KR19980081207A - Solvent System to Increase Permeability of Pharmaceutical Compounds - Google Patents

Abstract

The present invention relates to a composition comprising a topically active pharmaceutical compound or a buffered solvent system that enhances penetration of a medicament and a medicament. Buffer solvent systems can reduce the amount of the compound in the composition without significantly altering the efficacy of the pharmaceutical compound.

Description

Solvent System to Increase Permeability of Pharmaceutical Compounds

The present invention relates to pharmaceutical compounds in which penetration can be enhanced. This includes topical compositions for use in the treatment of skin diseases in which topically active pharmaceutical compounds or agents are usually relatively insoluble (or almost insoluble) in the drug or weak base but the drug may be a soluble compound that may change its mobility properties. It is not limited to this. More specifically, the present invention relates to the solubility of a buffered solvent system that can significantly alter the skin penetration of a pharmaceutical compound or medicament.

Seborrheic dermatitis is a skin disease in which the proliferation of epithelial cells is abnormally increased. This increase in skin cell production forms lesions on the skin surface. Although treatments vary, the interest in the present invention is in particular the use of imidazole antifungal agents.

Although its actual cause is still under discussion, it has been suggested that seborrheic dermatitis can be caused by fungal infections, which is why imidazole antimicrobials are very effective in their treatment. Literature references; Ford et al., In British Journal of Dermatology vol. 107, 691-695 (1982)] Kenoconazole has been described as Pyrosporum ovale (Pityrosporum orbiculare) or Marasezia purpur, an important etiological factor in seborrheic dermatitis. (American Patent No. 4,942,162 discusses the use of imidazole antimicrobials, in particular ketoconazole and clotrimazole, for the treatment of psoriasis and seborrheic dermatitis).

Treatment can be carried out in one of two forms, oral and topical. US 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. However, EP 396,184 describes the topical application of ketoconazole for the treatment of dermatological conditions, thereby enhancing its efficacy and stability. In addition, according to US Pat. No. 4,446,145, it is best to avoid oral therapies to treat a dermatological disorder if a topical alternative is available at any time.

Imidazoles can be mixed with other pharmaceutically active ingredients, although they are potent when used as the only active ingredient in a composition. WO patent application 87/04617 describes mixtures of urea and imidazole derivatives in various skin disease treatment compositions, but urea causes a temporary tingling sensation on the skin surface of the user. U. S. Patent 4,446, 145 describes a mixture of benzoyl peroxide and imidazole in a composition specifically used for the treatment of acne. U.S. Pat.No. 5,002,938 describes a stable gel formulation for topical administration of imidazole, wherein imidazole is mixed with steroids, but seborrheic dermatitis is a chronic recurring disease, so the stability of topical steroid formulations over long periods of time is suspected. That's right.

Another problem with the use of imidazoles is the delivery system. US Pat. No. 5,219,877 describes absorption enhancing gels for topical administration of imidazole using lauryl alcohol as absorption enhancer. However, the compositions described herein specifically require the omission of polyethylene glycol whose solubility properties are known in the art.

In fact, mixtures of glycols and other solvents are very effective means of enhancing the skin absorption of the active agents. British Patent Application No. 2,202,743 uses a mixture of propylene glycol and ethanol as soluble intermediates for the topical administration of myconazole nitrate and econasol nitrate, but the compositions described herein require urea to dissolve the active substance. Do. Similarly, Japanese Patent No. 60-61518 uses a lower alcohol-glycol system for local administration of clotrimazole, but the compositions described herein also require neutralizers and stabilizers.

Mixtures of lower alcohols and glycols are known in the art as acceptable pharmaceutical carrier systems. US Pat. No. 4,994,491 uses this kind of system to treat cancer with trans-retinoids. US Pat. No. 4,244,948 also describes the delivery capacity of this compound for topical administration of acetylsalicylic acid, where the system is described as a convenient vehicle.

The system Westwood Squibb Pharmaceuticals shoe Tikal, Inc. ray a Exeldem ^R prepared from lactide (1% alcohol to Kona sol nitrate), ortho Pharma shoe Monistat-Derm ^R (2% miconazole nitrate), available from Tikal Corporation and geurakso It is used in antifungal products such as Oxistat ^R (1% Oxyconazole Nitride) manufactured by Welcome Incorporated. Similarly US Pat. No. 5,476,852 describes a 2% ketoconazole topical gel formulation comprising propylene glycol and ethanol. However, these products require high concentrations (about 1 to 2%) of imidazole to function properly. Another example is Nizoral ^R [Janssen Pharmaceutica], a 2% ketoneconazole antifungal cream, which includes a slightly different solvent system. While these products are very effective, they also require large percentages of ketoconazole.

