'~'~

(0.025%), and plots of amount of drug release vs.
square root of time were compared.
Results and Discussion Solubility of AGN in the Gels The solubility of the drug was determined in the vehicle of the prototype gel (gel B), and all the other formulated gels in order to investigate the effect of the surfactants and cosolvent addition on drug solubilization in the gel. The solubility values obtained using the two methods (without carbomer and base vs. with propionic acid and base) were not significantly different. The drug solubility values obtained using propionic acid instead of carbomer are shown in Table VI.
Statistical Analysis of the Solubility Data It was of interest to determine if the amount of surfactant in the reference gel B (PS=0.2, PX=0.2, HG=2) had resulted in a significant increase in drug solubility. Therefore, a student's t-test was per-formed to compare the solubility of drug in gel B to the solubility in the two gels without surfactant.
These two gels were gel 3 (PS=0, PX=0, HG=2), and gel 10 (PS=0, PX=0, HG=0). The only difference between gels 3 and 10 were the concentration of hexylene glycol. The t-test (Table VII) indicated that the addition of surfactant had resulted in a significant increase in drug solubility. Eight gels had solu bility values which were not significantly different from the reference gel. These gels were #5, 6, 11, 12, 13, 16, 17, and 18 which contained the highest level of surfactants (Table V).

Table VI.
The Solubility of AGN in the Vehicle of the Various Formulated Gels (Propionic Acid Was Substituted for Carbomer) %Hexylene %Polysorbate %Poloxamer Solubility 1 col 40 407 (m ml) 0 0.0 0.0 0.014510.0003 0 0.0 0.2 0.067910.0044 0 0.0 0.4 0.087410.0066 0 0.2 0.0 0.052310.0027 0 0.2 0.2 0.069710.0032 0 0.2 0.4 0.080010.0040 0 0.4 0.0 0.089310.0088 0 0.4 0.2 0.077510.0008 0 0.4 0.4 0.086710.0060 2 0.0 0.0 0.020910.0017 2 0.0 0.2 0.073710.009 2 0.0 0.4 0.086310.0026 2 0 2 0.2 0.0 0.075910.0035 2 0.2 0.2 0.093810.0001 2 0.2 0.4 0.102010.0029 2 0.4 0.0 0.098010.0117 2 0.4 0.2 0.130010.0062 2 5 2 0.4 0.4 0.118010.0038 Table VII.
Student's T-Test Comparing Drug Solubility in the Vehicle of the Prepared Gels to Solubility in Gel B
Gels SolubilityStd. Dev. P Value Difference (m /ml (2 TAIL

1 0.073700 0.00086 0.024822 Significant 2 0.075859 0.00351 0.040707 Significant 3 0.020875 0.00175 0.002689 Significant 5 0.086249 0.00257 0.113846 Not significant 6 0.097950 0.01165 0.974439 Not significant 7 0.069730 0.00321 0.024199 Significant 8 0.067890 0.00448 0.026539 Si nificant 9 0.052275 0.00268 0.008625 Si nificant 10 0.014465 0.00029 0.002079 Significant 11 0.087410 0.00660 0.231684 Not significant 12 0.089315 0.00087 0.163089 Not significant 13 0.102035 0.00292 0.414257 Not significant 14 0.129750 0.00615 0.030781 Significant 15 0.077475 0.00088 0.034515 Significant 2 0 16 0.080015 0.00395 0.064712 Not si nificant 17 0.075105 0.00381 0.040134 Si nificant 18 0.086680 0.00597 0.193570 Not significant Gel 0.097621 0.00536 - -B

