WO1998043673A1 - Solvent system for enhanced penetration of pharmaceutical compounds - Google Patents

Solvent system for enhanced penetration of pharmaceutical compounds Download PDF

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Publication number
WO1998043673A1
WO1998043673A1 PCT/US1998/004033 US9804033W WO9843673A1 WO 1998043673 A1 WO1998043673 A1 WO 1998043673A1 US 9804033 W US9804033 W US 9804033W WO 9843673 A1 WO9843673 A1 WO 9843673A1
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Prior art keywords
drug
topical composition
accordance
pharmaceutical compound
active pharmaceutical
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PCT/US1998/004033
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English (en)
French (fr)
Inventor
Chakradhara Rao
Jue-Chen Liu
Jonas C. T. Wang
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Johnson & Johnson Consumer Companies, Inc.
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Publication date
Application filed by Johnson & Johnson Consumer Companies, Inc. filed Critical Johnson & Johnson Consumer Companies, Inc.
Priority to JP54163598A priority Critical patent/JP2001518879A/ja
Priority to BR9811458-1A priority patent/BR9811458A/pt
Priority to EP98908843A priority patent/EP0971746A1/en
Priority to IL13209698A priority patent/IL132096A0/xx
Priority to CA002285368A priority patent/CA2285368A1/en
Priority to AU66776/98A priority patent/AU6677698A/en
Priority to PL98335934A priority patent/PL335934A1/xx
Publication of WO1998043673A1 publication Critical patent/WO1998043673A1/en

