EA002267B1 - Healing, antiphlogistic, and antiinfectious medical product - Google Patents

Abstract

1. Healing, antiphlogistic, and antiinfectious medical product, comprising an active ingredient and a base, characterized in that as an active ingredient it comprises 1-desoxy-1-N-[methyl-(2-acridone-9-one-10-yl-acetate)]-ammonium-D-glucitol, and as a base - 1,2-propylene glycol and additionally, catapol as preservative, with the following ratio of the components, wt.%: 1-desoxy-1-N-[methyl-(2-acridone-9-one-10-yl-acetate)]-ammonium-D-glucitol 8,0-15,0 catapol 0,001-0,10 1,2-propylene glycol up to 100

Description

The invention relates to medicine and veterinary medicine, in particular, to medicines for external use, and can be used to treat infected superficial and deep wounds, burns, as well as inflammatory diseases of the skin and mucous membranes.

Currently, as wound healing, anti-inflammatory and anti-infectious drugs, drugs in various dosage forms for external and internal use are used.

Wound healing and anti-inflammatory preparations of internal use in solid dosage form for oral administration are known, such as tribenzoid, eskusan (Mashkovsky M.D., Medicines, Moscow, New Wave, 2000, 14th ed., Vol. 1, pp. 442-443 )

The disadvantage of internal drugs is the limited use associated with the presence of a wide range of contraindications, as well as insufficient effectiveness due to low bioavailability, which allows them to be used only as part of complex therapy.

Known wound healing and anti-inflammatory drugs for external use in the form of napkins and dressings (RF patent No. 2107516, prior. 03/27/1998, A 61b 15/00 Dressing for the treatment of wounds and method for its preparation), which are used in the form of applications on wound surfaces.

The disadvantages of such drugs include long periods of treatment, high consumption of drugs, limited use for complex pathologies complicated by purulent discharge.

Known wound healing and anti-inflammatory drugs in the form of creams and ointments containing the active substance, fat base and additives. So in the patent of the Russian Federation No. 2114611, prior. dated 12/21/1995, A 61K 9/06 describes a medicinal product containing genetically engineered human interferon alpha-2, vitamins E and C, a mixture of lanolin and petroleum jelly as an ointment base.

However, the vaseline-lanolin base in these drugs interferes with normal gas exchange, which reduces the wound healing activity of the drug, especially during sluggish processes.

Known wound healing drug Liniment methyluracil (RF patent No. 2007997, prior of 08.07.1992, A 61K 9/06) containing β-form of methyluracil as the active substance, and castor oil as the base. The drug has an increased wound healing activity due to the high bioavailability of the dosage form.

However, in this drug, the active substance does not have anti-infective and interferonogenic properties, which does not allow the treatment of infected wounds.

Known RF patent No. 2135474, prior. from 08/19/1998, which describes the finished dosage form for external use in the form of a 5% ointment containing acridonoacetic acid salt with 1 deoxy-1-methylamino-D-galactitol as the active substance, and glycerol, castor as the base oil and lanolin, in the following ratio of components, wt.%:

Acridonoacetic acid salt with 1-deoxy-1-methylamino-D-galactitol 5.0

Glycerin 10.0

Castor Oil 5.0

Lanolin 80.0

This ointment is selected as a prototype. Ointment of the above composition has a wound healing, anti-inflammatory and anti-infectious effect in the treatment of infectious diseases of the skin and mucous membranes.

However, the low bioavailability of the active substance and the low adhesive ability of the ointment lead to insufficient treatment of superficial and deep wounds. In addition, this ointment cannot be used in hard-to-reach cavities of the body due to the thick consistency of the base, which limits its scope.

In addition, during storage of such an ointment, the development of extraneous microflora and rancidity of the fat base is observed due to the absence of preservatives in its composition, which reduces the stability of the drug during storage.

The objective of the invention is the creation of a highly effective wound healing, anti-inflammatory and anti-infective medicinal product for external use, which has high bioavailability, stability of the dosage form during storage and allows you to effectively treat infected superficial and deep wounds, burns, as well as inflammatory diseases of the skin and mucous membranes, including hard to reach body cavities.

