RU2538079C1 - Composition for treating anal fissures - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a composition for treating anal fissures in the form of a hydrous gel, containing an active compound in the form of isosorbide dinitrate, a gelation agent, a neutralising agent and a solvent differing by the fact that the composition contains triethanolamine as the neutralising agent taken in equal proportions with the gelation agent which is presented by a lightly crosslinked polymer; the solvent is presented with a mixture of polyethyleneoxide and ethanol in ratio 5-6:1:3-4 with the ingredients of the composition taken in certain proportions, wt %.

EFFECT: invention provides higher clinical effectiveness and reduced length of treatment.

3 ex, 2 tbl

Description

The invention relates to medicine and the pharmaceutical industry, in particular to the creation, production and use of an agent containing, as an active component, isosorbide dinitrate in the form of a gel for the treatment of anal fissures.

The frequency of occurrence of an anal fissure, according to reversibility, is 20-23 cases per 1000 adult population, and among proctologic diseases it is one of the most frequent and ranges from 10 to 20% among them, women of young and middle age are more often sick, more than a third of patients are at working age. In some cases, inflammation is weak, but in other cases, inflammation is significant and sometimes accompanied by the appearance of a fistulous course. A non-healing wound in the anal canal does not withstand virulent infection of the contents of the rectum, and local or spreading to the pararectal fiber tissue can occur.

The etiological spectrum is very wide, constipation is considered one of the main causes of anal fissure, although in some cases patients do not complain of difficulty in defecation. Diarrhea, inflammatory changes in the anal canal of a different nature, the introduction of foreign bodies into the rectum, and also anal sex can also provoke the occurrence of an anal fissure. Anal fissure may be combined with hemorrhoids.

Therapeutic tactics depend on the stage of the disease. In acute and subacute anal fissure, a set of conservative measures is prescribed aimed at eliminating pain and sphincterospasm, with the ineffectiveness of the above or the presence of medical indications, treatment of a chronic fissure is usually surgical. Despite the existence of many conservative and surgical methods of treatment, the frequency of relapses and complications remains high.

A key role in the pathogenesis of chronic anal fissure is played by spasm of the internal anal sphincter. This leads to additional trauma to the anal fissure. A spasm disrupts blood circulation in the area of the anal fissure and, as a result, healing is worsened. A spasmodic sphincter complicates bowel movements and worsens the healing conditions of the anal fissure, increasing pain, while the spasm is aggravated and thus a “vicious circle” occurs.

It is known that treatment of acute anal fissure, especially the first to occur, should be started with conservative measures.

Among the non-surgical methods for treating the anal fissure, the most modern is the medical relaxation of the internal sphincter of the rectum by various pharmacological preparations. The most common among them was nitroglycerin in the form of 0.2-0.6% ointment. Crack healing during treatment with nitroglycerin ointment for 6 weeks was observed in 43-85.6% of patients. In this case, the relapse rate up to 36 weeks is 17-45%.

Drug relaxation of the internal sphincter with nitroglycerin ointment does not lead to the development of anal incontinence. Meanwhile, with its use, a sufficiently high frequency of relapse of the disease is noted, since many patients have secondary changes due to the prolonged existence of a chronic anal fissure. Lund JN, Armitage NC, Scholefield JH. Use of glyceryl trinitrate in the treatment of anal fissure. Br J Surg, 1996, 83: 776-777. Watson S.J., Kamm M.A., Nicholls R.J., Phillips RKS. Topical glyceryl trinitrate in the treatment of chronic anal fissure. Br J Surg, 1996, 83: 771-775 /.

The choice of drugs for local therapy is great (proctosedil, religion advance, ultraproct, proctoglivenol, etc.) - these drugs mainly have a local analgesic effect, but none of them affect the increased tone of the internal anal sphincter - the main link in the pathogenesis of this disease . A number of compounds have the ability to reduce the tone of smooth muscle tissue and, in particular, the internal anal sphincter.

For these drugs, the well-known fat base is most often used - vaseline, which interferes with the penetration of medicinal substances introduced into it into biological tissues - the smooth muscles of the anal canal. At the same time, the effect of local treatment is significantly reduced. Vaseline negatively affects the epithelium of the anal canal, clogging the pores of the tissues, the concentration of the active substance when passing through the mucous and submucosal layers decreases sharply and its penetration rate decreases. In addition, on the surface of the tissues of the anal canal, the fixation of vaseline-based drug compositions is difficult and its rapid outflow from the treatment surface is observed, and the effectiveness of the treatment depends on creating the necessary concentration of active substances in the muscle of the anal sphincter.

