Complex of biologically active drug

 

(57) Abstract:

The drug is intended for treatment of gastric ulcer and/or duodenal ulcer, gastritis and colitis mostly in cases when the microflora identified the bacterium Helicobacter pylori infection and for the treatment of many other inflammatory diseases. The product contains, by weight.h.: polyvinylbutyral ether (Vinylinum)-100,0; dichloride 1,2-ethylene-bis-(N-dimethylcarbamate)-ammonium(atoni) - 1,0-2,5 dichloride and 1,10-decametre-bis-(N,N-dimethylaminocarbonylmethyl)-ammonium(decamethoxin) 0.05 to 0.15. New drug improves the efficiency of the treatment of a wide range of inflammatory diseases, in particular the reduction in terms of therapeutic effect and/or .increased periods of remission. New drug helps to increase the resistance of patients to infections. 4 C.p. f-crystals, 4 PL.

The invention relates to the qualitative and quantitative composition of complex biologically active preparation on the basis of polyvinylbutyral ether. Various stated below the dosage form of this drug is intended for use in medicine and veterinary medicine, in particular for treatment:

gastric ulcer or two the lore of the patient revealed the bacterium Helicobacter pylori (hereinafter abbreviated as N. R.);

trophic (including recurrent) ulcers;

long-term healing of infected wounds, burns, pyodermia, pyococcal ulcers and Achimov (usually the leg);

itching dermatoses and microbial eczema;

hemorrhoids arbitrary etiology;

other inflammatory diseases of the rectum (for example, acute paraproctitis, proctitis and proctosigmoiditis (especially complicated fractures) and fistula;

erosive-ulcerative and ulcerative-necrotic radiation injuries of the skin, x-dermatitis;

acute and chronic inflammations of the mucous membrane of the vagina, fallopian tubes, ovarian, cervical erosion, cracking nipples, traumatic (in particular, generic) damage to the perineum;

stomatitis and

a number of other indolent chronic inflammatory diseases, due to the blurred forms of immunodeficiencies, which are characteristic of the population heavily polluted regions, for example, for residents of the areas adjacent to the Chernobyl NPP.

Due to the popularity of most of these diseases are complex, biologically active products should work together to meet several hardly compatible requirements:

at p is x, to be the products of the pharmaceutical industry and delivered in the pharmacy network, so they can be used both in clinical and outpatient and home;

thirdly, to have a minimum of contraindications;

fourth, to provide when using a pronounced synergistic effect.

Separate fulfill these requirements does not pose significant difficulties.

Indeed, it is widely known (mostly separate) the use of specific drugs for the treatment of inflammatory diseases of different etiologies or to improve the immune status of the organism.

An example is the drug De-Nol-based colloidal bismuth subcitrate, distributed in a suitable solid or liquid pharmaceutically neutral medium (see, for example: the prospect of a Dutch company Gist-brocades "De-Nol is a logical solution to the problem of treatment of gastritis and peptic ulcer or article P. I. Grigoriev and other "Comparative performance evaluation of comprehensive anti-ulcer treatment and monotherapy in the magazine "Soviet medicine", 1984, No. 2, S. 100-101).

Indeed, as shown in a hundred who eat traditional antiulcer complexes of 5-6 ingredients, tailor-made according to objective data about the patient, the experience and intuition of the attending physician, and including at least one cholinergic antagonist, at least one antacid and some reparants and antibiotics (for example: ActiveRecord, vitamins B1, B6, C, gastroporn or metronidazole).

However, as noted in the prospectus, first, among doctors, there is a strong prejudice to wimalasundera drugs because of the risk of encephalopathy in overdose due to careless or too long-term use and, secondly, these drugs are contraindicated in severe kidney dysfunction and unwanted pregnancy and lactation. Further, in the treatment of infected N. R. ulcer patients De-Nol should be combined with antibiotics (such as metronidazole or amoxicillin), which could cause nausea, diarrhea, dry mouth, fungal infections, pseudomembranous colitis, and General malaise.

And, finally, the applicability of De-Nol in the above wide range of diseases is not installed.

Now known a number of biologically active compounds with a very broad spectrum of action, which is to reduce the amount of review of the prior art is below R is La's most well-studied polyvinylbutyral ether, hereinafter referred to as the "Vinylinum" (see, for example, the book M. D. Mashkovsky. Medicines / a Manual of pharmacotherapy for physicians", ch. II, ed. 8th revised and enlarged extra - M.: Medicine, 1977, S. 371).