The problem is solved in that the wound healing, anti-inflammatory and anti-infective drug containing the active substance and the base according to the invention contains 1-deoxy-1-Y- [methyl- (2 acridon-9-on-10-yl-acetate) as the active substance )] - ammonium-D-glucitol, 1,2-propylene glycol as a base, and additionally, catapol as a preservative, in the following ratio, wt.%:

1-Deoxy-1-Ν- [methyl- (2-acridone9-one-10-yl-acetate)] -ammonium D-glucitol 8.0-15.0

Catapol 0.001-0.10

1,2-Propylene glycol Up to 100

The inventive preparation contains 1-deoxy-1-No. [Methyl- (2acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol, known as a biologically active substance with prolonged interferonogenic activity (EA) as an active substance patent No. 000382, prior dated 01/22/1998, C 07H 5/06) and used in solid dosage form for oral administration (RF patent No. 2115415, prior dated 15.03.1995, A 61K 9/20).

The authors of the present invention for the first time shown the wound healing and anti-inflammatory effect of 1-deoxy-1-Y- [methyl- (2acridon-9-one-10-yl-acetate)] - ammonium-D-glucitol, which is inherent only in the dosage form of the claimed drug, and namely, liniment, which in combination with the anti-infective properties of the active substance, can effectively treat both infected wounds and burns, and inflammatory diseases of the skin and mucous membranes.

As a basis, the claimed preparation contains 1,2-propylene glycol - a non-aqueous hydrophilic solvent with good penetrating ability, which ensures high bioavailability of the active substance in the affected tissue, thus increasing the effectiveness of the treatment and shortens the treatment time for superficial and deep wounds.

1,2-Propylene glycol has good adhesion and good wettability of the damaged surface, as a result, the drug does not form a surface film that impedes normal gas exchange, which together with the high bioavailability of the active substance increases the healing efficiency of wounds and burns.

In addition, 1,2-propylene glycol provides sufficient fluidity and rapid absorption of the drug into the mucous membranes, which allows it to be injected into hard-to-reach body cavities and increases the effectiveness of the treatment of inflammatory diseases of the upper urethra, middle ear, maxillary sinus, etc.

All of the above allows you to expand the scope of use of the claimed medicinal product and increases the effectiveness of the treatment of infected superficial and deep wounds and burns, as well as inflammatory diseases of the skin and mucous membranes.

As a preservative, the drug contains catapol. Catapol is known as an antiseptic (Pharmacopoeia Article 42-3126-95), however, its preservative properties have not been previously described.

Thus, the inventive wound healing, anti-inflammatory and anti-infective drug with experimentally established optimal ratio of components can improve the efficiency and reduce the treatment time of infected wounds and burns, as well as inflammatory diseases of the skin and mucous membranes, expand the scope of use of the drug and ensure storage stability.

The invention is as follows.

To prepare 100 l of a wound healing, anti-inflammatory and anti-infectious drug, take 50.0 l of 1,2-propylene glycol, 8 kg of 1-deoxy-1-Ν [methyl- (2-acridon-9-one-10-yl acetate)] -ammonium-D-glucitol and 0.1 kg of catapol and stirred until the components are completely dissolved. Then add 1,2-propylene glycol to obtain a volume of 100 l The resulting solution is filtered through a sterilizing filter type "Pall", poured into sterile bottles with a capacity of 5, 10 and 100 ml. The yield of the finished product is 98%. A 100 ml bottle contains 8 wt.% 1-deoxy-1-Y- [methyl- (2-acridon-9-one10-yl-acetate)] - ammonium D-glucitol, 0.1 wt.% Catapol and 1 , 2-propylene glycol - the rest.

In the table. Figures 1-6 show the results of experimental and clinical studies of a wound healing, anti-inflammatory, and anti-infectious drug.

In the table. 1, 2 shows data on the selection of the optimal composition of the claimed medicinal product.

In the table. 3-6 presents the results of the therapeutic efficacy of the claimed drug.

The choice of the optimal ratio of the components included in the inventive preparation was established experimentally.

Experience 1. The choice of the content of the active substance was carried out according to the bioavailability of the active substance. The experiment was carried out on chinchilla rabbits, divided into 9 groups of 9 animals. At pre obezvoloshenny and on scarified skin area of 5 cm ² was applied to the rabbit back of formulations with different contents of active substance the rate of 0.2 ml per 1 cm ^2. A special collar was put on the rabbit’s neck, preventing the drug from licking.

