DD297555A5 - ANTIMYCOTIC GEL FORMULATIONS - Google Patents

Abstract

An antifungal gel formulation effective with 0.2 to 2 * of an antifungal imidazole and 0.01 to 2.5 * of an anti-inflammatory 17-ester esterified corticosteroid is contemplated for topical administration. This composition is highly effective in the treatment of fungal infections and can be stored for long periods of time without cooling, without sacrificing therapeutic efficacy, while maintaining uniformity and stability of the gel.

Description

Combinations of low potency steroids with imidazoles. Such combination products never provide rapid relief of inflammatory symptoms, which is normally desirable in the treatment of a fungal infection.

A combination of a non-halogenated steroid of moderate potency with an antifungal imidazole would appear as an ideal option for the local treatment of fungal diseases. It was the object of the present invention to develop such a combination product.

The intermediate potency steroid used for the combination product of the present invention is a 17-ester steroid which has enhanced efficacy over the parent alcohol but has less undesirable side effects than the comparable halogenated steroids in potency. Examples of 17-esterified corticosteroids according to the present invention are hydrocortisone 17-acetate, hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydrocortisone 17-propionate, betamethasone 17-valerate, cortisone 17-acetate, prednisone 17- acetate and prednisone 17-valerate,

The steroids esterified in the 17-position per se have excellent stability in the usual formulations for topical application. In our investigations, the stability of topical formulations was tested by determining their tsov values, where t% represents the time in days in which a formulation loses 10% of its chemical and / or biological activity. A 0.2% hydrocortisone 17-valerate oil / water cream in this test was administered at room temperature (25 ° C ± 2 ° C) for 536 days, using a standard excess of 10% of the active ingredient in the cream in that the product possesses sufficient shelf life at room temperature (that is the time in which the potency decreases to 90% of that indicated on the package) of 1072 days or more than 2.9 years A cream formulation is generally for the patient Unfortunately, for aesthetics and ease of use, it is more pleasant to use than other topical formulations such as solutions, paraffin ointments, oils, etc. However, if one attempts to combine a 17-ester steroid with an antifungal imidazole, the stability of the 17-position becomes unfortunate In almost all the usual cream formulations, esterified steroid drastically reduced to an unacceptable level.We have to make a cream For developing a combination product of a 17-esteresterified steroid with an imidazole, for stability determination more than 60 different types of cream carvings have been prepared, among others oil / water creams, water / oil creams, high or low paraffin creams, low or low high content of a surfactant, with a high or low water content and with different content of propylene glycol. Almost all of the creams did not pass our stability test either because of the chemical instability of the 17-ester steroid or because of the physical instability of the emulsion due to the salting-out effect of the imidazole salt when used at a concentration of 1% or higher. The cream formulations often require the use of emulsifiers or surfactants to maintain their physical stability, as well as the use of preservatives to prevent microbial contamination. These additives tend to create an undesirable environment which can accelerate the hydrolysis of the 17-esterified steroids and the physical separation due to salting out. In addition, it is also known that imidazoles can also catalyze the hydrolysis of the esters ³ * ⁷ . Indeed, such degradation has been observed in our preliminary studies (see Table I below).

Table I Cleavage rates of hydrocortisone 17-valerate (HC 17-V) in the presence of 1% of an imidazole in different Creams for topical application at 25 ° C ± 2,0 ⁰ C. Formulations k, days " ^{1 #} ***

1. sulconazole nitrate 1% / 3.07 × 10 ^-3 24 HC 17-V 0.2% in aqueous alcoholic solution

2. sulconazole nitrate 1% / 5.96 × 10 ^-3 18 HC17-V0.2% in oil /

Water cream at pH 4.7,

3. sulconazole nitrate 1% / 7.40 χ 10 ~ ³ 14 HC 17-V0.5% in ointment

gem. USP XXI at pH 4.7

4. sulconazole nitrate 1% / 6.50 χ 10 " ³ 16 HC17-V0.2% in

Carbopol gel *

5. Sulconazole nitrate 1% / physically HC17-V0.2% in separate Methocel ** gel

6. sulconazole nitrate 1% / 2.24x10 ~ ³ 47 HC 17-V 0.2% in pure

Paraffin base

XXI 7. Econazolnitrat1% / 1.34 x10 ^"2 7.8 HC-17 V in 0.2% hydrophilic. Ointment gem. USP

Formulations k, days' »··

8. Miconazole nitrate 1% / 2.99 x 10 -2 ² HC17-V0.2% in oil /

water cream

9. Miconazolnhrat1% / 4.28 x10 ~ ² 2.5 HC-17 V0.2% in hydrophilic. Ointment USP XXI

10. Clotrimazole 1% A 4.39 x 10 " ³ 24 HC17-V0.2% in ot /

water cream

11. Clotrimazole 1% / 2.26 X10 ² "4.6 HC17-V 0.2% inhydro

phit.Salbegem.USPXXI

* Carbopol Gel Thickness Carboxy Vinyl Polymer High Molecular Weight (CTFA) [Cosmetic, Toiletry and Fragrance Association,

NewYorkJNamen: carbomer 934P, -940, -961).

