Gel dosage form

 

(57) Abstract:

The invention relates to a gel-like medications intended for the treatment of injuries of the skin and superficial tissues of humans and animals. The gel formulation as the basis - cross-linked copolymer of an unsaturated acid and a hydrophilic monomer, taken in a weight ratio of 1: 1-100, respectively, in quantities of from 1.0 to 15.0 wt. % and the medicinal substance of 0.001-5.0 wt.% and water to 100 wt.%. Gel dosage form has a high absorptive capacity in relation to liquids, improved consumer properties, soft, buttery consistency, atraumatic. 1 C.p. f-crystals, 2 tab.

The invention relates to a dosage form intended for the treatment of various lesions of the skin and superficial tissues (burns, wounds, skin diseases and other) people and animals.

The main requirements for such facilities, are primarily the capacity for effective absorption of wound exudate, good water and air permeability, high prolonging the ability to included in lekarstvennoj cotton-gauze funds are not available in the required quantities and, in addition, do not possess optimal properties. Thus, the sorption capacity of cotton usually does not exceed 14 g/g, and the gauze is often simply hydrophobic [1st all-Union conference "Modern approaches to the development of effective dressing devices and suture materials", M., 1989].

In recent years, attempts are being made to replace the cotton-gauze means of synthetic and natural polymeric materials. Thus, in EP N 514691 as a tool for healing wounds and burns are encouraged to use the collagen film thickness of 0.02-0.2 mm, capable of absorbing up to 15 g/g aqueous biological fluids. However, the data characterizing the absorption ability of the material far from the optimal values. In addition, the use of animal raw materials needed to obtain these films, it requires careful control and adversely affects the reproducibility in the synthesis, and, moreover, is associated with high cost.

Similar circumstances limit the scope burns funds on the basis of natural materials, proposed in U.S. patent N 5009899. Gelling composition get by mixing xanthan gum, resin white AIE "Helpers" (UK), which is a mixture of polyacrylamide and agar-agar, it has high adsorption capacity, good water and oxygen, does not stick to the wound. However, the presence of agar-agar is a good nutrient medium for pathogens, and cannot be used for the treatment of infected wounds [K. J. Quinn, Courtney J. M. //Biomaterials, V5, 1985, p. 369-377].

The closest to the technical nature of the claimed solution is the composition of the dosage form based on the swelled in a suitable solvent (usually water) cross-linked copolymer of a hydrophilic monomer, a hydrophobic monomer and an unsaturated acid with the addition of medicinal substances in the following ratio of components, wt.%:

Cross-linked copolymer of a hydrophilic monomer, a hydrophobic monomer and an unsaturated acid - 10,0-70,0

The medicinal substance is 0.001 to 10.0

Acceptable solvent - 25,0-85,0

[the application for a patent of Ukraine 95125484 from 26.12.95, published in bull. 4, 1998].

Known dosage form is suitable for the treatment of eye diseases and is characterized by long duration of release of the drug in combination with high strength properties, biocompatibility, and high gas permeability required for p is a lack of softness and plasticity, providing atraumatic application required in the treatment of burns and wounds. Known dosage form is characterized by inadequate for effective sorption of wound exudate-absorbing ability.

The objective of the invention is to provide dosage forms with along with sufficient prolonging ability, biocompatibility and permeability, still I high water-absorbing sposobnostey and atraumatic that would ensure the effective use of it for the treatment of skin lesions.

The problem is solved by the claimed invention is a composition of the dosage form on the basis swollen in the solvent cross-linked copolymer with added medicinal substance, which as the basis contains a cross-linked copolymer of an unsaturated acid and a hydrophilic monomer, taken in a weight ratio of 1:1-100, respectively, in the following ratio of components in the dosage form, wt.%:

Cross-linked copolymer of a hydrophilic monomer and an unsaturated acid - 1,0-30,0

The medicinal substance is 0.001 to 5.0

Solvent - the Rest is up to 100

As the hydrophilic monomer basis of the inventive dosage forms can containing the E. unsaturated acid, the basis of the claimed dosage forms may contain acrylic acid (AA) or methacrylic acid, or crotonic acid, or 2-acrylamide-2-methylpropylsulfonic acid.