It is therefore an object of the present invention to make a composition that can deliver the same therapeutic effect as a flow antifungal product of antifungal activity at slightly low concentrations.

It is also an object of the present invention to make a solvent system usable to enhance delivery of relatively insoluble pharmaceutical compounds which are weak acids or weak bases.

It is another object of the present invention to make solvent systems or acidic or basic, instantaneous soluble pharmaceutical compounds that can change the permeability.

The invention is more apparent from the following figures which illustrate the characteristics of some preferred embodiments.

1 graphically summarizes the skin permeability results from Experiments 1-4 in the formulation of ketoconazole, propylene glycol, ethanol and phosphate-citrate buffer.

FIG. 2 graphically summarizes skin permeability results from Experiment Run 6 in occluded formulations of ketoconazole.

FIG. 3 graphically summarizes the skin permeability results from Experiment Run 7 in gel formulations of ketoconazole under occlusion and non occlusion conditions.

The present invention includes a buffered solvent system capable of changing the delivery parameters of soluble and sparsely soluble locally active pharmaceutical compounds or reagents. Surprisingly, these buffering ingredients are added to a suitably balanced solvent system, eliminating the need for excess amounts of pharmaceutical compounds in topical compositions. In fact, a composition comprising only such a system requires a partial amount of pharmaceutical compound required for the product lacking such a system. This is really important because it accounts for the problem of clinical efficacy deficiencies that have long hampered these topical compositions.

The system includes, in addition to the locally active pharmacological compound or drug, a volatile solvent component, a nonvolatile solvent component and a buffer.

Topical compositions of this nature generally contain optional ingredients such as chelators, antioxidants, preservatives, gelling agents and sunscreens as well as other additives commonly used in the art.

The present invention is realized with a topical composition comprising a locally active pharmacological compound or drug (a) and a buffered solvent system (b) comprising a volatile component (i), a nonvolatile component (ii) and a buffer (iii). .

Locally active pharmacological compounds or drugs used in the compositions of the present invention may be selected from two classes, soluble and poorly soluble. Poor soluble compounds can be further classified into weak acids and weak bases.

Weak bases include compounds such as, for example, imidazoles, triazoles, steroidal anti-inflammatory agents, other antibacterial drugs, and the like.

Preferred imidazoles and triazoles include ketoconazole, myconazole, econazol, itraconazole, terconazole, saperconazole, fluconazole, metronidazole, clotrimazole, buttoconazole, oxyconazole, sulfaconazole, sulfonazole and Derivatives thereof are included, but are not limited thereto. The most preferred pharmaceutical ingredient selected from this group is ketoconazole. As is evident in the following examples, the imidazole and triazole are preferably in an amount of about 0 to about 1% (w / v), more preferably about 0.1 to about 0.3% (w / v).

Suitable steroidal anti-inflammatory agents include, but are not limited to, corticosteroids (eg hydrocortisone), dexamethasone, hydroxyltriamcinolone, α-methyl dexamethasone, dexamethasone sodium phosphite, beclomethasone dipropionate, clobetasol valerate, Desonide, desoxymethasone, desoxycorticosterone acetate, dichlorisone, diflorasone diacetate, diflucortolone valerate, flulandrenone, fluclolone acetonide, fludrocortisone, flumeta Hand pivalate, fluorinolone acetonide, fluorinide, fluorocortin butyl ester, fluorocrtolone, fluprednide (flupredenylidene) acetate, halogeninide, hydrocortisone acetate, hydrocortisone butyrate, methylprednini Zolone, Triamcinolone Acetonide, Cortisone, Corto Hand, flucetonide, fludrocrotisone, difluoroson diacetate, flulandrenolone acetonide, meridone, amsiafel, amcinapiide, equilibrium of betamethasone and esters thereof, chloroprednisone, chloroprednisone acetate, Clocortolone, Clecinolone, Dichlorisone, Difluredonate, Pluchloronide, Flunisolide, Fluorometholone, Fluperolone, Flupredisolone, Hydrocortisone valerate, Hydrocortisone cyclopentylpropionate, Hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone and mixtures thereof. Preferred steroid anti-inflammatory agents are dexamethasone and derivatives thereof, while dexamethasone sodium phosphite is most preferred. The steroid anti-inflammatory agent is preferably present in an amount of about 0 to about 5% (w / v).