After 30 minutes, the treated area was thoroughly wiped with distilled water, and a skin area with an epidermal layer 1 cm ² in size was excised under anesthesia, which was ultrasonically homogenized to extract the active substance with 100 ml of distilled water for 30 minutes. The resulting solution was filtered through a Sartorius type sterilizing filter, and the active substance concentration was determined spectrophotometrically at a wavelength of 408 nm.

The obtained experimental data are presented in table. 1 show that a bioavailability of more than 50% was obtained when the concentration of the active substance in the inventive preparation in the range from 8.0 to 15.0 wt.%. When the concentration of the active substance is less than 8.0 wt.%, The bioavailability is less than 50% and insufficient for the effective treatment of deep wounds and burns. At a concentration of more than 15.0 wt.%, The active substance does not completely dissolve in

1,2-propylene glycol forming a precipitate. When you try to further dissolve the active substance during heating, after cooling to room temperature, it partially crystallizes during storage, and this composition is unsuitable for use.

Experience 2. The choice of catapol content in the inventive preparation was carried out experimentally. We studied various concentrations of catapol in the range from 0 to 1.0 wt.%. Studies of a medicinal product with catapol concentrations of more than 1.0 wt.% Were not carried out, since such concentrations cause burns to the skin and mucous membranes (RLSAPTECAR, Second Edition, revised and updated, M., RLS-2000, p. 540).

The experiments were carried out on chinchilla rabbits, divided into 7 groups of 5 animals. At pre obezvoloshenny and on scarified skin area of 5 cm ² was applied to the rabbit back of a preparation containing 8 wt.% Of the active substance with various contents catapol the rate of 0.2 ml per 1 cm ^2. A special collar was put on the rabbit’s neck, preventing the drug from licking. After 30 minutes, an examination of the skin area was carried out to determine the presence of a locally irritating effect (itching, redness, burn). The next inspection was carried out after 24 hours

The results of the study are given in table. 2.

Studies have shown that when the concentration of catapol in the range of 0.0010.10 wt.%, The drug does not irritate the skin and is well tolerated by animals. With an increase in concentration above 0.10 wt.%, The drug irritates and sensitizes the skin and such a composition is not suitable for external use. Thus, the optimal concentration of catapol is 0.001-0.10 wt.%.

A study of the stability of the claimed drug during storage was carried out at a concentration of catapol in the range of 0.001-0.10 wt.%.

The presence or absence of microbial contamination of open vials with the preparation was determined during seven days of storage at room temperature by membrane filtration in accordance with the requirements of the State Pharmacopoeia, XI edition, issue 2, p. 187.

The study showed the preservation of biological activity and the complete absence of contamination of the drug with putrefactive bacteria and fungi during storage.

Thus, the optimal ratio of components to solve the problem in a wound healing, anti-inflammatory and anti-infective drug is a composition with the following ratio of components, wt.%:

1-Deoxy-1-B- [methyl- (2-acridon9-one-10-yl-acetate)] -ammonium-Dglucitol 8.0-15.0

Catapol 0.001-0.10, 2-Propylene glycol as a base Up to 100

Wound healing, anti-inflammatory and anti-infective efficacy of the claimed drug was evaluated in experimental studies in the treatment of burn wounds (experiment 3) and genital herpes (experiment 4).

Experiment 3. The experiment was conducted on 13 rabbits of the Chinchilla breed weighing 2.3-2.8 kg.

To simulate a thermal burn, the standard method was used (NI Kochetygov “On methods for reproducing thermal burns,” Leningrad: Medicine, 1964, p. 86). Burns were applied to the lateral thigh. Wool was removed from the side surface of the animal’s thigh and a ceramic crucible with a diameter of 1.5 cm, heated in a muffle furnace to 600 ° C, was applied to the skin for 5 s.

After that, a study was carried out in three groups of animals. In the first (control) group, treatment was not performed. In the second (experimental) group, the treatment was carried out with ointment made according to the prototype. In the third (experimental) group, the treatment was carried out by the claimed drug with an active substance concentration of 8.0 wt.%.

