RU2093152C1 - Antimycotic pharmaceutical composition (variants) - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: composition has an active component - terbinafine of the formula (I) given in description as an acid-additive salt or free base, %: 0.1-5.0; water 50-85; lower alcohol 5-35, and carrier - the rest up to 100. Composition has nonionogenic surface-active agent at ratio compound (I) : surface-active agent = 1:(0.5-15). Lower alcohol is ethanol. Surface-active agent - aliphatic alcohols polyhydroxyethylene ester. Composition can be prepared as a liquid monophase system, base for aerosol system, gel, liquid gel or lotion. Composition (variant) has terbinafine of the formula (I), water, lower alcohol and surface-active agent and prepared as an emulsion for local applying where oily phase has terbinafine and an aqueous one - 50-85 wt.-% water, 5-35 wt.-% lower alcohol and surface-active substance - the rest at mass ratio of terbinafine : surface-active substance = 1:(0.5-15) and mass ratio of terbinafine : oily phase = 1: (5-40). Isopropylmyristate is preferable oily phase. EFFECT: improved quality and property of composition. 7 cl

Description

и низший алканол.The invention relates to pharmaceutical compositions for topical application in the form of solutions, gels, liquid gels, emulsion gels and lotions that contain allylamine derivatives of the general formula I as a pharmacologically active agent

and lower alkanol.

 Such compositions may be, for example, non-greasy solutions, emulsion gels or lotions, all of which are liquids or viscous substances.

 In addition, this invention relates to a method for producing a pharmaceutical composition for topical application, comprising treating a compound of formula I with lower alkanol with the addition of additional excipients in an appropriate amount.

 Examples of solutions intended for topical application are the actual solutions or spray liquids, gels or liquid gels.

Water is preferably present in the compositions of this invention mainly in concentrations, the range of which by weight is, for example, in the range of 50-85%
The compound of formula I may be present, for example, in the form of a free base or in the form of an acid salt. The acid salt can be prepared from the free base in the usual manner, and the reverse process can also be carried out. Examples of acid salts are hydrochloride, lactate and ascorbate.

The compounds of formula I are known from the description of the Belgian patent N 853976 m of the application for Europatent N 24587. They belong to the class of antifungal alamine amines. Its generic name is terbinafine, and on sale it is known as "LAMISIL". Although terbinafine is very active in both local and oral administration, only local application in the form of a cream in which the drug is kept dissolved in the organic phase is widespread in practice; this only partially satisfies the needs of patients, and the technology of cream preparation is traditional and is suitable for certain conditions of the disease and certain types of skin. A topical application technology in the form of a composition according to this invention is highly desirable since it provides the following advantages:
faster and more complete extrusion of the drug from the membrane onto the skin and, therefore, higher efficiency;
lack of grease and sediment on the applications and, therefore, increased suitability for application to skin covered with hair;
increasing the ability of the skin to soften and, as a result, its better adaptability to applying the medicine to larger areas;
the effect of cooling the skin and, therefore, the best adaptability of the composition to application to the skin affected by seborrhea.

 However, the method of producing topical compositions with the advantages described above is difficult if a compound of formula I is used, since such a drug is poorly soluble in aqueous systems, so that it tends to stand out from the drug substance as a free base or as droplets, or even in the form of crystals, when it is used in the form of an acid salt or in the form of an emulsion gel based on oil or lotion, since the free base is less soluble in water than the corresponding acidic ol; in addition, a drug of this type tends to interact with anionic excipients. The use of the acid salt form is desirable and is a preferred embodiment of the present invention, since it can improve the solubility of the drug in an aqueous medium. However, the isolation of the free base from the equilibrium compositions of this invention presents a serious problem of reproducibility of the pharmacological effect of the stability of the properties of such a drug during storage.

 The above difficulties are exacerbated when they want to prepare single-phase formulations such as liquid gels and gels containing a compound of formula I in the form of a base or salt in the same phase in combination with classic carbomer thickeners (polyacrylic acid derivatives), which are typical gel fillers. The interaction of the components affects the formation of an insoluble complex or crystallization of the base. Thus, there is a need for improved forms for topical application, for example in liquid gels and gels.

 According to the proposed method according to this invention create an emulsion system in which the free base is dissolved in the oily phase. However, such systems cannot be applied to certain skin types and disease conditions, therefore, in many specific situations, the composition should be essentially free of fatty materials of fatty acids, esters of fatty acids and fatty alcohols; for example, cetyl stearates or palmitates, stearyl or cetyl alcohols are preferred. In addition, there is a need for the presence of water as the main element of such forms and in the absence of oils or fats, as well as for the free base to be in solution in equilibrium.

