WO2016118040A1

WO2016118040A1 - A gel containing nifedipine and lidocaine hydrochloride, use of same and a method for preparing same using nanotechnology

Info

Publication number: WO2016118040A1
Application number: PCT/RU2015/000034
Authority: WO
Inventors: Михаил Александрович ГЕТЬМАН
Original assignee: ОБЩЕСТВО С ОГРАНИЧЕННОЙ ОТВЕТСТВЕННОСТЬЮ "НоваМедика"; Михаил Александрович ГЕТЬМАН
Priority date: 2015-01-21
Filing date: 2015-01-21
Publication date: 2016-07-28
Also published as: WO2016118040A8

Abstract

The inventions relate to the pharmaceutical industry, including pharmaceutical compositions forming the base of gels, and methods for producing gels which are intended mainly for preventing and/or treating anal fissures, haemorrhoids and diseases associated therewith and for reducing sensations of pain after a haemorrhoidectomy. The inventions relate to compositions and preparation methods, and also to the use of gels including nifedipine and lidocaine hydrochloride. The gels are prepared using nanotechnology. The technical result is achieved by producing such a composition of a gel including nifedipine and lidocaine hydrochloride, each variant of which provides for robustness of the gel properties, transparency, and preservation of the stability of the properties for up to 2 years, and the use of which makes it possible to reduce the clinical symptoms of haemorrhoids, up to and including complete elimination of said symptoms, to heal an anal fissure, and to relieve pain syndrome, including after a haemorrhoidectomy. Furthermore, the technical result is achieved by creating such a method for preparing a gel including nifedipine and lidocaine hydrochloride using nanotechnology, which provides for robustness of the gel properties, transparency, and preservation of the stability of the properties for up to 2 years. All the proposed inventions are industrially applicable, and laboratory tests have shown that the presented subject matter is practically implementable and will be extensively used in the pharmaceutical industry.

Description

GEL CONTAINING NIFEDIPINE AND LIDOCAINE HYDROCHLORIDE,

ITS APPLICATION AND METHOD OF PREPARATION USING NANOTECHNOLOGIES

FIELD OF TECHNOLOGY

The invention relates to pharmaceuticals, including pharmaceutical compositions that form the basis of gels and to methods for producing gels intended mainly for use in the treatment of hemorrhoids and anal fissures, namely, the invention relates to compositions and methods for preparing gels, including nifedipine and lidocaine hydrochloride, the preparation of gels is carried out using nanotechnology.

BACKGROUND OF THE INVENTION

Currently, the current direction of pharmaceuticals is the creation of new dosage forms for external use, including fat-based dosage forms, for example, ointments.

Known drugs presented in the form of ointments or emulsions for external use using a fat base, including those containing nifedipine [1-3].

Nifedipine, being a calcium antagonist, is widely used in medicine, primarily in cardiology practice. Features of the mechanism of action, the predominant expanding effect on the peripheral vessels, arteries, determined the main niche of its use - the treatment of arterial hypertension [4].

Nevertheless, taking into account the mechanism of action of nifedipine, it can be successfully used for various other diseases requiring a vasodilating effect, for example, in proctology.

It was found that the transport of calcium ions through L-type calcium channels helps maintain tone in the anal sphincter [5].

Nifedipine, being a calcium channel blocker, prevents the transport of calcium ions into the cells and thereby reduces the tone of the anal sphincter. Reducing the spasticity of the anal sphincter is the main way to reduce pain in patients with hemorrhoids and anal fissure [6]. The pharmacological activity of nifedipine also causes a decrease in the intensity of the inflammatory reaction [7], has a modulating effect on microcirculation [8].

One of the factors for the development of defects in the mucous membrane of the anal canal is its ischemia caused by a spasm of the internal anal sphincter [9]. Nifedipine, eliminating its hypertonicity, improves blood supply to the ischemic mucosa and restores its functional state.

Thus, the local effect of nifedipine affects the main pathogenetic mechanisms underlying hemorrhoids, as well as the symptoms associated with the development of an anal fissure.

However, as a rule, fat-based products for external use are poorly absorbed, stain textile fibers, including clothing, and cause discomfort on the skin.

To eliminate the above disadvantages use means for external use, made on a water basis, including gels, which are one of the promising dosage forms.