Other antifungal agents may be selected from the group consisting of morphine and derivatives thereof and terbinafine and derivatives thereof. Preferred pharmaceutical ingredients are amorolpin and its derivatives, with amololpin hydrochloride being most preferred. These antifungal agents are preferably present in an amount of about 0 to about 5% (w / v).

The weakly acidic compounds useful in the compositions of the present invention may be selected from the group consisting of nonsteroidal anti-inflammatory agents (NSAIDs). These include, but are not limited to, oxycams, salicylates, acetic acid derivatives, phenamate, propionic acid derivatives, pyrazoles and mixtures thereof. Preferred examples of weak acids suitable for use in the present invention are salicylic acid, ibuprofen and indomethacin, although there are a number of other suitable acids. These weakly acidic compounds are preferably present in amounts of about 0.1% w / v to about 10% w / v.

Soluble pharmaceutical compounds or drugs can be acidic or basic, while buffered solvent systems change the acceptable parameters of these compounds to improve their transport properties and efficacy. Soluble pharmaceutical compounds include, for example, alpha hydroxy acids. Preference is given to 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 alpha hydroxy acids selected from the group consisting of glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, derivatives thereof and mixtures thereof. Preferably, the soluble pharmaceutical compound is present in an amount of about 4% by weight to about 15% by volume.

The volatile solvent component of the buffered solvent system may preferably be lower (C ₁ -C ₁₀ ) 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 acts as a penetration enhancer and, when evaporated, also has a cooling effect on the skin. The amount of volatile solvent in the system is determined by the topically active pharmaceutical compound or pharmaceutical compound used depending on the solubility and skin penetration of the drug. The criteria for defining a range of volatile solvents are the same regardless of the pharmaceutical compound or drug used. Too little volatile solvent in the system renders the drug insoluble, while too much volatile solvent can cause skin irritation.

The nonvolatile solvent portion of the buffer solvent system is selected from lower alkylene glycols and lower glycol polymers. Preferably, propylene glycol, polyethylene glycol and polypropylene glycol can be used. Most preferably, propylene glycol is used. Nonvolatile solvents lower the volatilization rate of volatile solvents and reduce the vapor pressure of the buffer solvent system. The amount of such nonvolatile solvent components is determined by the pharmaceutical compound or medicament used with the volatile solvent. If too little non-volatile solvent is present in the system, the pharmaceutical compound may crystallize due to evaporation of the volatile compound, while if too much is present, poor release of the drug from the solvent mixture results in poor bioavailability. Results.

The buffer component of the buffer solvent system may be selected from buffers conventionally used in the prior art. The purpose of using a buffer component is to keep the pharmaceutical compound or agent unionized. The choice of buffer only regulates the pH of the system at least about 0.5 units below the pKa of the pharmaceutical compound when the pharmaceutical compound is a weak acid, and when the pharmaceutical compound is a weak base, the pH of the system is lower than the pKa of the pharmaceutical compound. Limited only to the ability to adjust higher than 0.5 units. Again, the type and amount of buffer required for the system to function properly is determined by the pharmaceutical compound or medicament used. Some preferred buffers include citrate, phosphate and borate buffers and combinations thereof.

There are several optional ingredients that can be added to the topical composition. These include, but are not limited to, chelating agents, antioxidants, preservatives, gelling agents, sunscreens, sunscreens, retinoids, benzofuran derivatives, N-acetyl-L-cystine and derivatives thereof, skin protectants and vitamins. Preferred antioxidants are butylated hydroxytoluene (BHT), but Remington's Pharmaceutical Sciences, Gennaro, AR (Editor), 18th edition 1990. Mack Publishing Co., Easton, PA . pp. 1286-1288 are suitable among them ascorbic acid and derivatives thereof and vitamin E and derivatives thereof that can be used. Similarly, suitable gelling agents may include, but are not limited to, semisynthetic cellulose derivatives and synthetic polymers. Preferably, the gelling agent is hydroxypropylcellulose. Preservatives are also incorporated herein by reference in The Theory and Practice of Industrial Pharmacy, Lachman, L., Lieberman, H. A., and Kanig, J. l. 3rd edition, 1986. Lea Febiger, Philadelphia, PA. PP. 467, 521 and 553 may be selected from preservatives common in the art, but parabens, in particular methylparaben and propylparaben, are preferred. Preferred chelating agents include EDTA and citric acid, but EDTA is most preferred.