The solubility data were also analyzed with the use of RS/Discover~ software and response surface methodology (RSM). The goal was to find the combina-tion of polysorbate 40, poloxamer 407, and hexylene glycol concentrations which led to maximum drug solubility (within the range of studied factors).
Once the data for the factors and responses were entered into the worksheet, a model was fit to the data. Table VIII shows the least squares coeffici-ents. From the table it is clear that two of the interaction terms involving hexylene glycol are not significant. Therefore, these two terms were elim-V4~0 95133489 ~ ~ PCT/US95I07338 inated. The least square coefficients for the refined model are shown in Table IX.
Table VIII.
Least Squares Coefficients for Solubility Term Coeff. Std. Error Significance 1 76.911 2.122 PS 17.140 2.599 PX 13.896 2.599 HG 7.438 2.122 PS*PX -20.475 3.183 0.0001 PS*HG 3.190 2.599 0.2295 PX*HG -2.446 2.599 0.3545 Table IX.
Least Squares Coefficients for Solubility (Refined Model) Term Coeff. Std. Error Significance 1 76.911 2.135 PS 17.140 2.615 PX 13.896 2.615 HG 7.438 2.135 0.0015 PS*PX -20.475 3.203 0.0001 The model became simpler. The equation which fits the data is:
Solubility = 76.91 + 17.14 PS + 13.90 PX + 7.44 HG - 20.48 PS*PX
The residual values are the difference between the observed values and the fitted values of the response associated with the model. RS/Discover~
automatically studentizes the residuals so that they WO 95/33489 ~ ~ ~ ~ PCT/US95/07338 have a constant variance of one. To check whether there is any relationship between the magnitude of the residuals and the fitted values of the response, a plot of absolute values of the studentized residuals versus the fitted values was constructed (Figure 1).
Any type of relationship may indicate the need to transform the response. The plot suggests that there is no clear trend in the residuals and the model does not need to be refined.
A normal probability plot of the residuals shown in Figure 2 indicates that points on the plot fall very close to the line indicating that the model's residuals are normally distributed.
To determine if the model can be improved by transforming the response, the fit of the model is checked. RS/Discover~ produces a graph indicating the possible transformations and their effects on the logarithm of the sum of squares of the residuals (Figure 3). The transformation that results in the smallest value for this number produces the best fit.
Transformations below the dashed line are within the 95% confidence interval for the best transformation.
Since the untransformed response is below the line, the response was not transformed.
A three-dimensional response surface is shown in Figure 4. In order to determine the factor levels which result in maximum drug solubility, optimization was performed. As seen in Table X, when preparing a gel which contains between 0 to 0.4 polysorbate 40, poloxamer 407, and hexylene glycol, a maximum solubil-ity of 103.17 ~,g/ml can be obtained with Polysorbate 40 at level 0.4, Poloxamer 407 at level 0.0, and hexylene glycol at level 2.

WO 95/33489 ~- ~ ~ ~ ~ '~ PCT/US95107338 Table X.
Optimization of Drug Solubility Factor Range Initial Optimal setting value Polysorbate 40 0 to 0.4 0.2 0.4 Poloxamer 407 0 to 0.4 0.2 0.0 Hexylene glycol 0 to 2 2 2 Response Solubility Maximize 97.6~,g/ml 103.17 ~,g/ml In vitro Release of Gels Drug release was studied from all seventeen formulated gels as described previously. The release profiles for each gel were an average of six runs, and were plotted as % Drug released vs. Square root of time. The release profiles for these gels are shown in Figures 5-8.
Release Studies of Prepared Gels From the plots of % Drug Released vs. Square Root of Time, it is seen that the average amount of drug released from 200 mg of any of the formulations was approximately 70% over a 44 hour period. The highest release rate was observed for the prototype gel which contained 0.2% polysorbate 40, 0.2% Poloxamer 407, and 2% hexylene glycol. The lowest release rate was observed with gel 3 (PS=0, PX=0, HG=2). The average variability observed within each run was approximately 5.56%.

Slopes of the Release Profiles In order to compare the release rates of drug from each formulation, the slope of the linear portion of the plot of % Drug released vs. Square root of time was computed for each of the 18 gels. The value of the calculated slopes are shown in Table XI. The slope for each plot was obtained as an average of six runs and based on a correlation coefficient (R2) >
0.94800.
Table XI.
Slope Values Calculated from the Release Profiles of the Formulated Gels Gel Concentration ~ (PS,PX,HG) Slope t Std Dev. R

