Wound healing, anti-inflammatory and anti-infective drug

 

(57) Abstract:

The invention relates to medicine and veterinary medicine, in particular to medicines for external use, and can be used for the treatment of infected superficial and deep wounds, burns, and inflammatory diseases of the skin and mucous membranes. The invention lies in the fact that the drug contains as active substance 1-deoxy-1-N-[methyl-(2-acridin-9-one-10-yl-acetate)]-ammonium-D-glucitol, as the basis - 1,2-propylene glycol and optionally as a preservative - katapola at a certain ratio of components. The invention provides a drug with high bioavailability, stability of the dosage form during storage and enable you to effectively treat infected surfaces, including hard-to-reach cavities of the body. 6 table.

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

Currently, as lekarstvennyh forms for external and internal use.

Known wound-healing and anti-inflammatory drugs internal use in solid dosage form for oral administration, such as tribenzoate, aescusan (Mashkovsky M. D. Medicines. M: New Wave, 2000, 14 ed., T. 1, pp. 442 - 443).

Disadvantages preparations for internal use is the limited application associated with the presence of a wide range of contraindications, as well as with poor performance due to low bioavailability, which allows their use only as part of complex therapy.

Known wound-healing and anti-inflammatory drugs for external application in the form of wipes and bandages (RF patent N 2107516, prior. 27.03.98 year , A 61 L 15/00 "Dressing for the treatment of wounds and how you can get it"), which are used in the form of applications on the wound surface.

The disadvantages of these drugs include: long-term treatment, a high consumption of drugs, the limited application of complex pathologies, acute purulent secretions.

Known wound-healing and anti-inflammatory drugs in the form of creams and ointments containing the active substance, fatty base and additives. Thus, in the patent of Russian Federation N 2114611, prior, 2, vitamins E and C, a mixture of lanolin and vaseline as ointment bases.

However, lanolin base in these drugs interferes with the normal gas exchange, which reduces wound healing activity of the drug, especially when slow processes.

Known wound-drug "Liniment methyluracil (RF patent N 2007997, prior, from 08.07.92, And 61 K 9/06), containing as active substance form methyluracil, and as the base castor oil. The drug has increased wound healing activity due to the high bioavailability of the dosage form.

However, in this drug active substance does not possess anti-infective and interferonogenna properties, which does not allow to treat infected wounds.

Known RF patent N 2135474, prior, from 19.08.98, which describes the finished dosage form for external application of 5% ointment, containing as active substance salt greenexpo acid with 1-deoxy-1-methylamino-D-galactitol, and as the basis glycerin, castor oil and lanolin, in the following ratio, wt.%:

Sol greenexpo acid with 1-detoxing selected as a prototype.

The ointment of the above composition has wound-healing, anti-inflammatory and anti-infective action in the treatment of infectious diseases of skin and mucous membranes.

However, the low bioavailability of the active substance and the low adhesive ointments lead to the lack of effectiveness of the treatment of superficial and deep wounds. In addition, this ointment may not be used in inaccessible body cavities due to the thick consistency framework that limits the scope of its application.

In addition, when storing such ointments observed the development of foreign flora and rancid fat basis in the absence of its composition preservatives, which reduces the stability of the drug product when stored.

The objective of the invention is to provide a highly effective wound-healing, anti-inflammatory and anti-infective drug for external use, with high bioavailability, stability of the dosage form during storage and allows effective treatment of infected superficial and deep wounds, burns, and inflammatory diseases of the skin and mucous membranes, including tolocally and anti-infective drug, a containing the active substance and the basis, according to the invention contains as active substance 1 - deoxy-1-N- [methyl- (2-acridin-9-one-10-yl-acetate)]-ammonium-D-glucitol, as the basis-1,2-propylene glycol, and optionally, as a preservative-katapola, in the following ratio, wt.%:

1-Deoxy-1-N-[methyl-(2-acridin-9-one-10-yl - acetate)]-ammonium-D-glucitol - 8,0-15,0

The katapola - 0,001-0,10

1,2-Propylene glycol - 100

The claimed preparation contains as the active substance 1-deoxy-1-N-[methyl-(2-acridin-9-one - 10-yl-acetate)]-ammonium-D-glucitol, known as the biologically active substance possessing prolonged interferonogenna activity (EA patent N 000382, prior, from 22.01.98,, C 07 H 5/06) and used in solid dosage form for oral administration (patent RF N 2115415, prior, from 15.03.95 year, A 61 K 9/20).

