RU2190394C1 - Pharmaceutical composition possessing antimycotic activity and method of its production - Google Patents

Abstract

FIELD: medicine, particularly, production of soft medicinal form designed for treatment of various mycoses of skin. SUBSTANCE: pharmaceutical composition contains terbinaphine hydrochloride, base, conserving agent, antioxidant, emulsifier, lipophil component and solvent, and may additionally include keratolytic at preset content of components. The invention also describes the method of producing pharmaceutical composition possessing antimycotic activity. EFFECT: increased antibacterial and antiinframmatory properties. 13 cl, 1 dwg, 1 tbl, 5 ex

Description

 The invention relates to medicine and can be used to obtain a soft dosage form intended for the treatment of various skin mycoses.

 Known drugs of the azole series, for example, ketoconazole, for the treatment of mycotic infections of the skin (RF Patent 2126256, CL A 61 K 31/57, publ. 1999.02.20). Ketoconazole is an antifungal imidazole drug with a wide range of effects against fungi and yeast, such as Candila spp. , Blastomyces dermatitidis, Coccidioides immitis, Criptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, Malassezia furfur, Aspergillus spp. , Sporothirix schekii, however, it is not effective against dermatophytes.

 Highly effective antifungal drugs with a wide spectrum of action are compositions containing terbinafine as a pharmacologically active agent (RF Patent 2093152, CL A 61 K 31/135, publ. 1997.10.20).

In Russia, several dosage forms of terbinafine hydrochloride for external use are registered:
- Lamisil (Lamisil) - cream 1% (tube 15 g) Novartis Pharma, Switzerland;
- Exifine (Exifine) - cream 1% (tube 10 g) Dr. Reddy's Laboratories, India;
- Lamisil (Lamisil) - solution for external use 1%, bottle of 30 ml, Novartis Pharma, Switzerland;
- Lamisil (Lamisil) - spray for external use 1%, a bottle with a spray of 30 ml, Novartis Pharma, Switzerland.

 The closest to the claimed technical essence and the achieved result, selected as a prototype, is Lamisil cream 1% firm Novartis Pharma, Switzerland (VIDAL Handbook, Medicinal Products in Russia, M., AstraFarmService, 2001, p. B-305) .

 The cream contains terbinafine hydrochloride 1%, benzyl alcohol, isopropyl myristate, sorbitan monostearate, sodium hydroxide, polysorbate 60, stearyl alcohol, cetyl alcohol, cetyl palmitate, demineralized water.

 A disadvantage of the known cream is its insufficient antibacterial and anti-inflammatory properties, which makes the cream ineffective in complicated forms of mycoses.

 Information on the method for producing Lamisil cream is not available in the literature.

 The problem solved by the invention is the preparation of a pharmaceutical composition having, in addition to high antifungal activity, antibacterial and anti-inflammatory properties.

 The technical result from the use of the invention is to increase the antibacterial and anti-inflammatory properties of the drug.

This result is achieved in that the pharmaceutical composition having antifungal activity, containing terbinafine hydrochloride, a base, a preservative, an antioxidant, an emulsifier, a lipophilic component and a solvent, additionally contains keratolytic in the following components, wt.%:
Terbinafine hydrochloride - 0.9-1.1
Base - 48.0-67.0
Preservative - 0.1-0.8
Antioxidant - 0.05-0.12
Emulsifier - 2.5-11.0
Lipophilic component - 5.0-15.0
Keratolytic - 0.3-0.7
Solvent - Other
As a base, the pharmaceutical composition may contain polyethylene oxide 400 and polyethylene oxide 1500, sodium benzoate as a preservative, dibunol as an antioxidant, distilled monoglyceride and emulsifier 1 as an emulsifier, olive oil as a lipophilic component, propylene glycol as a solvent, urea as a keratolytic.

 The indicated result is also achieved by the fact that the method of obtaining a pharmaceutical composition having antifungal activity consists in mixing the base with a preservative and emulsifiers, adding a lipophilic component and a previously prepared solution of terbinafine hydrochloride in a solvent with the addition of an antioxidant and keratolytic, emulsifying the cream, cooling and mature for ripening.