At room temperature it has the form of a thick viscous light yellow practically insoluble in water liquid, able to be combined with vegetable oils. Vinylinum practically non-toxic, has no contraindications and effective:

first, in the treatment of boils and carbuncles, trophic ulcers, cut, sliced, firearms and other (in particular, chronic) wounds, burns and frostbite by applications in pure form or in the form of solutions in oils or emulsions (ointments) and

secondly, in the treatment of peptic ulcer of stomach and duodenum gastritis and colitis receiving per os capsules made of pharmacologically inert material (usually gelatin).

Treatment of peptic ulcer disease to achieve a pronounced therapeutic effect is usually 16-18 days. therapeutic effect is achieved due to the enveloping and bacteriostatic action.

However, due to the insolubility of Vinylinum in water (and therefore, due to the almost complete exclusion of diffusion in bi is to the superficial contact with parts of the body of the patient.

Considerably more opportunities for therapeutic effect when using drugs on the basis of infinitely soluble in water (and, respectively, in an arbitrary liquid biological environments) ionogenic surface-active substances such as Quaternary ammonium bases.

One of such preparations with antibacterial and fungicidal activity - dichloride 1,10-decametre-bis-(N, N - dimethylaminocarbonylmethyl)ammonium or what is the same thing. 1,10-decametre-bis-[N-dimethyl-(carbinoxamine)-ammonium] dichloride, hereinafter referred to as the "decamethoxin" (see VFS 42-1814-88, approved by the USSR Ministry of health 05.05.1988 year).

Decamethoxin slightly toxic contraindicated for use only if you are hypersensitive and highly effective solutions based on water:

in the treatment and prevention of applications, plugging, irrigation, enemas and inhalation purulent and / or fungal infections, including severe diseases such as abscess or multiple cysts of the lung, or such intractable diseases as ulcerative-necrotic gingivitis, dystrophic and inflammatory forms of periodontal disease, periodontitis and periostitis, and

when antisepticise and skin of patients in the area of the surgical field.

However, its high solubility leads to rapid removal from the cavities and, especially, to the surfaces of the body. Often (usually when trying to treat peptic ulcer disease) this property makes it ineffective, and in most cases leads to a frequent repetition of the procedures to obtain good therapeutic effect.

Similar physico-chemical and farmakologicheskie property has a drug of the same class - dichloride 1,2-ethylene-bis(N-dimethylcarbamate)-ammonium, hereinafter referred to as "atone" (see decree. book, S. 366). Unlike decamethoxinum atony:

active against antibiotic resistant strains of Staphylococcus aureus and can serve as an antidote when staphylococcal intoxications;

in small (of the order of 0.05 to 0.25 %) concentrations has local anesthetic effects;

when introduced into the body stimulates the metabolism and contributes to some of the increasing concentration of gamma globulin in peripheral blood;

when applications 2% ointment significantly reduces the time of healing of erosive-ulcerative and ulcerative-necrotic radiation and burn injury of the skin.

However, as in cases where de is atorney practice.

And finally, well-known sulfoxide, hereinafter referred to as the "Dimexidum (see Instructions on its use, approved 16.06.72 the USSR Ministry of health). At temperatures above 16oC it represents a moving liquid, easily soluble in water and freely diffusing through the skin or mucous membranes in the deep soft tissues of the patients both in pure form and in conjunction with dissolved in it other medicines.

Dimexide slightly toxic, has a strong local anesthetic action, anti-inflammatory and antimicrobial activity and is able to sensitize drug resistant microflora. This led to its use as an analgesic (especially with injuries, arthritis, radiculitis), disinfectant (mainly in the skin-plastic surgery) and transport medium for the introduction of other drugs through the skin or mucous membranes.

However, at therapeutic concentrations (20-90% aqueous solution) and doses (up to 0.5 l 25-50% solution of applications per day) dimexide can cause allergic reactions. In addition, for the application of Dimexidum there are serious contraindications, pregnancy-related, heavy is, and comatose States.

Therefore, the main direction of extension of the scope of such drugs is the creation of complexes that would provide a reduction of the side effects of each ingredient and enhancing therapeutic effect of the aggregate.

From the known products of this type to offer to the technical nature of the closest of complex biologically active agent on the basis of Vinylinum with the addition of 0.2-0.5% etoniya (see I. M. Kazan and A. I. Kulinenko. Application etoniya in the treatment of some diseases of the mucous membranes of the oral/practical medicine. - Lviv, 1970, S. 157-158).

Describes the complex was successfully used for the treatment of disease of various etiologies. Further, it was shown that it is applicable and in gynecological practice for the treatment of cervical erosion with the use of vaginal tampons.