The animals were examined daily, the condition and size of the burn wound were determined. On days 7, 14 and 28, burn wounds were totally excised along with a section of healthy skin and subjected to histological examination. The results of the experiment are presented in table. 3.

In the control group, a site of dry coagulation necrosis, clearly limited from the surrounding healthy tissue, was formed at the site of the thermal burn immediately after its application. After 1 day, a demarcation line of the damaged epidermis 3-4 mm in size formed around this zone. Starting from day 2, a fibrin film formed on the surface of the burn wound, which thickened and became darker during the first week. In the next 7 days, hyperimia was observed on the periphery of the burn and an inflammatory cushion formed. At the same time, the size of the lesion was significantly reduced. By the 14th day from the beginning of the experiment, the lesion decreased due to the growth of tongues into it from the periphery of the epidermis. By day 28, the burn wound has completely healed.

In the 2nd group of rabbits, healing of the burn wound occurred in a shorter time than in the 1st group, however, local inflammation was significantly expressed during the entire treatment period. The shape of the burn wound changed due to the uneven growth of the epidermis. By the 21st day, the wound completely epithelized from the edges, and by the 28th day it completely healed.

In group 3, the best results were noted. During the first seven days, an intense local inflammatory reaction was observed, however, already on the 14th day the inflammation completely disappeared, and the burn wound was epithelized due to the creeping of the regenerating epithelium from the edges. Complete fusion of the wound healing epithelium occurred on day 21 of treatment, which was 7 days earlier than in group 2 (prototype) and two weeks earlier than in the control group.

Experiment 4. The experiment was carried out on 36 male guinea pigs weighing 250-300 g, which were infected with the herpes simplex virus of the second type in the form of a virus-containing suspension with an infectious titer of 5-6 bd CPD ₅₀ / ml on the scarified surface of the penis according to the method of S. S. Marennikova ( Questions of Virology, 1986, No. 1, pp. 59-65).

Studies were carried out in 3 groups of twelve animals: the first (control) without treatment, the second (experimental) - treatment with the prototype, the third (experimental) - treatment with the claimed drug with an active substance concentration of 8.0 wt.%. The treatment was carried out 48 hours after infection by the use of drugs, rubbing them into the affected surface three times a day for 8 days.

In animals of the control group, after 2448 h, redness, swelling and vesicle vesicles appeared at the site of infection. 72 hours after infection, the clinical picture of genital herpetic inspection was pronounced: fusion of individual pustules, the appearance of painful ulcers, bleeding surfaces and orchitis were noted. In some animals, the infection assumed a generalized character, expressed in the form of paresis and paralysis of the hind limbs and subsequent death on day 9-10.

The dynamics of the development of the infectious process was evaluated by the severity of the main signs of the disease. The severity was determined by a conventional four-point scale, taking into account four main signs: mucosal hyperimia, edema, specific virus-induced elements (vesicles, pustules, ulcers), orchitis and assigning a score from 0 to 4 to each of them (Marennikova S.S., Questions of Virology 1986, No. 1, p. 5965).

For example, the absence of hyperimia was estimated at 0 points, weak redness - 1 point, pronounced redness on a small area of skin - 2 points, pronounced redness on a significant area of skin - 3 points, pronounced redness on a large area of skin - 4 points. Such an assessment for all of the above characteristics was carried out for 15 days for all groups of animals and calculated the average score in each group based on one animal. The calculation results are presented in table. 4.

As can be seen from the data given in table. 4, reflecting the dynamics of the severity of the infectious process, the peak incidence in all groups of animals falls on the third day after infection. The average value of points characterizing the most pronounced development of clinical symptoms in the control group was 11.6 (the maximum possible value of 16 points - all 4 signs of the disease are pronounced and evaluated at 4 points; the minimum possible value of 0 points - all 4 signs of the disease are absent). The severity of the manifestations of infection in the control group of guinea pigs not receiving treatment was higher throughout the observation period compared with the animals of the experimental groups. The therapeutic effect of the claimed preparation and prototype was observed starting from the 2nd day of treatment and exceeded the prototype by the 3-4 day course of treatment by visual assessment of the clinical picture.