The authors of the present invention first shown wound healing and anti-inflammatory activity of 1-deoxy-1-N-[methyl-(2-acridin-9 - one-10-yl-acetate)] -ammonium-D-glucitol, which is inherent only in the dosage form of the inventive preparation, namely, liniment, which in combination with anti-infective properties of the active substances, can effectively be treated as inficere, the proposed product contains 1,2-propylene - non-aqueous hydrophilic solvent with good penetrating ability, which provides a high bioavailability of the active substance in the affected tissue, thus increasing the efficiency of therapeutic effects and shortens the treatment of 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 interferes with normal gas exchange, which in combination with the high bioavailability of the active substance increases the effectiveness of healing of wounds and burns.

In addition, 1,2-propylene glycol provides sufficient fluidity and rapid absorption of the drug in the mucous membranes that allows you to enter it in a difficult to reach area of the body and increases the effectiveness of treatment of inflammatory diseases of the upper section of the urethra, middle ear, sinuses etc.

All of the above allows you to expand the use of the claimed medicinal preparation and increases the efficiency of the treatment of infected superficial and deep wounds, ogogo which contains katapola. The katapola known as an antiseptic (Pharmacopeia 42-3126-95), but its preservative properties have not previously been described.

Thus, the claimed wound healing, anti-inflammatory and anti-infective drug when experimentally established the optimum ratio of components allows to increase efficiency and reduce the time of treatment of infected wounds and burns, as well as inflammatory diseases of the skin and mucous membranes, to expand the use of the drug and to provide stability during storage.

The invention is as follows.

To prepare 100 liters of wound healing, anti-inflammatory and anti-infective drug take 50,0 liters of 1,2-propylene glycol, 8 kg of 1-deoxy-1 - N-[methyl-(2-acridin-9-one-10-yl-acetate)]-ammonium-D-glucitol and 0.1 kg of katapola and stirred until complete dissolution of the components. Then add 1,2-propylene glycol to a final volume of 100 liters. The resulting solution was filtered through a sterilizing filter type "pall", poured into sterile vials of 5, 10 and 100 ml. Output of the finished product in 98%. The bottle of capacity of 100 ml contains 8 wt.% 1-deoxy-1-N-[methyl-(2-acridan-9-it-10 is alleny the results of experimental and clinical studies of wound healing, anti-inflammatory and anti-infective drug.

In table. 1, 2 shows the selection of the optimal composition of the claimed medicinal preparation.

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

The choice of the optimum ratio of components in the inventive preparation was determined experimentally.

Experience 1. The choice of active ingredient content was carried out in terms of bioavailability of the active substance. The experiment was carried out on rabbits of the Chinchilla breed, divided into 9 groups of 9 animals. On pre-obezbasheny and clarificatory area of skin on the back of a rabbit the size of 5 cm2inflicted compositions with different content of active substance at the rate of 0.2 ml per 1 cm2. On the neck of the rabbit wore a special collar that prevents kisiwani of the drug.

After 30 minutes, carefully wipe the treated area with distilled water and anesthetized cut the skin with epidermal layer of size 1 cm2which is homogenized by ultrasound for extraction of active substances with 100 ml of distilled water for 30 minutes Recip is ncentratio of the active substance at a wavelength of 408 nm.

The obtained experimental data are presented in table. 1, show that the bioavailability of more than 50% obtained when the concentration of the active substance in the claimed preparation in the range of from 8.0 to 15.0 wt.%. When the concentration of the active substance is less than 8.0 wt.%, bioavailability of less than 50% and is insufficient for effective treatment of deep wounds and burns. At concentrations of more than 15.0 wt.% the active substance is not fully dissolved in 1,2-propylene glycol, forming sludge. When you try the further dissolution of the active substance during heating, after cooling to room temperature, it undergoes partial crystallization during storage and this structure is unfit for use.

Experience 2. The content of katapola in the present preparation was carried out experimentally. We studied the different concentrations of katapola in the interval from 0 to 1.0 wt.%. Study drug concentrations katapola more than 1.0 wt.% was not carried out, because such concentrations cause burns to the skin and mucous membranes (RLS-PHARMACIST, second Edition, revised and expanded, M., radar-2000, page 540).

Experiments were performed on rabbits of the Chinchilla breed, divided into 7 groups of 5 animals. On preprepared, containing 8 wt.% active substances with different content of katapola at the rate of 0.2 ml per 1 cm2. On the neck of the rabbit wore a special collar that prevents kisiwani of the drug. After 30 min was performed site inspection of the skin to determine the presence of irritant effects (itching, redness, burns). The following examination was performed within 24 hours.