In the proposed solution the solvent performs a dual function - on the one hand it should swell cross-linked polymer, and on the other, it should dissolve entered the medicinal substance.

The solvent can be used distilled water, saline, ethanol, propanol, glycerol, diethylene glycol, DMSO, vegetable oils and other solvents, properties which permit their use in pharmacy.

As a medicinal substance can be used with a wide range of drugs used for treatment of burns, wounds, skin diseases. and for the transcutaneous administration of drugs used for treatment of other diseases. In particular, can be used antibacterial drugs (eg, chlorhexidine), local obezbolivaushee (e.g., lidocaine), enzymes (e.g. trypsin, chymotrypsin), antibiotics (such as gentamicin, erythromycin), antivirals (such as acyclovir), antifungals (eg, miconazole) and a number of other drugs.

As will be until the iSlate and hydrophilic monomer therein, the ratio of the weight Dolen polymer base and solvent, determining the necessary degree of swelling, helped to create a new dosage form with popisannoe water-absorbing capacity and improved consumer properties: buttery consistency and atraumatically that will ensure the effective CE application for the treatment of burns, wounds and other skin damage.

Saleemul dosage form obtained as follows.

The basis for the dosage form, according to the invention receive the technology. traditional to obtain crosslinked polymers [Encyclopedia of Polymer Science and Engineering. Hydrogels. V. 7. P. 783-805. John Wiley &. Sons. New York. 1987]. Mix the calculated amount of an unsaturated acid, a hydrophilic monomer, a crosslinking agent, initiator (or initiator mixture and solvent. The resulting solution was filtered from mechanical impurities, Tegaserod and fill in the form for carrying out polymerization. The polymerization is carried out at a temperature of 20-80oWith, depending on the type of initiator. Within one hour of material removed from the forms and subjected to the washing of the residual amounts of unreacted substances by storage in distilled water should the speed discoloration of 0.1 % solution of potassium permanganate. Then the basis for the dosage form is mixed with the calculated quantity of a drug (or a mixture of several drugs), thoroughly mixed and homogenized.

Below are just some examples of specific implementation of the invention, however, other variants of the invention, do not go essentially beyond that limited by the claims.

Example 1

Mix 0.25 ml of acrylic acid. 10 g of acrylamide, 10 ml of 0.2% aqueous solution of N, N'-methylene-bis-acrylamide - linking agent, was added a solution of the components of the redox initiator mixture) ml of 10% aqueous solution of potassium persulfate and K) ml of 10% aqueous solution of sodium metabisulfite, and 49.75 ml of solvent is distilled water. The resulting solution was filtered from mechanical impurities, Tegaserod and fill in the form for carrying out polymerization. The polymerization is carried out at a temperature of 25oC. within one hour of material removed from the forms and subjected to the washing of the residual amounts of unreacted substances by incubation in distilled water for 3 days with multiple water change. Then to the resulting zignago drug chlorhexidine digluconate and mix thoroughly. Received dosage form is sealed and sterilized by autoclaving at a temperature of 120oC.

Example 2

Mix 2 ml of acrylic acid, 10 g of acrylamide, 10 ml of 0.2% solution of schiwago agent is N, N'-methylene-bis-acrylamide, add 15 ml of 10% aqueous solution of the initiator is ammonium persulfate, and 63 ml of solvent is distilled water. The resulting solution was filtered from mechanical impurities, Tegaserod and fill in the form for carrying out polymerization. The polymerization is carried out at a temperature of 65oC. within one hour of material removed from the forms and subjected to the washing of the residual amounts of unreacted substances by incubation in distilled water for 3 days with multiple water change. Then it collected in this way the basis for the dosage form add 10 ml of 10% aqueous solution of the local anesthetic is lidocaine and mix thoroughly. Received dosage form is sealed and sterilized by autoclaving at a temperature of 120oC.