 According to another aspect of the present invention, it has been found that the liberation of the free base in aqueous solutions, for example in topical solutions, can be avoided by the use of suitable solubilizers that are nonionic, such as a nonionic surfactant. As solubilizers, water-soluble or water-miscible compatible with the drug substance and with additional excipients present in the composition are preferable. In addition, solubilizers must be skin tolerant. The solubilizers should have the effect of improved penetration of the drug into the skin in the absence of any irritation.

Examples of solubilizers acceptable for topical solutions are:
a) reaction products of natural or hydrogenated castor oil and ethylene oxide. Such products can be obtained in a known manner, for example by reacting natural or hydrogenated castor oil with ethylene oxide, for example at a molar ratio of (1:35) (1:60), with the possible removal of the polyethylene glycol component from the product, for example according to the methods described in DOS 1182388 and 1518819.

Particularly suitable for use for the purposes under consideration are various detergents commercially available under the trade name "Cremophor". The following products are particularly suitable:
"Cremophor RH 40" having a saponification number of about 50-60, an acid number <1, an iodine number <1, a water content (Fisher) <2% n $\genfrac{}{}{0ex}{}{\text{60}}{\text{D}}$ about 1.453-1.457; and HLB about 14-16;
"Cremophor RH 60" having a saponification number of about 40-50, an acid number <1, an iodine number <1, a water content (Fisher) of 4.5-5.5% n $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ about 1.453-1.457; HLB about 15-17;
"Cremophor EL" having a molecular weight (determined by steam osmometry) of about 1630, a saponification number of about 65-70, an acid number of about 2, an iodine number of about 28-32; n $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ about 1,471.

For use as such, various tensides are known under the trade name "Nikkol". For example, "Nikkol HCO-60" is a reaction product of hydrogenated castor oil and ethylene oxide, showing the following characteristics: acid value 0.3; saponification number 47.4; hydroxyl number 42.5; pH (5%) 4.6; color index registered by the American Health Association (APHA), 40; melting point (MP) 36.0 ^o C; freezing point 32.4 ^o C; H ₂ O content (% KF) 0.03.

b) Polyoxyethylene esters of sorbitol and fatty acids or polysorbates, for example of the type commercially known under the trade names "Tween" (Feoler 2, p. 1300-1304) and "Armotan" (Fiedler 1, p. 172), including products such as:
"Tween 20" -polyoxyethylene (20) sorbitan monolaurate;
"Tween 40" polyoxyethylene (20) sorbitan monopalmitate;
"Tween 60" polyoxyethylene (20) sorbitan monostearate;
"Tween 65" polyoxyethylene (20) sorbitan tristearate;
"Tween 80" polyoxyethylene (20) sorbitan monooleate;
"Tween 85" polyoxyethylene (20) sorbitan trioleate;
"Tween 21" -polyoxyethylene (20) sorbitan monolaurate;
"Tween 61" polyoxyethylene (20) sorbitan monostearate;
"Tween 81" polyoxyethylene (20) sorbitan monooleate.

 c) Polyoxyethylene fatty acid esters, for example, polyoxyethylene stearic acid esters of the type commercially known under the trade name "Myri" (Fiedler 2, p. 834-835), as well as polyoxyethylene fatty acid esters known in the commercial market under the trade the name "Cetiol HE" (Fiedler 1, p. 283 284).

 d) Copolymers of polyoxyethylene and polyoxypropylene, for example of the type known under the trade names "Fluronic" and "Emkalyx" (Fiedler 2, p. 956-958).

 e) Polyoxypropylene fatty alcohol esters, for example stearyl polyoxyethylene ether, oleyl ether or cetyl ether, for example of the type known under the trade name “Brij” (Fiedler 1, p. 222-224), for example, “Brij 78” and “Brij 96 "as well as" Cetomacrogol 1000 "(Fiedler 1, p. 284).

Preferred solubilizers are those indicated in a, b, c, e, in particular "Cetomacrogol 1000" ^R and "Tween 20" ^R. Particularly preferred is "Cetomacrogol 1000" ^R.