Mixing the base with a preservative of sodium benzoate and emulsifiers is carried out at a temperature of 60-80 ^o C, emulsification of the cream - 28-55 ^o C. Cool the cream to 28-35 ^o C.

A solution of terbinafine hydrochloride in a propylene glycol solvent is prepared at a temperature of 40-55 ^o C.

The active substance in the proposed pharmaceutical composition is terbinafine hydrochloride (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethanamine hydrochloride of the general formula C ₂₁ H ₂₅ N • HCl m. m 327.90 - a highly effective antifungal drug, belongs to the group of allylamines.

 Terbinafine acts by suppressing squalene epoxidase in the cell membrane of the fungus. This leads to a deficiency of ergosterol and intracellular accumulation of squalene, which causes the death of the pathogen cell.

 It has a fungicidal effect on dermatophytes, mold and some dimorphic fungi, yeast and yeast-like fungi. It can act fungistatically on some types of yeast. It is active against pathogens of dermatomycosis (Trichophyton, including T. rubrum, T. mentagrophytes, T. tonsurans, T. verrucosum, T. violaceum; as well as Microsporum canis and Epidermophyton floccosum); Candida yeast-like fungi (mainly Candida albicans); Pityrosporum orbiculare (Malassezia furfur) - the causative agent of colorful lichen.

As the active substance in the proposed pharmaceutical composition can be used, for example, terbinafine hydrochloride company TRANS-MEDICA, series TB0040999, HAMBURG, which meets the requirements of the regulatory documentation of the company, as a lipophilic component - olive oil, for example, according to VFS 42-1776-92; propylene glycol as a solvent, for example, according to VFS 42-1594-86 or TU 6-09-2434-81; as emulsifier - emulsifier 1 - fused mixture of alcohols of synthetic primary higher fractions C ₁₆ -C ₂₀ with sodium salts of sulfoesters of the same alcohols, for example, according to FS 42-3821-99, and distilled monoglyceride, for example, according to TU 10-04-1197 -95; as a base, polyethylene oxide 400 (polyethylene glycol 400, polyoxyethylene 400), for example, according to FS 42-1242-96 and polyethylene oxide 1500 (polyethylene glycol 1500), for example, according to FS 42-1885-96.

 To stabilize the active substance and to prevent redox processes, the antioxidant dibunol (butylhydroxytoluene) was used, for example, according to FS 42-3460-97. To preserve the composition and optimize the pH, sodium benzoate is used, for example, according to FS 42-2458-94.

 As a keratolytic and clathrate former, urea is used in the composition, for example, according to GOST 6691-77.

 The components included in the composition can also be used in imported production authorized in the Russian Federation.

 The proposed pharmaceutical composition contains the following ratio of components, wt. %: terbinafine hydrochloride - 0.9-1.1, preferably 1.0; dibunol - 0.05-0.12, preferably 0.1; urea - 0.3-0.7, preferably 0.5; olive oil - 5.0-15.0, more preferably 10.0; distilled monoglyceride 0.5-3.0, more preferably 1.5; sodium benzoate 0.1-0.8, preferably 0.5; polyethylene oxide 1500 28.0-37.0, more preferably 33.0; polyethylene oxide 400 20.0-30.0, more preferably 25.0; emulsifier 1 2.0-8.0, preferably 5.0, propylene glycol - the rest.

 The proposed ratio of active substance and target additives is optimal, found experimentally and provides the necessary quality of the drug and its therapeutic effect.

 A decrease in the amount of terbinafine hydrochloride below 0.9 wt.%, And the amount of urea below 0.3 wt.% Reduces the effectiveness of the drug. An increase in the amount of terbinafine hydrochloride over 1.1 wt.% Is impractical because it is determined by the therapeutic dose.

 An increase in the amount of urea over 0.7 wt.% Affects the quality of the cream, as it can cause skin irritation. An increase in the amount of dibunol more than 0.12 wt.% Is technologically impractical, and a decrease in its amount is less than 0.05 wt. % reduces the quality of the drug. An increase in the amount of olive oil more than 15.0 wt.% Reduces the quality of the cream during storage, and a decrease in its amount less than 5.0 wt.% Affects the quality of the drug by reducing absorption.

