RU2314800C2 - Agent possessing antifungal effect and method for its preparing - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents, in particular, to a drug showing antifungal effect prepared as ointment formulation and based on terbinafine hydrochloride. Invention proposes agent possessing antifungal effect and comprising terbinafine hydrochloride, rare-cross-linked polyacrylic acid, nipagin, Tween-80, vaselin oil, propylene glycol, sodium hydroxide and purified water wherein these components are taken in the definite ratio. Also, invention relates to a method for preparing this antifungal agent. Invention provides the high therapeutic effect of agent, increasing storage time, high stability against oxidation, high tropicity to skin and low cost.

EFFECT: improved and valuable medicinal and pharmaceutical properties of agent.

5 cl, 14 tbl, 3 ex

Description

The invention relates to the field of pharmaceutical chemistry and relates to the production of an antifungal drug in the form of terbinafine ointment.

Modern medicine has a wide range of antifungal drugs manufactured by the industry in various dosage forms. An example is the antibiotic griseofulvin in the form of tablets and liniment, the synthetic preparation clotrimazole in the form of ointments and creams, preparations of various chemical groups: ointment dekamin, ointment zincundane, ointment undecine, ointment mycoseptin, powder quinofungin, solution for external use nitrofungin and others. However, many antifungal drugs, possessing a wide fungicidal spectrum of action, proved to be insufficiently effective against dermatophytes, which are often the causative agent of mycotic infections of the skin (MD Mashkovsky "Medicines", Kharkov, "Torsing", 1997, v.2, p. 381-390).

In recent decades, antifungal agents based on derivatives of N-methylnaphthalene, in particular terbinafine (lamisil), have been actively developed. The drug is known in different dosage forms for oral (ovale) and external (ointment, cream) use. It has a wide spectrum of antifungal activity, exerting a fungicidal effect, including on dermatophytes, mold fungi, and some dimorphic fungi. It is known that with topical application (in the form of an ointment or cream) terbinafine preparations are slightly absorbed and have a slight systemic effect. When administered orally in the form of tablets, absorption occurs quickly and intensively, providing a stable systemic effect, however, in this case, it must be borne in mind that terbinafine has a number of side effects and contraindications; in particular, terbinafine is not recommended during pregnancy and lactation, as well as children; in elderly patients, there may be impaired liver and kidney function (M.D. Mashkovsky, ibid.).

Known antifungal composition for external use on the basis of terbinafine described in Patent RU 2093152 _C1, publ. 1997 year

Imported antifungal creams based on imported terbinafine are registered in the Russian Federation:

- Lamisil (Lamisil) - 1%, the company Novartis Pharma, Switzerland;

- Exiflne (Exiflne) - 1%, Dr. Reddy's Laboratories, India.

An antifungal cream containing terbinafine hydrochloride, benzyl alcohol, nipagin, stearic acid, polysorbate, cetyl alcohol, liquid paraffin, sodium hydroxide, glycerin and water with a certain content of components is known from domestic preparations (patent RU 2207124, 2002).

The closest in technical essence is an antifungal agent for external use, containing terbinafine hydrochloride, sodium benzoate, propylene glycol, polyethylene oxide 1500 and 400, distilled monoglyceride, emulsifier No. 1, olive oil, dibunol, urea and purified water at a certain content of components (patent RU 2190394 , 2001).

The objective of the present invention is to provide a domestic product based on terbinafine in the form of an ointment with good adsorption, fast absorption, high oxidation stability, long shelf life, and high therapeutic effect.

The technical result obtained by using the invention is expressed in a high therapeutic effect, increased shelf life, high oxidation stability, high tropism to the skin, low cost.