Example 3

Mix 5 ml of acrylic acid, 15 g of acrylamide,10 ml of 0.2% aqueous crosslinking agent solution of N,N'-methylene-bis-okrilennoi water. The resulting solution was filtered from mechanical impurities, Tegaserod and fill in the form for carrying out polymerization. The polymerization is carried out at a temperature of 55oC. within one hour of material removed from the forms and subjected to the washing of the residual amounts of unreacted substances by incubation in distilled water for 3 days with multiple water change. Then it collected in this way the basis for the dosage form is added 2 ml of a 20% aqueous solution of chlorhexidine digluconate and 10 ml of 10% aqueous lidocaine solution and mix thoroughly. Received dosage form packaged in tubes and subjected to radiation sterilization according to the standard procedure.

Example 4

Mix 1 ml of crotonic acid, 10 g of acrylamide, 10 ml of 0.2% aqueous solution of N,N'-methylene-bis-acrylamide - linking agent, was added a solution of the components of the redox initiator mixture of 10 ml of 10% aqueous solution of potassium persulfate and 10 ml of 10% aqueous solution of sodium metabisulfite, and 49 ml of solvent is distilled water. The resulting solution was filtered from mechanical impurities, Tegaserod and fill in the form to be polimergas the hillshade from residual amounts of unreacted substances by incubation in distilled water for 3 days with multiple water change. Then it collected in this way the basis for the dosage form is added 2.5 ml of a 20% aqueous solution of a bactericidal drug chlorhexidine digluconate and mix thoroughly. Received dosage form is sealed and sterilized by autoclaving at a temperature of 120oC.

Example 5

Mix 5 ml akrilovoi acid, 10 g of N-vinyl-pyrrolidone, 10 ml of 1-aqueous solution etilenglikolevykh - linking agent, was added a solution of the components of the redox initiator mixture of 10 ml of 10% aqueous solution of potassium persulfate and 10 ml of 10% aqueous solution of sodium metabisulfite, and 55 ml of solvent is distilled water. The resulting solution was filtered from mechanical impurities, Tegaserod and fill in the form for carrying out polymerization. The polymerization is carried out at a temperature of 25oC. within one hour of material removed from the forms and subjected to the washing of the residual amounts of unreacted substances by incubation in distilled water for 3 days with multiple water change. Then it collected in this way the basis for the dosage form is added 2.5 ml of 20% aqueous solution BG sealed and sterilized by autoclaving at a temperature of 120oC.

The composition of the samples of the inventive dosage form obtained according to examples 1-5 are shown in table. 1.

Example 6 (comparative)

Received a dosage form in a known manner, according to the description of the patent application N 95125484 (prototype).

Mixing 2.0 g of acrylamide, 1.0 ml crotonic acid, 1.0 ml of Acrylonitrile, 2.0 ml of 1.0% aqueous solution of N, N'-methylene-bis-acrylamide, 0.75 ml of a 0.4% aqueous solution of potassium persulfate and 0.3 ml of a 1% solution of sodium metabisulfite. The resulting composition was filtered from mechanical impurities and poured into molds to obtain protivougrevoe film. After one hour, the mold was separated, and the obtained product was extracted and subjected to washing from the residual neproreagirovavshikh substances by incubation in distilled water for 12 h with three replacement water. Then a basis for dosage forms dried at a temperature of 40oWith and subjected to swelling in the solution of the antibiotic, kanamycin sulfate with a concentration of 15% within 24 hours

Received a formulation of the following composition, wt.%:

Cross-linked copolymer of acrylamide, acrylic acid and Acrylonitrile - 28

The medicinal substance (kanamits is transparent, have a soft gel-like consistency, easy to apply on the skin and are distributed on its surface.