 An increase in the amount of distilled monoglyceride of more than 3.0 wt.%, As well as a decrease of less than 0.5 wt.%, Is technologically impractical. An increase in the amount of sodium benzoate more than 0.8 wt.% Can cause an intolerance reaction, and a decrease of less than 0.1 wt.% Affects the quality of the drug during storage as a result of microbial contamination.

 An increase in the amount of polyethylene oxide 400 more than 30.0 wt.% Affects the quality of the cream during storage, and a decrease of less than 20.0 wt.% Affects the technological properties of the cream. The increase in the number of polyethylene oxide 1500 more than 37.0 wt. % is technologically impractical and reduces the elasticity of the cream, and a decrease in its amount less than 28.0 wt.% affects the quality of the drug during storage.

 An increase in the amount of emulsifier 1 of more than 8.0 wt.% Is not technologically feasible, and a decrease of less than 2.0 wt.% Affects the quality of the cream during storage. Propylene glycol in the proposed composition is a solvent and it is introduced in an amount of up to 100 wt.%.

 As a lipophilic component, castor, corn, soy and stone seed oils, a preservative - nipagin, nipazole, germal 115, dovicil, lauricidin and their various combinations can be used as an antioxidant α-tocopherol acetate.

 The pharmaceutical composition of the invention is prepared as follows.

First, the following components are mixed in a certain sequence: polyethylene oxide 400 is mixed with an aqueous solution of sodium benzoate, distilled monoglyceride is added, followed by emulsifier 1 and polyethylene oxide 1500. The mixture is stirred at a temperature of 60-80 ^o C until the components are completely melted, cooled to a temperature of 45-55 ^o C and add olive oil to obtain an emulsion. The process of preparation of the emulsion is carried out with constant stirring and a temperature of 28-55 ^o C.

A solution of terbinafine hydrochloride is prepared by adding dibunol to propylene glycol at a temperature of 45-60 ^o C. Urea and terbinafine hydrochloride are added to the solution at a temperature of 40-55 ^o C.

A solution of terbinafine hydrochloride is added to the emulsion and the cream is emulsified at a temperature of 28-55 ^o C. The emulsification time depends on the volume of downloads. Cool the resulting cream to a temperature of 28-35 ^o C, determined by the requirements of the process, for example, 15-20 minutes. Ready cream is aged for ripening 20-24 hours.

 The resulting cream is a soft consistency of white or white with a yellowish tint, with a weak specific odor, pH from 3.5 to 5.5.

 Impurities are allowed in the preparation, each of which should not exceed 0.5%. The total content of all impurities, determined by high performance liquid chromatography (HPLC), is not more than 2%.

 Example 1

30.0 kg of polyethylene oxide 400 and a pre-prepared aqueous solution of 0.5 kg of sodium benzoate in 2.0 kg of purified water are loaded into a cream preparation reactor. An anchor mixer is turned on at a speed of 50-60 rpm. Stir until a homogeneous solution. Turn on the heating and heat the mixture in the reactor to 60-65 ^o C. In the reactor load 0.5 kg of monoglyceride distilled in small portions with the stirrer, and then 2.0 kg of emulsifier 1 also in small portions and with the stirrer. Stirred for 10-15 minutes and add 37.0 kg of polyethylene oxide 1500 also in small portions with the stirrer working. Mix the mixture at 75-80 ^o C until the components are completely fused. The completeness of fusion of the components is checked visually by taking a sample with a sampler. 16.52 kg of propylene glycol are loaded into another reactor to prepare a solution of terbinafine hydrochloride in propylene glycol, include heating and an anchor stirrer at a speed of 50-60 rpm. The contents of the reactor are heated to a temperature of 55-60 ^o C. Add to the reactor 0.08 kg of dibunol and mix until a homogeneous solution. By starting cold water into the jacket of the reactor, cool the solution to a temperature of 50-55 ^o C. Load 0.5 kg of urea and 0.9 kg of terbinafine hydrochloride powder into the reactor and mix until a homogeneous mass is obtained.