The problem is solved in that an ointment based on terbinafine is proposed, containing terbinafine in the form of a hydrochloride, a rare crosslinked polyacrylic acid, Tween-80, liquid paraffin, sodium hydroxide, nipagin, propylene glycol and purified water with the following ingredients, wt.%:

terbinafine hydrochloride 0.9-1.1 rare crosslinked polyacrylic acid 1.0-2.0 nipagin 0.05-0.15 twin 80 0.5-1.5 liquid paraffin 2.0-7.0 propylene glycol 5.0-15.0 sodium hydroxide 0.2-0.6 purified water rest

As a basis, the proposed tool contains a rare cross-linked polyacrylic acid, which also acts as a thickener, which gives the ointment optimal viscosity, improves structure formation. Gel ointment is easier to apply on the skin, does not interfere with gas and air exchange of the skin. The proposed agent contains nipagin as a preservative, tween-80 as an emulsifier and stabilizer, liquid paraffin as a lipophilic component, propylene glycol as a solvent, as well as sodium hydroxide as a pH regulator and a builder and water. Vaseline oil is resistant to oxidation, which makes the drug stable during storage and provides comfort when using the ointment by the consumer.

The indicated result is also achieved by the fact that the method for producing an antifungal agent consists in dissolving a preservative nipagin in a portion of the water, cooling the solution, adding rare cross-linked polyacrylic acid with stirring and allowing it to swell; hydroxide dissolved in a portion of water is introduced into the resulting suspension to form a gel and at the same time neutralize the mixture to pH = 4.8-5.3; then a pre-prepared solution of terbinafine hydrochloride in propylene glycol is added to the resulting mass with the addition of a mixture of paraffin oil, tween-80 and sodium hydroxide solution. The finished ointment is a homogeneous white emulsion with a pH = 4.0-6.0.

The preservative is dissolved in water at 50-60 ° C.

A solution of terbinafine hydrochloride in a propylene glycol solvent is prepared at t = 40-50 ° C, then a solution of sodium hydroxide is added to the mixture to transfer terbinafine hydrochloride to terbinafine base, since it is shown that the base penetrates the upper layers of the skin more easily.

The active substance of the proposed tool terbinafine hydrochloride belongs to the group of allylamines and is a highly effective antifungal agent. As the active substance in the claimed tool can be used, for example, terbinafine hydrochloride company "Chemo Iberica SA", Spain, ND 42-11219-00, corresponding to the requirements of the regulatory documentation of the Russian Federation, as a base - rare cross-linked polyacrylic acid, for example, MARS, Arespol, Karbopol, Zakap; MARS produces LLC NPP Rosma, Dzerzhinsk TU-6-02-221-96, ARESPOL produces AOZT Biofarmos TU 2219-005-29053342-97; as an emulsifier - tween-80 (polyoxyethylene-20-sorbitan monomate, for example, according to FS 42-2540-88).

To preserve the ointment, nipagin (4-hydroxybenzoic acid methyl ester) is used.

The lipophilic component is vaseline oil, for example, according to the TFC, p. 481.

Propylene glycol is used as a solvent, for example, according to the European Pharmacopoeia, 4.2002

Sodium hydroxide is used as a pH regulator and structurant, for example, according to GOST 4328-77, chemical grade

To dissolve the components of the product, purified water is used, for example, according to FS 42-2519-97.

The ingredients that make up the ointment can be both domestic production and imported, approved for use in the Russian Federation.

The claimed agent having an antifungal effect, contains the following ratio of components, wt.%: Terbinafine hydrochloride - 0.9-1.1, preferably 1.0; rare cross-linked polyacrylic acid - 1.0-2.0, preferably 1.5; tween-80 - 0.5-15, preferably 1.0; Vaseline oil - 2.0-7.0, more preferably 5.0; sodium hydroxide - 0.2-0.6, preferably 0.4; nipagin - 0.05-0.15, preferably 0.1; propylene glycol - 5.0-15.0, more preferably 10.0; purified water - the rest.

A decrease in the amount of terbinafine hydrochloride below 0.9 wt.% Reduces the effectiveness of the drug, and an increase in its content above 1.1 wt.% Is impractical, as it is determined by the therapeutic dose.

A decrease in the number of rare crosslinked polyacrylic acid below 1.0 wt.% Leads to a decrease in the viscosity of the ointment, and an increase in the content of rare crosslinked polyacrylic acid above 2.0 wt.% Is technologically impractical.

A decrease in the amount of nipagin below 0.05 wt.% Leads to a decrease in the quality of the drug during storage as a result of microbial contamination. An increase in nipagin content above 0.15 wt.% Can cause an allergic reaction.