The advantage of the gel dosage form is the prolonged action, the presence of a moisturizing effect and ease of use.

According to their biopharmaceutical characteristics, gels are close to ointments and creams, but have a number of differences, for example, when it gets on your skin or clothes, the gel, unlike an ointment, is easily washed off with water, leaving no residue, which is an obvious advantage that enhances the patient’s compliance with the prescribed treatment [ 10].

However, due to the hydrophobicity of the active substance, the creation of gels and pharmaceutical compositions of nifedipine in an aqueous medium is very difficult. To create them, you need to use a special group of chemicals - solubilizers and solvents.

It is known, for example, that the invention relates to medicine and pharmacology and is a medicinal composition for the treatment of anal fissures, comprising a base, a drug that reduces spasms of smooth muscle muscles, lidocaine, contains tizol gel as a base, and as a drug that reduces smooth spasms muscle muscles - nifedipine or nitroglycerin, and the components in the composition are contained in a certain ratio in grams. The invention provides effective treatment for reducing the concentration of active substances, reducing side effects, reducing the duration of treatment [1 1].

As you know, the cause of the anal fissure is damage to the wall of the anal canal, including with constipation, therefore, usually for the prevention and treatment, laxatives are used, as well as nitroglycerin ointment 0.2%, which is currently considered to be one of the most important components of the conservative treatment of anal fissure, since nitroglycerin relaxes the muscles of the anal sphincter, removing its spasm, which is one of the pathogenetic factors of the development of the fissure, since it leads to ischemia, that is, to n impaired blood flow. However, when using nitroglycerin ointment, it is necessary to apply a small amount, since in large doses it can be absorbed into the systemic circulation and cause headaches, dizziness [12].

The use of calcium channel blockers is also known, including, for example, nifedepine or diltiazem and other drugs that are used in the treatment of heart diseases, but have recently found their application in the treatment of anal fissures, the principle of which is the same as that of nitroglycerin ointments - they relieve spasm of the anal sphincter [12].

Despite the available examples of the use of nifedipine and other similar agents as a calcium channel blocker, there is a need to create a drug that would ensure the stability of properties, transparency, and maintaining stability for a period of at least two years. which would also provide an optimal reduction of pain symptoms in the presence of anal fissures, hemorrhoids, until they completely stop, healing of the anal fissure and relief of pain, including after hemorrhoidectomy, in which the nifedipine content would be optimal, and the required bioavailability would be ensured by dissolution of the active substance in the aquatic environment.

The technical result, to which the data of the invention are directed, is to obtain such a gel composition, including nifedipine and lidocaine hydrochloride, each variant of which provides stability of gel-like properties, transparency, preservation of stability of properties for up to 2 years, the use of which allows to reduce the clinical symptoms of hemorrhoids, up to their complete exclusion, healing of the anal fissure and relief of pain, including after hemorrhoidectomy. In addition, the technical result to which the present invention is directed is the creation of such a method of preparing a gel comprising nifedipine and lidocaine hydrochloride, using nanotechnology, which would ensure the stability of the gel-like properties, transparency, maintaining stability for a period of at least two years.

SUMMARY OF THE INVENTION

The technical result is achieved by the fact that it is proposed:

- a gel comprising nifedipine, lidocaine hydrochloride, additionally comprising poloxamer 188, macrogol 400, nipagin, nipazole, poloxamer 407, Cekol 2000 T or Karbopol Ultrez 10, purified water, which prevents and / or treats anal fissures, hemorrhoids, reduces pain after hemorrhoidectomy and related diseases with a ratio of ingredients, wt.%:

nifedipine 0,01-0,4 lidocaine hydrochloride 0.02-2.0 poloxamer 407 1.0-19.0 poloxamer 188 0.01 - 10.0 macrogol 400 0.01-34 nipagin 0.01-0.07 nipazol 0, 01-0,03 Cekol 2000 T 0, 01-5,0 or Karbopol Ultrez 10 0, 01-1,5 purified water the rest

- and also proposed the use of a gel comprising nifedipine, lidocaine hydrochloride, poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, Cekol 2000 T or Carbopol Ultrez 10, purified water, as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases, reducing pain after hemorrhoidectomy as a means to prevent and / or treating anal fissures, hemorrhoids and related diseases, reducing pain after hemorrhoidectomy in the ratio of ingredients, wt.% :

nifedipine 0.01-0.4 lidocaine hydrochloride 0.02-2.0 poloxamer 407 1.0-19.0 poloxamer 188 0,01 - 10,0 macrogol 400 0,01-34 nipagin 0,01-0,07 nipazole 0,01-0,03