 * MethCMrelGelistemethyletherethercellulosetCrTANamenrMethylcellulose.bramble nameiMethocelMC.cellulosemethylether).

*** t _{M% is} for reducing the content of hydrocortisone-17-valerate to 90% of the original required time.

** · * is the decomposition speed of the component HydrocortIson-17-fatherate.

On the basis of our investigations it is to be assumed that the necessity of the use of emulsifiers and

surfactants in most cream formulations causes increased reactivity of the 17-ester steroid with water and the imidazole molecules, resulting in rapid hydrolysis of the 17-esterified steroid (see formulations 2,3 and 7-11 in Table I). ,

Several commonly used gel formulations that contain no emulsifier and no surfactant Gelling agents are prepared, namely carboxylic acid polymers sold under the trade names Carbopol 934 and Carbopol 940 available, and a methyl ether of cellulose, available under the trade name Methocel MC, were for

used the combination products. As can be seen from Table I, there was still a rapid cleavage on the

Carbon atom observed in the 17-position of the steroid ester. Similarly, in a subsequent experiment, it was found that a mixture of imidazole with hydrocortisone 17-valerate itself in

pure paraffin is rapidly hydrolyzed. It is believed that insufficient dispersibility is the deficiency

Stability in pure paraffin caused (see Table I, Formulation 6). Since it is known that the ester hydrolysis is influenced by the pH, the stability of an imidazole and an in

17 position of esterified steroid in an oil / water cratering system adjusted to different pH values.

The results (Table II) show that a simple pH change does not ensure the required stability. Table II Cleavage rates of hydrocortisone-17-VaIerat 0.2% in the presence of 1% Sulconazolnitrat in a hydrophilic Ointment according to USP XXl (an oil / water cream) at 25 "C ± 2 ° C at different pH values

pH k days "

2,10 2,10 χ 10 " ³ 50

4,00 3,8OxIO " ³ 28

4.70 4.45 X10 " ³ 24

6,50 5,20 X 10 ~ ³ 20

It has been proposed to reduce the effective steroid in conjunction with certain stabilizers (eg EDTA, antioxidants) or the amount of propylene glycol used in the formulations * " ¹⁰ to prevent cleavage of the hydrocortisone and its derivatives Steroid formulations of the prior art, despite the use of stabilizers and despite reducing the concentration of propylene glycol, have not been able to obtain locally applicable solutions, gels or creams of a combination product which have sufficient long-term stability (2 years or more).

Thus, to meet a still unmet need to obtain a combination of an antifungal imidazole with an antitammatory 17-ester esterified corticosteroid in a topically applicable formulation which has been maintained for at least 2 years at room temperature (25 ° C It is thus the object of the present invention to provide such a stable combination product from which the imidazole and the 17-esterified steroid can readily be absorbed through the skin Also, to provide a formulation of the combination product that can be applied to the affected part of the skin, namely the wound site, without it flowing to the healthy parts of the skin.This latter property would reduce the undesirable side effects caused by absorption by the skin Tissue in the environment could be evoked on egg n Minimum limits. Not only would such a combination product cause rapid relief of the symptoms and complete remedy of the fungal infection, but it would also minimize the risk of unwanted side effects.

Accordingly, the present invention is intended to provide a topical antifungal treatment which effectively induces rapid symptom relief and complete remedy of the fungal infection while minimizing the risk of undesirable side effects.

Within the scope of the invention, a locally applicable gel formulation of a sterically esterified steroid of moderate potency and an antifungal imidazole is also to be developed which is readily dispersible and which has good physical and chemical stability without having to be refrigerated and without the need for special additives such as emulsifiers, surfactants or antimicrobial preservatives.

These locally applicable gel formulations of steroids and imidazoles esterified at 17 should also have other desirable properties, namely, cosmetic compatibility and the possibility of accurately dosing the effective amounts of the two drugs to the affected site. It is also within the scope of the invention to provide gel formulations which can be applied locally which accelerate the delivery of a steroid and an imidazole esterified in the 17-position to the diseased sites concerned and thus bring about a maximum therapeutic advantage.

The present invention will be explained in more detail by the specific examples and the following description. Thus, the present invention relates to a stable gel formulation for local administration comprising a therapeutically effective amount of a mixture of an antimycotically active imidazole and an anti-inflammatory 17-ester steroid in a vehicle comprising (a) a solvent mixture for the imidazole and the sterically esterified steroid, substantially a lower alkanol in combination with a dihydroxy alcohol or a trihydric alcohol or a mixture of the two, and (b) an amount of hydroxypropyl cellulose or hydroxyethyl cellulose sufficient to form a gel. These formulations may contain from 0% to 20% by weight of water. Brief description of the drawings:

FIG. 1 shows the amount of hydrocortisone-17-valerate penetrated into the skin per unit time from an aqueous or anhydrous gel formulation according to the invention in comparison to the amount per unit time of hydrocortisone-17-valerate from a cream or ointment formulation.

