RU2153352C1 - Pharmaceutical composition showing wound-healing and anti-inflammatory effect - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: pharmaceutical coposition has tumor necrosis alpha-factor, hyaluronic acid, dimethylsulfoxide and polyethylene oxide in the following ratio of components, wt.-%: tumor necrosis alpha-factor, 0.001-0.01; hyaluronic acid, 0.1-1.0; dimethylsulfoxide, 5.0-15.0 and polyethylene oxide, the balance. Composition is used for treatment of infection-inflammatory diseases, among them in complex therapy of acute and chronic gynecological inflammatory diseases, in complex therapy of herpetic and other viral infections, in treatment of urogenital infections and in treatment of sluggish wounds. EFFECT: enhanced therapeutic effectiveness, broadened spectrum of use. 1 cl, 2 tbl, 8 ex

Description

 The invention relates to medicine and relates to pharmaceutical compositions having wound healing and anti-inflammatory effects.

 A known pharmaceutical composition having a wound healing and anti-inflammatory effect, containing, wt.%: Mucopolysaccharide 1-10, dimethyl sulfoxide (DMSO) 5-20, ointment base, the rest [RF Patent N 2021811, cl. A 61 K 31/725, publ. 10/30/94. Bull. N 20]. As a mucopolysaccharide, the composition contains chondroitin sulfate isolated from animal feed. The known composition is used mainly for the treatment of diseases of the joints (arthritis, arthrosis, etc.).

The disadvantages of the known composition are:
a narrow range of therapeutic effects;
insufficient wound healing activity;
unsatisfactory transdermal properties, since the ointment base (lanolin, petroleum jelly) penetrates weakly into the subcutaneous structures.

 The closest to the claimed composition of the prototype is a pharmaceutical composition with a wound healing effect, including a polypeptide that is a growth factor for fibroblasts (FGF) and a water-soluble polysaccharide selected from the group comprising chitosan and its derivatives, with a mass ratio of polypeptide: polysaccharide 1: 5-1000000 . The composition is an aqueous solution or lyophilisate. The concentration of a polypeptide with RFF activity is from 0.1 to 500 μg / ml, preferably from 0.5 to 300 μg / ml, and the concentration of chitosan or its derivatives is 1-300 mg / ml in the composition. The known composition is suitable for the treatment of long healing wounds, as well as burns and ulcers of the mucous membranes. The known composition is applied to the treated wound with a thin layer or in the form of an application on sterile gauze napkins [RF Patent N 2080872, class. A 61 K 38/02, publ. 06/10/97. Bull. N 16].

The disadvantages of the known composition are:
a narrow spectrum of use of the composition (only for the treatment of long healing wounds);
nonspecific binding of a large part of RFF due to absorption, which leads to an overdose of the active component and the impossibility of accurate dosing of RFF;
non-optimal dosage form of the composition in the form of aqueous solutions, which leads to an unreasonably high consumption of the composition when applied to a wound.

 An object of the invention is to expand the scope of the composition while maintaining a high therapeutic activity of the latter.

The technical task is achieved by the proposed pharmaceutical composition containing a polypeptide that is a tumor necrosis factor-alpha (TNF-alpha), hyaluronic acid, dimethyl sulfoxide and polyethylene oxide in the following ratio, wt.%:
TNF-alpha - 0.001-0.01
Hyaluronic acid - 0.1-1.0
Dimethyl sulfoxide - 5.0-15.0
Polyethylene Oxide - Else
The drug (conventional name "Algilur") is obtained in the form of a gel, liniment or ointment. The type of dosage form depends on m.m. used polyethylene oxide and a quantitative ratio with other components of the composition.

 TNF-alpha belongs to a large group of natural proteins, specifically cytokines, which are the central regulators of inflammation and the immune response and form a network of signals that provide protective properties of the body. The action of TNF in vitro also includes antiviral activity, which has been demonstrated for a number of DNA and RNA-containing viruses and various types of cells [Mestan J., Digel W., Jmitnoacht S. Antiviral effects of recombinant tumor necrosis factor in vitro. //Nature.- 986.-323, N 6088.- P. 816-819].

 An important role is played by the effects of TNF on vascular endothelial cells. Thus, the appearance of a binding factor with neutrophils under the influence of TNF on the surface of endothelial cells can contribute to the penetration of the latter into the lesion.

 Activated macrophages and monocytes are a natural source of TNF-alpha. After their isolation and study, evidence was given of the antiviral effect of TNF, fungicidal, antibacterial and antiparasitic actions. Basic information about TNF, including methods of isolation and preparation, structure and biological activity, its mechanism and corresponding areas of their clinical study are presented in numerous specialized literature [Clark R.A.F., Henson P.M. Molecular and cellular biology of wound repair. // Plenum Press. N.Y. & London. 1988. 616. P. Nedospasov S.A., Turetskaya R.L., Shakhov A.N.// Tumor necrosis factors. In the book: Results of science and technology. Immunology. 1988. T. 22. S. 91-125].

