RU2281102C2 - Pharmaceutical composition possessing anti-allergic and anti-inflammatory effect - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal preparation. As an active component the composition comprises the combination of betamethasone dipropionate and gentamycin sulfate and special additives comprising nipagin, propylene glycol, medicinal vaseline oil, Trilon B, emulsifier agent, buffer substances and water. The pharmaceutical composition is prepared as cream. Invention provides the multidirected therapeutic effect with the useful life of the composition 2 years.

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

4 cl, 2 tbl, 3 ex

Description

The invention relates to medicine and relates to a pharmaceutical agent for the treatment of skin diseases, especially various types of eczema, dermatitis, neurodermatitis, psoriasis, etc.

Treatment of dermatoses is of particular importance in connection with an increase in their frequency, including among children, as well as in connection with the increase in severe, often resistant to therapy forms of these diseases, as well as complicated by various infections. The incidence of allergic dermatosis is 6-15%, psoriasis - 2-4% of the world's population, which determines the relevance of the problem and socio-economic significance.

Currently, there is a tendency to increase the number of patients with common chronic dermatoses with a tendency to dissemination of skin rashes, as well as the attachment of bacterial and fungal infections (Mashkillayson A.L., Golousenko I.Yu. Experience in the use of Triderm cream // News, Dermatology and venereology. - 1995. No. 1, p. 48-49).

A significant place in the treatment of chronic dermatoses belongs to rationally selected external therapy. Among the wide range of drugs used for this purpose, drugs containing corticosteroids play a special role, especially one of the most active drugs in this direction - betamethasone.

Betamethasone has a pronounced anti-inflammatory and anti-allergic effect and is used in various modifications (betamethasone dipropionate, valerate, disodium phosphate, acetate), preferably dipropionate. Compositions containing betamethasone as the active substance are in the form of various dosage forms: tablets, injections, suspensions, creams, ointments, lotions.

Oral administration of betamethasone, like other corticosteroids, for the purpose of systemic therapy can cause serious complications (Cushing's syndrome, diabetes, problems with the gastrointestinal tract, etc.) and local use of the drug avoids these side effects. However, long-term topical use of betamethasone can cause activation of viral, bacterial and fungal infections. One way to reduce the likelihood of side effects, as well as to supplement and enhance the action of betamethasone, is to create medicines that contain a combination of betamethasone with other active substances.

A number of patents describe combinations of betamethasone with various antibacterial drugs in order to reduce or completely suppress the side activation of viral and bacterial infections.

British Patent 2192787, 1988, describes a preparation for eliminating excessive granulation containing betamethasone and oxytetracycline or chlortetracycline. The drug may be in the form of a fat cream. US patent 4013792, 1977, describes an anti-inflammatory ointment for treating dermatoses containing betamethasone and neomycin sulfate. UK patent 2049416, 1981, describes a veterinary drug containing one or more adrenal cortex hormones (e.g., betamethasone) and one or more thyroid-stimulating hormones releasing hormones, as well as additional antimicrobial agents: tetracycline, chlortetracycline, oxytetracycline, neom kanamycin, sulfathiazole and many others. The composition is made in the form of an ointment that treats eczema, allergic diseases.

More detailed pharmacological studies have shown that one of the most successful combinations of betamethasone is its combination with gentamicin.

Japanese Patent 60156608, 1985, describes an ointment containing 2-10 parts by weight, preferably 3-7 parts by weight. a mixture of alcohol and water with a ratio of 1: 1-9: 1, 0.1-6 weight.h. surfactants, preferably non-ionic, 75-97 parts by weight higher paraffinic hydrocarbon, preferably containing 16-40 carbon atoms and 0.02-2 parts by weight, preferably 0.02-0.04 parts by weight, sodium pyrosulfate as the base. 1 g of ointment contains 0.2-5 mg of betamethasone (in the form of ether) and 0.2-5 mg of gentamicin sulfate. Amount of water - as much as possible to dissolve as much hormone as possible. Further studies showed that ointments containing anti-inflammatory corticosteroids have several disadvantages: they are sticky and unpleasant when applied to the skin, have insufficient contact with the skin, which is why steroids penetrate poorly through it.

These shortcomings are eliminated by creams. A cream for topical application containing betamethasone valerate (0.122%) and gentamicin sulfate (0.1% in terms of gentamicin) (Schering-Plow Labo NV, Belgium) under the name "Celestoderm-B with Garamycin" is supplied to the Russian market . Known under the name "Garazon" eye ointment, eye and ear drops containing 1 g or 1 ml of the drug betamethasone sodium phosphate 1 mg and gentamicin sulfate 3 mg (Mashkovsky MD, "Medicines", M., New LLC Wave ", 2004, V.2, p.36).