Figure 2 shows the amount of Sulconazolnitrats penetrated into the skin per unit time from an aqueous or anhydrous gel formulation according to the invention in comparison to the amount per unit time of sulconazole nitrate from creams or aqueous solutions.

In the course of various experiments carried out, it had been found that the stability of formulations containing both imidazoles and 17-esterified steroids appeared to be dependent on dispersibility. For example, stability in creams or solutions has been improved as the concentration of water in these formulations has decreased. Also viscous creams and pure paraffin bases did not show good stability. Thus, only cream formulations in which the steroids esterified in the 17-position and the imidazoles have a better solubility can achieve a satisfactory stability due to their better dispersibility, which reduces the mutual action of these two compounds.

Imidazoles are insoluble in most aqueous and nonaqueous solvents, including water. They can only be solubilized in aqueous media if they contain high concentrations of surfactants (more than 10%). At a high concentration of these surfactants, however, the steroids esterified in the 17-position are rapidly hydrolyzed.

It has now been found that the only means in which the 17-esterified steroids and the imidazoles are soluble, uniformly dispersed and stable are certain organic solvents. Specifically, the solvent mixtures are for both active components consisting essentially of a lower alkanol in combination with a dihydroxy alcohol or a trihydroxy alcohol or mixtures of both. Examples of suitable dihydroxy alcohols are hexanediols such as 2-ethyl-1,3-hexanediol and glycols such as ethylene glycol, propylene glycol and 1,3-butylene glycol. The most preferred glycol is propylene glycol. Examples of trihydroxy alcohols are hexane triols such as 1,2,6-hexanetriol. The term "lower alkanols" includes alcohols such as methanol, ethanol, propanol, isopropanol, butanol and the like The most preferred lower alkanols are isopropanol and ethanol or mixtures of these two Preferably, the dihydroxy alcohol is used in an amount of 0 to 45 wt. The amount of imidazole and steroid penetrating the skin per unit of time may be varied by varying the amount of oxyhydric alcohol in an amount of from 0 to 40% by weight and the lower alkanol in an amount of from about 30 to 65% by weight Higher concentrations of alcohol give a higher depot effect and increased penetration into the skin per unit of time, but higher alcohol concentrations increase skin irritation, which becomes very strong at concentrations above 60% by weight a balance can be found between the desire to record the speeds Increasing the effect components through the skin, especially the imidazole component, and the desire to obtain a non-irritating product.

As shown in Table III, the formulations of the present invention increase the stability of the 17-esterified steroids almost 5 to 40 times in terms of t9o% units. The substantial improvement in stability seen here stands in marked contrast to the instability found in other cream and gel formulations. 10% excess of the esterified steroid in the 17-position allows the statement of 2 years expiration time at room temperature on the packages. Alletgov values of Table III below were determined at 25 ° C ± 2 ° C.

Table III Decomposition rates of hydrocortisone 17-valerate in the presence of 1% of an imidazole in the gel formulations of

present invention at 25 ° C ± 2 ° C>

1) R & D Product No.30159-b-19-A (FN7-969-06}

ingredients Wt .-% t _M %. days t9o% .Tage t9o%, day sulconazole 1 Hydrocortisone 17-valerate 0.2 440 477 506 SD alcohol 40 50 propylene glycol 30 Wt .-% Wt .-% PPG-ö-ceteth-20 12.3 1 1 (Polycondensation product from poly 0.2 0.2 propylene glycol and cetyl alcohol) 35 50 isopropyl 5 40 30 hydroxypropyl 0.9 12.3 12:45 salicylic acid 0.5 5 5 ascorbic acid palmitate 0.1 5 0.75 FN 7-969-06, " ¹ 0.9 0.5 Result of 0.5 0.1 chemical stability 2.39 χ 10 "* 0.1 2) R & D Product No.30159-B-23-A (FN7-994-02} ingredients sulconazole Hydrocortisone 17-valerate SD alcohol 40 propylene glycol PPG-5-ceteth-20 water isopropyl hydroxypropyl salicylic acid ascorbic acid palmitate FN7-994-02 IcTage " ¹ Result of chemical stabilizer 2.20 x 10 "* 3) (FN7-944-18) ingredients miconazole Nitrate Hydrocortisone 17-valerate SD alcohol 40 propylene glycol PPG-5-Ceteth20 isopropyl hydroxypropyl salicylic acid ascorbic acid palmitate FN7-994-18 k.day " ¹ Result of chemical stability 2.08 x 10 "*