Cekol 2000 T 0, 01-5.0 or Carbopol Ultrez 10 0, 01-1.5 purified water the rest

- in addition, a gel is proposed that includes a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, auxiliary substances that provide the required stability and rheological properties, including poloxamer 407, poloxamer 188, macrogol 400 , nipagin, nipazole, Cekol 2000 T or an aqueous solution of arbopol Ultrez 10, purified water, with a ratio of ingredients, wt.%:

calcium channel blocker

including nifedipine 0, 01-0,4 local anesthetic, including:

lidocaine hydrochloride 0, 02-2.0 auxiliary substances that provide the required stability and rheological properties, including:

poloxamer 407 1.0-19.0 poloxamer 188 0, 01 - 10.0 macrogol 400 0, 01-34 nipagin 0, 01-0.07 nipazole 0, 01-0.03

Cekol 2000 T 0, 01-5.0 or Carbopol Ultrez 10 0, 01-1.5 purified water the rest

- and also proposed the use of a gel, including a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, auxiliary substances that provide the required stability and rheological properties, including poloxamer 407, poloxamer 188, macrogol 400 , nipagin, nipazole, Cekol 2000 T or an aqueous solution of Carbopol Ultrez 10, purified water, as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases, reduce pain after hemorrhoidectomy, with the ratio of ingredients, wt.%:

calcium channel blocker

including nifedipine 0, 01-0,4 local anesthetic, including:

Cekol 2000 T 0, 01-5.0 or Carbopol Ultrez 10 0, 01-1.5 purified water the rest

- in addition, a method is proposed for preparing a gel comprising nifedipine and lidocaine hydrochloride using nanotechnology, in which about 1, 0 - 19.0 g of poloxamer 407 and about 0.01 - 10.0 g of poloxamer 188 are placed in a measuring cup, protected from light, with a capacity of the order of 0 - 150 ml, add about 18

- 47 ml of purified water, mix and leave to dissolve until a colorless transparent solution 1 is formed, then about 0.02 - 2 g of lidocaine hydrochloride is placed in a measuring cup with a capacity of about 0-50 ml, about 0-10 ml of purified water is added and mixed until of dissolution, solution 2 is obtained, for the preparation of a suspension of nifedipine of the order of 0.01 to 0.4 g of nifedipine is placed in a measuring glass, protected from light, with a capacity of about 0 - 50 ml, add about 0.01 - 34 g of macrogol 400 or about 0 , 01 - 34 g of purified water and mix, then solution 2 is added to solution 1, a suspension of nifedipine is added to the resulting solution, the pH of the solution is adjusted to 2.5–9.5 by any known method, including a unimolar solution of sodium hydroxide or a unimolar solution of hydrochloric acid, and purified water is added to a total of about 93 - 95 g and stirred for 1-9 hours, including including, on a magnetic stirrer at a temperature of the order of 20-37 ° C, constantly monitoring the pH, including using a pH meter, then the resulting solution is left to stand for at least 15 minutes, filtered, including through filter paper, into a measuring cup protected from the action of light, and measure the pH, which, if necessary, adjusted to values of 2.5-9.5, to the resulting aqueous solution add about 0.01 - 0.07 g of nipagin and about 0.01 - 0, 03 g of nipazole and stirred until dissolved, then to prepare the gel to the resulting aqueous solution is added frequently m gel-forming substance: about 0.01 to 5 g of Cekol 2000 T carboxymethyl cellulose derivative or about 0.01 to 1.5 g of an aqueous solution of acrylic acid derivative of Carbopol Ultres 10, which is prepared by mixing 0.01-1.5 g of Carbopol Ultres 10 and 0.01 - 5.5 g of purified water, followed by stirring until a gel forms, the resulting gel is Packed in containers designed for this.