The compounds of formula I and the solubilizer are advantageously present in the composition of the solution for topical application in a weight ratio of from about 1: 0.5 to about 1:15, preferably from about 1: 1 to about 1:10. The compounds of formula I advantageously comprise, by weight of the total composition, from about 0.5 to about 2%
In the simplest form, the topical solutions of this invention consist only of a drug substance and a lower alkanol solvent. Such an alkanol solvent is preferably miscible with water when used in the composition of this invention. The lower alkanol solvents of this invention are physiologically tolerated C ₁ -C ₄ alcohols, for example isopropanol or, predominantly, ethanol. The concentration of alkanol and composition by weight can vary over a wide range, for example from about 5 to about 90%, or from about 5 to about 35%. A typical concentration range for a liquid composition is from about 25 to about 45%, for example 25-35%, and for a viscous composition for example gel, from about 5 to about 15%, for example 10%
Solutions can be packaged in traditional glass vials equipped with dispensers, or in more sophisticated packaging media, such as plastic vials without spraying devices or with spraying devices.

Due to the fact that the application of the thickened solution is simpler, it may be desirable to use a liquid gel or a clear gel. This can be achieved by using conventional thickener additives in the solutions described above. Suitable components for this include, for example:
polymethacrylates, for example of the type that is commercially known under the trade name "Eudisprt" (Fiedler 1, p. 485-486);
cellulose derivatives, including, for example, ethyl, propyl, methyl and hydroxypropyl methyl cellulose;
polyvinyl resins, for example ethenoplasts and polyvinylpyrrolidones, as well as other polymers, including gelatin, alginates, pectins, tragacanum gum, Arabian gum and xanthan gum;
materials such as silica gel, bentonite and magnesium aluminum silicate.

The amount of these components is sufficient when it reaches (as a percentage of the total weight of the composition) 20% predominantly up to 10%. The most acceptable amounts are from about 0.5 to about 15%, for example (by weight of the whole composition) from about 1 to about 3%
The compositions of the topical solutions of this invention can be obtained by carrying out a process comprising dissolving a compound of formula I in the form of a free base or in the form of an acid salt together with a solubilizer in an appropriate container and then adding the required amount of excipients. If you want to get a thickened solution or gel, then a thickener is added to the system in the usual way.

 This invention provides stable emulsion gels and lotions. When an emulsion gel or lotion based on a carbomer thickener is required as a compound of formula I applied to the skin, the same problems arise with the interaction of the free base and an anionic polymer as described above for aqueous solutions. It was found that these interactions can be avoided and stable emulsion gels and lotions are obtained when an oily phase such as isopropyl myristate and carbomer are added to the compound of formula I, mainly in the form of a free base. The result is stable emulsion gels and lotions that have all the beneficial properties of the gel and avoid the interaction of the drug with carbomer.

In the emulsion gels and lotions according to this invention, the ratio of the weights of the compounds of formula I and the oily phase is from about 1: 5 to about 1: 40, mainly from about 1: 7 to about 1:20. The oily phase is predominantly isopropyl myristate. It is present mainly in a concentration by weight corresponding to 10%
The compound of formula I comprises from about 0.1 to about 5% by weight of the composition, preferably from about 0.5 to about 3%. Mostly water, lower alkanol and the oily phase (if any) together comprise from about 83 to about 96% by weight composition. Conventional additives are, in particular, thickeners such as carbomers (polyacrylic acid derivatives), which are known and commercially available under the trade name "Carbopol" (Fiedler 1, p. 206-207), for example, "Carbopol 934 P" or "Carbopol 1342" . Other possible excipients are, for example, emulsifiers such as sorbitan monolaurate ("SPan 20" ^R ) and polysorbate 20 ("Tween 20" ^R ). Carbomers stabilize the emulsion to the desired condition with little or no emulsifier content, giving stable emulsion gels and lotions, in particular when Carbopol 1342 carbomer is used.

 Thus obtained emulsion gels and lotions have improved cosmetic properties distribution on the skin and the absence of salting; from the point of view of reducing or absence of traditional emulsifiers in the composition, such substances also exhibit improved pharmacological properties, in particular better tolerance when applied to infected skin areas and, often, to inflamed skin areas. An additional advantage of this invention is that the appearance and consistency of the final composition can be easily adjusted by changing the proportion of thickener (carbomer) in the composition.

 The emulsion gels and lotions of this invention can be prepared by a process comprising dissolving a compound of formula I in the form of a free base or in the form of an acid salt and corresponding additional excipients, for example, in a suitable oily phase such as isopropyl myristate.