Continuation Table III

4) (FN 7-994-19) Ingredients Econazole nitrate Hydrocortisone 17-valerate SD Alcohol 40 Propylene glycol PPG-5-Ceteth-20 Isopropyl myristate Hydroxypropyl cellulose Salicylic acid Ascorbic acid palmitate

Wt .-%

0.2 50 30

12.45 "

0.75

0.5

0.1

FN7-994-19 k.days " ¹ tgos.Tage W, days Result of chemical stability 3.33 χ 10 "* 316 434 5) (FN 7-944-20) ingredients Wt .-% Wt .-% clotrimazole 1 1 Hydrocortisone 17-valerate 0.2 0.2 SD alcohol 40 50 50 propylene glycol 30 22 PPG-5-ceteth-20 12.45 15 isopropyl 5 5 hydroxypropyl 0.75 4.99 salicylic acid 0.5 0.9 ascorbic acid palmitate 0.1 0.5. FN 7-944-20 k.days " ¹ 0.2 Result of chemical stability 2.42 x 10 " ⁴ 0.2 7) (FIM 8-1094-20) 0.01 ingredients sulconazole Hyd roco rtiso n-17-va lerat t9o * days SD alcohol 40 2-ethyl-1,3-hexanediol 316 1,2,6-hexanetriol Isopropyl myristate ·· - water hydroxypropyl salicylic acid BHT (2,6-di-tert-butyl-4-methyl-phenol) BHA (2-tert-butyl-4-methylphenol + S-tert.ButyM-methylphenol) Disodium salt of EDTA (Ethylenediaminetetraacetic acid) 1 η NaOH to adjust the pH to 4 FN 8-1094-20 k.days " ¹ Results of chemical stability 3.33 x 10 " ⁴

In addition to the two components and the solvent mixture, the present gel formulations require sufficient amount of either hydroxypropyl cellulose or hydroxyethyl cellulose to form a gel. As previously mentioned, other gelling agents such as methyl cellulose or gels of carboxyvinyl polymers give unstable gel formulations. In general, the gelling agent is used in a concentration of 0.1 to 5%. A general recipe comprising gel formulations in the context of the present invention is given below. All quantities are expressed in weight percent.

-9- 297 General Gel Formulation in Weight Percentages

component Amount in% by weight Antimycotic imidazole 0.2-2.0 17-esterified steroid 0.01-2.5 Lower alkanol 30-65 dihydroxy 0-45 trihydroxy 0-40 Gel-forming agent 0.1-5 water 0-20 softener 0-30 perfume 0-2.0 preservative 0-1.5

Both anhydrous and aqueous gel formulations are encompassed by the present invention. Anhydrous formulations contain as essential components the two active ingredients, the dihydroxy alcohol and / or the trihydroxy alcohol, the lower alkanol and the yellowing agent. They may also contain other components commonly used in gel formulations, e.g. Plasticizers such as PPG-5-ceteth-20, PPG-10-glucosemethyl ether, PPG-20-gtucosemethyl ether, PG-dioctanate, methylgluceth-10, methylfgluceth-20, iso-decanoic acid neopentanoate, glycerin, mineral oil, etc. (preferably in an amount of up to 30%, more preferably 5-30%), antioxidants such as ascorbic palmitate, BHT, BHA, etc. Chelating agents such as EDTA and other preservatives salicylic acid, perfumes (to about 2%), dyes, agents that accelerate penetration into the skin, etc.

The preferred gel formulations of the present invention, whether aqueous or anhydrous, contain a plasticizer. The most preferred plasticizers are isopropyl myristate, PPG-5-ceteth-20, PPG-20-glucosemethyl ether, or mixtures thereof.

A preferred anhydrous gel formulation of the present invention contains 1% sulconazole nitrate and 0.2% hydrocortisone 17-valerate-forming composition:

Component% by weight of succinazole nitrate 1

Hydrocortisone-17-diate 0.2 Ethric alcohol 61.3 Propylene glycol 25 Isopropyl myristate 5 Hydroxypropylcellulose 2 Salicylic acid 0.5

PPG-5-Ceteth-20 5

Another preferred anhydrous gel formulation is the following formulation:

Component% by weight Sulconazit nitrate 1

Hydrocortisone 17-vaferate 0.2 Ethyl alcohol 50 Propylene glycol 30

PPG-5-ceteth-20 17,45

Hydroxypropylcellulose 0.75 Salicylic acid 0.5 Ascorbic palmitate 0.1

Aqueous gel formulations of the present invention contain, in addition to the components described above for the anhydrous formulations. Water in an amount up to 20%, more preferably an amount of about 5 to 10%. For the aqueous gel formulation, it is necessary to maintain the pH of the formulation within 3-5. This can be done, if necessary, using the usual pharmaceutically acceptable acids and bases. A preferred aqueous gel formulation of the present invention has the following formulation:

Component% by weight Sulconazole nitrate 1 Hydrocortisone-17-diate 0.2

Ethanol 61.3

Propylene glycol 20

Water TO

Isopropyl myristate 5 Hydroxypropylcellulose 2 Salicylic acid 0.5

The gel formulations of the present invention may be obtained by conventional mixing of the components described above. The preparation of an aqueous formulation can be described as follows: ethanol, propylene glycol and water are mixed, and in the solvent mixture salicylic acid, the plasticizer, the

Preservative and / or the antioxidant dissolved. 25% of the solution is used to dissolve the sulconazole nitrate, in another 25% the hydrocortisone 17-valerate is dissolved. The gelling agent is then added to the remaining 50% and vigorously stirred for more than 45 minutes to hydrate the gel. After completion of the gelation process, the solutions of sulconazole nitrate and hydrocortisone 17-valerate are added separately to the gel to obtain the final product.

The gel formulations of the present invention are clear and stable; if a 10% excess of the active ingredients is used, the preparations have an expiration date of 2 years and more at room temperature.

It has surprisingly been found that the gel formulations of the present invention also allow a desirable increased penetration per unit time of the imidazole and the 17-esterified steroid into the skin. For example, in the combination product, the penetration of the esterified steroid in the 17-position into the skin can be adjusted so that it corresponds to that of the known ointments and creams with 17-esterified steroids, while in the antifungal imidazoles a significantly increased penetration into the Skin per unit time as compared to currently available imidazole solutions and creams (see Figures 1 and 2). This salient feature of the gel formulations makes it possible to achieve an effective concentration of the imidazoles against fungal diseases, while still maintaining a sufficient concentration of the 17-esterified steroid. Figure 1 shows that, when compared to creams and ointments of hydrocortisone-17-valerate on the market, the aqueous gel of the present invention achieves at least equal penetration into the skin per unit of time while the anhydrous gel has a somewhat enhanced effect he brings. Figure 2, when compared to solutions and cream formulations of sulconazole nitrate, shows that with both the aqueous and anhydrous gel formulations of the present invention, a substantially increased penetration of the antifungal imidazole into the skin per unit time is achieved. As previously mentioned, the penetration of the gel formulations of the present invention into the skin can be affected by the content of the lower alkanol in the formulations, with higher alkanol concentrations accelerating penetration into the skin per unit time. We have found that the lower alkanol should be used in an amount of about 30-65% and the dihydric alcohol in an amount of 0-45% and / or the trihydric alcohol in an amount of 0-40% for optimum stability through the skin and to achieve freedom from irritation.

The rules for topical treatment with the formulations of the present invention are that the formulations are applied directly to the skin at the site of the fungal infection. The frequency of administration and its duration will depend on the severity and nature of the infection, the response of the individual patient and related factors in the medical assessment by the referring physician and by the patient. In general, the gel formulation is administered at least daily, preferably two or three times a day, until complete suppression of the fungal infection.

The following examples of pharmaceutical compositions of the present invention are intended to illustrate these in detail without, however, limiting them.

example 1

Preparation of an aqueous gel with 1% sulconazole nitrate and 0.2% hydrocortisone-17-valerate

Wt .-%

Sulconazole nitrate 1

Hydrocortisone 17-valerate 0.2

Ethanol 50

Propylene glycol 33 isopropyl myristate 5

Water 5

PPG-5-ceteth-20 4,2

Hydroxypropylcellulose 0.9

Salicylic acid 0.5

Ascorbic palmitate 0.2

1 η NaOH for adjustment to pH 4

5.1 kg of ethanol, 3.3 kg of propylene glycol and 0.5 kg of isopropyl myristate were placed in a suitable mixing vessel. Then, with vigorous stirring, 0.420kg of PPG-5-ceteth-20 was added and mixing was continued until the reaction mixture was uniform. Then, with vigorous stirring, 0.020kg of ascorbic acid palmitate, 0.105kg of sulconazole nitrate and 0.050kg of salicylic acid were added slowly, and mixing was continued until everything was dissolved. Into a separate mixing vessel was added 0.075 kg of water, then 0.004 kg of NaOH was added slowly and roughened until the solution was clear. To the original mixing vessel was then added 0.004 kg of water and the NaOH solution with further stirring for 5-10 minutes until a uniform consistency was obtained. The pH of the reaction mixture was determined to be 4.1. 0.025 kg of water and 0.022 kg of hydrocortisone 17-valerate were then added to the mixing vessel and vigorous stirring was continued for 15 minutes. Then, again with vigorous stirring, 0.090 kg of hydroxypropyl cellulose was added, stirring was continued for about 2 hours to give the desired gel.