The proposed invention is as follows:

In a method for preparing a gel comprising nifedipine and lidocaine hydrochloride using nanotechnology, about 1.0-19.0 g of poloxamer 407, for example 1.0 g or 10.0 g, or 19.0 g and about 0.01-10 , 0 g of poloxamer 188, for example, 0.01 g or 5.0 g, or 10.0 g is placed in a measuring cup, protected from light, with a capacity of the order of up to 150 ml, for example, 50 ml or 100 ml, or 150 ml, add about 18 - 47 ml of purified water, for example, 18 ml or 30 ml, or 47 ml, mix and leave to dissolve until a colorless transparent solution 1 is formed. Next, about 0.01 - 2 g of lidocaine drochloride, for example, 0.01 g or 0.5 g, or 2 g, is placed in a measuring cup with a capacity of up to 50 ml, about 10 ml of purified water is added and mixed until dissolved to obtain a solution of 2. To prepare a suspension of nifedipine of the order of 0.01 to 0.4 g of nifedipine, for example, 0.01 g or 0.1 g, or 0.04 g is placed in a measuring glass, protected from light, with a capacity of about 50 ml, about 0.01 - 34 g are added macrogol 400, for example, 0.01 g or 15 g, or 34 g, or of the order of 0.01 - 34 g of purified water, for example, 0.01 g or 15 g, or 34 g and mixed. Then, solution 2 is added to solution 1, a suspension of nifedipine is added to the resulting solution, the pH of the resulting solution is adjusted to 2.5-9.5, for example, to 2.5 or to 7.5, or to 9.5, by any known method, including a one-molar solution of sodium hydroxide or a one-molar solution of hydrochloric acid, add purified water to a total amount of the order of 93 - 95 g, for example, up to 93 g or 94 g, or 95 g, and mix for 1-9 hours, for example, 1 hour or 4 hours, or 9 hours, including, for example, on a magnetic stirrer at a temperature of the order of 20-37 ° C, for example, at 20 ° C or at 30 ° C, or at 37 ° C, constantly monitoring the pH, including using a pH meter, then the resulting solution is left to stand for at least 15 minutes, filtered, including through filter paper, into a measuring cup protected from light, and measure the pH, which, in the case of necessary, adjusted to a value of 2.5-9.5. About 0.01-0.07 g of nipagin, for example 0.01 g or 0.03 g, or 0.07 g, and about 0.01-0.03 g of nipazole, for example 0, are added to the resulting aqueous solution. 01 g or 0.02 g or 0.03 g and stirred until dissolved, then to prepare the gel, about 0.01 to 5 g of a Cekol 2000 T carboxymethyl cellulose derivative, for example, 0.01 g or 1, are added in portions of the order of 0.01 to 5 g g, or 5 g, or of the order of 0.01 to 1.5 g of an aqueous solution of the acrylic acid derivative of Carbopol Ultrez 10, for example, 0.01 g or 1 g, or 1, 5 g, which is obtained by mixing 0.01 - 1, 5 g Carbopol Ultrez 10, for example ep, 0.01 g or 1 g, or 1.5 g, with 0.01 - 5.5 g of purified water, for example, with 0.01 g or 1 g, or 1, 5 g, followed by stirring until a gel forms, the resulting gel is packed in containers intended for this ..

The proposed gel, which includes nifedipine, lidocaine hydrochloride, poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, Cekol 2000 T or Carbopol Ultrez 10, purified water, is used as a means to prevent and / or treat anal fissures, hemorrhoids, reduce pain after hemorrhoidectomy and related diseases with a ratio of the following ingredients, wt.%:

nifedipine 0.01-0.4 lidocaine hydrochloride 0.01-2.0 poloxamer 407 1.0-19.0 poloxamer 188 0.01-10.0 macrogol 400 0.01-34 nipagin 0.01-0.07 nipazole 0.01-0.03

Cekol 2000 T 0.01-5.0 or Carbopol Ultrez 10 0.01-1.5 purified water the rest

A gel is used, including nifedipine, lidocaine hydrochloride, poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, Cekol 2000 T or Carbopol Ultrez 10, purified water, as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases, reduce pain after hemorrhoidectomy with a ratio of ingredients, wt.%:

nifedipine 0.01 - 0.4 lidocaine hydrochloride 0.01 - 2.0 poloxamer 407 1.0 - 19.0 poloxamer 188 0.01 - 10.0 macrogol 400 0.01 - 34 nipagin 0.01 - 0.07 nipazole 0.01 - 0.03