 The oily phase can be emulsified with the corresponding aqueous phase, and then introduced into a pre-prepared gel concentrate containing carbomer and additional appropriate fillers. In this manufacturing mode, the interaction of the compounds of formula I and carbomer is avoided during the process. Advantageously, the carbomer is neutralized before mixing with the aqueous phase.

The compositions may contain additional ingredients, for example:
complex agents, for example ethylene diamine tetraacetate (disodium salt);
flavorings;
pigments.

 The compositions of this invention may also contain conventional additives for adjusting the pH to an acceptable value for treating the skin. This can be done by adding a pharmaceutically tolerable base or acid to the composition and adjusting the pH or by adding a pharmaceutically tolerable buffer system to the composition. In addition, the composition may contain preservatives and / or antioxidants, for example, in an amount whose weight is 0.5-1% of the weight of the entire composition. These can be, for example, ascorbyl palmitate, sodium pyrosulfite, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), tocopherols, for example α-tocopherol (vitamin E), benzyl alcohol, propyl or methyl p-hydroxybenzoates.

The compositions of this invention are applicable for the same indications as other topical compositions, for example, for mycoses, and in the same doses, for example, in those doses that are confirmed by standard clinical trials. Typical effective doses are achieved when the concentration of the active agent on the tissues of the treated skin is in the range of 10-10000 ng / cm ² . Preferred concentrations on skin tissues are in the range of 500-2000 ng / cm ² , for example 1000 ng / cm ² , as prescribed by standard pharmacological tests. However, in standard tests, both higher and lower effective doses can be detected. For example, effective concentrations of the drug on the tissues of the treated skin can be achieved when, for example, a compound of formula I is applied to the infected skin area in the form of, for example, a one percent composition of the present invention at a dosage of, for example, 5 mg of active agent per day on a skin area about 100 cm ² .

 In the following examples, all temperatures are in degrees Celsius (r.t. room temperature).

Example 1. A topical solution of 1% (sprayable 1% solution)
Ingredient Amount (g / 100g)
The compound of formula I in the form of hydrochloride 1.0
Polyethoxy-20-cetylstearyl ether (eg "Cetomacrogol 1000") 2.0
Propylene glycol 5.0
94% ethanol in a weight ratio of 25.0
Demineralized water 67.0
Example 2. Gel 1%
Ingredient Amount (g / 100g)
The compound of formula I in the form of hydrochloride 1.0
Disodium dihydrate dihydrate (eg "Komplexon III") 0.02
Polysorbate 20 (for example, "Tween 20") 2.0
Sodium pyrosulfate 0.02
Propylene glycol 0.70
Hydroxypropyl cellulose (eg "Klucel HF") 1.50
94% ethanol in a weight ratio of 35.0
Demineralized water 59.76
Example 3. Liquid gel 1%
Ingredient Amount (g / 100g)
The compound of formula I in the form of hydrochloride 1.00
Disodium dihydrate dihydrate (eg "Komplexon III") 0.02
Sodium pyrosulfate 0.02
Polyethoxy 40 Hydrogenated Castor Oil (eg Cremophor PH 40) 1.00
Hydroxypropyl cellulose (eg "Klucel CF") 2.00
94% ethanol in a weight ratio of 35.0
Demineralized water 70.96
Example 4. Emulsion gel 1%
Ingredient Amount (g / 100g)
A) The compound of formula I in the form of a free base of 1.00
C) Butylhydroxytoluene 0.02
I) Sodium hydroxide tablets 0.10
D) Benzyl alcohol 1.00
G) Carbomer 934 (e.g. "Carbopol 934 P") 1.00
E) Sorbitan monolaurate (e.g. "Span 20") 1.00
F) Polysorbate 20 (e.g. "Tween 20") 1.00
H) 94% ethanol in a weight ratio of 10.00
B) Isopropyl myristate 10.00
Demineralized water 70.88
From the above ingredients, a pharmaceutically tolerable emulsion gel is obtained, the method for its preparation is as follows.

 I. A, B, C, D, E and F are mixed, slightly warmed up until all solid particles are dissolved.

II. In an appropriate container or device equipped with a stirrer and homogenizer, approximately half the dose of water is heated to 60-70 ^o C.

 III. The substance obtained as a result of stage I is slowly added to the water heated in stage II, stirring and homogenizing until a homogeneous emulsion with an appropriate droplet size is obtained; concentrated emulsion is cooled to rt

 IV. In a separate container, a basic carbomer gel is prepared by dispersing the carbomer in H and the second half of water, and then neutralizing with I.