B (0.2,0.2,2) 13.587110.9982 0.9904 1 (0,0.2,2) 11.344610.2873 0.9483 2 0 2 (0.2,0,2) 10.144710.7870 0.9950 3 (0,0,2 7.447710.2806 0.9924 5 (0,0.4,2) 9.938210.9804 0.9958 6 (0.2,0,2) 12.052311.5882 0.9833 7 (0.2,0.2,0) 11.954711.3305 0.9517 2 5 8 (0,0.2,0) 10.142910.5636 0.9947 9 (0.2,0,0) 10.041110.0055 0.9841 10 (0,0,0) 9.934010.3207 0.9954 11 (0,0.4,0) 10.325310.1522 0.9809 12 (0.4,0,0) 1074510.4200 0.9922 30 13 (0.2,0.4,2) 9.620110.1916 0.9869 14 (0.4,0.2,2) 11.495110.3704 0.9869 15 (0.4,0.2,0) 11.143210.2825 0.9928 16 (0.2,0.4,0) 10.825011.1877 0.9920 17 (0.4,0.4,2) 11.824610.5878 0.9872 3 5 18 (0.4,0.4,0) 11.408910.6560 I 0.9798 Statistical Analysis of Slope Data As with drug solubility, it was of interest to determine if the amount of surfactant in the reference gel B (PS=0.2, PX=0.2, HG=2) had resulted in a signif-icant increase in drug release. Therefore, a stu-dent's t-test was performed to compare the release rate of drug in gel B to the release rate from the two gels without surfactant; gel 3 (PS=0, PX=0, HG=2), and gel 10 (PS=0, PX=0, HG=0). The t-test (Table XII) indicated that the addition of surfactant had resulted in a significant increase in the release of the drug from gel B. In addition, the t-test revealed that the release of drug from the reference gel was signifi-cantly higher than most gels except gel 6 (0.4,0,2), gel 7 (0.2,0.2,0), and gel 17 (0.4,0.4,2).

WO 95/33489 ~ ~ ~! PCTIUS95107338 Table XII.
Student's t-test Comparing Drug Release (Slopes) from the Prepared Gels to Release from Gel B
GELSSlo Std R2 P value (2 Difference a Dev. TAIL) 1 11.34460.287340.948290.002510 Si nificant 2 10.14470.787070.989230.001860 Significant 3 7.4477 0.280620.981560.000002 Significant 5 9.9382 0.980450.990420.000440 Significant 6 12.05231.588280.983320.138900 Not significant 7 11.95471.330480.951720.103840 Not significant 8 10.14290.563640.994660.003750 Significant 9 10.04110.005450.984140.002780 Significant 10 9.3390 0.320710.995440.002530 Si nificant 1l 10.32530.152230.980890.004220 Significant 12 10.27450.410970.992250.004210 Significant 13 9.6201 0.191630.986920.001610 Significant 14 11.49520.370360.986850.029800 Significant 2 0 15 11.14320.282530.992820.015770 Significant 16 10.82511.187670.991960.004400 Significant 17 11.82460.587810.987200.057890 Not si nificant 18 11.40890.656020.979770.028520 Si nificant Gel 13.58710.998250.99043 B - -Next, the release data obtained form all the gels were analyzed using RS/Discover~ software and response surface methodology (RSM). The goal was to find the combination of Polysorbate 40, Poloxamer 407, and hexylene glycol concentrations which led to maximum drug release within the range of studied factors.
A model containing interaction terms was fit to the release data. The equation is shown below. Table XIII shows the least squares coefficients.

WO 95/33489 . _ ~~ ~ PCT/US95/07338 Slope = 10.94 + 0.88 PS + 0.38 PX + 0.30 HG - 0.42 PS*PX + 0.48 PS*HG + 0.04 PX*HG
Table XIII.
Least Squares Coefficients for Release Rate Term Coeff. Std. Error Significance 1 10.942 0.2174 PS 0.884 0.2442 PX 0.379 0.2648 HG 0.304 0.2174 PS*PX -0.424 0.3440 0.2239 PS*HG 0.480 0.2842 0.0983 PX*HG 0.0438 0.2648 0.8695 From the Table it is observed that the inter-action coefficients were not significant. Therefore, it was decided to divide the drug release data into two categories based on the amount of hexylene glycol present in the gels (HG=0 vs. HG=2). Each group was analyzed separately.
First, the release data from the nine gels not containing hexylene glycol were analyzed. A quadratic model was used to fit the release data. Table XIV
shows the least squares coefficients. The equation is shown below:
Slope = 11.29 + 0.40 PS + 0.34 PX + 0.19 PS*PX
- 0.31 PS2 - 0.66 PXZ