Known medicinal composition for the treatment of anal fissures, including a base, a substance that reduces spasms of smooth muscle, lidocaine. According to the invention, the composition contains tizol gel as a base, and nifedipine or nitroglycerin (US Pat. RF No. 2483721) as a substance that reduces spasms of smooth muscle muscles.

It should be noted that nifedipine has some contraindications. When using nifedipine, redness of the face and skin, headache associated with a decrease in the tone of the vessels of the brain are often observed. Nausea, dizziness, swelling of the lower extremities, hypotension, and drowsiness are also possible. Drowsiness often develops. These contraindications require caution when prescribing the drug, in particular, with heart failure, severe arterial hypotension, pregnancy, breastfeeding. It is advisable to prescribe the drug in reduced doses under the mandatory control of blood pressure.

A known method of pharmacological sphincterotomy based on the local use of isosorbide dinitrate (IDN) in the treatment of anal fissures (Utzig MJ, Kroesen FJ, Buhr HJ Concepts in pathogenesis and treatment of chronic anal fissure - a review of the literature. - American Journal of Gastroenterology. - 2003 . - vol. 98., N5. - P.968 - 974 /.

In addition, isosorbide dinitrate is widely used in medicine as a means for treating cardiovascular diseases in the form of tablets, as a spray, in the form of a patch (Nitrosorbid and Cardiket. Izomak-retard Izomak, Sorboperkuten preparations).

The closest prototype to the claimed technical solution relates to a composition for the treatment of anal fissures in the form of an aqueous gel containing, as active compounds, a mixture of isosorbide dinitrate with nifedipine or diltiazem, a gelling agent with a neutralizing agent and a solvent (WO 2002003973, publ. January 2002). The amount of isosorbide dinitrate in the composition is 0.1-0.4 wt.%. As a gelling agent used lipophilic substance selected from the group consisting of polyethylene glycol and polypropylene glycol. The composition contains dimethyl sulfoxide as a solvent for isosorbide dinitrate. and a second vasodilating active component selected from the group of nifedipine or diltiazem. The disadvantage of the prototype is: the solvent used is an allergen and a very active absorption promoter, which can lead to a systemic side effect on the cardiovascular system; the presence in the composition of lactose and a preservative (nipagin, nipazole).

The task to which the proposed technical solution is directed is to increase the effectiveness of treatment by creating a form of the drug in the form of a gel, which is a thermodynamically stable homogeneous system that provides uniform dosing of the active substance into the skin, by creating a solvent system that is safe against microbial contamination, reducing treatment time by increasing the rate of penetration of the active substance into the area of the anal fissure.

The solution to this problem is achieved through the use of a composition for the treatment of anal fissures in the form of an aqueous gel containing, as an active compound, isosorbide dinitrate, a gelling agent with a neutralizing agent and a solvent, while the composition contains triethanolamine as a neutralizing agent, taken in equal amounts with a gelling agent, in the quality of which is used cross-linked acrylic polymer, and as a solvent, a mixture of polyethylene oxide with ethyl alcohol and water is used at a ratio of 5-6 : 1: 3-4, in the following ratio of components in the composition, wt.%:

isosorbide dinitrate 0.1-1.0 gelling agent 0.8-2.0 triethanolamine 0.8-2.0 solvent the rest is up to 100

Rare cross-linked acrylic polymer is produced in Russia under the trade name Arespol (TU 2219-005-29053342-97). It is a fine white powder, disperses well in water, forming a viscous gel. Gels based on a rare crosslinked acrylic polymer have several advantages over other gelling agents: when applied to the skin, they form the thinnest smooth films that are well distributed on the mucous membranes and skin surface, providing a prolonged effect of the preparations, more fully and evenly release the drug substance, thus providing pharmaceutical its availability. They have the fastest effect in connection with the presence of a drug substance in dissolved form.

The authors used a triethanolamine neutralizing agent to obtain a gel from a dispersion of a cross-linked acrylic polymer. The efficiency of structure formation and the magnitude of the structural viscosity of the selected gel significantly depends on the pH value and the polymer used. The triethanolamine-neutralized gel used has a constant effective viscosity value after reaching a pH of 5.8 up to a pH of 9.0, after which a slight decrease in effective viscosity is observed. The lower limit of the content of the gelling agent in the preparation is due to the insufficient viscosity of the composition, which does not allow fixing it on a part of the body (drains); the upper limit is determined by purely technological difficulties, since the viscosity of the solution becomes excessively high for mixing and packaging of the final product.

As a result of the experiment in the presence of alcohol in the composition of the proposed gel, the use of sodium or potassium hydroxide as a neutralizing agent is unacceptable, since precipitation of the alcoholates occurs.