The mixers are turned on and 10.0 kg of olive oil is added. Emulsify the mixture for 10 minutes. Continuing mixing, load the solution of terbinafine hydrochloride in the cream reactor. Emulsify the cream at a temperature of 50-55 ^o C for 30 minutes. Turn on the pump for circulation and cool the reactor by starting cold water into the jacket of the reactor. Cool the cream to a temperature of 30-35 ^o C for 15 minutes. The pump is turned off from circulation, the mixers are turned off, and the finished cream is pumped into a mobile collector for storing cream and kept for 24 hours to mature.

 Get 100 kg of cream that meets the requirements of a pharmaceutical agent.

 Example 2

 Analogously to example 1, but with the following amounts of components: polyethylene oxide 400 30.0 kg; a solution of 0.1 kg of sodium benzoate in 2.0 kg of water; 3.0 kg distilled monoglyceride; 28.0 kg of polyethylene oxide 1500; 8.0 kg of emulsifier 1; 16.55 kg of propylene glycol; 0.05 kg of dibunol; 0.3 kg of urea; 1.0 kg terbinafine hydrochloride; 11.0 kg of olive oil.

A solution of terbinafine hydrochloride in propylene glycol is prepared at a temperature of 40-45 ^o C, mixing the base with an emulsifier at a temperature of 60-65 ^o C, emulsifying the cream at a temperature of 45-50 ^o C, and its cooling at a temperature of 28-30 ^o C. Get 100 kg of cream that meets the requirements of ND per pharmaceutical agent.

 Example 3

Differs from example 1 in the sequence of loading the ingredients. In the reactor for the preparation of the solution, 2 kg of water, 0.8 kg of sodium benzoate, 20.0 kg of polyethylene oxide 400 are loaded, stirring and heating of the reactor are reached until the temperature reaches 60-65 ^o C. After dissolving the powder, 8.0 kg of emulsifier 1, 2 are loaded , 0 kg of distilled monoglyceride, 28.0 kg of polyethylene oxide 1500. Further preparation of the cream is similar to example 1, but with the following amounts of the remaining components: terbinafine hydrochloride 1.1 kg, urea 0.7 kg, propylene glycol 22.28 kg, dibunol 0.12 kg, olive oil 15.0 kg. Emulsification of the cream is carried out at a temperature of 50-55 ^o C, a solution of terbinafine hydrochloride is prepared at a temperature of 50-55 ^o C, the cream is cooled to 28-30 ^o C. Receive 100 kg of cream that meets the requirements of ND on a pharmaceutical agent.

 Example 4

A feature of the technology is that the preparation of a solution of terbinafine hydrochloride is carried out at a temperature of 45-50 ^o With the addition of 26.4 kg of propylene glycol, 0.5 kg of urea, 0.1 kg of dibunol and 1.0 kg of terbinafine hydrochloride. Otherwise, the technology is similar to example 1, but with the following amounts of the remaining components: polyethylene oxide 400–25.0 kg, water 2.0 kg, sodium benzoate 0.5 kg, distilled monoglyceride 1.5 kg, polyethylene oxide 1500–33, 0 kg, emulsifier 1 - 5.0 kg, olive oil - 5.0 kg. Mixing the base with sodium benzoate and emulsifiers is carried out at a temperature of 65-70 ^o C, emulsification of the cream at 50-55 ^o C. The cream is cooled to a temperature of 30-35 ^o C. Receive 100 kg of cream that meets the requirements of ND for pharmaceutical substance.

 Example 5

 A feature of the technology lies in the temperature conditions at the stage of emulsification. The cream is prepared with the following ratios of components: terbinafine hydrochloride - 1.0 kg, polyethylene oxide 1500 - 33.0 kg, polyethylene oxide 400 - 25.0 kg, distilled monoglyceride - 1.5 kg, emulsifier 1 - 5.0 kg, olive oil - 5.0 kg, sodium benzoate - 0.5 kg, urea - 0.5 kg, dibunol - 0.1 kg, purified water - 2.0 kg, propylene glycol - 26.4 kg.

A preservative solution (from 0.5 kg of sodium benzoate and 2.0 kg of water) is mixed with 25.0 kg of polyethylene oxide 400 and heated to a temperature of 65-70 ^o C. In the solution, with stirring, load 1.5 kg of distilled monoglyceride; 5.0 kg of emulsifier 1 and 33.0 kg of polyethylene oxide 1500.