WO 95/33489 PCTlUS95/07338 Table XIV.
Least Squares Coefficients for Release Rate Data (Gels not Containing Hexylene Glycol) Term Coeff. Std. Error Significance 1 11.286 0.4336 PS 0.404 0.2482 PX 0.338 0.2278 PS*PX 0.185 0.3040 0.5511 PS2 -0.309 0.3820 0.4297 PX2 -0.659 0.4184 0.1348 As seen from the table, the interaction terms are not significant. Eliminating these terms leads to a linear model which does not fit the data well. This indicates that there is not sufficient data within the ranges studied to fit a suitable model. The equation which fits the data is:
Slope = 11.29 + 0.40 PS + 0.34 PX
The release data obtained from gels containing hexylene glycol at 2% were also fit using a quad-ratic model. The least squares coefficients are shown in Table XV.
It is observed that all the interaction terms are significant. The equation which fits the data is:
Slope = 13.20 + 1.16 PS + 0.28 PX - 0.88 PS*PX
1.02 PSZ

WO 95/33489 ! ~ ~ PCT/US95/07338 Table XV.
Least Squares Coefficients for Release Rate Data (Gels Containing 2% Hexylene Glycol) Term Coeff. Std. Error Significance 1 13.196 0.3977 PS 1.160 0.2874 PX 0.282 0.2857 PS*PX -0.878 0.3453 0.0179 PS2 0.025 0.3484 0.0314 PX2 -2.311 0.4365 0.0001 To determine whether there is any relationship between the magnitude of the residuals and the fitted values of the response, a plot of absolute values of the studentized residuals versus the fitted values was constructed (Figure 9). The plot suggests that there is no clear trend in the residuals and the model does not need to be refined.
A normal probability plot of the residuals shown in Figure 10 indicates that points on the plot fall very close to the line indicating that the model's residuals are normally distributed.
To determine if the model can be improved by transforming the response, the fit of the model is checked. The graph showing the possible transforma-tions and their effects on the logarithm of the sum of squares of the residuals is shown in Figure 11.
Transformations below the dashed line are within the 95% confidence interval for the best transformation.
Since the untransformed response is below the line, the response is not transformed.

~~.~~ ~ i z~

A three dimensional plot showing the effect of polysorbate 40 and Poloxamer 407 (when HG=2) on slope is shown in Figure 12.
In order to determine the levels of surfactants which result in maximum drug release rate, optimiza-tion is performed. As seen in Table XVI, when prepar-ing a gel which contains between 0 to 0.4% polysorbate 40 and poloxamer 407, and 0 to 2% hexylene glycol, a slope of 13.53 can be obtained with 0.32% polysorbate 40, 0.18% poloxamer 407, and 2% hexylene glycol.
Table XVI.
Optimization of Drug Release Rate Factor Range Initial Optimal Setting Value Polysorbate 40 0 to 0.4 0.2 0.32 Poloxamer 407 0 to 0.4 0.2 0.18 Response Slope Maximize 13.59 13.53 Correlation Between Solubility and Release In order to investigate a possible correlation between drug solubility and the rate of drug release, a plot of slope of release profile vs. square root of solubility of drug in gel was constructed. The highest correlation coefficient obtained was 0.5553 which was for drug solubility in solutions without carbomer or base (Figure 13). Therefore, it was concluded that within the range of surfactant and co solvent studied there was no correlation observed between drug release and solubility.

W'O 95133489 ~ ~ ~ ~ PCT/US95/07338 Maximizing Solubility and Release The final statistical analysis involved the simultaneous optimization of the two responses studied; drug solubility and release rate. This analysis was performed in order to identify the concentration of the two surfactants and cosolvent which could be used in producing a gel with maximum solubility and release. RS/Disccver~ does not perform simultaneous optimizations, however it is possible to optimize one of the responses while constraining the range of the other response. This is an iterative process.
For this purpose, slope was maximized while the range of solubility was constrained. The results of the process are shown in Table XVII. It was concluded that a maximum slope of 12.02 can be obtained by preparing a gel containing 0.4o polysorbate 40, 0.0 %
poloxamer 407, and 2% hexylene glycol. The range of drug solubility in this gel is calculated to be between 102 to 108~,g/ml.
Table XVII.
Simultaneous Optimization of Drug Solubility and Release Rate Factor Range Initial Optimal Setting Value Polysorbate 40 0 to 0.4 0.2 0.4 Poloxamer 407 0 to 0.4 0.2 0.0 Hexylene glycol 0 to 2 2 2 Response Slope Maximize 13.59 12.02 Solubility 102to108~g/ml97.6~,g/m1107.99 ~Cg/ml WO 95133489 ~ PCTIUS95107338 Effect of Druct Particle Solubility on Drug' Release From the solubility data indicated in Table VII
it is apparent that approximately 90% of the drug is present in the aqueous based gel in the form of solid particles. In order to determine if the rate of dissolution of the particles is limiting the rate of drug release, the data obtained from the in vitro release study was analyzed (Table XVIII). From the data it is observed that the rate of drug release remains constant even after three hours, beyond the point where 10% of the drug (the total amount of drug saturating the aqueous gel) is released. Therefore, it is concluded that the solubility of the drug particles in the gel is not rate limiting.