However, this complex was not sufficiently effective in the treatment of gastric ulcer or duodenal ulcer, gastritis and (especially ulcerative) colitis in cases when the microflora of patients was identified bacterium N. R. In particular, the average time to extinction of the Kli is littelest remission was about 10 months.

In relation to other, mainly inflammatory diseases scope of the specified complex and effectiveness of treatment was close to vineline with minor improvements, due to the surface activity etoniya and therefore more dense viscous contact Vinylinum with exposed therapeutic effects of the skin or mucous membranes.

Therefore, the basis of the invention is by completion of the composition and changes in the ratio of ingredients to create a complex of biologically active drug, which would have a synergistic effect and, thus, would increase the effectiveness of treatment (in particular, the reduction in terms of therapeutic effect and / or increased periods of remission) in a wide range of predominantly inflammatory diseases and would increase the resistance of patients to infections.

The problem is solved by the fact that the complex of biologically active preparation containing polyvinylbutyral ether (Vinylinum) dichloride and 1,2-ethylene-bis-(N-dimethylcarbamate)-ammonium (atony), according to the invention further comprises dichloride 1,10-decametre-bis-(N,N-dimethylbenzoic parts):

Vinylinum - 100,ON

Atony - 1,0-2,5

Decamethoxin - 0,05 -0,15

Introduction decametoxyn in complex biologically active drug at the specified ratio of ingredients provides the widest range of anti-inflammatory and antimicrobial action and helps to reduce the duration of therapeutic effect, lengthening periods of remission in recurrent disease and to improve the resistance of patients to infections, lower is confirmed by experimental and clinical data.

The first additional difference is that the ingredients are taken in the following ratio (in mass units):

Vinylinum - 100,0

Atony - 1,0 - 2,0

Decamethoxin - 0,05 -0,15

The drug is so narrowed by the ratio of ingredients is the most effective in the treatment of peptic ulcers, hemorrhoids and other anal diseases, long-term healing of infected wounds, burns, pyodermia, pyococcal ulcers and Achimov tibia. A second difference is that the ingredients are taken in the following ratio (in mass units):

Vinylinum - 100,0

Atony - 1,5 - 2, 5

Decamethoxin - 0,05 - 0,15

The drug is so narrowed sootnoshenie the VNO-ulcerative and ulcerative-necrotic radiation injuries of the skin and x-dermatitis.

The third additional difference is that the ingredients are taken in the following ratio (in mass units):

Vinylinum - 1100,0

Atony - 1,0 - 1,5

Decamethoxin - 0,05 - 0,10

The preparation of this narrowed the ratio of ingredients is the most effective in the treatment of acute and chronic inflammation of the mucous membrane of the vagina, cracked nipples, traumatic (in particular, generic) damage to the perineal and cervical erosion.

Fourth difference is that the preparation additionally contains dimethylsulfoxide and that the ingredients are taken in the following ratio (in mass units):

Vinylinum - 100,0

Atony - 1,0 - 1,5

Decamethoxin - 0,05 - 0,10

Dimethyl sulfoxide - 3,0 - 5,0

The drug with the same qualitative composition and the ratio of ingredients is especially effective in the treatment of inflammation and subsequent obstruction of the fallopian tubes and inflammation of the ovaries.

Further, the invention is illustrated with specific examples of the composition of the proposed drug (see table. 17), a description of its method of preparation and storage conditions and the results of comparative tests.

As can be seen from the table.1, examples 4 and 5 relate to the minimum level 7 and 9 for compositions in which it corresponds to the boundaries of the declared range: other examples set the ratio within the boundaries of the claimed range.

The method of manufacture of the proposed drug in the General case is as follows.

The primary dosage form is an aqueous emulsion.

As its water base is plain distilled water at the rate of 15 ml per 100 g of Vinylinum, which is the base ingredient and a lot of which lead all calculations.

In the specified quantity of water dissolve the required specific recipe number etoniya, then decamethoxinum, and if it is provided in a specific recipe - Dimexidum.

The holder of a high-speed stirrer fix a beaker containing 100 g of Vinylinum, include the drive and slowly (usually with the help of a dropper) under vigorous stirring injected aqueous solution etoniya and decamethoxinum (or these ingredients and Dimexidum). Stirring is continued after completion of the dose specified solution for at least 15 minutes to obtain a thick white creamy emulsion that is able to be stored without separation at a temperature of about 20oC for at least six months.

scientists portion of the drugs used to treat or direct introduction of therapeutic doses per os (which is preferable for continuous readjustment of the gastrointestinal tract), or when pronounced emetic reactions in individual patients after the encapsulation, for example in the well-known gelatin shells.