A decrease in the amount of tween-80 below 0.5 wt.% Leads to a decrease in the stability of the ointment. An increase in the amount of tween-80 above 1.5 wt.% Is not technologically feasible.

An increase in the amount of Vaseline oil above 7.0 wt.% Reduces the resistance of the ointment to oxidation during storage.

The decrease in the content of Vaseline oil below 2.0 wt.% Does not provide the desired consistency of the ointment, worsens its technological properties.

An increase in the amount of propylene glycol above 15.0 wt.% Reduces the technological quality of the drug.

A decrease in the amount of propylene glycol below 5.0 wt.% Reduces the solubility of the active substance and reduces the absorption of the ointment.

A change in the sodium hydroxide content below 0.2 wt.% And above 0.6 wt.% Leads to a change in the optimal pH range of the ointment and reduces the therapeutic effect.

An antifungal agent according to the invention is prepared as follows.

First, nipagin is dissolved in the purified water, the process is carried out by heating with t = 50-65 ° C. Then the solution is cooled, rare-crosslinked polyacrylic acid is introduced into it with stirring, and the mixture is left to swell for 18-24 hours. Part of the sodium hydroxide is dissolved in part of the water and added to neutralize the swollen suspension to pH = 4.8-5.3. When swelling, the suspension turns into a gel. A solution of terbinafine hydrochloride in propylene glycol is prepared by heating to 40-50 ° C. A mixture of liquid paraffin and tween-80 is introduced into the solution with vigorous stirring to obtain an emulsion. The remainder of sodium hydroxide is introduced into the emulsion in the form of a 20% solution.

Then the resulting emulsion is mixed and the gel of the rare crosslinked polyacrylic acid, the ointment is left for ripening. The finished ointment is a homogeneous white emulsion, the pH of the ointment is from 4.0 to 6.0.

The shelf life of the ointment is 6 years.

The invention is illustrated by the following examples.

Example 1

The claimed tool has the following qualitative and quantitative composition, wt.%:

terbinafine hydrochloride 1,0

rare crosslinked polyacrylic acid 1,5 nipagin 0.10 twin 80 1,0 liquid paraffin 5,0 propylene glycol 10.0 sodium hydroxide 0.4 purified water rest

Example 2

70.0 kg of purified water is loaded into the reactor, heated to 50-65 ° C, 0.10 kg of nipagin are added, and the preservative is completely dissolved. Coolant is fed into the jacket, cooled to 40-45 ° С, a thickener - rare cross-linked polyacrylic acid is introduced, homogenized until a homogeneous suspension is formed, left for 18-24 hours to swell. 0.24 kg of sodium hydroxide is dissolved in 10 kg of water, the solution is loaded into the MARS slurry reactor, mixed and homogenized until a uniform gel forms; pH gel 4.8-5.3. In another reactor, 10 kg of propylene glycol are charged, the stirrer is turned on, and 1.0 kg of terbinafine hydrochloride is loaded, mixed until a uniform solution is formed. The dissolution temperature is 40-50 ° C. 0.16 kg of sodium hydroxide is dissolved in a separate container in 1.0 kg of purified water. The solution is introduced into the solution of terbinafine hydrochloride, stirred until a homogeneous emulsion is formed, 5.0 kg of vaseline oil are loaded and 1.0 kg of tween-80 are emulsified. Enter the emulsion of terbinafine into the gel, mix, homogenize until a uniform ointment is formed. pH 5.0-6.0. Get 100 kg of ointment that meets the requirements of a pharmaceutical agent.

Example 3

It differs from Example 2 in temperature conditions and the order of loading of components.