Example 2

Wt .-%

Sulconazole nitrate 1 Hydrocortisone 17-valerate 0.2

Ethanol 5 °

Propylene Glycol ³⁰

PPG-5-Ceteth-20 12.3

Isopropyl myristate ⁵ Hydroxypropylcellulose 0.9 Salicylic acid 0.5 Ascorbic palmitate 0.1 Example 3

Wt .-%

Sulconazole nitrate 1 Hydrocortisone 17-valerate 0.2

Ethanol ³⁵

Propylene Glycol ⁴⁰

PPG-5-ceteth-20 ^{12 '3}

Water ⁵

Isopropyl myristate 5 Hydroxypropylcellulose 0.9 Salicylic acid ° · ⁵ Ascorbic acid palmitate ° < ¹ Example 4

Wt .-%

Miconazole nitrate 1 Hydrocortfson-17-VaIerat 0,2

Ethanol ⁵⁰

Propylene Glycol ³⁰

PPG-5-Ceteth-20 12,45

Isopropyl myristate 5 Hydroxypropylcellulose 0.75 Salicylic acid 0.5 Ascorbic palmitate 0.1 Example 5

Wt .-%

Econazole nitrate 1 Hydrocortisone 17-valerate 0.2

Ethanol ⁵⁰

Propylene Glycol ³⁰

PPG-5-Ceteth-20 12.45

Isopropyl myristate 5 Hydroxypropylcellulose 0.75 Salicylic acid ° - ^& Ascorbic acid palmitate 0.1 Examples

Wt .-%

Sulconazole nitrate 1 Hydrocortisone 17-valerate 0.2 Isopropanol ^ O Propylene Glycol ³⁰

PPG-5-ceteth-20 12 ^'45

Isopropyl myristate 5 Hydroxyethyl cellulose 0.75

Salicylic acid ° · ⁵

Ascorbic acid palmitate ° »1

Example 7

percentages by weight sulconazole 1 Hydrocortisone 17-valerate 0.2 ethanol 50 2-ethyl-1,3-hexanediol 22 propylene glycol 15 isopropyl 5 water 4.99 hydroxypropyl 0.9 salicylic acid 0.5 BHT 0.2 BHA 0.2 Disodium salt of EDTA 0.01 1 η NaOH to adjust the pH to 4.0 Example 8 percentages by weight sulconazole 1 Hydrocortisone 17-valerate 0.2 ethanol 50 1,2,6-hexanetriol 27 2-ethyl-1,3-hexanetriol 7.5 isopropyl 7.5 PPG-20-glucose methyl ether 5 hydroxypropyl 0.9 salicylic acid 0.5 BHT 0.2 BHA 0.2

Overview of literature references

1. Wortzel, M.Y., H., A double blind study comparing the superiority of a combination anti-fungal (clotrimazole / steroidal (betamethasone dipropionate)) product. Cutis 30: 258 (1982).

2. Katz, HI, Bard, J., Cole, GW, Fischer, S., McCormick, GE, Medansky, RS, Nesbitt, LT, and Rex, IH, SCH 370 (clotrimazole-betamethasone dipropionate) cream in patints with tinea cruri ortinea corporis. Cutis, 34 (2), 183-188 (1984).

3. Bruice, T.C., and Schmir, G.L., Arch. Biochem. Biophys. 63: 484 (1956).

4. Bruice, T.C., and Schmir, G.L., Imidazole catalysis. I. The catalysis of the hydrolysis of phenylacetates by imidazole. J. Am. Chem.Soc.79: 1663-1669 (1957).

5. Bruice, T.C., and Schmir, G.L., Imidazole catalysts. II. The reaction of substituted imidazoles with phenylacetates in aqueous solution. J. Am. Chem. Soc. 80: 148-156 (1958).

6. Bender, M.L., and Turnquest, B.W., General Basic catalysis of ester hydrolysis and its relationship to enzymatic hydrolysis. J. Am. Chem. Soc. 79: 1656-1662 # (1957).

7. Judge Gedeon Vegy, stable antifungal and antiinflammatory ointment. JP 76576.

8. Yip, Y.W., Po, LW. and Irwin, W.J., Kinetics of decomposition and formulation of hydrocortisone butyrate in semi-aqueous and gel systems. J. Pharm. 72: 776-781 (1983).

9. Gupta V.D., Effect of vehicles and other active ingredients on stability of hydrocortisone. J. Pharm. 67: 299 (1978).

10. Hansen, J., and Bundgaard, H. Studies on the stability of corticosteroids. V. The degradation pattern of hydrocortisone in aqueous solution. Int. J. Pharm. 6: 307-319 (1980).