In Russia, Belogent cream (Belupo, Croatia) and Diprogent cream (Schering-Plow, Belgium) are registered. These preparations contain betamethasone dipropionate (0.064%) and gentamicin sulfate (0.1% in terms of gentamicin) on a cream basis (State Register of Medicines. - T.1. - M.: MH RF, 2002. - 1300 p.) .

However, there is no information on the specific composition of excipients in the preparations. It is also known that many microorganisms develop resistance to antibiotics, which can significantly reduce the therapeutic effectiveness of the drug.

The objective of this invention is to create a medicinal product in the form of a soft dosage form that comprehensively affects diseased tissues and exhibits a multidirectional therapeutic effect - anti-allergic, anti-inflammatory and antibacterial, without reducing the latter with prolonged use, meets the requirements of the State Pharmacopoeia of the XI edition and has a shelf life of 2 years .

The problem is solved by a pharmaceutical composition with anti-allergic and anti-inflammatory effects, including as a active substance a combination of betamethasone dipropionate and gentamicin sulfate and target additives: nipagin, propylene glycol, medical paraffin oil, Trilon B, emulsifier, buffer substances and water, in the following ratio of components, mas .%:

Betamethasone Dipropionate 0.05-0.08 Gentamitacin sulfate 0.05-0.15 Nipagin 0.02-0.30 Propylene glycol 10.9-29.60 Medical liquid paraffin 15.0-30.0 Trilon B 0.45-0.55 Emulsifier 1.0-9.0 Buffer substances 0.5-1.5 Water up to 100 g

The new pharmaceutical composition is in the form of a soft dosage form, preferably in the form of a cream.

The proposed ratio of active substance and target additives is found experimentally and is optimal, providing a combined pharmaceutical composition that meets all the requirements of the State Pharmacopoeia XI ed. and shelf life of at least 2 years (see table 2).

One of the conditions that determine the quality and safety of a medicinal product for topical use is the effectiveness of antimicrobial preservatives. Nipagin, which exhibits antimicrobial activity in wide pH ranges from 3 to 8, was chosen as the latter. Nipagin has a wide spectrum of antimicrobial activity against bacteria and fungi, in addition, in combination with some other auxiliary substances, for example, propylene glycol, it exhibits a synergistic antimicrobial action.

The basis for the inclusion in the pharmaceutical composition of a hydrophilic solvent - propylene glycol is the good solubility of nipagin and betamethasone dipropionate in it, which greatly simplifies the process of obtaining the cream. In addition, propylene glycol itself has a certain preservative effect, and at a concentration above 10% it eliminates the inhibitory effect of surfactants on the antimicrobial effect of nipagin. In addition, propylene glycol provides the pharmaceutical composition with the ability to absorb exudate, i.e. has a drying effect.

As a result of studying the anti-inflammatory, antiexudative and drying effects of various compositions of the oil phase, the most optimal base was chosen in which liquid paraffin is used as an oil phase.

A mixture of cetostearyl ester of macrogol 20 and cetostearyl alcohol was used as emulsifiers. The study of the rheological properties of the pharmaceutical composition made it possible to determine the optimal concentration of emulsifiers - 5-9%, as well as the ratio of cetostearyl ether of macrogol 20 and cetostearyl alcohol in the range from 1.0: 6.0 to 3.0: 4.0, more preferably from 1.1 : 5.9 to 1.5: 5.5. The studies carried out allowed to obtain a stable disperse system, the rheological properties of which provide the necessary consistency and physical stability of the pharmaceutical composition.

The pH of the pharmaceutical composition should be in the range from 4.5 to 6.0, preferably from 5.0 to 5.5. These pH values are most favorable for the skin, as well as for the stabilization of nipagin during storage of its aqueous solutions. In addition, at a pH below 4.5, the decomposition of betamethasone propionate begins. To obtain the desired pH of the cream, as well as for the stability of betamtazone dipropionate and nipagin, a buffer system was selected containing a mixture of sodium phosphate disubstituted and potassium phosphate monosubstituted in a ratio of from 1: 1 to 1:39, preferably from 1: 4 to 1:13.

It is known that in many microorganisms, antibiotic aminoglycosides can develop resistance. To prevent this phenomenon, surfactants and hydrophilic non-aqueous solvents (cetyl ester of macrogol 20, propylene glycol), as well as Trilon B, increasing the permeability of the microbial cell wall and enhancing the sensitivity of microorganisms to antibacterial agents, were introduced into the cream.

The specific anti-inflammatory activity of the proposed composition was studied on a model of acute aseptic dextran inflammation of the foot of rats, with double cutaneous applications (for 30 minutes and at the time of administration of the phlogic agent) in sexually mature male rats. According to experimental data, double therapeutic and prophylactic skin applications of the studied drug cause a pronounced statistically significant anti-inflammatory effect, which is expressed in a decrease in the growth of foot edema in comparison with control untreated animals, and this effect is practically indistinguishable from the effect of standard samples (Belogent and Diprogent) )

An experimental study of the antiallergic action of the claimed composition was carried out on a model of DNCB dermatitis in guinea pigs. Morphological studies showed that the developed drug has a pronounced specific anti-allergic, antipruritic and anti-inflammatory effect, almost indistinguishable from the action of standard samples.