Because each included in a complex of ingredients itself is widely known, approved for clinical use and are used in concentrations which are significantly less pharmacologically acceptable that means the possibility of combining them in recipes practitioners, to the extent the obtained complexes were used directly in terms of clinics in compliance with all contraindications, which are known for each of the ingredients.

Most research has been conducted on patients with peptic ulcer of the stomach, the microflora of the gastrointestinal tract which reliably microbiologically (on crops of smears obtained fibrogastroscopy biopsies flank areas ulcers), histologically after staining similar biopsies of 0.01% acridine orange) and biochemically (according to the results of determining the activity of urease was detected N. R.

Examined patients with similar age, medical history and clinical manifestations initially brought in 4 groups of 15 patients each (with pring vegetable oil with a daily dose of 2.5 mg/kg of body weight.

Patients of the second group was administered per os to 0.15% of the same emulsion decametoxyn with a daily dose of 0.2 mg/kg of body weight.

Patients of the third group was administered per os clean Vinylinum capsules with a capacity of 1.4 g once (after 4-5 hours after an early dinner) 4 capsules per day.

Patients of the fourth group was administered per os offered a complex of biologically active drug products indicated for Vinylinum method.

The treatment was performed before the onset of remission.

The obtained average results are given in table. 2.

After receiving the clearly positive results when using the proposed drug is manufactured in accordance with examples of formulations 1, 2 and 3, were treated even 753 patients. The results were averaged and the data obtained are shown in the last row of table 2.

In addition, in the same table 2 enabled independently obtained data on the effectiveness of the treatment of ulcer patients using the above conventional therapy and results "monotherapy with De-Nol.

As can be seen from table 2 for all considered parameters in the proposed complex of biologically active drug zivnosti, which clearly indicates pronounced synergistic interaction Vinylinum and these two Quaternary ammonium bases.

In the process of treatment 768 patients who have been prescribed according to the invention, the formulation according to example 1 of table 1 was used in 65, the formula in example 2 - 683-x and formulation from example 3 in 20 cases.

Differences in the effectiveness of treatment in these subgroups were not significant.

Thus, patients of the first sub-group receiving the drug with minimal content etoniya and decamethoxinum, somewhat later (average 7 days) disappeared manifestation of clinical symptoms of peptic ulcer disease and is also slightly longer (average 13 days) was the healing of the ulcer niche, but at the time of remission, this delay is almost not affected.

Patients of the second subgroup all listed in table 2, the timing was almost within range of deviations from the mean in the range from +3.0 to -3,0%.

Finally, in patients of the third subgroup was virtually no noticeable increase in the remission period on the background of a slight (up to half a day) reduce periods of disappearance of clinical symptoms anvendelse examples of formulations 6 and 7 of table 1 were used in the treatment of purulent-inflammatory diseases occurred on the background of household injuries with extensive abrasions and contusions.

Treating patients of both sexes aged 18 to 50 years old who have:

within 1-2 days after injury began acute inflammation with swelling and pain,

within 4-5 days came not improve with conventional therapy with antibiotics, and

through laboratory studies were identified antibiotic-resistant or ntibiotikozawisimos strains Golden or epidermal Staphylococcus.

While the drugs used by applications on magnitnye and surrounding edematous surface in 304 cases for treatment revealed (preparation according to example 6) and in 219 cases newsrussia ulcers (preparation according to example 7).

Served as control group patients, respectively, from 218 and 115 persons, treatment which is used only atony as a 2% ointment on the basis of lanolin, and 74 and 86 persons, treatment which is used only decamethoxin in a 0.2% water-glycerol solution. Clean Vinylinum in the control did not apply, because in pyo-inflammatory processes he manifests a well-known mainly bacteriostatic (not antibacterial) effect and in the cases of clearly inappropriate.

All patients were residents of Kyiv is a result of the Chernobyl NPP.

Clinically all patients at the end of the first day of treatment of complex biologically active substance according to example 6 in areas of inflammation was observed a significant decrease in swelling, redness and pain, but on the second-fourth day - a noticeable clearing from pus, further reduce swelling up to the disappearance and the almost complete absence of redness and pain even when the pressure in the vicinity of inflammation.

The preparation according to example 7 to the end of the first-second day helped to reduce swelling, and alleviate pain, and by the end of the third-fourth days usually caused breakthrough (sometimes even deeply localized) ulcers with heavy drainage of pus, an almost complete disappearance of redness and visible relief of the General condition of patients. When using pure etoniya or net decamethoxinum similar improvements were observed with a lag of a day or two and were less pronounced.

The proportion of patients (% of total number in the appropriate group), which by the end of the first week of treatment almost completely stopped the inflammatory process and began the healing of wounds, are shown in table 3.