WO 95!33489 ~ ~ ~ PCTIUS95/07338 Table XVIII.
The Amount of Drug Released at Given Time Intervals (0.1% AGN Gel, formula 8606X, Lot# 10169) Time (hr) fount Released o Drug Released (mg) 1 0.007250.0005 3.6259 2 0.006900.0005 7.0805 3 0.006260.0004 10.2129 4 0.006240.0004 13.3310 5 0.006000.0003 16.3225 6 0.005700.0002 19.1727 7 0.005510.0003 21.9270 8 0.005260.0003 24.5573 9 0.004960.0004 27.0367 12 0.023780.0024 38.9273 15 0.017270.0018 47.5600 18 0.009010.0009 52.0643 21 0.005820.0006 54.9760 Effect of Membrane on Drug Release In order to investigate the possibility of the silicone membrane being rate limiting, the slope of the release profile for drug diffusion through the gel was compared to the slope of the release profile obtained from a saturated solution of the drug (Figure 14). The slope of the linear portion of the curve for the gel was 13.587~0.973, and the slope obtained from the saturated solution was 46.652~0.998 indicating that drug release from the saturated solution was much higher than drug release through the gel. Therefore, this membrane was found to serve as a suitable support membrane offering no resistance to the diffusion of the drug.

Effect of Drug Concentration on Release Rate The results of the drug release study using 0.1%, 0.05%, and 0.025% have shown that drug release from the gel containing 0.1% is approximately 60% higher than the release of drug from the 0.05% gel, while drug release from the 0.05% gel is also 60% higher than the 0.025% gel (Figure 15). Therefore, the in vitro release method has distinguished changes in drug release due to changes in drug concentration. Also, the results indicate that the drug release from the gel is more similar to drug release from solution, since drug release from suspensions containing twice as much drug is expected to provide only 40% increase in drug release rate (according to Higuchi's theory).
conclusion The effect of varying the concentrations of polysorbate 40, poloxamer 407, and hexylene glycol on the release and solubility of AGN in a gel indicated that the gel exhibited maximum solubility and release of the drug, AGN. This gel contained 0.2% polysorbate 40, 0.2% poloxamer 407, and 2% hexylene glycol. In addition, another gel was also identified which exhibited drug solubility and drug release that were not significantly different from the prototype gel.
This second gel (gel 6) contained 0.4% polysorbate 40 and 2% hexylene glycol, but did not contain poloxamer.
All other ingredients were available at the same concentration for both gels.
Although there has been hereinabove described a stable gel formulation and method suitable for appli-cation in topical treatment of acne and psoriasis, in accordance with the present invention, for the purpose WO 95133489 ~ ~ ~ ~ ~ ~3 ~ PCT/US95107338 of illustrating the manner in which the invention may be used to advantage, it should be appreciated that the invention is not limited thereto. Accordingly, any and all modifications, variations, or equivalent arrangements which may occur to those skilled in the art, should be considered to be within the scope of the present invention as defined in the appended claims.