 In the proposed composition, TNF-alpha helps to remove inflammatory reactions by activating the mononuclear phagocyte system, as well as enhancing the production of prostaglandins that contribute to the synthesis of serum immunoglobulins.

 The hyaluronic acid (HA) included in the composition is a natural high molecular weight mucopolysaccharide obtained from bird crests (TU 9316-014-0566401) in a known manner (RF Patent N 2102400, class C 08 B 37/08, publ. 20.01.98. Bull. N 2).

 HA is one of the most important components of connective tissue, characterized by high viscosity, elasticity, specific ability to bind water and proteins.

 Due to its high hydrophilicity, this polymer already in low concentrations (0.1%) forms highly viscous gels with water, which have a unique ability to moisturize the skin and mucous membranes. In the proposed composition used HA in a concentration of 0.1-1.0%. HA has a disinfecting, anti-inflammatory and wound healing effect in the composition, promotes the regeneration of the epithelium, prevents the formation of granulation tissues, adhesions, scars, reduces swelling and reduces skin itching. Another, no less important, function of HA in the composition of the claimed composition is the stabilization of TNF-alpha, a decrease in its absorption and binding to receptors located in inflamed tissues.

 As a transmitter, DMSO was introduced into the composition, which easily penetrates through biological membranes, including through skin barriers, thereby enhancing the diffusion of active drugs to their destination. DMSO also has anti-inflammatory and analgesic effects.

 An indifferent synthetic polymer, polyethylene oxide (PEO) with m.m., was introduced into the composition as a carrier. 1000-6000 Yes, mainly 1500 Yes, approved for use in medicine. PEO base has significant advantages over fatty bases, as it has high penetration, accelerating the absorption of intact skin and mucous membranes of the active substances of the composition. PEO is non-toxic, soluble in water, stabilizes and prolongs the therapeutic activity of TNF-alpha.

 A significant difference between the claimed pharmaceutical composition is that it contains TNF-alpha as an active polypeptide, as a water-soluble polysaccharide-HA, and additionally contains DMSO as a transmitter and preservative, and PEO as a base in experimentally selected, optimal ratios, which allows you to increase the therapeutic activity of the composition, expand its scope and improve the organoleptic properties of the latter.

 When using the components of the claimed composition in exorbitant amounts, the therapeutic effectiveness of the drug decreases, and the organoleptic properties deteriorate.

 The proposed composition is obtained by mechanical mixing of the components at room temperature until a homogeneous mass is formed. The finished composition is a uniform, colorless mass of a jelly-like or ointment-like consistency.

 The wound healing effect of the composition was studied on a chemical burn model in chinchilla rabbits of both sexes, with a body weight of 3-3.5 kg. A chemical burn was caused by applying optimal volume of 70% sulfuric acid to the depilated surface of the back skin of rabbits. Treatment began on the 5th day after the burn, at the stage of the formed wound. On the wound surface was applied a composition containing, wt.%: TNF-alpha - 0.005; GK - 0.5; DMSO - 10; PEO - the rest. The composition was applied to the skin daily, three times, for 10 days. To assess the wound healing activity of the drug, a histological examination of wound biopsy samples taken at different times after the start of treatment was performed. Studies have shown that the claimed composition accelerates wound healing and directs the process of reparative skin regeneration along the organotypic pathway. So, after two applications of the composition in the lesion, the absence of granulation tissue, the presence of young loose tissue and young epidermis were tested, which was not observed in the control. The result of the treatment was the full restoration of all layers of the epidermis, hair follicles and glands. The regenerate in architectonics was not much different from intact skin. Fibrous scar was absent.

 The toxicity of the composition was investigated on white outbred mice with a body weight of 20-22 g by cutaneous applications for 3 months. It was found that the proposed composition is not toxic and does not cause histological disorders of the epidermis, dermis and subcutaneous tissue.

 The inventive composition was tested in clinical conditions in various fields of medicine: in surgery to accelerate wound healing, in dermatology for the treatment of burns, ulcers and radiation injuries, in gynecology for the treatment of acute and chronic gynecological inflammatory processes. The tests showed that the developed pharmaceutical composition has a pronounced wound healing and anti-inflammatory effect and can be recommended in practice as a promising drug.

 As a result of a search by sources of patent and scientific and technical information, no information was found on the pharmaceutical composition with a wound healing and anti-inflammatory effect similar to that claimed.

 The invention is illustrated by the following examples of the preparation of specific formulations of the claimed composition and its use.