Claims (23)

Anspruch [en] A stable gel formulation for topical administration characterized by (a) a therapeutically effective amount of a mixture of an antimycotically active imidazole and an anti-inflammatory 17-esterified steroid, (b) a solvent system consisting essentially of a lower alkanol in combination with a dihydroxy alcohol or a trihydric alcohol or a mixture of the two, and (c) an amount of hydroxypropyl cellulose or hydroxyethyl cellulose sufficient to gel. 2. A gel formulation according to claim 1, characterized by a content of water up to an amount of about 20 wt .-% and by a pH of about 3 to about 5. 3. A gel formulation for topical administration characterized by (a) about 0.2 to 2% by weight of an antimycotic imidazole, (b) about 0.01 to 2.5% by weight of an anti-inflammatory 17% esterified steroid, (c) about 0 to 20% by weight of water, (d) about 30 to 65% by weight of a lower alkanol solvent for the imidazole and the steroid 17-ester, (e) about 0 to 45% by weight of a dihydroxy alcohol as solvent for the imidazole and the steroid 17-ester or about 0 to 40% by weight of a trihydroxy alcohol, or a mixture of the two, and (f) about 0.1 to 5% by weight of hydroxypropylcellulose and / or hydroxyethylcellulose as gelling agent wherein said formulation has a pH of from about 3 to about 5 in the presence of water. A gel formulation according to claim 3, characterized by (a) about 0.2 to 2% by weight of an antimycotic imidazole, (b) about 0.01 to 2.5% by weight of an anti-inflammatory 17% esterified steroid (c) about 0 to 20% by weight of water, (d) about 30 to 65% by weight of a lower alkanol solvent for the imidazole and the steroid 17-ester, (e) about 0 to 45% by weight. % of a dihydroxy alcohol as a solvent for the imidazole and steroid ester, and (f) about 0.1 to 5% by weight of hydroxypropyl cellulose and / or hydroxyethyl cellulose as a gelling agent. 5. A gel formulation according to claim 3, characterized by (a) about 0.2 to 2 wt .-% of an antifungal imidazole, (b) about 0.01 to 2.5 wt .-% of an anti-inflammatory 17-position esterified (C) about 0 to 20% by weight of water, (d) about 30 to 65% by weight of a lower alkanol as solvent for the imidazole and the steroid ester, (e) about 0 to 40% by weight of a trihydroxy alcohol solvent for the imidazole and the steroid ester; and (f) about 0.1 to 5% by weight of hydroxypropylcellulose and / or hydroxyethylcellulose as the gelling agent. A gel formulation according to claims 1, 2, 3, 4 or / and 5 characterized by an additional level of up to about 30% by weight of a gel vehicle soluble plasticizer. A gel formulation according to claims 1, 2, 3, 4, 5 and / or 6, characterized by the additional content of an effective amount of a preservative. 8. A gel formulation according to claims 1,2,3,4,5,6 and / or 7, characterized by the additional content of a perfume. 9. A stable gel formulation for topical administration characterized by (a) about 0.2 to 2% by weight of an antimycotic imidazole, (b) about 0.01 to 2.5% by weight of an anti-inflammatory 17% esterified steroid , (c) about 30 to 65% by weight of ethanol or isopropanol or a mixture of the two, (d) about 0 to 45% by weight of propylene glycol or of 2-ethyl-1,3-hexanediol or a mixture of the two, ( e) about 0 to 40% by weight of 1,2,6-hexanetriol and (f) 0.1 to 5% by weight of hydroxypropylcellulose and / or hydroxyethylcellulose as gelling agent. A gel formulation according to claim 9, characterized by the additional content of up to 30% of a gel vehicle soluble plasticizer. A gel formulation according to claim 10, characterized in that the plasticizer is isopropyl myristate, PPG-5-ceteth-20, PG-dioctanate, methylgluceth-10, iso-decanoic acid, glycerol, mineral oil, methylgluceth-20, PPG-10-glucosemethylether, PPG- 20-glucosemethyläther or a mixture of the above. A gel formulation according to claim 11, characterized in that the plasticizer is isopropyl myristate, PPG-5-ceteth-20 or PPG-20-glucosemethyl ether or a mixture thereof. A gel formulation according to claims 9, 10, 11 and / or 12, characterized by the additional content of an effective amount of a preservative. 14. A stable anhydrous gel formulation for topical administration characterized by the following formula: 16. A stable gel formulation for topical administration characterized by (a) from about 0.2% to 2% by weight of an antimycotic imidazole, (b) from about 0.01% to 2.5% by weight of an anti-inflammatory 17% esterified ester (C) about 30 to 65% by weight of a lower alkanol as a solvent for the imidazole and the steroid ester, (d) about 0 to 45% by weight of a dihydroxy alcohol as a solvent for the imidazole and the steroid ester, (e) about 0-40% of a trihydric alcohol solvent for the imidazole and the steroid ester, (f) water up to 20% by weight, and (g) about 0.1 to 5% by weight of hydroxypropyl cellulose and hydroxyethyl cellulose, wherein this formulation has a pH of 3 to 5. 17. A stable gel formulation according to claim 16, characterized by the additional content of up to about 30% by weight of a gel vehicle-soluble plasticizer. 18. A gel formulation according to claim 16 or 17, characterized by the additional content of an effective amount of a preservative. 