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    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • This invention relates to pharmaceutical compositions whose penetration is capable of being enhanced.
  • This includes, but is not limited to, topical compositions for the treatment of skin disorders wherein the topically active pharmaceutical compound or drug is normally a relatively insoluble (or “poorly soluble") weak acid or weak base, however, the drug may also be a soluble compound whose delivery characteristics can be altered.
  • this invention concerns the solubilizing capabilities of a buffered solvent system which makes it possible to significantly alter the dermal penetration of pharmaceutical compounds or drugs.
  • Seborrheic dermatitis is a skin disorder characterized by an abnormal increase in the proliferation of epidermal cells. This increase in skin cell production causes the formation of lesions on the surface of the skin. Though treatments vary, the use of imidazole antifungals is of particular interest to the present invention.
  • 4,942,162 discusses the use of imidazole antifungals, specifically ketoconazole and clotrimazole, for the treatment of psoriasis and seborrheic dermatitis. This treatment can come in one of two forms - oral and topical.
  • U.S. Pat. No. 4,491,588 describes the use of ketoconazole and metronidazole for the treatment of seborrheic dermatitis in a composition formulated for oral administration.
  • European Pat. Application No. 396,184 states that by topically applying ketoconazole for the treatment of dermatologic conditions, its efficacy and safety are enhanced.
  • 5,002,938 describes a stable gel formulation for the topical administration of imidazoles, wherein the imidazoles are combined with a steroid, but seborrheic dermatitis is a chronic relapsing disease, therefore, the safety of the topical steroid preparations over a long period of time is questionable.
  • 2,202,743 utilizes the combination of propylene glycol and ethanol as a dissolving intermediary for the topical administration of miconazole nitrate and econazole nitrate, but the composition described therein requires the presence of urea to solubilize the active ingredients.
  • Japanese Pat. No. 60-61518 uses a lower alcohol-glycol system for the topical administration of clotrimazole, but the composition described therein also requires both a neutralizer and a stabilizer.
  • the present invention includes a buffered solvent system which is capable of changing the delivery parameters of both soluble and poorly soluble topically active pharmaceutical compounds or drugs.
  • this buffering component to a properly balanced solvent system eliminates the need for excessive amounts of the pharmaceutical compound in topical compositions.
  • a composition including this system only requires a fractional amount of the pharmaceutical compound necessary in products which lack this system. This is truly important because it addresses the problem of lack of clinical efficacy which has plagued these topical compositions for so long.
  • the system comprises a volatile solvent component, a nonvolatile solvent component and a buffer in addition to the topically active pharmaceutical compound or drug.
  • Topical compositions of this nature generally contain such optional ingredients as chelators, antioxidants, preservatives, gelling agents and sunscreens as well as others commonly used in the art.
  • Figure 1 is a graphical summary of the skin permeability results from experimental Runs 1 through 4 in the formulation of ketoconazole, propylene glycol, ethanol and phosphate-citrate buffer.
  • Figure 2 is a graphical summary of the skin permeability results from experimental Run 6 in the occluded formulations of ketoconazole.
  • Figure 3 is a graphical summary of the skin permeability results from experimental Run 7 in the gel formulations of ketoconazole under both occluded and nonoccluded conditions. Detailed Description of the Invention
  • the present invention is embodied in a topical composition
  • a topical composition comprising: a) a topically active pharmaceutical compound or drug, and b) a buffered solvent system comprising: i) a volatile solvent component, ii) a nonvolatile solvent component, and i ⁇ ) a buffer.
  • topically active pharmaceutical compound or drug used in the compositions of this invention may be chosen from two categories: soluble and poorly soluble. Poorly soluble compounds may be further categorized as weak acids and weak bases.
  • Weak bases include such compounds as imidazoles, triazoles, steroidal anti-inflammatory agents, other antifungal drugs and the like.
  • the preferred imidazoles and triazoles include, but are not limited to, ketoconazole, miconazole, econazole, itraconazole, terconazole, saperconazole, fluconazole, metronidazole, clotrimazole, butoconazole, oxiconazole, sulfaconazole, sulconazole and their derivatives.
  • the most preferred pharmaceutical compound selected from this group is ketoconazole.
  • the imidazoles and triazoles are preferably in an amount of from about 0% (w/v) to about 1% (w/v) and more preferably from about 0.1% (w/v) to about 0.3% (w/v).
  • Suitable steroidal anti-inflammatory agents may include, although are not limited to, corticosteroids such as hydrocortisone, dexamethasone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone sodium phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dichlorisone, diflorasone diacetate, diflucortolone valerate, flurandrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinonide, fluocortin butyl ester, fluocortolone, fluprednidene (fluprednylidene) acetate, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylpred
  • difluorosone diacetate difluorosone diacetate, flurandrenolone acetonide, medrysone, amciafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chloroprednisone acetate, clocortolone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluorometholone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone, and mixtures thereof may be used.
  • the preferred steroidal anti-inflammatory agents are dexamethasone and its derivatives, while dexamethasone sodium phosphate is most preferred.
  • the steroidal anti-inflammatory agents are preferably present in an amount of from about 0% (w/v) to about 5% (w/v) .
  • antifungal drugs can be chosen from the group consisting of morpholine and its derivatives and terbinafine and its derivatives.
  • Preferred pharmaceutical compounds are amorolfine and its derivatives, while amorolfine hydrochloride is most preferred.
  • These antifungal drugs are preferably present in an amount of from about 0% (w/v) to about 5% (w/v) .
  • Weakly acidic compounds useful in the compositions of this invention may be selected from the group consisting of non-steroidal anti-inflammatory agents (NSAID's) . These include, but are not limited to, oxicams, salicylates, acetic acid derivatives, fenamates, propionic acid derivatives, pyrazoles and mixtures thereof.
  • NSAID's non-steroidal anti-inflammatory agents
  • Preferred examples of weak acids suitable for use in the present invention are salicylic acid, ibuprofen and indomethacin though many other appropriate weak acids exist. These weakly acidic compounds are preferably present in an amount of from about 0.1% (w/v) to about 10% (w/v) .
  • Soluble pharmaceutical compounds or drugs can be either acidic or basic, wherein the buffered solvent system changes the permeability parameters of these compounds to enhance their delivery characteristics and efficacy.
  • Soluble pharmaceutical compounds include, for example, alpha hydroxy acids. Preferred are alpha hydroxy acids selected from the group consisting of alkyl hydroxycarboxylic acids, aralkyl and aryl 2- hydroxycarboxylic acids, polyhydroxy-carboxylic acids and hydroxy-polycarboxylic acids. Most preferred are those alpha hydroxy acids selected from the group consisting of glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, their derivatives and mixtures thereof.
  • the soluble pharmaceutical compounds are present in an amount of from about 4% (w/v) to about 15% (w/v) .
  • the volatile solvent component of the buffered solvent system may preferably include lower alkyl alcohols, lower alkyl glycols and lower glycol polymers. More preferably, the volatile solvent is selected from the group consisting of ethanol and isopropanol. Most preferably, the volatile solvent is ethanol.
  • the volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates.
  • the amount of volatile solvent in the system is determined by the pharmaceutical compound being utilized, depending upon the solubility and skin penetration of said topically active pharmaceutical compound or drug. The criteria which limit the range of the volatile solvent remain the same, regardless of which pharmaceutical compound or drug is used. Too little volatile solvent in the system will render the drug insoluble, while an excess of the volatile solvent may cause irritation to the skin.
  • the nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers.
  • propylene glycol, polyethylene glycol and polypropylene glycol may be used.
  • propylene glycol is used.
  • the nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system.
  • the amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the sy ⁇ tem, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess will result in a lack of bioavailability due to poor release of drug from solvent mixture.
  • the buffer component of the buffered solvent system may be selected from any buffer commonly used in the art.
  • the purpose of the buffer component is to ensure that the pharmaceutical compound or drug mostly remains in unionized state.
  • the choice of buffer is only limited by its ability to adjust the pH of the system to be at least about 0.5 units below the pKa of the pharmaceutical compound when the pharmaceutical compound is a weak acid, and at least about 0.5 units above the pKa of the pharmaceutical compound when the pharmaceutical compound is a weak base.
  • the pharmaceutical compound or drug being used dictates the type and amount of buffer needed for the system to function properly.
  • Some preferable buffers include citrate, phosphate and borate buffers and combinations thereof. There are several optional ingredients which can be added to the topical composition.
  • antioxidants include, but are not limited to, chelators, antioxidants, preservatives, gelling agents, sunscreens, sunblocks, retinoids, benzofuran derivatives, N-acetyl-L-cysteine and derivatives thereof, skin protectants and vitamins.
  • the preferred antioxidant is butylated hydroxytoluene (BHT) , though ascorbic acid and its derivatives and vitamin E and its derivatives are also among suitable agents that may be employed as discussed in Remington ' s Pharmaceutical Sciences , Gennaro, A. R. (Editor) , 18th edition 1990. Mack Publishing Co., Easton, PA. pp. 1286 - 1288. which is hereby incorporated by reference.
  • appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives and synthetic polymers.
  • the gelling agent is hydroxypropylcellulose.
  • the preservatives can be selected from those common in the art as discussed in The Theory and Practice of Industrial Pharmacy, Lach an, L. , Lieberman, H. A., and Kanig, J. L. 3rd edition, 1986. Lea & Febiger, Philadelphia, PA. pp. 467, 521 and 553, which is also incorporated by reference, though the parabens, especially methylparaben and propylparaben, are preferred.