Cekol 2000 T 0.01 - 5 or Carbopol Ultrez 10 0.01 - 1.5 purified water the rest

A variant of the proposed gel is proposed, which includes a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, prepared as follows: to an aqueous solution including nifedipine, lidocaine hydrochloride, auxiliary substances that provide the required stability and rheological properties including poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole in a dark place add Cekol 2000 T 0-34 g, or an aqueous solution of Carbopol Ultrez 10 purified water, with wearing ingredients, wt.%:

calcium channel blocker

including nifedipine 0, 01-0,4 local anesthetic, including:

poloxamer 407 1.0-19.0 poloxamer 188 0, 01 - 10.0 macrogol 400 0, 01-34 nipagin 0,01-0,07 nipazole 0,01-0,03 Cekol 2000 T 0,01-5, 0 or Carbopol Ultrez 10 0, 01-1.5 purified water the rest The resulting gel is mixed and packaged,

The use, as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases, reduce pain after hemorrhoidectomy, a gel including a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, excipients providing the required stability and rheological properties, including poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, gelling agent, including Cekol 2000 T or aqueous Carbo solution ol Ultrez 10, purified water at a ratio of ingredients, wt.%:

calcium channel blocker

including nifedipine 0, 01-0,4 local anesthetic, including:

Cekol 2000 T 0, 01-5.0 or Carbopol Ultrez 10 0, 01-1.5 purified water the rest

The proposed gel in all the presented options provides high efficiency in eliminating the symptoms of chronic anal fissure, external hemorrhoids, reducing pain after hemorrhoidectomy. Examples of gels are presented in the Table.

The effectiveness of the proposed gel was tested on rats.

The gel was applied perianally, twice a day for fourteen days, to rats with a model of anal fissure. The use of the gel made it possible to completely eliminate the morphological changes characteristic of the anal fissure, that is, to achieve complete healing in 95% of the tested rats, namely in 38 out of 40 animals. In the control group in which the gel base was used without active active substances - nifedipine and lidocaine, the proportion of animals with resolution of symptoms of anal fissure was 15%, namely, six out of forty animals.

The gel was applied perianally and rectally, twice a day for fourteen days to rats with a model of acute hemorrhoids. The use of the gel completely eliminated the manifestations of hemorrhoids in 92.5% of the animals, thirty-seven out of forty animals), while in the control group receiving treatment with a gel base, complete resolution of the manifestations of hemorrhoids was achieved in 45% of the animals, namely, 18 out of forty animals.

The effectiveness of the gel in reducing pain after hemorrhoidectomy was evaluated in rats indirectly. It is known that the main cause of pain after surgery to remove hemorrhoids is a spasm of the anal sphincter. Therefore, the resolution of pain in rats with a hemorrhoid model was assessed as a stable restoration of anorectal manometry to the initial level. The gel was applied perianally and rectally, twice a day for fourteen days. The use of the gel made it possible to return the anorectal manometry index to the initial level in all 40 animals, while in the control group receiving gel base treatment, a complete restoration of the indicator was observed only in 17.5% of the animals, namely, 7 out of forty animals.

The above examples illustrate, but do not exhaust all possible applications of the proposed inventions.

The technical result was achieved by obtaining such a composition of the gel, including nifedipine and lidocaine hydrochloride, each version of which provides stability of the gel-like properties, transparency, preservation of stability of properties for up to 2 years, the use of which allows to reduce the clinical symptoms of hemorrhoids, up to their complete elimination, healing of the anal cracks and relief of pain, including after hemorrhoidectomy.

In addition, the technical result was achieved by the creation of such a method of preparing a gel, including nifedipine and lidocaine hydrochloride using nanotechnology, which ensures the stability of gel-like properties, transparency, maintaining the stability of properties for up to 2 years. INDUSTRIAL APPLICABILITY

The proposed pharmaceutical compositions that form the basis of gels, a method for the production of gels are mainly intended to prevent and / or treat anal fissures, hemorrhoids and related diseases, reduce pain after hemorrhoidectomy. The invention relates to compositions and methods of preparation, as well as to the use of gels, including nifedipine and lidocaine hydrochloride. The preparation of gels is carried out using nanotechnology.

The proposed gel, in all the presented variants, obtained by the proposed method, provides, when applied, high efficiency in eliminating the symptoms of chronic anal fissure, external hemorrhoids, reducing pain, up to their elimination.