When creating the isosorbide dinitrate gel, a storage-stable form of the solute was obtained in a therapeutically significant concentration in a physiologically acceptable solvent. The ability to penetrate deeply into tissues and the ability to serve as a conductor for a medicinal substance make the proposed composition a unique drug. The combination of components in the composition represents a completely new approach to the treatment of anal fissures.

The proposed composition was obtained as follows.

Example 1. The technology for the gel 0.5% isosorbide dinitrate (IDN)

Taking into account that IDN is supplied by the manufacturer in the form of a loose mixture with lactose (30/70), pure IDN was isolated by recrystallization, since dissolving IDN with lactose is not possible in those solvents that are suitable for cutaneous use. Inhomogeneous compositions are formed that irritate the skin.

1.1 Preparation of solvent system

We prepare a mixture consisting of 5 parts of polyethylene oxide (PEO-400), 1 part of ethyl alcohol 95% and 4 parts of water, mix until completely mixed.

1.2 the preparation of the basis of the gel

We measure out 37.5 parts of the obtained solvent system into a glass and add 1 part of a rare cross-linked acrylic polymer, which was used Arespol (TU 2219-005-29053342). Leave for swelling, after swelling add 1 part of triethanolamine (neutralizing agent).

1.3. Dissolution of IDN

Weigh 0.5 parts of IDN into the flask, then add 60 parts of the solvent system, mix until the IDN is completely dissolved.

1.4 Obtaining IDN gel

Add the IDN solution to the obtained gel base, mix until gel uniformity, pH 5.8-6.5.

Example 2. The study of the solubility of IDN in the solvent system

The obtained results of the solubility of IDN are summarized in table 1.

Example 3. Testing samples in experiments in vivo

Samples were made of 30.0 g of gel with an IDN content of 0.1-1.0%. As a comparison drug, a suspension ointment prepared according to prescription by grinding tablets IDN on a vaseline basis containing 0.5% of the active substance was used. The results are summarized in table 2.

As can be seen from table 2, testing of samples in experiments in vivo, showed the effectiveness of treatment using the claimed composition and the absence of side effects. An increase in the amount of active compound is impractical because there is a rise in price of treatment. An increase in the concentration of IDN does not significantly affect the effectiveness of treatment, but increases the risk of developing systemic side effects.

The analysis of publications, as well as the comparative experience with the use of prescription (using tablets) ointments with IDN on a liquid paraffin make promising the development of a gel form of IDN for local therapy of anal fissures. The proposed IDN gel for processing the anus is easily applied using a special applicator and is easily squeezed out of the tube, does not contaminate the patient’s skin and clothing, does not cause discomfort on the skin after application, is well washed off the skin during the wound toilet, and also does not have a systemic effect on the body at a high rate of onset of the analgesic effect after application due to the presence of the active substance in dissolved form.

Based on the experiments, an acceptable solvent system was selected and their combination with a gelling agent for further use in the treatment of anal fissures, providing high pharmaceutical availability in the absence of side effects. Thus, the selected solvent system made it possible to obtain experimental IDN gel samples based on rare-crosslinked acrylic polymers.

Table 1 №№ solvent system, ratio The ratio of IDN / r-l The result of the dissolution of IDN in this solvent system PEO SE 95% water one 7 - 3 1: 200 Slow formation of a solution of 0.5%, dehydration of the wound is possible 2 6 - four 1: 200 Very slow 0.5% solution formation 3 6 one 3 1: 200 The rapid formation of a solution of 0.5% four 5 one four 1: 200 The rapid formation of a solution of 0.5% 5 3 one 6 1: 200 When water is added, the solution becomes cloudy, the solution is not stable 6 5 2 3 1: 200 Discomfort due to SE, the solution is not stable

Table 2 No. The composition of the drug,% The result IDN Gelling agent,% Triethanolamine,% Solvent% one 0.1 0.8 0.8 Up to 100% healing, pain disappeared on day 11 2 0.5 1,2 1,2 Up to 100% Complete healing, pain disappeared on day 10 3 1,0 2.0 2.0 Up to 100% Complete healing, pain disappeared on day 10 Comparative Sample - IDN Ointment four 0.5 Vaseline up to 100% - - Incomplete healing, pain disappeared on day 30

Claims (1)

Composition for treating anal fissures in the form of an aqueous gel, containing as an active compound isosorbide dinitrate, a gelling agent, a neutralizing agent and a solvent, characterized in that the composition contains triethanolamine as a neutralizing agent, taken in equal amounts with a gelling agent, which is used as a cross-linked acrylic polymer, and as a solvent, a mixture of polyethylene oxide with ethyl alcohol and water is used at a ratio of 5-6: 1: 3-4, with the following ratio of components in the comp position, wt.%:
isosorbide dinitrate 0.1-1.0 gelling agent 0.8-2.0 triethanolamine 0.8-2.0 solvent the rest is up to 100