Claims (7)

1. A stable gel formulation for topical treatment of skin conditions in humans, said stable gel formulation comprising:
an active agent having activity for treat-ment of acne and psoriasis, said active agent comprising:
Ethyl-6-[2-(4,4 dimethylthiochroman-6-yl]
nicotinate; and a plurality of nonaqueous vehicles for both solubilizing said active agent and forming a gel therewith, said nonaqueous vehicles enabling topical application of the gel to a skin condition, said plurality of vehicles each being present in amounts, and in combination, to control release of the active agent from the gel to the skin condition, said plurality of nonaqueous vehicles comprising three vehicles comprising Polysorbate 40, Poloxamer 407 and Hexylene glycol.
2. A stable gel formulation for topical treatment of skin conditions in humans, said stable gel formulation comprising:
an active agent having activity for treat-ment of acne and psoriasis, said active agent comprising:
Ethyl-6-[2-(4,4 dimethylthiochroman-6-yl]
nicotinate; and a plurality of nonaqueous vehicles for both solubilizing said active agent and forming a gel therewith, said nonaqueous vehicles enabling topical application of the gel to a skin condition, said plurality of vehicles each being present in amounts, and in combination, to control solubility of the active agent in the gel, said plurality of nonaqueous vehicles comprising three vehicles comprising Polysorbate 40, Poloxamer 407 and Hexylene glycol.
3. The formulation according to claim 2 wherein the range of concentration is up to 0.4% for Polysorbate 40 and Poloxamer 407 and up to 2% for Hexylene glycol to produce maximum solubility of the active agent in the gel.
4. A stable gel formulation for topical treat-ment of both acne and psoriasis comprising an effective amount of a compound having the formula Ethyl-6-[2-(4,4-dimethylthiochroman-6-yl]nicotinate in a pharmaceutical carrier comprising:
(a) water;
(b) edetate disodium;
(c) ascorbic acid;
(d) Carbomer 934P;
(e) Poloxamer 407;
(f) polyethylene glycol;
(g) Polysorbate 40;
(h) hexylene glycol;
(i) butylated hydroxytoluene;
(j) butylated hydroxyanisole;
(k) benzyl alcohol; and (l) tromethamine.
5. The formulation according to claim 4 wherein the Polysorbate 40 is present in an amount up to about 0.4% by weight, Poloxamer 407 is present in an amount up to about 0.4% by weight, and hexylene glycol is present in an amount up to about 2% by weight.
6. The formulation according to claim 4 wherein the Polysorbate 40 is present in an amount of about 0.32% by weight, the Poloxamer 407 is present in an amount of about 0.18% by weight, and the hexylene glycol is present in an amount of about 2% by weight.
7. A method for preparation of a formulation for topical treatment of both acne and psoriasis comprising the steps of:
1) mixing purified water, edetate diso-dium, ascorbic acid and Carbomer 934P until the carbomer is dispersed to form a part I;
2) mixing purified water, Poloxamer 407 to form a part II;
3) adding part II to apart I and homogeniz-ing part I and part II;
4) mixing polyethylene glycol, Polysorbate 40, hexylene glycol, butylated hydroxytoluene and butylated hydroxyanisole and heating to dissolve the compounds;
5) cooling the mixture of step 4) to room temperature and adding benzyl alcohol and ethyl-6-[2-(4,4-dimethylthiochroman-6-yl]nicotinate thereto to form a part III;
6) mixting purified water and tromethamine to form part IV;
7) adding part III to the homogenized mixture of Part I and II while stirring and thereafter adding part IV with mixing until homogeneous.
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ES2173958T3 (en) 2002-11-01
PT1147778E (en) 2006-12-29
DE69526344T2 (en) 2002-11-07
ATE336263T1 (en) 2006-09-15
IL122359A (en) 2001-08-26
DE69535184D1 (en) 2006-09-28
EP1147778B1 (en) 2006-08-16
ES2269296T3 (en) 2007-04-01
IL114049A0 (en) 1995-10-31
TW379143B (en) 2000-01-11
DE69535184T2 (en) 2007-08-23
ATE215836T1 (en) 2002-04-15
IL114049A (en) 2000-08-31
EP1147778A1 (en) 2001-10-24
WO1995033489A1 (en) 1995-12-14
EP0764032A1 (en) 1997-03-26
AU693905B2 (en) 1998-07-09
EP0764032B1 (en) 2002-04-10
AU2821895A (en) 1996-01-04
DE69526344D1 (en) 2002-05-16
US6258830B1 (en) 2001-07-10
US5914334A (en) 1999-06-22
CA2191773A1 (en) 1995-12-14
IL122358A (en) 2001-01-28
DK1147778T3 (en) 2006-12-18
ZA954599B (en) 1996-01-26

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