Suitable sunscreens include, for example, p-aminobenzoic acid (PABA), salts thereof and derivatives thereof, anthranilates, salicylates, cinnamic acid derivatives, dihydroxycinnamic acid derivatives, trihydroxycinnamic acid derivatives, hydrocarbons, Dibenzal acetone and benzalacetophenone, naphthol-sulfonate (sodium salt of 2-naphthol-3,6-disulfonic acid and 2-naphthol-6,8-disulfonic acid), dihydroxynaphthoic acid and salts thereof, o- and p-hydroxybiphenyldisulfonates, coumarin derivatives, quinoline salts, quinoline and derivatives thereof, uric acid and biliruic acid, tannic acid and derivatives thereof, hydroquinone, benzophenone and hydroxy or methoxy substituted benzo Phenone, 4-isopropyldibenzoylmethane, butylmethoxybenzoylmethane and etocrylene. Most preferred sunscreen agents useful in the compositions of the present invention are 2-ethylhexyl-p-methoxycinnamate, butylmethoxydibenzoylmethane, 2-hydroxy-4-methoxybenzophenone, octyldimethyl-p-aminobenzoic acid and their Mixture.

However, the secret of the present invention is the ratio of volatile solvent to buffered nonvolatile solvent in a buffered solvent system. As demonstrated in the following examples, when such a system is used in combination with ketoconazole as a locally active pharmaceutical compound, the preferred proportion of the component is from about 5 to about 15% of the nonvolatile component and from about 40 to about 455 component. And about 45 to about 50% buffer. The required concentration of ketoconazole is only about 0.3% when compared to seven times as many values in commercial compositions lacking such systems when such systems are used.

The proportion of components in the buffered solvent system depends on the solubility characteristics of the pharmaceutical compound or drug under consideration. The composition may take the form of a solution, gel, lotion, cream, ointment or the like. The following are several examples illustrating possible aspects of the present invention.

Example 1

Topical Formulation of 0.3% Ketoconazole Solution and Gel

Chemically, ketoconazole is (±) cis-1-acetyl-4- [4-[[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3- Dioxolan-4-yl] methoxy] phenyl] piperazine and has the formula:

0.3% ketoconazole gel is prepared by first preparing 0.1 μ of pH 6.00 phosphate-citrate buffer. Disodium EDTA is dissolved in buffer. Methylparaben, propylparaben, BHT and ketoconazole are dissolved in ethanol. Propylene glycol is then added to the ethanol solution and mixed well. Then a buffer containing EDTA is added. Hydroxypropylcellulose (Clucell HF) is slowly added to the solution while stirring. The gel is hydrated for 24 hours and the final pH is adjusted to 7.00 with HCl.

Example 2

0.3% Ketoconazone Composition

Thirteen solutions of 0.3% ketoconazone are prepared by varying the ratio of propylene glycol, ethanol and buffer. The composition is schematically shown in Table 1 below.

Solvent composition Composition Propylene Glycon (ml) Ethanol (ml) Buffer (ml) pH ABCDEFGHIJKLM 6040202020202010305515 20406040404060603045550.01M HCl solution 40 20-water 20-water 20-water 404040203040504045 8.888.367.896.007.008.007.007.007.007.007.004.007.00

In all other compositions in Compositions A, B and C, the aqueous phase is water without buffer if the buffer is a phosphate-citrate buffer system. Hydrochloric acid in composition L is used as the solvent system.

Example 3

Penetration Study of 0.3% Ketoconazone Compositions

Permeability of ketoconazole from solution A through M as defined in Example 2 was studied through human carcass skin using Franz diffuse cells. Franz diffuse cells are composed of high donor cells and low donor cells, where the skin is placed between them. An open cap that accesses the epidermis for administering donor cells or for other purposes. The test substance / formulation is placed over the epidermal area in the donor cell. Donor cells are left open in the atmosphere under a non-closed state and tightly sealed under a closed state. Donor and recipient cells are fixed together by clamps. The dose of recipient cells is 10 ml and the cross-cut region of cells in contact with the skin is 0.6362 cm (0.9 cm in diameter). A heat jacket is placed around the awarding chamber and heated with an external circulating water bath. A teflon coated stirring rod is placed in the awarding chamber and an isotonic phosphate-citrate buffer of pH 5 is used as the receptor solution to fill the chamber. During the course of the experiment, a small volume of receptor solution is withdrawn from the chamber for analysis and replaced to keep the volume of solution constant.

Three scattering cells are used to analyze the composition of each solvent and to close the cells (unless otherwise noted). At the end of 48 hours of continuous experiments, the skin is separated into epidermis and dermis, and extracted with 10 ml of methanol to analyze the ketoonasol content. The results of the permeability analysis are shown in Table 2.