The effectiveness of the therapeutic effect of the claimed drug in comparison with the prototype was determined by the number of completely healthy animals on the 6th day of treatment and the number of dead animals on the 10th day after infection as a result of generalization of the process. The results are presented in table. 5.

As can be seen from the data presented in table. 5, the claimed drug superior to the prototype in maximum therapeutic effect by 16.7%, and also 100% prevented the generalization of herpetic infection, due to the higher bioavailability of the drug compared to the prototype.

Thus, the preparation of the claimed composition exhibits high wound healing, anti-inflammatory and anti-infective effectiveness and reduces the treatment time for infected wounds and burns.

Wound healing and anti-inflammatory efficacy of the claimed drug was evaluated in the treatment of patients with acute rhinosinusitis and purulent urethritis.

The treatment of acute rhinosinusitis was carried out in 30 patients aged 30 to 60 years. All patients had pronounced hyperimia of the nasal mucosa, swelling of the nasal concha, narrowing of the lumen of the common nasal passages. The drug with a concentration of the active substance of 8.0 wt.% Was applied by application to the nasal mucosa twice a day.

Assessment of therapeutic efficacy was based on the subjective sensations of patients and the results of rhinoscopy. After the first treatment, positive dynamics were noted during the course of the disease: relief of breathing, decrease in nasal discharge, cessation of burning and dry nose. On the 3rd day of treatment, in most patients hyperimia of the nasal mucosa disappeared, a full recovery occurred in 80% of cases, which indicates the high therapeutic efficacy of the claimed drug and can reduce the treatment time for acute rhinosinusitis.

Purulent urethritis was treated in 55 patients aged 17 to 46 years in two groups of patients - experimental and control. All patients had abundant purulent mucous discharge from the urethra, itching and burning during urination, and general malaise. Urethroscopy showed hyperimia of the urethral mucosa, its swelling and the presence of erosion. Diagnosis of the pathogen by the method of high-quality polymerase chain reaction (PCR) in the discharge from the urethra showed the presence of chlamydia (SyuatuFa 1 guyota118) and ureaplasma (IgEARITA sheaShut).

In the control group (20 patients), only basic etiotropic treatment with a macrolide antibiotic azithromycin was carried out orally at 200 mg 2 times a day for 10 days.

In the experimental group (35 patients), against the background of basic antibiotic therapy, the claimed drug was used containing 8.0 wt.% Of the active substance by intraurethral instillation through a cannula of 5 ml 1 time per day for 10 days. The effectiveness of treatment was assessed by the combination of clinical signs and elimination of the pathogen by PCR. The treatment results are presented in table. 6.

The above results show that in patients of the control group purulent-mucous discharge ceased, in most patients there was no pain during urination, itching in the urethra decreased.

However, studies on the presence of the pathogen showed that in most cases complete cure did not occur: in 70% of patients, PCR showed the presence of the pathogen.

In the second group, patients stopped purulent-mucous discharge from the urethra, itching, burning and pain during urination. Urethroscopy showed a significant reduction in mucosal erosion. An analysis of the presence of the pathogen by PCR showed the presence of chlamydia and ureaplasma in only 4 patients.

Thus, the treatment results in the experimental group of patients were significantly better than in the control. The use of the claimed drug against the background of basic antibiotic therapy reduces urethral infection, which reduces the likelihood of a relapse of the disease.

Wound healing, anti-inflammatory and anti-infectious drug of the claimed composition is a highly effective drug with high bioavailability, stability of the dosage form during storage and allows you to effectively treat infected surface and deep wounds, burns, as well as inflammatory diseases of the skin and mucous membranes, including in hard-to-reach body cavities .