  • Preferred chelators include EDTA and citric acid, though EDTA is most preferred.
  • Suitable sunscreens may include, for example: p- aminobenzoic acid (PABA) , its salts and its derivatives, anthranilates, salicylates, cinnamic acid derivatives, dihydroxycinnamic acid derivatives, trihydroxycinnamic acid derivatives, hydrocarbons, dibenzalacetone and benzalacetophenone, naphthol-sulfonates (sodium salts of 2-naphthol-3 , 6-disulfonic and of 2-naphthol-6, 8- disulfonic acids) , dihydroxynaphthoic acid and its salts, o- and p- hydroxybiphenyldisulfonates, coumarin derivatives, quinine salts, quinoline and its derivatives, uric and vilouric acids, tannic acid and its derivatives, hydroquinone, benzophenones and the hydroxy- or methoxy- substituted benzophenones, 4- iso
  • sunscreens useful in the compositions of the present invention are 2-ethylhexyl-p- methoxycinnamate, butylmethoxydibenzoylmethane, 2- hydroxy-4-methoxybenzophenone, octyldimethyl-p- aminobenzoic acid and mixtures thereof.
  • the key to the present invention is the ratio of volatile solvent to nonvolatile solvent to buffer in the buffered solvent system.
  • the preferred ratio of ingredients is about 5% to about 15% of the nonvolatile solvent, from about 40% to about 45% of the volatile solvent and from about 45% to about 50% of the buffer.
  • the requisite concentration of ketoconazole is only about 0.3% when this system is utilized, compared with values seven times that much in commercial compositions which lack this system.
  • the ratio of the components in the buffered solvent system depends upon the solubility characteristics of the pharmaceutical compound or drug under consideration.
  • the composition may take the form of a solution, gel, lotion, cream, ointment, and the like. Following are several examples which are meant to illustrate possible embodiments of the present invention.
  • ketoconazole is ( ⁇ ) cis-l-acetyl-4-[4-
  • a 0.3% ketoconazole gel was made by first preparing a 0.1 ⁇ pH 6.00 phosphate-citrate buffer. Disodiu EDTA was dissolved into the buffer. Methylparaben, propylparaben, BHT and ketoconazole were dissolved in ethanol. Propylene glycol was then added to the ethanol solution and mixed well. The buffer containing EDTA was then added. Hydroxypropylcellulose (Klucel HF) was slowly added to the solution while stirring. The gel was allowed to hydrate for 24 hours and the final pH was adjusted to 7.00 using 1M HCl.
  • Klucel HF Hydroxypropylcellulose
  • EXAMPLE 2 0.3% Ketoconazole Compositions Thirteen solutions of 0.3% ketoconazole were prepared in varying proportions of propylene glycol, ethanol and buffer solution. The compositions are outlined in Table 1 below. Table 1: Solvent Compositions
  • compositions A, B and C the aqueous phase was water, without a buffer, while in all of the other compositions (with the exception of composition L) the buffer was a phosphate-citrate buffer system.
  • composition L hydrochloric acid was used as the solvent syste .
  • Franz diffusion cell consisted of an upper donor cell and a lower receiver cell, wherein the skin was placed between them.
  • the donor cell was an open cap, allowing access to the epidermis for dosing or other purposes.
  • the test material/formulation was placed on the epidermal surface in the donor cell.
  • the donor cell was left open to the atmosphere under nonoccluded conditions, and tightly sealed under occluded conditions.
  • the donor and receiver cells were held together with a clamp.
  • the capacity of the receiver cell was 10 ml, and the cross- sectional area of the cells in contact with the skin was 0.6362 cm 2 (0.9 cm diameter).
  • a thermal jacket was positioned around the receiver chamber and was heated with an external circulating water bath.
  • a Teflon coated stirring bar was placed in the receiver chamber and an isotonic phosphate-citrate buffer of pH 5.00 was used as a receptor solution to fill this chamber.
  • small volumes of the receptor solution were drawn from the chamber for analysis and replaced to keep the volume of the solution constant.
  • Three diffusion cells were used to evaluate each solvent composition and the cells were occluded (except where stated otherwise) .
  • the skins were separated into epidermis and dermis, extracted with 10 ml of methanol and assayed for ketoconazole content.
  • the permeability results are set forth in Table 2.
  • compositions A, B and C solutions of ketoconazole were prepared in varying proportions of propylene glycol, ethanol and water.
  • compositions D, E and F the final pH of the ketoconazole buffered solutions was adjusted to 6.00, 7.00 or 8.00 using 1 M HC1.
  • compositions G, H and I the pH of maximum permeability and retention in the skin layers (pH 7.00) was selected from Run 2, and propylene glycol, ethanol and buffer compositions were varied.
  • experimental Run 4 compositions A, B and C
  • solutions of ketoconazole were prepared in varying proportions of propylene glycol, ethanol and water.
  • compositions D, E and F the final pH of the ketoconazole buffered solutions was adjusted to 6.00, 7.00 or 8.00 using 1 M HC1.
  • compositions G, H and I the pH of maximum permeability and retention in the skin layers (pH 7.00) was selected from Run 2, and propylene glycol, ethanol and buffer compositions were varied.
  • experimental Run 4
  • compositions J, K and L propylene glycol composition was fixed at 5%, and ethanol and pH 7.00 buffer compositions were varied in compositions J and K.
  • the permeability of ketoconazole from compositions J and K was compared with the permeability of ketoconazole in hydrochloric acid (composition L) described in U.S. Pat. No. 4,569,935.
  • the pH of the drug solution L was 4.00.