All the inventions presented are industrially applicable, have passed laboratory tests, are practicable and will find wide application in the pharmaceutical industry.

INFORMATION SOURCES:

1. Perrotti P, Dominici P, Grossi E, Cerutti R, Antropoli C. Topical nifedipine with lidocaine ointment versus active control for pain after hemorrhoidectomy: results of a multicentre, prospective, randomized, double-blind study. Can J Surg. 2010 Feb; 53 (l): 17-24

2. Katsinelos P, Kountouras J, Paroutoglou G, Beltsis A, Chatzimavroudis G, Zavos C, Katsinelos T, Papaziogas B. Aggressive treatment of acute anal fissure with 0.5% nifedipine ointment prevents its evolution to chronicity. World J Gastroenterol. 2006 Oct 14; 12 (38): 6203-6

3. Hugo Almeida, Maria Helena Amaral, Paulo Lobao, Jose Manuel Sousa Lobo. Pluronic F-127 and Pluronic Lecithin Organogel (PLO): Main Features and their Applications in Topical and Transdermal Administration of Drugs. J Pharm Pharmaceut Sci.l5 (4) 592 - 605, 2012

4. ESH Scientific Council: / ESC Committee for Practice Guidelines. 2013 ESH / ESC Guidelines for the management of arterial hypertension. European Heart Journal. 2013.34: 2159-2219.

5. Cook TA, Brading AF, Mortensen NJ. Differences in contractile properties of anorectal smooth muscle and the effects of calcium channel blockade. Br J Surg, 1999; 86 (l): 70-5.

6. Gorfme SR. Treatment of benign anal disease with topical nitroglycerin. Dis Colon Rectum 1995; 38: 453-7.9. Katoh N, Hirano S, Kishimoto S, Yasuno H. Calcium channel blockers suppress the contact hypersensitivity reaction (CHR) by inhibiting antigen transport and presentation by epidermal Langerhans cells in mice. Clin Exp Immunol, 1997; 108: 302-8

8.0shiro H, Kobayashi I, Kim D, Takenaka H, Hobson RW 2nd, Duran WN. L-type calcium channel blockers modulate the microvascular hyperpermeability induced by plateletactivating factor in vivo. J Vase Surg, 1995; 22: 723-39.

9. Schouten WR, Briel JW, Auwerda JJ. Relationship between anal pressure and anodermal blood flow. The vascular pathogenesis of anal fissures. Dis Colon Rectum, 1994; 37: 664-669.

Yu.Pertsev I.M., Zupanets I.A. Pharmaceutical and biomedical aspects of drugs. T. 1. Kharkov: Publishing House of the NFAA; 1999.

1 1. Patent RU J ° 2483721

12. http://proctology.eurodoctor.ru/analfissuretreatment/ Table. Examples of suggested gel options

JVe Ingredients Composition for Ingredient Ratio per 100 g of aqueous p / p gel preparation

solution, g

1. nifedipine 0.01 or 0.1 or 0.4 from the range of values: 0.01 - 0.4

2. lidocaine hydrochloride 0.02 or 0.5 or 2

from the range of values: 0.02 - 2

3. Poloxamer 407 1 or 10 or 19

from the range of values: 1-19

4. Poloxamer 188 0.01 or 5.0, or 10.0

from the range of values: 0.01-10

5. Macrogol 400 0.01 or 15 or 34

from the range of values: 0.01 - 34

6. Cekol 2000 T 0.01 or 1 or 5

or from the range of values: 0.01 - 5

Carbopol Ultrez 10 0.01 or 1 or 1.5

from the range of values: 0.01 - 1.5

7. nipagin 0, 01 or 0.03 or 0.07

from the range of values: 0, 01 -0.07

8 nipazole 0.01 or 0, 02 or 0.03

from the range of values: 0, 01 - 0.03

9. the water purified the rest

Claims

GEL INCLUDING NIFEDIPINE AND LIDOCAINE ANHYDROCHLORIDE

(OPTIONS)

APPLICATION OF A GEL INCLUDING NIFEDIPINE AND LIDOCAINE

HYDROCHLORIDE (OPTIONS)