Permeability Results of A to M Compositions (Standard Value for Ketoconazole at 1% Concentration) Solvent Composition (PG: Ethanol: Aq Phase) pH Dose delivered up to 36 hours (ug) Epidermal weight (ug) Dermal weight (ug) A (60:20:20 water) 8.88 11.13 8.07 ± 6.60 1.83 ± 1.87 B (40:40:20 water) 8.36 2.03 6.13 ± 1.23 3.17 ± 1.40 C (20:60:20 water) 7.89 5.03 23.03 ± 25.73 7.00 ± 8.53 D (20:40:60 buffer) 6.00 22.63 15.07 ± 1.33 8.67 ± 3.60 E (20:40:40 buffer) 7.00 29.87 22.53 ± 3.87 12.10 ± 3.47 F (20:40:40 buffer) 8.00 21.53 16.53 ± 8.13 8.83 ± 4.27 G (20:60:20 buffer) 7.00 39.27 47.67 ± 40.40 25.13 ± 13.87 H (10:60:30 buffer) 7.00 136.60 89.80 ± 31.37 48.27 ± 20.97 I (30:30:40 buffer) 7.00 41.60 60.47 ± 41.97 25.20 ± 19.83 J (5:45:50 buffer) 7.00 133.47 219.27 ± 90.67 * 55.10 ± 20.90 K (5:55:40 buffer) 7.00 143.60 353.93 ± 121.13 * 38.73 ± 1.97 L (0.01 M HCl) 4.00 64.77 339.47 ± 27.30 ± J gel-unclosed (5:45:50 buffer) 7.00 5.23 32.63 ± 10.37 11.371.30 M gel-unclosed (15:40:45 buffer) 7.00 2.83 24.73 ± 2.00 8.301.27 2% Ni-Ral ^R Cream 7.60 0.47 15.41 ± 4.85 1.981.02 Non-closed 7.00 J gel-closed 7.00 46.43 83.47 ± 4.10 41.7710.40 J gel-no closure 7.00 3.17 47.87 ± 17.97 5.37 ± 2.07 M gel-closed 7.00 9.80 53.37 ± 13.60 18.90 ± 9.00 M gel-non-closed 7.00 2.03 29.70 ± 4.13 2.83 ± 1.10 * Epidermal blot technique is inconsistent with previous serial experiments Drug levels in the dermis seem reasonable.

In continuous experiment 1 (compositions A, B and C), ketoconazole solutions are prepared in various proportions of propylene glycol, ethanol and water. In continuous experiment 2 (compositions D, E and F), the final pH of the ketoconazole buffer solution is adjusted to 6.00, 7.00 or 8.00 using 1M HCl. In continuous experiment 3 (compositions G, H and I), the pH (pH 7.00) of maximum permeability and preservation in the skin layer was chosen in continuous experiment 2, and propylene glycol, ethanol and buffer compositions varied. In continuous experiment 4 (compositions J, K and L), the propylene glycol composition was fixed at 5% and the ethanol and pH buffer compositions varied in compositions J and K.

The permeability of ketoconazole from compositions J and K is compared with that of ketoconazole in hydrochloric acid (composition L) described in US Pat. No. 4,569,935. The pH of the pharmaceutical solution L is 4.00.

Based on the results from the continuous experiments 1 to 4, the solvent compositions J, H and K have maximum permeability and retention in the skin. This is a schematic of the accumulated amount of ketoconazole penetrating the skin over time, as shown in FIG. 1. After 48 hours, compositions J, H and K are at least twice the permeability of other compositions.

Compositions J and M are preferred, which have a lower alcohol content because the high alcohol amount in the formulation irritates sensitive skin in patients with seborrheic dermatitis. Other solvent compositions containing less alcohol are attempted, but 0.3% ketoconazole forms a suspension in such compositions.

0.3% Ketoconazole Forms Suspension Composition Propylene Glycol (ml) Ethanol (ml) pH 7.00 Buffer (ml) I 5 40 55 II 10 30 60 III * 10 40 50 IV 15 30 55

As described in Table 3, 0.3% ketoconazole only forms a solution in any proportion of solvent mixture. To prepare a 0.3% ketoconazole solution, the ethanol content must be greater than 40% or the propylene glycol content must be greater than 10%, with the buffer making up the remainder of the composition. Within this concentration range, the composition exhibits minimal hypersensitivity reactions and physically stable and acceptable levels of bioavailability.