  • solvent compositions J, H and K had maximum permeabilities and retention in the skin. This is shown in Figure l, a graph of the cumulative amount of ketoconazole which permeated the skin over time. After 48 hours, compositions J, H and K had more than twice the permeability of other compositions. Since a high amount of alcohol in the formulation can irritate the sensitive skin of patients with seborrheic dermatitis, compositions J and M , which had lesser amounts of alcohol were preferred. Other solvent compositions with less ethanol were tried, but 0.3% ketoconazole formed suspensions in those compositions.
  • ketoconazole forms a solution only in certain proportions of solvent mixture.
  • either the ethanol content should be greater than 40% or the propylene glycol content should be greater than 10%, wherein the buffer makes up the rest of the composition. Within this range of concentrations, the composition functions with minimal irritation and acceptable levels of bioavailability while being physically stable.
  • Solvent compositions J and M were modified with the addition of a chelating agent, an antioxidant and preservatives to prepare gels. They were prepared by first dissolving BHT, methylparaben and propylparaben in ethanol, and then adding propylene glycol and phosphate- citrate buffer containing disodium EDTA. These solutions were then gelled with 2% w/v of hydroxypropylcellulose (high viscosity grade) and adjusted to pH 7.00, the pH of maximum skin penetration and retention, which is also the pH of maximum chemical stability for ketoconazole.
  • a chelating agent an antioxidant and preservatives
  • Citrate Buffer (with 0.05% w/v disodium EDTA)
  • ketoconazole gels of formulations J and M were compared with the permeability of ketoconazole from 200 mg of Nizoral ® cream under nonoccluded conditions.
  • ketoconazole gels J and M were studied for permeability across the human cadaver skin under both occluded and nonoccluded conditions.
  • the data from experimental Run 5 is not analyzed as the skin samples used to test permeability were found to be defective.
  • Run 5 compared occluded compositions of Nizoral, J, K and M.
  • Figure 3 is a graph of Run 7 depicting the cumulative amount of ketoconazole which permeated the skin over time. Under occluded conditions. Gel J had somewhat better permeation abilities than Gel M. Under nonoccluded conditions, however, the two gel formulations behaved similarly.
  • ketoconazole Permeability and retention of ketoconazole in the skin layers increased with decreased percentage of propylene glycol in the solvent. This could have been due to poor release of ketoconazole from higher propylene glycol proportions.
  • Compositions H, J and K with 5 to 10% propylene glycol had maximum permeability and skin retention suggesting that the buffered solvent system had reached its maximum thermodynamic activity for ketoconazole.
  • Permeability results from Runs 6 and 7 indicate that the occluded cells have higher permeabilities and higher drug levels in the skin than the nonoccluded cells.
  • the ketoconazole levels in receiver cells and skin layers for J and M gels in nonoccluded cells are comparable to those of Nizoral ® cream even though, the gels had only 1/7 of
  • ketoconazole strength of Nizoral ® cream will be higher in seborrheic dermatitic skin which is more permeable than normal skin.
  • NSAID's Salicylic acid, ibuprofen and indomethacin are all poorly soluble in water. While their solubilities are better in pure ethanol [37% (w/v), 100% (w/v) and 2.0% (w/v) respectively] , the problems of dermal irritation described earlier become an issue. When placed in two extreme buffered solvent systems of propylene glycol, ethanol and 0.1 ⁇ phosphate-citrate buffer of pH 6.00, their solubilities are as outlined in Table 6.
  • Salicylic acid 35% w/v 20% w/v Ibuprofen 70% w/v 20% w/v Indomethacin 1 . 5% w/v 1. 0% w/v
  • the ibuprofen was supplied by Spectrum Chemical Mfg.
  • the indomethacin was supplied by Sigma Chemical Co . , St. Louis , MO and the salicylic acid was supplied by Sigma Chemical Co . , St . Louis , MO.
  • Hydrocortisone solubility is 1.27% (w/v) in propylene glycol, 2.50% (w/v) in ethanol and 0.028% (w/v) in water.
  • Betamethasone dipropionate is sparingly soluble in ethanol (1 gram dissolves in 30 to 100 ml) , and practically insoluble in water (1 gram dissolves in more than 10,000 ml).
  • the solubility of two steroidal anti-inflammatory drugs was studied in two extreme buffered solvent systems of propylene glycol, ethanol and 0.1 ⁇ phosphate-citrate buffer of pH 6.00 in the compositions outlined in Table 7.
  • Hydrocortisone 2.5% w/v 1. 5% w/v Betamethasone 3. 0% w/v 0.75% w/v dipropionate
  • hydrocortisone and betamethasone dipropionate were supplied by Spectrum Chemical Mfg. Corp . , Gardena , CA .
  • Amorolfine is a morpholine derivative applied topically as the hydrochloride salt in the treatment of fungal nail and skin infections.
  • a 0.25% cream is applied once a day to treat skin infections, including various forms of tinea.
  • a lacquer containing the equivalent of 5% amorolfine is painted onto the affected nail once or sometimes twice a week until the nail has regenerated.
  • Amorolfine base is poorly soluble, though its hydrochloride salt should be soluble to an extent of greater than 5% in water and ethanol based upon its chemical structure.
  • Alpha Hydroxy Acids Alpha hydroxy acids (AHAs) are highly soluble in aqueous solutions throughout the pH range. Their solubility was studied in two extreme solvent compositions, propylene glycol : ethanol : 0.1 ⁇ phosphate-citrate buffer of pH 6.00 at 10:80:10 and
  • Glycolic acid > 20% w/v 18% w/v Lactic acid > 20% w/v >20% w/v Malic acid 19% w/v 10% w/v Tartaric acid 10% w/v 8% w/v Citric acid 16% w/v 10% w/v