The samples of examples 1-5 were tested on the following parameters: absorption capacity, prolonging ability, especially consistency.

For comparison, the same performance was tested in a sample of known dosage forms of the prototype, obtained in example 6.

Absorptive capacity was assessed by the degree of swelling of the dosage form in distilled water (Q1) and saline solution (Q2) and was determined (g/g) by the gravimetric method, according to the formula:

Q=Mn-Mc/Mc,

where Mnand Mwithis the mass of swollen and dried sample, respectively.

Prolonging capacity (T) was estimated by the time halving the concentration of drug preparedata (or mixture of drugs in dosage form, in hours.

Features texture (softness) was evaluated out of line, and the depth in the sample (L) standard cone for 5 seconds at 25oWhen the total load 150, This method is used in the estimation of volumetric and mechanical properties of the plastic is ENES in table 2, for comparison, data on known properties of the dosage form (prototype).

As can be seen from the table 2 data, samples dosage forms in accordance with the invention have a high absorptive capacity in relation to the physiological solution and water, have a long duration of release of the contained drug substances and a soft texture that provides comfort and efficiency in the treatment of burns and other injuries and diseases of the skin. Comparisons of these data with indicators of well-known pharmaceutical forms shows that the invention provides significant advantages of the proposed structure in comparison with the prototype of the indicators of absorptive capacity and volumetric and mechanical properties (softness).

Biomedical and Toxicological tests of the claimed dosage forms, held at the Institute of gerontology of the Academy of medical Sciences of Ukraine, showed that the investigated samples dosage forms for cutaneous application in rats belong to the class of low-toxic compounds. Was demonstrated pronounced antimicrobial activity of the sample l is to use it for the treatment of infected wounds, in particular, burn injury, where the factor of infection plays a significant role in the development of burn endogenous intoxication.

In the experiment on animals was studied burns effect of said sample. To do this, in the experiments on rats reproduced thermal burns - surface (II-IIIa degree) and deep (IIIA-IIIB degree), causing burn disease, and studied the effect of dosage forms with 0.25 % chlorhexidine on morphological, hematological and biochemical indicators of the severity of burn injuries, speed healing, and to judge the effectiveness of the studied tools.

Studies have shown that under the influence of the dosage form, applied to superficial burns for 3 weeks, there was a reduction in the healing time of burn injuries by 15%. Pathological studies of the skin on the 18 day confirmed the anti-inflammatory and antimicrobial action of the drug. After treatment in the underlying tissue of the skin was no inflammatory infiltration, on the surface of the defect is not discovered colonies of microbes. Also shown is the effect of the drug on the regeneration of the epidermis in clade atraumatically application and prevents the wound from drying out, creating a moist environment. promote epithelialization. Thus, on the basis of obtained data we can conclude that the studied samples dosage forms with 0.25 % chlorhexidine digluconate possess significant pharmacological activity. The main mechanism of action of the drug is associated with its anti-bacterial properties and elimination of microbial factor, making a significant contribution to the development of burn endogenous intoxication, and, as a consequence, reducing the degree of intoxication in toxico-infectious period of burn disease.

1. Gel dosage form for the treatment of wounds and burns on the basis swollen in the solvent crosslinked copolymer of an unsaturated acid and a hydrophilic acrylic monomer with the addition of medicinal substance, characterized in that it provides the ratio of unsaturated acid and a hydrophilic acrylic monomer or vinylpyrrolidone in the copolymer is 1:1-100, respectively, as the solvent used water in the following ratio, wt.%:

Cross-linked copolymer of an unsaturated acid and a hydrophilic monomer or vinylpyrrolidone, taken in the ratio of 1:1-100, respectively - 1,0-15,0

Lek is e unsaturated acids it contains acrylic acid, or methacrylic acid, or crotonic acid, or 2-acrylamide-2-methylpropanesulfonate.

 

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