Example 4

Preparation of Ketoconazole Gel Compositions

Solvent compositions J and M are modified by addition of a chelating agent, an antioxidant and a preservative to produce a gel. These are prepared by first dissolving BHT, methylparaben and propylparaben in ethanol followed by addition of phosphate-citrate buffer comprising propylene glycol and disodium EDTA. These solutions are then gelled with 2% w / v hydroxypropylcellulose (high viscosity grade) and adjusted to pH 7.00, which is the pH of maximum chemical stability for ketoconazole and also the pH of maximum skin penetration and retention.

Solvent Compositions J and M Modified to Prepare Gels ingredient Composition J Composition M Propylene glycol 5ml 15 ml ethanol 45 ml 40ml 0.1u pH 6.00 Phosphate-Citrate Buffer with 0.05% w / v Disodium EDTA 50 ml 45 ml BHT 50 mg 50 mg Methylparaben 200 mg 200 mg Propylparaben 20mg 20mg

In Experimental Example 6, the ketoconazole gels of Formulations J and M are compared for ketoconazole permeability from 200 mg of nizoral cream under non-occluded conditions. In Experimental Example 7, ketoconazole gels J and M are studied for permeability across human body skin in both occluded and unoccluded conditions. The data of Experimental Example 5 were not analyzed because the skin samples used to test permeability were found to be defective. Example 5 compared as shown in FIG. 2 occludes the compositions of nizoral, J, K and M. FIG.

3 is a graph of Example 7 showing the accumulated amount of ketoconazole penetrating the skin over time. Under the occluded conditions, gel J has a somewhat better permeability than gel M. However, under unoccluded conditions the two gel formulations behave similarly.

The unbuffered solution shown in Example 1 (neutral pH 7.89-8.88) with water as one of the ingredients has lower permeability and lower drug content than the compositions of Gels J and M. The same is true for ketoconazole in 0.01 M hydrochloric acid solution (composition L), which is less permeable and less dwelling in the dermis than in propylene glycol, ethanol and pH 7.00 buffer solvent mixtures.

The permeability and retention of ketoconazole in the skin layer increases with decreasing percentage of propylene glycol in the solvent. This may be due to poor release of ketoconazole from higher crophilene glycol ratios. Compositions H, J and K with 5-10% propylene glycol have maximum penetration and skin retention, which suggests that the buffer solvent system reaches its maximum thermodynamic activity against ketoconazole.

Permeability results from Runs 6 and 7 indicate that occluded cells have higher intradermal permeability and higher drug levels than unoccluded cells. Ketoconazole levels in the skin layer for J and M gels in receptor cells and in unoccluded cells are compared to the strength of nizoral creams even when the gel has only 1/7 of the ketoconazole strength of Nizoral ^R cream. These levels will be higher in sebaceous dermatitis skin, which is more permeable than normal skin.

Example 5

Thermal Stability Analysis of 0.3% Ketoconazole Compositions

Accumulated thermal stability analysis was performed on gel formulations J and M at 30 ° C. (sampling time is 16 weeks), 40 ° C. (sampling time is 8 and 16 weeks), and 50 ° C. (sampling time is 4, 8, 13 and 16 weeks). To perform. This sample is filled into glass vials and placed at an appropriate temperature. The data in Table 5 shows that the drug is very stable in both of these formulations. Samples degraded to less than 5% within 16 weeks are stored at 50 ° C. Light pink is observed in 13 and 16 week old samples studied at 50 ° C.

Stability Results (Residual%) of Ketoconazole Gel Formulation at 0.3% at pH 7.00 compare Early 4 weeks50 ℃ 8 weeks 40 ℃ 50 ℃ 13 Note 50 ℃ 30 ℃ 16 Note 40 ℃ 50 ℃ J 100 97.08 98.51 97.08 97.09 99.65 98.44 95.77 M 100 97.70 98.67 96.86 97.79 99.77 98.61 97.09

Example 6

Solubility of Non-steroidal Anti-inflammatory Drugs (NSAID's)

Salicylic acid, ibuprofen and indomethacin are all poorly soluble in water. Even if their solubility is better in pure ethanol (37% (w / v), 100% (w / v) and 2.0% (w / v), respectively), the skin irritation problems described above can be caused. When placed in two extremely buffered solvent systems of propylene glycol, ethanol and 0.1 μ phosphate-citrate buffer at pH 6.00, their solubility is summarized in Table 6.

Solubility of NSAID's NSAID Solubility in 10:80:10 (PG: ethanol: buffer) 80:10:10 Solubility in (PG: ethanol: buffer) Salicylic acid 35% w / v 20% w / v Ibuprofen 70% w / v 20% w / v Indomethacin 1.5% w / v 1.0% w / v

Ibuprofen is supplied from a trader (Specturm Chemical Mfg. Corp., Gardena, Calif.). Indomethacin is supplied by a trader (Sigma Chemical Co., St. Louis, MO) and salicylic acid is supplied by a trader (Sigma Chemical Co., St. Louis, MO).