 Example 1

To prepare 100 g of the composition, 100 mg of HA is dissolved in 5 ml of water, then 10 g of DMSO, 84.89 g of PEO and 10 mg of TNF-alpha are added. The mixture is thoroughly mixed to a homogeneous mass and Packed in a container of dark glass. Store during the year at a temperature of (+4) - (+10) ^o C.

 Composition formulations were prepared similarly containing optimal and boundary amounts of components, examples 2-6 (table 1).

 Table 1 shows 5 examples of developed formulations of the composition in addition to example 1 above. The experiments showed that a quantitative increase in the components in the formulation (example 6) does not lead to any significant increase in the clinical effect, but only leads to an increase in the cost of production of the composition. The most optimal clinical effect were the formulations shown in examples N 1.3 and N 4.5.

 Example 7

 Patient X was admitted to the surgical department of the clinic with a diagnosis of thermal burn of the right forearm, II-III degree.

 Obno: on the anterolateral surface of the forearm there are sections of infected burn wounds 5 x 6.5 cm and 6.0 x 7.5 cm in size. Tissues around the burn surface are hyperemic and painful. The treatment of the proposed composition of the following composition, wt. %: TNF-alpha-0.001, GK-0.1, DMSO-5.0, PEO-94.89.

 Before applying the composition, an antiseptic treatment of the wound was performed and an ointment was applied to the surface of the wound at the rate of 1 ml per 0.5 dm. sq. followed by closure of the last sterile dressing.

 Bandages were changed once a day. On the third day of treatment, the wound surface was cleansed of purulent-necrotic discharge, active epithelization of the edges of the wound began. On the 16th day of treatment, the surface of the wounds was covered with epithelium by 95%, the patient was discharged in satisfactory condition without impaired hand function.

 Example 8

 Patient K., 21 years old, turned to a antenatal clinic for chronic erosion of the cervix.

 From the anamnesis: sick for about a year, was treated on an outpatient basis without significant improvement.

 Ob-but: on the cervix there is a section of the wound surface measuring 1.5 square meters. see Schiller test and the reaction to acetic acid is positive. Cytological examination of the smear showed the presence of signs characteristic of the inflammatory process (smear type 1). PCR tests for the presence of chlamydia, uroplasmosis and trichomon are negative. The patient was treated with cervical erosion by the proposed composition containing, wt.%: TNF-alpha - 0.01, HA - 1.0, DMSO - 15.0, PEO - 83.99. The composition in the form of a gel was applied to the wound surface of the cervix in the form of tampons in an amount of 1-2 g once a day for 12 days. Active epithelization of the erosive surface began after 4 procedures and ended after 12 procedures. The total duration of treatment is 12 days. No complications or relapses were observed.

 Due to the presence of a combination of TNF-alpha, HA, DMSO and PEO in the proposed composition, the therapeutic activity of the drug is enhanced, which allows the composition to effectively reduce the inflammatory response in wounds and ulcers, to reduce edema, hyperemia, and the production of humoral factors that form in the zone of damage or inflammation, significantly reduce the vital activity of the bacterial flora and the growth of microbes, cleanse wounds and ulcers from necrotic plaque, accelerate epithelization and healing with a good cosmetic effect. Data on the effectiveness of treatment of wound processes from the use of the claimed composition in comparison with treatment with the known drugs "Vagotil" and "Salcoseryl" are presented in table 2.

 From table 2 it is seen that the claimed composition has a higher therapeutic activity compared to known means, and also allows to reduce the treatment time and reduce the consumption of the drug for the course of treatment.

Using the proposed composition will allow, in comparison with the known:
expand the possibility of using the composition in the treatment of long-term non-healing wound processes of various localization and etiology;
improve the structural parameters of the composition (gel, ointment), since the use of aqueous solutions of the prototype composition leads not only to an unreasonably high consumption of the active component, but also creates additional difficulties in keeping the composition on a wound with a complex surface relief;
reduce the consumption of the drug for the course of treatment;
shorten the treatment period.

 The inventive composition will expand the arsenal of funds with wound healing and anti-inflammatory effects, and can be recommended for the treatment of acute and chronic inflammatory processes in surgical, gynecological practice, as well as in dermatology and other fields of medicine.

Claims (1)

A pharmaceutical composition having a wound healing and anti-inflammatory effect, containing a polypeptide, a water-soluble polysaccharide and a base, characterized in that it contains tumor necrosis factor-alpha as a polypeptide, and hyaluronic acid as a polysaccharide, polyethylene oxide as a base, and additionally contains dimethyl sulfoxide with the following components, wt.%:
Tumor Necrosis Factor-alpha - 0.001 - 0.01
Hyaluronic acid - 0.1 - 1.0
Dimethyl sulfoxide - 5.0 - 15.0
Polyethylene Oxide - Else

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