Preveden the imposition of Dimexidum promoted practical adjustment of the effectiveness of treatment of public and private ulcers on the timing of the release of pus.

Complex drugs, containing per 100 m H. Vinylinum 0,9 m H. etoniya and 0.04 m H. decametoxyn according to example 4 of table. 1 and 2.7 m H. etoniya and 0.17 m H. decametoxyn according to example 5 of Fig. 1, were prepared as described above, in the preclinical phase, used in veterinary practice for the treatment of infectious mastitis in cattle. Drugs used by applications under the plaster in comparison with combinations of Vinylinum and antibiotics.

For the formulations from example 4, it was found that in comparison with the use of Vinylinum in combination with the antibiotics penicillin, the cure time was reduced on average by no more than two days, and for the formulation according to example 5, that the drug, despite a significant advantage over combinations of Vinylinum with antibiotics and with the preparation according to example 4, sometimes exerted a stimulating effect on the animals and caused the desire to get rid of the patch.

The preparations according to the formulations 8 and 9 from table 1 were used respectively in gynecological practice for the treatment of acute and chronic inflammation of the vaginal mucosa and is caused by inflammation of the fallopian tube occlusion.

Treatment is Atami.

In the control was used with a 0.5% aqueous solutions etoniya and 0.05% aqueous solutions of decamethoxinum with the addition of 0.9% NaCl in an electrophoretic effect through the abdominal wall, under which the electrode was placed at the level of the uterus is impregnated with a solution flannel lining, and overlapping the second electrode tropicanoe put the gasket on the sacrum at a current of 5-10 mA for 10-15 each session within 1-12 days.

Vinylinum separately not used.

Aggregated data about the results of treatment are shown in table.4.

As can be seen from table 4, simpler and more affordable treatment at home treatment proposed drug is much more effective.

1. Complex of biologically active preparation containing polyvinylbutyral ether (Vinylinum) dichloride and 1,2-ethylene-bis-(N-dimethylcarbamate)-ammonium (atony), characterized in that it further comprises dichloride 1,10-decametre-bis-(N, N-dimethylaminocarbonylmethyl)-ammonium (decamethoxin), and the ingredients are taken in the following ratio, wt.h.:

Vinylinum - 100,0

Atony - 1,0 - 2,5

Decamethoxin - 0,05 - 0,15

2. Complex of biologically active drug under item 1, ex is - 1,0 - 2,0

Decamethoxin - 0,05 - 0,15

3. Complex of biologically active drug under item 1, characterized in that the ingredients are taken in the following ratio, wt.h.:

Vinylinum - 100,0

Atony and 1.5 - 2.5

Decamethoxin - 0,05 - 0,15

4. Complex of biologically active drug under item 1, characterized in that the ingredients are taken in the following ratio, wt.h.:

Vinylinum - 100,0

Atony - 1,0 - 1,5

Decamethoxin - 0,05 - 0,10

5. Complex of biologically active drug under item 4, characterized in that it further comprises dimethyl sulfoxide, these ingredients are taken in the following ratio, wt.h.:

Vinylinum

100,0

Atony - 1,0 - 1,5

Decamethoxin - 0,05 - 0,10

Dimethyl sulfoxide - 3,0 - 5,0

 

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SUBSTANCE: antiseptic ointment comprises cationic surface-active substance, lower glycols, polyethylene glycols, water and ethylene glycol monophenolic ester and higher polyethylene glycols taken in the definite ratio of components. As cationic surface-active substance ointment comprises N-alkyl-N-alkoxycarbonylmethylhexahydroazipinium chloride or alkyldimethylbenzylammonium chloride, or cetylpyridinium bromide, or cetylpyridinium chloride, or 1,2-ethylenebis-(N-methylcarbdecyloxymethyl)ammonium dichloride, or ethylhexadecyldimethylammonium chloride, or chlorhexidine; as lower glycol ointment comprises 1,2-propylene glycol or polyethylene glycol-300, or polyethylene glycol-400; as higher polyethylene glycol ointment comprises polyethylene glycol-1500 or polyethylene glycol-3000, or polyethylene glycol-4000, or polyethylene glycol-6000. Ointment elicits the high antibacterial activity, broad spectrum of bactericidal effect and low irritating effect with respect to udder skin. Invention can be used for sanitary-hygienic treatment of udder of lactating cows for prophylaxis and rapid healing external damages of udder and nipples (arising cracks), prophylaxis of mastitis, enhancing milk purity by microbiological indices.

EFFECT: valuable antiseptic properties of ointment.

2 cl, 1 tbl, 22 ex

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