Example 7

Solubility of steroidal anti-inflammatory drugs

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 poorly soluble in ethanol (1 g dissolved in 30-100 ml) and practically insoluble in water (1 g dissolved in 10.000 ml or more). Two steroidal anti-inflammatory agents were studied in two extremely buffered solvent systems, propylene glycol, ethanol and 0.1 μ phosphate-citrate buffer (pH 6.00) in the compositions listed in Table 7.

Solubility of steroidal anti-inflammatory drugs Anti-inflammatory drugs 10: 80: 10 Solubility in PG: Ethanol: Buffer Solubility in 80: 10: 10 (PG: Ethanol: Buffer) Hydrocortisone 2.5% w / v 1.5% w / v Betamethasonedipropionate 3.0% w / v 0.75% w / v

Both hydrocortisone and betamethasone dipropionate are found in Spectrum Chemical Mfg. is supplied by corp.

Example 8

Availability of Amololpin

Amorolpin is a morpholine derivative applied topically as a salt with hydrochloride in the treatment of nail and skin infections by fungi. 0.25% cream is applied once a day to treat skin infections including various forms of Tynea. For the treatment of nail infections caused by dermatophyte, yeast and mold, a rocker containing a significant amount of 5% amololpin is applied to infected nails once or sometimes 2 times per week until the nails are regenerated. Apply twice. Although the amorphine base is poorly soluble, its hydrochloride salt should be at least 5% soluble in water and ethanol based on its chemical structure.

Example 9

Solubility of alpha hydroxy acid

Alpha hydroxy acids (AHAs) are highly soluble in aqueous solutions over the entire pH range. Their solubility was studied in two extreme solvent compositions of 10:80:10 and 80:10:10, propylene glycol: ethanol: 0.1μ phosphate-citrate buffer, pH 6.00. Approximate solubility is listed in Table 8.

Approximate Availability of AHAs Alpha hydroxy acid 10: 80: 10 Solubility in PG: Ethanol: Buffer Solubility in 80: 10: 10 (PG: Ethanol: Buffer) 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

The invention is illustrated by several embodiments of possible aspects, and it is understood that they are not intended to be limiting.

The buffered solvent system of the present invention, consisting of a topically active pharmaceutical compound or a buffered solvent system that enhances penetration of a medicament and a medicament, can reduce the amount of the compound in the composition without significantly altering the efficacy of the pharmaceutical compound.

Claims (39)