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  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/US1998/004033 1997-03-31 1998-03-03 Solvent system for enhanced penetration of pharmaceutical compounds WO1998043673A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP54163598A JP2001518879A (ja) 1997-03-31 1998-03-03 薬剤化合物の向上した浸透性のための溶媒システム
BR9811458-1A BR9811458A (pt) 1997-03-31 1998-03-03 "sistema solvente para penetração melhorada de compostos farmacêuticos"
EP98908843A EP0971746A1 (en) 1997-03-31 1998-03-03 Solvent system for enhanced penetration of pharmaceutical compounds
IL13209698A IL132096A0 (en) 1997-03-31 1998-03-03 Solvent system for enhanced penetration of pharmaceutical compounds
CA002285368A CA2285368A1 (en) 1997-03-31 1998-03-03 Solvent system for enhanced penetration of pharmaceutical compounds
AU66776/98A AU6677698A (en) 1997-03-31 1998-03-03 Solvent system for enhanced penetration of pharmaceutical compounds
PL98335934A PL335934A1 (en) 1997-03-31 1998-03-03 Solvent system of increased penetration into pharmaceutical compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82909197A 1997-03-31 1997-03-31
US08/829,091 1997-03-31

Publications (1)

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WO1998043673A1 true WO1998043673A1 (en) 1998-10-08