The fusion of the base with emulsifiers is carried out at a temperature of 65-70 ^o C. The completeness of fusion of the components is checked visually.

The preparation of terbinafine hydrochloride solution is carried out in stages. First, at a temperature of 55-60 ^o With stirring, in 26.4 kg of propylene glycol, 0.1 kg of dibunol is dissolved. After complete dissolution of the dibunol, the solution is cooled to a temperature of 45-50 ^o C, enter 0.5 kg of urea and 1.0 kg of terbinafine hydrochloride. Stirring is continued until a clear solution is obtained.

The preparation of the emulsion is carried out at a temperature of 40-50 ^o C and stirring with an anchor mixer, by sequentially introducing 5.0 kg of olive oil and a solution of terbinafine hydrochloride in propylene glycol into the base. The emulsion is stirred for 10-15 minutes, after which it is cooled to a temperature of 28-33 ^o C. Further emulsification is carried out using an Ultra-Turrax type mixer (or RPA-2800 or GART-220-Sh-5) while cooling. Ready cream is aged for maturing no more than a day. Get 100 kg of cream that meets the requirements of ND on a pharmaceutical agent.

Mixing the base of the cream with sodium benzoate and emulsifiers is carried out at a temperature of 60-80 ^o C, preferably 60-65 ^o C, since at a temperature below 60 ^o C the fusion process slows down, and a temperature increase of more than 80 ^o C can lead to the destruction of incoming components and economically impractical.

The preparation of terbinafine hydrochloride solution is carried out at a temperature of 40-55 ^o C, preferably 45-50 ^o C, since a decrease in temperature below 40 ^o C increases the solubility time of dibunol, and an increase of more than 55 ^o C does not exclude the destruction of the active substance.

Emulsification of the cream is carried out at a temperature of 28-55 ^o C, preferably 50 ^o C, since at a temperature below 28 ^o C is the thickening of the base, and at temperatures above 55 ^o C may negatively affect terbinafine hydrochloride.

 Biological tests were performed on a model of candidiasis in mice.

In the experiments, nonlinear mice weighing 20–25 g were used. The model of cutaneous candidiasis in mice was reproduced in accordance with the recommendations given by Harley, Ray, and Wildfener [1, 2, 3]. For infection, a 3-day-old Candida albicans culture grown on Saburo solid medium was used. To increase sensitivity to Candida albicans, mice were previously (3 days prior to infection) once administered s.c. hydrocortisone at a dose of 5 mg / kg and alloxan at a dose of 200 mg / kg, as well as a pre-clipped skin area with a 0.5% solution hydrocortisone acetate and 0.25% neomycin solution (starting 3 days before infection and within 2 days after infection). In preliminary experiments, the infectious dose of Candida albicans, 10 ¹¹ microbial bodies / mouse, was determined, which was injected subcutaneously into mice in a volume of 50 μl in a pre-prepared area. Treatment with 1% creams of the proposed composition and Lamisil began on the third day after infection. The ointment was applied in a thin layer on the affected area of the skin and around it once a day until the signs of inflammation disappeared. The degree of damage (SP) was evaluated by a 3-point system, based on the following criteria:
1 point - hyperemia, edema <5 mm;
2 points - hyperemia, edema> 5 mm;
3 points - edema> 5 mm, ulceration.

На основе этих результатов рассчитывали в группах среднее время (от начала лечения) полного излечения (снижение индекса СП до 20% от начального) и среднее время снижения индекса СП на 50% (скорость выздоровления). Результаты представлены в таблице.The drawing shows graphs of changes in the degree of damage (SP) in different groups of mice during treatment with 1% Lamisil creams and the proposed composition,

Based on these results, the average time (from the start of treatment) of the total cure (decrease in the SP index to 20% of the initial) and the average time for the decrease in the SP index by 50% (rate of recovery) were calculated in the groups. The results are presented in the table.