(a) topically active pharmaceutical compounds or drugs and a buffered solvent system comprising (b) a volatile solvent component, (ii) a nonvolatile solvent component, and (iii) a buffer component that functions to maintain the pH of the composition such that the pharmaceutical compound is in a mostly nonionic state Topical composition comprising a. The topical composition of claim 1 wherein the topically active pharmaceutical compound or drug is a poorly water soluble weak base. The topical composition of claim 1 wherein the topically active pharmaceutical compound or drug is a poorly water soluble weak acid. The topical composition of claim 2, wherein the topically active pharmaceutical compound or drug is selected from the group consisting of imidazole, triazole, steroidal anti-inflammatory agents, and other antibacterial agents. The topical composition of claim 4 wherein the topically active pharmaceutical compound or drug is about 0.01 to about 5% (w / v). The topical composition according to claim 5, wherein the topically active pharmaceutical compound or drug is imidazole or triazole. The method of claim 6, wherein the topically active pharmaceutical compound or drug is ketoconazole, myconazole, echonazol, itraconazole, terconazole, seperconazole, fluconazole, metronidazole, clotrimazole, buttoconazole, oxyconazole Topical compositions selected from the group consisting of sulfaconazole, sulfonazole, terbinafine and derivatives thereof. The topical composition of claim 7 wherein the topically active pharmaceutical compound or drug is about 0 to about 1% (w / v) ketoconazole. The topical composition according to claim 5, wherein the topically active pharmaceutical compound or drug is a steroidal anti-inflammatory agent. The topical composition of claim 9, wherein the topically active pharmaceutical compound or drug is dexamethasone sodium phosphate. The topical composition according to claim 5, wherein the topically active pharmaceutical compound or drug is selected from the group consisting of amorolpine and derivatives thereof. The topical composition according to claim 11, wherein the topically active pharmaceutical compound or drug is amorolpine hydrochloride. The topical composition of claim 3 wherein the topically active pharmaceutical compound or drug is a nonsteroidal anti-inflammatory agent. The topical composition of claim 13 wherein the topically active pharmaceutical compound or drug is about 0.1 to about 10% (w / v). The topical composition of claim 14, wherein the topically active pharmaceutical compound or drug is selected from the group consisting of salicylic acid, ibuprofen and indomethacin. The topical composition of claim 1 wherein the topically active pharmaceutical compound or drug is readily soluble in water. The topical composition of claim 16, wherein the topically active pharmaceutical compound or drug is alpha hydroxy acid. The topical composition of claim 17 wherein the topically active pharmaceutical compound or drug is about 4 to about 15% (w / v). The topical composition of claim 18, wherein the topically active pharmaceutical compound or drug is selected from the group consisting of glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, derivatives thereof and mixtures thereof. The topical composition of claim 1 wherein the volatile solvent component is a lower (C ₁ -C ₆ ) alkyl alcohol. The topical composition of claim 20 wherein the volatile solvent component is selected from the group consisting of ethanol and isopropanol. The topical composition of claim 21 wherein the volatile solvent component is ethanol. The topical composition of claim 1 wherein the nonvolatile solvent component is selected from the group consisting of lower alkylene glycols and derivatives thereof and lower glycol polymers. The topical composition of claim 23 wherein the nonvolatile solvent component is selected from the group consisting of propylene glycol, polyethylene glycol and polypropylene glycol. The topical composition of claim 24 wherein the nonvolatile solvent component is propylene glycol. The topical composition of claim 1 wherein the buffer is selected from the group consisting of citrate, phosphate, borate buffer systems, and combinations thereof. The topical composition of claim 26, wherein the buffer is a phosphate-citrate buffer system. The topical composition of claim 2, wherein the pH of the buffer system is maintained at 0.5 units or greater than the pKa of the topically active pharmaceutical compound or drug when the topically active pharmaceutical compound or drug is basic. The topical composition of claim 3, wherein when the topically active pharmaceutical compound or drug is acidic, the pH of the buffer system is maintained at less than 0.5 unit than the pKa of the topically active pharmaceutical compound or drug. The method of claim 1, wherein the chelating agents, antioxidants, preservatives, gelling agents, sunscreens, sunblocks, retinoids, benzofuran derivatives, N-acetyl-L-cysteine and derivatives thereof, skin protectants and vitamins A topical composition further comprising, but not limited to, any component containing a compound in any compatible formulation. The topical composition of claim 1 wherein the composition is in the form of a liquid, lotion, gel, cream or ointment. a) about 0.3% ketoconazole and b) topical composition comprising i) about 40% to about 45% ethanol, ii) about 5% to about 15% propylene glycol and iii) about 45% to about 50% phosphate-citrate buffer . The topical composition of claim 32, further comprising EDTA, BHT, methylparaben, propylparaben, and hydroxypropylcellulose. 33. The topical composition of claim 32, wherein the composition is in the form of a liquid, lotion, gel, cream or ointment. A method of treating seborrheic dermatitis, psoriasis or complications thereof, comprising topically applying a composition according to claim 32 to a skin area infected with a skin disease. (a) a topically active pharmaceutical compound or medicament comprising a weak base that is poorly soluble in water; And (b) iii) a volatile solvent component; Ii) nonvolatile solvent components; And Iii) a topical composition comprising a buffer solvent system comprising a buffer component that acts to maintain the pH of the composition at least 0.5 units above the pKa of the topically active pharmaceutical compound or medicament. (a) a topically active pharmaceutical compound or medicament comprising a weak acid that is poorly soluble in water; And (b) iii) a volatile solvent component; Ii) nonvolatile solvent components; And Iii) a topical composition comprising a buffer solvent system comprising a buffer component that acts to maintain the pH of the composition at less than 0.5 units above the pKa of the topically active pharmaceutical compound or medicament. (a) a topically active pharmaceutical compound or medicament comprising an azole compound; And (b) iii) a volatile solvent component; Ii) nonvolatile solvent components; And Iii) a topical composition comprising a buffer solvent system comprising a buffer component that acts to maintain the pH of the composition at least 0.5 units above the pKa of the topically active pharmaceutical compound or medicament. (a) a topically active pharmaceutical compound or medicament comprising a non-scaloidal anti-inflammatory agent and a weak acid compound selected from the retinoic acid group; And (b) iii) a volatile solvent component; Ii) nonvolatile solvent components; And Iii) a topical composition comprising a buffer solvent system comprising a buffer component that acts to maintain the pH of the composition at less than 0.5 units above the pKa of the topically active pharmaceutical compound or medicament.