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PCT/US1998/004033 WO1998043673A1 (en) 1997-03-31 1998-03-03 Solvent system for enhanced penetration of pharmaceutical compounds

Country Status (14)

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EP (1) EP0971746A1 (es)
JP (1) JP2001518879A (es)
KR (1) KR19980081207A (es)
CN (1) CN1252003A (es)
AR (1) AR012217A1 (es)
AU (1) AU6677698A (es)
BR (1) BR9811458A (es)
CA (1) CA2285368A1 (es)
CO (1) CO5050328A1 (es)
HU (1) HUP0001739A3 (es)
IL (1) IL132096A0 (es)
PL (1) PL335934A1 (es)
WO (1) WO1998043673A1 (es)
ZA (1) ZA982662B (es)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000072818A1 (en) * 1999-05-27 2000-12-07 The Procter & Gamble Company Topical compositions providing improved treatment of skin or scalp fungal infections
WO2002070455A1 (en) * 2001-02-07 2002-09-12 Novartis Ag Malic acid addition salts of terbinafine
WO2002074290A3 (en) * 2001-03-15 2004-02-19 Agis Ind 1983 Ltd Dermatological preparations containing a nsaid
WO2007068699A1 (de) 2005-12-13 2007-06-21 Beiersdorf Ag Transparentes sonnenschutzmittel
WO2009028495A1 (ja) * 2007-08-27 2009-03-05 Nihon Nohyaku Co., Ltd. 真菌性皮膚炎用剤
US8147852B2 (en) 2006-08-03 2012-04-03 Barrier Therapeutics, Inc. Modified azole compounds as antifungal and antibacterial agents
US20140194375A1 (en) * 2007-07-25 2014-07-10 Ixodes Ag Topical antibiotic composition for the prevention of lyme disease
US9839611B2 (en) * 2013-09-10 2017-12-12 Insys Development Company, Inc. Sublingual buprenorphine spray
US10105444B2 (en) 2010-07-08 2018-10-23 Dow Pharmaceutical Sciences, Inc. Compositions and methods for treating diseases of the nail
US10245257B2 (en) 2013-11-22 2019-04-02 Dow Pharmaceutical Sciences, Inc. Anti-infective methods, compositions, and devices
US10342875B2 (en) 2013-10-03 2019-07-09 Dow Pharmaceutical Sciences, Inc. Stabilized efinaconazole compositions
US10512640B2 (en) 2008-01-03 2019-12-24 Dow Pharmaceutical Sciences, Inc. Compositions and methods for treating diseases of the nail

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2232855C (en) * 1997-04-10 2007-10-09 Roche Consumer Health (Worldwide) Sa Pharmaceutical formulation
MY129350A (en) * 2001-04-25 2007-03-30 Bristol Myers Squibb Co Aripiprazole oral solution
JP5435836B2 (ja) * 2003-07-03 2014-03-05 大正製薬株式会社 外用抗真菌剤組成物
JP4784051B2 (ja) * 2003-07-03 2011-09-28 大正製薬株式会社 容器への吸着を防止した外用抗真菌組成物
CN115745757B (zh) * 2022-11-07 2024-04-26 中国人民解放军军事科学院军事医学研究院 一种液态多甘醇柱芳烃衍生物的合成及对经皮药效分子缓释的应用

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EP0331382A2 (en) * 1988-02-29 1989-09-06 Pfizer Inc. Transdermal flux enhancing compositions
US5028606A (en) * 1988-11-29 1991-07-02 Janssen Pharmaceutica N.V. (1H-azol-1-ylmethyl)substituted quinoxaline derivatives
EP0672422A1 (en) * 1994-02-05 1995-09-20 Il-Dong Pharm. Co., Ltd. Antiinflammatory and analgesic transdermal gel

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EP0331382A2 (en) * 1988-02-29 1989-09-06 Pfizer Inc. Transdermal flux enhancing compositions
US5028606A (en) * 1988-11-29 1991-07-02 Janssen Pharmaceutica N.V. (1H-azol-1-ylmethyl)substituted quinoxaline derivatives
EP0672422A1 (en) * 1994-02-05 1995-09-20 Il-Dong Pharm. Co., Ltd. Antiinflammatory and analgesic transdermal gel