60.0 kg of purified water is charged into the reactor. 10 kg are heated to 50-65 ° C, 0.10 kg of nipagin is introduced, mixed until the preservative is completely dissolved. Download to the reactor. A thickener is introduced - a rare crosslinked polyacrylic acid, homogenized until a homogeneous suspension is formed. 0.24 kg of sodium hydroxide is dissolved in 10 kg of water, the solution is loaded into a reactor with a suspension of rare cross-linked polyacrylic acid, mixed and homogenized until a uniform gel is formed; the pH of the gel is 4.8-5.3. In another reactor, 10 kg of propylene glycol are loaded, the stirrer and heating are turned on, 1.0 kg of terbinafine hydrochloride is loaded, stirred until a uniform solution is formed. The dissolution temperature is 40-50 ° C. 0.16 kg of sodium hydroxide is dissolved in a separate container in 1.0 kg of purified water. The solution is introduced into the solution of terbinafine hydrochloride, stirred until a homogeneous emulsion is formed. 5.0 kg of vaseline oil and 1.0 kg of tween-80 are loaded into a separate container, mixed, loaded into a solution of terbinafine, emulsified. Enter the emulsion of terbinafine into the gel, mix, homogenize until a uniform ointment is formed. pH 5.0-6.0. Get 100 kg of ointment that meets the requirements of a pharmaceutical agent.

The proposed antifungal agent has passed biological tests.

The work was performed at the Institute of Toxicology of the Ministry of Health of the Russian Federation, St. Petersburg. The drug Lamisil, 1% Kerm, manufactured by Novartis Firm AG, Switzerland, registered in the Russian Ministry of Health, was used as a comparison drug. In this case, the volume before clinical trials was determined:

- "Guiding teaching materials on the experimental and clinical study of new drugs", parts 1, 3 (Official publication of the Pharmacological Committee. M., 1985);

- "Rules for the preclinical safety assessment of pharmacological agents (GLP)" (RD64-126-91. M., 1992);

- "Rules for preclinical studies of the safety and efficacy of pharmacological substances" (in the book "Manual on the experimental (preclinical) study of new pharmacological substances". M., Ministry of Health of the Russian Federation, "Remedium", 2000, pp. 7-17);

- "Guidelines for the study of the general toxic effects of pharmacological substances" (ibid., P. 18-24).

The toxicity parameters of the ointment were determined in an acute experiment under conditions of its intragastric administration (mouse and rat) and application to rats' scarified skin on the back. In a subacute experiment, the effect of ointment at doses of 500 and 2500 mg / kg was studied with application to regularly scarified skin on rats for 30 days.

In an acute experiment with dermal application of lethal effects, it was not possible to achieve. The results of the subacute experiment showed that in animals in general there was no development of pathological changes in the functions of the studied organs and systems, as well as dystrophic, destructive, focal sclerotic changes in parenchymal cells and stroma of the studied organs.

No local irritant effect was detected.

In terms of acute toxicity and in the effect on the physiological parameters of experimental animals under the conditions of a subacute experiment, the studied drug practically does not differ from the comparison drug and in this respect is bioequivalent to the latter.

The study of the allergenic properties of the ointment based on the reaction of general anaphylaxis, the reaction of immune complexes, the conjunctival test and the indirect mast cell degranulation reaction showed that the claimed agent does not have an allergenic effect.

The experiment identified:

- the effect on the motor and research activity of rats (tables 1 and 2);

- the effect on the duration of hexenal sleep (table 3);

- the effect on the functional state of the kidneys (table 4, 5 and 6);

- effect on cardiovascular activity (table 7 and 8);

- the effect on peripheral blood counts (table 9 and 10);

- the effect on the main biochemical parameters of peripheral blood (tables 11 and 12);

- the effect on the nature of the myelogram (tables 13 and 14).

Impact on motor and research activity.

Tables 1 and 2 present data on the effect of the claimed drug and the comparison drug on the spontaneous motor activity of rats (SDA). Rats were placed one at a time and the registration chamber of the automatic registrar "Coulburn Instruments", where for every 5 minutes for 35 minutes they recorded the number of movements.

AO data for all experimental groups show a general decrease in SDA by the end of the study (a typical phenomenon in conditions of re-placement of an animal in a measuring chamber). No differences between the groups are detected: the value of F ₀ = 0.11, which makes it possible to exclude the effect of the use of both drugs on the studied indicator.

Effect on the duration of hexenal sleep

The detoxifying function of the liver was evaluated by the duration of hexenal sleep. This experiment was conducted on 5 rats of each sex from each group in a warm and quiet room. The animal was weighed and a 90 mg / kg hexenal solution was injected intraperitoneally, and 0.9% NaCl was the solvent. The data are presented in table 3.