Table 1

The concentration of the active substance in the preparation, wt.% The concentration of the active substance in the preparation, mg The concentration of the active substance in the epidermis after 30 min, mg Bioavailability % The quality indicators of the dosage form 5,0 1,0 0.36 ± 0.01 36.0 (low) homogeneous, transparent, viscous solution (suitable) 8.0 1,6 0.82 ± 0.01 51.2 (high) homogeneous, transparent, viscous solution (suitable) 10.0 2.0 1.05 ± 0.01 52.6 (high) homogeneous, transparent, viscous solution (suitable) 12.0 2,4 1.89 ± 0.02 78.6 (high) homogeneous, transparent, viscous solution (suitable) 15.0 3.0 2.64 ± 0.03 88.4 (high) homogeneous, transparent, viscous solution (suitable) 20,0 4.0 2.60 ± 0.03 65.3 (high) precipitate (not suitable for use)

table 2

The concentration of catapol in the drug, wt.% The effect on the skin of rabbits Preservation of sterility for 7 days Note 0 Skin after treatment with a solution without visible changes for 24 hours Does not withstand sterility The solution is suitable for treatment. 0.001 Skin after treatment with a solution without visible changes for 24 hours Sterile The drug is suitable for treatment 0.05 Skin after treatment with a solution without visible changes for 24 hours Sterile The drug is suitable for treatment 0.10 Skin after treatment with a solution without visible changes for 24 hours Sterile The drug is suitable for treatment 0.15 Hypersensitivity 1 hour after treatment to external influences. Peeling of the skin at the treatment site after 24 hours Sterile The drug is not suitable for treatment 0.50 Severe redness 1 h after treatment. Rabbits worry and try to lick the treatment site for 10-15 minutes. Severe skin peeling after 24 hours Sterile The drug is not suitable for treatment 0.75 Severe redness and irritation of the skin 1 hour after treatment. Rabbits worry and try to lick the treatment site for 20-30 minutes. Severe skin peeling after 24 hours Sterile The drug is not suitable for treatment 1,0 Severe skin irritation followed by edema and hyperemia Sterile The drug is contraindicated for treatment

Table 3

Group of animals The average size of the burn wound, cm 1 day 7 days 14 days 21 days 28 days 1 control group (without treatment) 12.5 ± 0.2 7.6 ± 0.2 3.1 ± 0.1 1.7 ± 0.2 0.48 ± 0.1 Experimental group 2 (prototype treatment) 12.3 ± 0.1 5.4 ± 0.3 3.79 ± 0.2 0.9 ± 0.1 0 Experimental group 3 (treatment with the claimed drug) 12.8 ± 0.1 6.2 ± 0.2 1.3 ± 0.1 0 0

Table 4

Days after infection The dynamics of the severity of the infectious process (in points per 1 animal) 1 control group (without treatment) Experimental group 2 (prototype treatment) Experimental group 3 (treatment with the claimed drug) one 2.6 2.6 2.6 2 6.2 5,0 5,0 3 11.6 9.8 8.0 4 6.4 6.2 5.8 5 6.1 5,6 4.7 6 6.0 5.8 4.2 7 5.3 4.7 3,7 8 3.0 1.3 1,0 nine 2.0 0.7 0.5 10 0 0 0

Table 5

Group of animals The number of completely healthy animals on day 6,% The number of dead animals on day 10,% 1 control group (without treatment) 8.33 25.0 Experimental group 2 (prototype treatment) 33.3 16.6 Experimental group 3 (treatment with the claimed drug) 50,0 0

Table 6

Indicators Control group, people,% Experienced group, people,% before treatment after treatment before treatment after treatment The presence of chlamydia and ureaplasma in the discharge 20 (100) 14 (70) 35 (100) 4 (11.4) Itching and burning in the urethra 20 (100) 11 (55) 35 (100) 2 (5.7) Urethral inflammation 12 (60) 11 (55) 19 (54.3) 2 (5.7) Pain during urination 20 (100) 5 (25) 35 (100) 5 (14.2) The presence of erosion of the urethral mucosa 7 (35) 5 (25) 12 (34.2) 3 (8.5) The presence of purulent-mucous discharge 20 (100) 0 (0) 35 (100) 0 (0)

CLAIM

Claims (1)

Wound healing, anti-inflammatory and anti-infectious medicinal product containing an active substance and a base, characterized in that it contains 1-deoxy-1-Ν [methyl- (2-acridon-9-on-10-yl-acetate)] as an active substance -ammonium-D-glucitol, as a base, 1.2 propylene glycol and, in addition, as a preservative, catapol in the following ratio of components, wt.%: 1-Deoxy-1-Ν- [methyl- (2-acridone9-one-10-yl acetate)] - ammonium-Dglucitol Catapol 1,2-propylene glycol 8.0-15.0 0.001-0.10 To 100