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

Studies have shown that when the concentration of katapola in the range 0.001-0.10 wt.% the product does not irritate the skin and is well tolerated by animals. By increasing the concentration above 0.10 wt.% the drug is irritating and sencibilisiruet skin and this composition is not suitable for outdoor use. Thus, the optimum concentration of katapola 0.001 to 0.10 wt.%.

The study of the stability of the proposed drug during storage was carried out at a concentration of katapola in the range 0.001-0.10 wt.%.

The presence or absence of microbial contamination of opened vials of the drug were determined within seven days of storage at room temperature by the method of membrane filtration in accordance with the requirements of the State Pharmacopoeia, XI edition, issue 2, page 187.

Escaparate putrefactive bacteria and fungi during storage.

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

1-Deoxy-1-N- [methyl-(2-acridin-9-one-10-yl-acetate)]-ammonium-D-glucitol - 8,0-15,0

The katapola - 0,001-0,10

1,2-Propylene glycol as the base - To 100

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

Experience 3. The experiment was carried out in 13 rabbits of the Chinchilla breed weight 2,3 - 2,8 kg

For modeling thermal burn used standard method (Kochetygova N. I. ways of playing thermal burns, L.: Medicine, 1964, page 86). The burns were applied to the lateral surface of the thigh. The plot side of the thigh of the animal was removed coat and applied to the skin ceramic crucible with a diameter of 1.5 cm, and heated in a muffle furnace up to 600oC, and for 5 sec.

After that carried out the study in three groups of animals. In the first (control) group treatment does not show the group the treatment was performed by the claimed preparation with a concentration of active substance 8.0 wt.%.

Animals were daily inspected, determined the condition and size of burn wounds. At 7, 14 and 28 days of burn wounds totally cut out together with a plot of healthy skin and subjected to histological examination. The results of the experiment are presented in table. 3.

In the control group in place of a thermal burn immediately after application formed the dry land of coagulation necrosis, strictly delimited from the surrounding healthy tissue. After 1 day around this area formed the line of demarcation damaged epidermis size 3-4 mm Starting from the 2nd day on the surface of the burn wounds was formed fibrin film, which was totalsales and became darker in the first week. In the next 7 days on the periphery of the burn was observed hyperemia and formed inflammatory roller. The dimensions of the lesion were significantly decreased To 14-th day since the start of the experiment, the tumor shrank by growing it with the periphery of the epidermis in the form of languages. By the 28th day of burn wound completely zarzuelas.

In the 2nd group of rabbits healing of burn wounds occurred in a shorter time than in the 1st group, however, and during the whole period of treatment was significantly expressed in local was vocalensemble from the edges, and by the 28th day fully healed.

In the 3rd group were awarded the best results. During the first seven days there was intense local inflammatory reaction, however, on the 14th day the inflammation was completely gone and the burn wound epithelials by napoletane regenerating epithelium from the edges. Complete fusion of epithelial wound healing occurred on the 21st day of treatment, which is 7 days earlier than in the 2nd group (prototype) and two weeks earlier than in the control group.

Experience 4. The experiment was carried out on 36 male Guinea pigs weighing 250-300 g were infected with herpes simplex virus type II in the form of virus.terima suspension infectious titer 5-6 Lg JRS50/ml scarificing the surface of the penis by the method of Marennikova S. C. (Questions Virology, 1986, No. 1, pp. 59-65).

Studies were performed on 3 groups of twelve animals: the first (control) - no treatment, the second (experimental) treatment of prototype, the third (experienced) - treatment of the claimed product with the concentration of the active substance 8.0 wt. %. Treatment was carried out at 48 hours after infection by the use of drugs, rubbing them into the skin surface three times a day for 8 days.

Rovkuly. 72 hours after infection the clinical picture of genital herpes infection was pronounced: it was noted merge individual pustules, the appearance of painful ulcers, bleeding surfaces and orchitis. In some animals the infection took generalized nature, expressed in the form of paresis and paralysis of the hind limbs and the subsequent death at 9-10 day.

Dynamics of infection was assessed by severity of core symptoms of the disease. Severity was determined by conventional four-point scale, scale, taking into account the four basic characteristics: hyperemia mucosa, edema, specific virusinduced elements (vesicles, pustules, ulcers), orchitis and assigning each of them a score from 0 to 4 (Marennikova S. C., Questions of Virology, 1986, No. 1, pp. 59-65).