Table 3
The effect of the compared drugs on the duration of hexenal sleep (min, M ± m) Study Dates (days) Experimental group and gender The control 500 mg / kg 2500 mg / kg M F M F M F The claimed tool 52.9 ± 6.9 46.8 ± 6.5 66.2 ± 6.9 55.5 ± 3.4 48.3 ± 9: 1 52.9 ± 6.9 67.4 ± 6.2 30th day 63.5 ± 7.5 60.0 ± 6.1 64.8 ± 6.9 52.5 ± 11.1 59.4 ± 6.3 65.6 ± 7.4 Lamisil Background 48.5 ± 6.4 66.6 ± 6.9 45.9 ± 5.7 59.4 ± 7.8 52.3 ± 8.0 51.7 ± 6.2 30th day 60.5 ± 7.6 61.5 ± 6.1 45.9 ± 6.4 48.2 ± 7.9 55.3 ± 6.1 61.0 ± 7.2

The data obtained indicate the absence of significant changes in the duration of hexenal sleep in all experimental groups after a 30-day application of the drug.

Effect on the functional state of the kidneys.

Urinalysis and assessment of the functional activity of the kidneys by the secretion of phenol-red were performed in the background and on the 30th day, at the end of the experiment. The data obtained are presented in tables 4-6.

As you can see, urine indices in all experimental groups are close, no significant differences between any groups are detected.

Table 6
The effect of the compared drugs on the secretory function of the kidneys of white white rats (the amount of allocated paint in mg / 100 g weight, M ± m) Study Dates (days) Experimental group and gender The control 500 mg / kg 2500 mg / kg M F M F M F The claimed tool Background 0.085 ± 0.002 0.088 ± 0.0009 0.103 ± 0.007 0.090 ± 0.003 0.097 ± 0.002 0.087 ± 0.005 30th day 0.081 ± 0.003 0.091 ± 0.005 0.084 ± 0.006 0.095 ± 0.003 0.085 ± 0.003 0.081 ± 0.003 Lamisil Background 0.089 ± 0.003 0.085 ± 0.002 0.104 ± 0.0008 0.106 ± 0.007 0.102 ± 0.009 0.087 ± 0.002 30th day 0.078 ± 0.002 0.094 ± 0.004 0.094 ± 0.007 0.086 ± 0.003 0.112 ± 0.007 0.075 ± 0.003

As can be seen from the tables, significant changes in the excretory function of the kidneys when using ointments in white rats were not observed. There were no significant differences in this indicator of the experimental groups from the control, as well as between themselves.

Effect on cardiovascular activity

Data on the effect of administration of subacute 30-day administration of the drug on systological blood pressure are presented in table 7, for heart rate in table 8.

Table 7
The effect of the compared drugs on the systological blood pressure in white rats (mmHg, M ± m) Study Dates (days) Experimental group and gender The control 500 mg / kg 2500 mg / kg M F M F M F The claimed tool Background 120.8 ± 6.8 116.5 ± 5.6 119.4 ± 3.8 121.0 ± 6.5 114.7 ± 9.2 124.2 ± 3.3 30th day 105.4 ± 6.4 113.5 ± 6.0 101.6 ± 6.0 110.4 ± 4.1 116.5 ± 4.0 117.0 ± 4.9 Lamisil Background 121.5 ± 6.3 124.1 ± 5.2 111.5 ± 5.0 117.4 ± 5.7 122.3 ± 7.4 117.5 ± 3.8 30th day 113.7 ± 6.5 112.7 ± 4.3 112.2 ± 4.9 114.7 ± 6.3 117.0 ± 5.9 110.5 ± 5.2

The level of blood pressure slightly changed in all groups - by about 6.5 mm Hg. Differences between groups are not detected.