19. A gel formulation according to claims 16,17 and / or 18, characterized in that the lower alkanol is ethanol, isopropanol or a mixture of the two. 20. A gel formulation according to claims 16,17,18 and / or 19, characterized in that the dihydroxy alcohol is propylene glycol, 2-EthyM, 3-hexanediol or a mixture of the two. A gel formulation according to claims 16, 17, 18, 19 and / or 20, characterized in that the trihydric alcohol is 1,2,6-hexanetriol. 22. A gel formulation according to claims 17,18,19,20 and / or 21, characterized in that the plasticizer isopropyl myristate, PPG-5-ceteth-20, PG-dioctanate, methylgluceth-10, Neopentansäureisodecylester, glycerol, mineral oil, methyl Gluceth-20, PPG-10-glucosemethyläther, PPG-20-glucosemethyläther or a mixture of the above. A gel formulation according to claim 22, characterized in that the plasticizer is isopropyl myristate, PPG-5-ceteth-20, PPG-20-glucosemethyl ether or a mixture thereof. 24. A stable aqueous gel formulation for topical administration characterized by the following formula: For this 2 pages drawings The present invention relates to a stable gel formulation for the local administration of a combination of a antifungal acting imidazole and an anti-inflammatory acting in the 17-position esterified steroid. The product is especially for / treating fungal diseases such as tinea capitis. Tinea corporis or tinea cruris suitable. The decomposition of the 17-ester steroid by water and by the antifungal imidazole during storage is drastically reduced by the present gel formulation. A fungus or fungus is a microscopic type of plant cell that grows on and under the skin Conditions can cause an infection. Such infections caused by fungi are among the oldest People have known infections and have long been considered a very significant public health problem been recognized. If the fungal infection affects the head, it is known as tinea capitis; if it affects the foot, it is considered Tinea pedis LAthletenfuß ", dermatophytosis of the foot) is known, when it occurs on the body, it is called Tina corporis and if she appears on the groin, known as the tiniea cruris. A variety of methods have been used to treat fungal infections, including the use of Potassium iodide, Whitfield's ointment, undecylenic acid, antibiotics (e.g., nystatin or amphotericin B), griseofulvin and of the antifungal imidazoles such as miconazole, clotrimazole, econazole and sulconazole. Although the systemic administration of antibiotics such as nystatin or amphotericin B has been used with some success the low bioavailability and systemic toxicity of these agents has their utility in the treatment of Restricted fungal infections The imidazoles were the first broad-spectrum antimycotics and they are of considerable importance in clinical practice. you broad spectrum of antifungal activity, which extends to most pathogenic fungi, has an important Progress in antifungal therapy has been made. By the term "antifungal imidazo!" As used herein is meant any agent that has in the molecule Imidazole ring as a functional group and has a local antifungal effect. A large number of suitable Imidazoles have been described in the literature, they are well known in the art. Examples of suitable antifungal acting imidazoles include but are not limited to sulconazoinitrate, econazole nitrate, miconazole nitrate and clotrimazole. The fungal infections are generally characterized by signs of redness and dandruff and symptoms such as itching and accompanied by painful burning. The clinical treatment of fungal infections requires at least 2 to 4 weeks to complete relief from the symptoms. Recently, it has been found that fungal infections can be effectively treated with a combination product, the Contains corticosteroids and antimycotic imidazoles. It is known that the sensitivity of the fungal organisms changes with its life cycle; Spores are more resistant to treatment than mycelia. Steroids can cause fungal spores to produce mycelia, making them more sensitive to treatment. It is also known that Steroids induce vasoconstriction at the site of administration. This efficacy can be the elimination of the antifungal agent from the site of administration delaying or preventing the antifungal agent from becoming longer in the body Epidermis Remains It is therefore believed that a locally administered anti-inflammatory agent is a direct and immediate one Ameliorate the inftammatory component of the affection. The combination product should then have a Provide rapid relief of the symptoms and eliminate the infection completely. Because of this concept, recent combinations of an antifungal agent and an anti-inflammatory agent have been proposed for the treatment of Fungal diseases developed. At present, commercially available combination preparations based on this concept Lotrison cream (clotrimazole 1% / betamethasone dipropionate 0.05%), Daktocort cream (miconazole nitrate 2% / hydrocortisone 1%) and Canestan HC cream (clotrimazole 1% / hydrocortisone 1%). Katz and other dermatologists ¹ * ² found that Lotrison cream was better than 1% clotrimazole and 0.05% Betamethasone dipropionate alone. Despite its clinical benefits, lotus cream has some undesirable effects Properties. It contains a fairly highly fluorinated steroid, betamethasone dipropionate, which is cosmetically quite dangerous can be when applied to wondering spots. Other undesirable effects are skin atrophy, Rebound phenomenon and telengiectasia. Other combination products of this type which are commercially available, e.g. Daktocortcreme and Canistan-HC-Creme, are