 As can be seen from the table, the time to decrease the SP index by 50% in the group of mice treated with the cream of the proposed composition was 5.5 days compared to 8.10 days in the control. The rate of recovery in groups of animals treated with the cream of the proposed composition and Lamisil did not differ significantly and were significantly higher than in the group of control animals. The total cure time for animals with drugs of the proposed composition and Lamisil was 7.43 and 7.22 days, respectively, which was significantly lower compared to 9.75 days in control mice.

 The results obtained indicate that the proposed pharmaceutical composition has a pronounced antifungal activity. According to the severity of the effect, the proposed composition is not inferior to the comparison product 1% cream Lamisil ("Sandoz", Switzerland).

The drug in the form of a cream for external use is recommended for the following fungal diseases:
- fungal infections of the skin caused by dermatophytes (dermatophytosis);
- yeast infections of the skin, mainly candidiasis;
- multi-colored (pityriasis) lichen, and in this case only local application is effective;
- mycoses of the hands and feet with skin lesions and / or onychomycosis of single nails from the distal or lateral edges;
- as a supplement to therapy with systemic oral antimycotics or with contraindications to their use.

 When applied topically, less than 5% of the dose is absorbed, so the systemic effect of the drug is very slight.

 The drug is lipophilen, it is characterized by keratinotropy, with external use it, in connection with this, has a speed of action.

 In addition to antifungal activity, the drug also has antibacterial and anti-inflammatory properties, which allows its use in complicated forms of mycoses.

Literature
1. Harley R. Effect route of entry of Candida albicans on the histogenesis of the lession in experimental candidosis in the mouse. -J.Pathol. Bacteriol., 1966, v. 92, p. 578-583.

 2. Ray T.L. Animal models of experimental Candida infection of the skin. In: Model in Dermatology, v. 1, p. 41-45, Karger, Basel, 1985.

 3. Wildfener A. Der Einflusse von Neomicin und Hydrocortizone auf die experimentelle Kutane Candidamykose des Kaninchens.- Mykosen, 1972, v.15, p. 193-197.

Claims (12)

1. A pharmaceutical composition having antifungal activity, containing terbinafine hydrochloride, a base, a preservative, an antioxidant, an emulsifier, a lipophilic component and a solvent, characterized in that it additionally contains keratolytic in the following ratio, wt.%:
Terbinafine hydrochloride - 0.9-1.1
Base - 48.0-67.0
Preservative - 0.1-0.8
Antioxidant - 0.05-0.12
Emulsifier - 2.5-11.0
Lipophilic component - 5.0-15.0
Keratolik - 0.3-0.7
Solvent - Other
2. The pharmaceutical composition according to claim 1, characterized in that it contains urea as a keratolytic.  3. The pharmaceutical composition according to claims 1 and 2, characterized in that it contains polyethylene oxide 400 and polyethylene oxide 1500 as a base.  4. The pharmaceutical composition according to claims 1 to 3, characterized in that it contains sodium benzoate as a preservative.  5. The pharmaceutical composition according to claims 1 to 4, characterized in that it contains dibunol as an antioxidant.  6. The pharmaceutical composition according to claims 1-5, characterized in that as an emulsifier it contains distilled monogoglyceride and emulsifier 1.  7. The pharmaceutical composition according to claims 1-6, characterized in that it contains olive oil as a lipophilic component.  8. The pharmaceutical composition according to claims 1 to 7, characterized in that it contains propylene glycol as a solvent.  9. The method of obtaining the pharmaceutical composition according to claims 1-8, which consists in mixing the base with a preservative and emulsifiers, adding a lipophilic component and a pre-prepared solution of terbinafine hydrochloride in a solvent with the addition of an antioxidant and keratolytic, emulsify the cream, cool and stand for ripening . 10. The method according to claim 9, characterized in that the solution of trebinafine hydrochloride in propylene glycol is prepared at 40-55 ^o C. 11. The method according to PP.9 and 10, characterized in that the mixing of the base with sodium benzoate and emulsifiers is carried out at 60-80 ^o C. 12. The method according to PP.9-11, characterized in that the preparation of the emulsion and emulsification of the cream is carried out at 28-55 ^o C. 13. The method according to PP.9-12, characterized in that the cream is cooled to 28-33 ^o C.

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