Table 8
The effect of the compared drugs on heart rate in rats Study Dates (days) Experimental group and gender The control 500 mg / kg 2500 mg / kg M F M F M F The claimed tool Background 402 ± 16 397 ± 15 418 ± 18 409 ± 13 408 ± 11 421 ± 17 30th day 402 ± 21 415 ± 16 364 ± 13 390 ± 15 406 ± 17 389 ± 13 Lamisil Background 415 ± 16 429 ± 15 414 ± 23 403 ± 17 416 ± 14 420 ± 21 30th day 383 ± 20 436 ± 15 411 ± 17 376 ± 16 442 ± 23 383 ± 20

Analysis of the results shows the absence of differences between the experimental groups from the control in terms of heart rate. On the 30th day, the value of the criterion of intergroup difference - the value of F ₀ - was equal to 0.71 at a critical value of F of _{0.95; 10.90} = 1.99.

Impact on peripheral blood counts

Hematological and biochemical blood tests were performed at the end of the study. Blood was obtained after simultaneous guillotination. The data obtained are presented in tables 9 and 10.

Statistical analysis of the obtained data does not reveal significant differences between all experimental groups in any of the indicators (for all indicators, the criterion for the heterogeneity of the groups was below the critical value). Data showing the effect on the basic biochemical parameters of the peripheral blood of white rats are presented in tables 11 and 12.

As follows from the data presented in tables 11 and 12, when exposed to animals of the claimed means and preparation, comparisons of differences in basic biochemical parameters were not detected.

Influence on the nature of the myelogram

Simultaneously with the selection of blood for hematological studies, the thigh bone was removed from slaughtered animals for the study of myelogram. The results of the study are presented in tables 13 and 14.

As can be seen from the results presented in tables 13 and 14, there were no differences between the claimed agent and the comparison drug according to the effect on the nature of the myelogram of white rats.

The therapeutic effect of the claimed drug was also studied in 10 patients with a verified diagnosis: dermatomycosis of the feet.

Patients were divided into 2 equal groups:

Group 1 received treatment with Lamisil cream;

Group 2 received treatment with the claimed agent.

All patients were applied with a thin layer on the skin of the feet and rubbed the studied drugs 2 times a day daily on the dried affected areas. Patients in group 1 noted the cessation of itching on the affected after 7 hours, in group 2 - after 5 hours from the start of treatment.

In these groups, the severity of clinical manifestations decreased after 1-2 days from the start of treatment.

Complete cure occurred in both groups after 8 days.

The results of the study showed that the claimed drug has a pronounced antifungal effect, not inferior to the comparison drug. At the same time, a good absorbency of the product was noted due to its high tropism to the skin.

Thus, the proposed antifungal agent has a pronounced specific effect, long shelf life, high tropism to the skin, low cost, which makes it possible to widely use its medical practice.

Claims (5)

1. An agent having an antifungal effect, including terbinafine hydrochloride, a base, a preservative, an emulsifier, a lipophilic component and a solvent representing propylene glycol, characterized in that it contains a rare cross-linked polyacrylic acid as a base, nipagin as a preservative, and tween- as an emulsifier 80, as a lipophilic component, vaseline oil, and also additionally contains sodium hydroxide and water in the following ratio, wt.%: terbinafine hydrochloride 0.9-1.1 rare crosslinked polyacrylic acid 1.0-2.0 nipagin 0.05-0.15 twin 80 0.5-1.5 liquid paraffin 2.0-7.0 propylene glycol 5.0-15.0 sodium hydroxide 0.2-0.6 purified water rest 2. The method of obtaining funds according to claim 1, characterized in that the preservative is dissolved in water at 50-65 ° C, the solution is cooled, the base is added to it with stirring, left to swell, sodium hydroxide is added to the resulting suspension until the mixture reaches pH 4 , 8-5.3, a pre-prepared solution of terbinafine hydrochloride in a solvent is added to the resulting mass with the addition of a mixture of the lipophilic component and an emulsifier and sodium hydroxide solution, cooled and allowed to mature. 3. The method according to claim 2, where the preservative is dissolved in water at t = 50-65 ° C. 4. The method according to claim 2, where to achieve a pH of 4.8-5.3, sodium hydroxide is added in an amount of 60% of the total amount of sodium hydroxide. 5. The method according to claim 2, where 40% sodium hydroxide of the total amount of sodium hydroxide is used to transfer terbinafine hydrochloride to the base.