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOHNSON, M.E., ET AL.: "Synergistic effects of chemical enhancers and therapeutic ultrasound on transdermal drug delivery", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 85, no. 7, July 1996 (1996-07-01), pages 670 - 679, XP002070144 *
MONTANA, J.B., ETAL.: "A double-blind, vehicle-controlled study of the safety and efficacy of fungoid tincture .RTM. in patients with distal subungual onychomycosis of the toes.", CUTIS, vol. 53, no. 6, 1994, pages 313 - 316, XP002070145 *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000072818A1 (en) * 1999-05-27 2000-12-07 The Procter & Gamble Company Topical compositions providing improved treatment of skin or scalp fungal infections
WO2002070455A1 (en) * 2001-02-07 2002-09-12 Novartis Ag Malic acid addition salts of terbinafine
US7488759B2 (en) 2001-02-07 2009-02-10 Novartis Ag Malic acid addition salts of terbinafine
WO2002074290A3 (en) * 2001-03-15 2004-02-19 Agis Ind 1983 Ltd Dermatological preparations containing a nsaid
WO2007068699A1 (de) 2005-12-13 2007-06-21 Beiersdorf Ag Transparentes sonnenschutzmittel
US8147852B2 (en) 2006-08-03 2012-04-03 Barrier Therapeutics, Inc. Modified azole compounds as antifungal and antibacterial agents
US20140194375A1 (en) * 2007-07-25 2014-07-10 Ixodes Ag Topical antibiotic composition for the prevention of lyme disease
US9610244B2 (en) * 2007-07-25 2017-04-04 Ixodes Ag Topical antibiotic composition for the prevention of lyme disease
WO2009028495A1 (ja) * 2007-08-27 2009-03-05 Nihon Nohyaku Co., Ltd. 真菌性皮膚炎用剤
US8492421B2 (en) 2007-08-27 2013-07-23 Nihon Nohyaku Co., Ltd. Agent for fungal dermatitis
US8835479B2 (en) 2007-08-27 2014-09-16 Nihon Nohyaku Co., Ltd. Agent for fungal dermatitis
US10512640B2 (en) 2008-01-03 2019-12-24 Dow Pharmaceutical Sciences, Inc. Compositions and methods for treating diseases of the nail
US11872218B2 (en) 2008-01-03 2024-01-16 Bausch Health Ireland Limited Compositions and methods for treating diseases of the nail
US11213519B2 (en) 2008-01-03 2022-01-04 Bausch Health Ireland Limited Compositions and methods for treating diseases of the nail
US10105444B2 (en) 2010-07-08 2018-10-23 Dow Pharmaceutical Sciences, Inc. Compositions and methods for treating diseases of the nail
US10828369B2 (en) 2010-07-08 2020-11-10 Dow Pharmaceutical Sciences, Inc. Compositions and methods for treating diseases of the nail
US9839611B2 (en) * 2013-09-10 2017-12-12 Insys Development Company, Inc. Sublingual buprenorphine spray
US10342875B2 (en) 2013-10-03 2019-07-09 Dow Pharmaceutical Sciences, Inc. Stabilized efinaconazole compositions
US10864274B2 (en) 2013-10-03 2020-12-15 Bausch Health Ireland Limited Stabilized efinaconazole formulations
US10828293B2 (en) 2013-11-22 2020-11-10 Dow Pharmaceutical Sciences, Inc. Anti-infective methods, compositions, and devices
US10245257B2 (en) 2013-11-22 2019-04-02 Dow Pharmaceutical Sciences, Inc. Anti-infective methods, compositions, and devices
US11654139B2 (en) 2013-11-22 2023-05-23 Bausch Health Ireland Limited Anti-infective methods, compositions, and devices

Also Published As

Publication number Publication date
AR012217A1 (es) 2000-09-27
HUP0001739A2 (hu) 2000-12-28
KR19980081207A (ko) 1998-11-25
CN1252003A (zh) 2000-05-03
AU6677698A (en) 1998-10-22
EP0971746A1 (en) 2000-01-19
PL335934A1 (en) 2000-05-22
BR9811458A (pt) 2000-09-19
CO5050328A1 (es) 2001-06-27
CA2285368A1 (en) 1998-10-08
JP2001518879A (ja) 2001-10-16
ZA982662B (en) 1999-09-30
HUP0001739A3 (en) 2001-04-28
IL132096A0 (en) 2001-03-19

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