 V. The base emulsion obtained by performing step III is added to the base gel, and then the whole composition is mixed at rt. until a homogeneous emulsion gel is obtained.

Example 5. Emulsion gel one percent
Ingredient Amount (g / 100g)
A) The compound of formula I in the form of a free base of 1.00
C) Butylhydroxytoluene 0.02
I) Sodium hydroxide tablets 0.10
D) Benzyl alcohol 0.50
G) Carbomer 934 (e.g. "Carbopol 934 P") 1.00
E) Sorbitan monolaurate (e.g. "Span 20") 1.00
F) Polysorbate 20 (e.g. "Tween 20") 5.00
H) 94% ethanol in a weight ratio of 10.00
B) Isopropyl myristate 10.00
Demineralized water 71.33
From the above ingredients, a pharmaceutically tolerable emulsion gel is obtained, the method for its preparation is as follows.

 I. A, B, C, D, E and F are mixed, slightly warmed up until all solid particles are dissolved.

II. In an appropriate container or device equipped with a stirrer and homogenizer, approximately half the dose of water is heated to 60-70 ^o C.

 III. The substance obtained as a result of stage I is slowly added to the water heated in stage II, stirring and homogenizing until a homogeneous emulsion with an appropriate droplet size is obtained; concentrated emulsion is cooled to rt

 IV. In a separate container, a basic carbomer gel is prepared by dispersing the carbomer in H and the second half of water, and then neutralizing with I.

 V. The base emulsion obtained by performing step III is added to the base gel, and then the whole composition is mixed at rt. until a finished emulsion gel is obtained.

Example 6. Lotion one percent
Ingredient Amount (g / 100g)
A) The compound of formula I in the form of a free base of 1.00
C) Propyl p-hydroxybenzoate 0.03
D) Methyl p-hydroxybenzoate 0.10
G) a 25% solution of ammonia in a weight ratio of 0.36
F) Carbomer (e.g. "Carbopol 1342") 0.60
B) Isopropyl myristate 5.00
H) 94% ethanol in a weight ratio of 10.00
E) Demineralized water 82.91
A pharmaceutically tolerable lotion is obtained from the above ingredients as follows:
I. A is dissolved in B at rt

II. In a suitable device equipped with a stirrer and homogenizer, C and D are dissolved in E while heating to 90 ^° C; then the solution is cooled to a temperature of the order of 30-40 ^o C.

 III. F is dispersed in the solution obtained after performing stage II; the homogeneously dispersed composition is then neutralized with G, and the result is an opalescent thickened solution.

 IV. The organic solution obtained after performing stage I is then emulsified into the thickened solution obtained after performing stage III, mixing and homogenizing until the lotion has a drop of the corresponding size of 2-20 μm.

 V. And finally, in the substance obtained after performing stage IV, add H and mix until then, until you get the final product.

Claims (6)

1. Antimycotic pharmaceutical composition containing as an active principle terbinafine of the formula I

in the form of an acid addition salt or free base, a carrier and target additives, characterized in that it contains water, a lower alcohol and a nonionic surfactant as target additives in a weight ratio of compound I and surfactant of 1 0.5 15 and the following content of components, wt. Compound I 0.1 5.0
Water 50 85
Lower alcohol 5 35
Media Else
2. The composition according to claim 1, characterized in that as the lower alcohol it contains ethanol.  3. The composition according to paragraphs. 1 and 2, characterized in that as a surface-active agent it contains polyoxyethylene ether of fatty alcohols.  4. The composition according to PP.1 to 3, characterized in that it is a liquid single-phase system.  5. The composition according to claim 4, characterized in that it is the basis for the aerosol system, gel, liquid gel or lotion.  6. An antimycotic pharmaceutical composition containing, as an active principle, terbinafine of the formula I according to claim 1 in the form of an acid addition salt or a free base and target additives, characterized in that it contains water, a lower alcohol and a surface-active agent as target additives and is an emulsion for topical application, in which the oil phase contains compound I, and the aqueous phase contains 50 to 85 wt. water, 5 35 wt. lower alcohol and the rest of the surfactant, and the mass ratio of compound I surfactant is 1 0.5 15 and the mass ratio of compound I oil phase is 1 5 40.  7. The composition according to claim 6, characterized in that it contains isopropyl myristate as the oil phase.