For example, the absence of hyperemia was estimated at 0 points, mild redness - 1 point, clearly marked redness on a small skin area - 2 points, clearly marked redness on significant skin area - 3 points, pronounced redness on extensive skin area - 4 points. Such an assessment on all of the above characteristics was carried out for 15 days for all groups of animals and vicev table. 4.

As can be seen from the data given in table. 4, reflecting the dynamics of the severity of the infectious process, with the peak incidence in all groups of animals falls on the third day after infection. The average value of the scores featuring the most pronounced development of clinical symptoms in the control group was 11.6 (maximum value of 16 points - all 4 symptoms for pronounced and assessed 4 points; the minimum possible value of 0 points - all 4 symptoms for absent). The severity of manifestations of infection in the control group of Guinea pigs not receiving treatment, was higher during the whole observation period compared with the animals of the experimental groups. therapeutic effect of the proposed drug and the prototype was observed starting from the 2nd day of treatment and on 3-4 day course of treatment on visual assessment of the clinical picture was superior to the prototype.

The effectiveness of therapeutic action of the proposed drug in comparison with the prototype was determined by the number of fully healthy animals on the 6th day of treatment and the number of dead animals on the 10th day after infection in the generalization process. The results obtained are presented in table. 5.

Thus, the preparation of the inventive composition shows high wound-healing, anti-inflammatory and anti-infective efficiency and shortens the treatment of infected wounds and burns.

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

Treatment of acute rhinosinusitis was carried out in 30 patients aged 30 to 60 years. In all patients there was a strong hyperemia nasal mucosa, abahlali turbinates, narrowing of the lumen of the common nasal passages. The drug concentration of the active substance to 8.0 wt.% inflicted by application to the mucous membrane of the nose twice a day.

Assessment of clinical effectiveness was based on the subjective feelings of the patients and results rinoskopii. After the first treatment was noted positive dynamics and course of the disease: relief of breathing, decrease the secretions of the nose, the cessation of burning and dryness in the nose. On the 3rd day of leczenia, that indicates a high therapeutic efficacy of the proposed drug and can shorten the period of treatment of acute rhinosinusitis.

The treatment of purulent urethritis was performed in 55 patients aged from 17 to 46 years in the two patient groups - experimental and control. All patients were observed purulent, mucous discharge from the urethra, itching and burning during urination, General malaise. Ureteroscopy showed hyperemia mucous membrane of the urethra, its swelling and the presence of erosions. Diagnosis of the pathogen using qualitative polymerase chain reaction (PCR) in the discharge from the urethra showed the presence of chlamydia (Chlamydia trachomatis) and ureaplasmas (Ureaplasma urealiticym).

In the control group (20 patients) was performed only basic causal treatment macrolide antibiotic azithromycin oral 200 mg 2 times a day for 10 days.

In the experimental group (35 patients) against baseline antibiotic therapy was used the claimed medicinal preparation containing 8.0 wt.% the active substance, by be installations through the cannula 5 ml of 1 times a day for 10 days. The treatment efficiency was evaluated on a set of clinical signs and elimination of the pathogen by PCR. The results of the cluster continued purulent mucus, most patients have no pain when urinating, decreased itching in urethra.

However, studies on the presence of the pathogen showed that in most cases, full recovery has not come: in 70% of patients PCR showed the presence of the pathogen.

In the second group of patients stopped purulent mucous discharge from the urethra, itching, burning and pain during urination. Ureteroscopy showed a significant decrease in erosion of the mucosa. Analysis of the presence of the pathogen by PCR revealed the presence of chlamydias and ureaplasmas in only 4 patients.

Thus, the results of the treatment in the experimental group patients was significantly better than the control. The use of the proposed drug on the background of basic antibiotic therapy reduces infection of the urethra, reducing the chance of relapse.

Wound healing, anti-inflammatory and anti-infective drug product for the claimed composition is a highly effective drug that has a high bioavailability, stability of the dosage form during storage and allows you to effectively treat infected superficial and deep wounds, burns, and inflammatory C is engaged, anti-inflammatory and anti-infective drug product containing an active substance and a base, characterized in that the active substance it contains 1-deoxy-1-N-[methyl-(2-acridin-9-one-10-yl-acetate)] -ammonium-D-glucitol, as the basis - 1,2-propylene glycol and optionally as a preservative - katapola in the following ratio, wt.%:

1-Deoxy-1-N-[methyl-(2-acridin-9-one-10-yl-acetate)]-ammonium-D-glucitol - 8,0 - 15,0

The katapola - 0,001 - 0,10

1,2-Propylene Glycol - Up To 100.0

 

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