A pharmaceutical composition based on betamethasone dipropionate and gentamicin sulfate meets all regulatory requirements and has a shelf life of at least 2 years (see table 2).

The inventive tool can be obtained by known methods used for the preparation of soft dosage forms.

The following examples illustrate the invention.

A typical example. In reactor No. 1, pre-weighed betamethasone dipropionate and nipagin are dissolved in parts of propylene glycol at a temperature of 60-65 ° C with stirring. In reactor No. 2, with stirring at room temperature, dissolve gentamicin sulfate in part of the water. In reactor No. 3, pre-weighed sodium phosphate disubstituted and potassium phosphate monosubstituted are placed and dissolved at room temperature and stirring in part of water. The remaining water, previously weighed Trilon B, propylene glycol, cetostearyl alcohol, macrogol cetostearyl ether 20 and medical vaseline oil are loaded into reactor No. 4. The mass in the reactor is heated to 70-75 ° C with stirring, emulsified and cooled to 55-60 ° C, after which the solution from reactor No. 1 is introduced into the emulsion. With constant stirring, the mass in the reactor No. 4 is cooled to a temperature of 35-40 ° C and then solutions are introduced sequentially from reactors No. 2 and No. 3. With constant stirring, the mass in the reactor No. 4 is cooled to room temperature and the cream is Packed in tubes.

Specific embodiments of the invention are presented in table 1.

The resulting cream based on betamethasone dipropionate and gentamitacin sulfate meets all regulatory requirements and has a shelf life of at least 2 years (see table 2).

Table 1 Ingredients Content, wt.% Examples one 2 3 Betamethasone Dipropionate 0,064 0.02 0.18 Gentamicin sulfate 0.10 0.25 0.02 Nipagin 0.20 0.02 0.30 Propylene glycol 21.7 10.9 29.6 Medical liquid paraffin 20,0 15.0 30,0 Cetostearyl ether macrogol 20 1.30 1.00 3.00 Cetostearyl alcohol 5.70 6.00 4.00 Trilon B 0.50 0.1 1,0 Sodium Phosphate Disubstituted 0.10 0.02 0.50 Potassium phosphate monosubstituted 0.90 0.50 0.99 Water up to 100 up to 100 up to 100

table 2 Name
quality indicator Actual figures Quality Standards Example 1 Example 2 Example 3 Description Cream white or almost white White cream White cream White cream pH 4.5 to 6.0 5,0 5.1 4.9 Uniformity The cream should be uniform Homogeneous Homogeneous Homogeneous Microbiological purity According to GF XI and rev. Number 3 Compliant Compliant Compliant Quantitative In 1 g of the drug: definition content of betamethasone dipropionate - from 0.180 to 0.220 mg - 0,207 - - from 0.576 to 0.704 mg 0.640 - - - from 1,620 to 1,980 mg - - 1,790 gentamicin sulfate content - from 0.180 to 0.220 mg - - 0.198 - from 0.900 to 1.350 mg 1,100 - - - from 2.250 to 2.750 mg - 2,525 - Shelf life 2 years 2 years 2 years 2 years

Claims (4)

1. A pharmaceutical composition with anti-allergic and anti-inflammatory effects, comprising as an active ingredient a combination of betamethasone dipropionate and gentamicin sulfate and target additives, characterized in that it contains nipagin, propylene glycol, medical vaseline oil, trilon B, emulsifier as target additives which it contains a mixture of cetostearyl ester of macrogol 20 and cetostearyl alcohol in a ratio of 1: 6 to 3: 4, buffer substances, in which it contains a mixture of sodium ia phosphate disubstituted and potassium phosphate monosubstituted in a ratio of 1: 1 to 1:39, and water in the following ratio of components, wt.%: Betamethasone Dipropionate 0.05-0.08 Gentamitacin sulfate 0.05-0.15 Nipagin 0.02-0.30 Propylene glycol 10.9-29.60 Medical liquid paraffin 15.0-30.0 Trilon B 0.45-0.55 Emulsifier 1.0-9.0 Buffer substances 0.5-1.5 Water Up to 100 2. The pharmaceutical composition according to claim 1, characterized in that the ratio of cetostearyl ester of macrogol 20 and cetostearyl alcohol is from 1.1: 5.9 to 1.5: 5.5. 3. The pharmaceutical composition according to claim 1, characterized in that the ratio of sodium phosphate disubstituted and potassium phosphate monosubstituted is from 1: 4 to 1:13. 4. The pharmaceutical composition according to 1, characterized in that it is made mainly in the form of a cream.