METHOD FOR PREPARING A GEL INCLUDING NIFEDIPINE AND LIDOCAINE HYDROCHLORIDE USING NANOTECHNOLOGY

FORMULA

1. A gel comprising nifedipine, lidocaine hydrochloride, additionally comprising poloxamer 188, macrogol 400, nipagin, nipazole, poloxamer 407, Cekol 2000 T or Karbopol Ultrez 10, purified water, which prevents and / or treats anal fissures, hemorrhoids, reduces pain after hemorrhoidectomy and related diseases with a ratio of ingredients, wt.%:

2. The use of a gel comprising nifedipine, lidocaine hydrochloride, poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, Cekol 2000 T or Carbopol Ultrez 10, purified water, as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases with it, reducing pain after hemorrhoidectomy as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases, reducing pain after hemorrhoidectomy with the ratio of ingredients, wt.%: nifedipine 0, 01-0.4 l dokaina hydrochloride 0, 02-2,0 1,0-19,0 Poloxamer 407 Poloxamer 188 0 01 - 10.0 macrogol 400 0, 01-34 nipagin 0,01-0,07 nipazole 0,01-0,03 Cekol 2000 T 0,01-5,0 or Karbopol Ultrez 10 0 01-1,5 water purified the rest

Z. Gel, including a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, auxiliary substances that provide the required stability and rheological properties, including poloxamer 407, poloxamer 188, macrogol 400, nipagin, nipazole, Cekol 2000 T or an aqueous solution of Carbopol Ultres 10, purified water, with a ratio of ingredients, wt.%:

calcium channel blocker

including nifedipine 0, 01-0,4 local anesthetic, including:

poloxamer 407 1, 0-19.0 poloxamer 188 0, 01 - 10.0 macrogol 400 0, 01-34 nipagin 0, 01-0.07 nipazole 0, 01-0.03

Cekol 2000 T 0, 01-5.0 or Carbopol Ultrez 10 0, 01-1.5 purified water the rest

4.Application of a gel, including a calcium channel blocker, including nifedipine, a local anesthetic, including lidocaine hydrochloride, auxiliary substances that provide the required stability and rheological properties, including poloxamer 407, poloxamer 188, macrogol 400, nipagin , nipazole, Cekol 2000 T or an aqueous solution of Carbopol Ultrez 10, purified water, as a means to prevent and / or treat anal fissures, hemorrhoids and related diseases, pain relief after hemorrhoidectomy, with the ratio of ingredients, wt.%:

calcium channel blocker

including nifedipine 0, 01-0,4 local anesthetic, including:

or Karbopol Ultrez 10 0, 01-1, 5 purified water the rest

5. A method of preparing a gel comprising nifedipine and lidocaine hydrochloride using nanotechnology, in which about 1.0 to 19.0 g of poloxamer 407 and about 0.01 to 10.0 g of poloxamer 188 are placed in a light-protected measuring cup with a capacity of about 0 - 150 ml, add about 18 - 47 ml of purified water, mix and leave to dissolve until a colorless transparent solution 1 is formed, then about 0, 02 - 2 g of lidocaine hydrochloride is placed in a measuring cup with a capacity of about 0 - 50 ml, add about 0 - 10 ml of purified water and mix they are dissolved until a solution of 2 is obtained, for the preparation of a suspension of nifedipine of the order of 0.01 to 0.4 g of nifedipine is placed in a measuring cup, protected from light, with a capacity of about 0-50 ml, add about 0.01 to 34 g of macrogol 400 or about 0.01 - 34 g of purified water and mixed, then solution 2 is added to solution 1, a suspension of nifedipine is added to the resulting solution, the pH of the solution is adjusted to 2.5-9.5 by any known method, including a unimolar solution of sodium hydroxide or with a unimolar solution of hydrochloric acid, add purified water to a total amount of the order of 93 - 95 g and stirred for 1-9 hours, including using a magnetic stirrer at a temperature of about 20-37 ° C, constantly monitoring the pH, including using a pH meter, then the resulting solution is left to stand for at least 15 minutes, filtered, including through filter paper, in a measuring cup, protected from light, and measure the pH, which, if necessary, adjusted to values of 2.5-9.5, to the resulting aqueous solution add about 0.01 - 0.07 g of nipagin and of the order of 0.01 - 0.03 g of nipazole and mixed until dissolved, then to prepare the gel, the gelling substance is added in portions to the resulting aqueous solution: about 0.01 - 5 g of Cekol 2000 T carboxymethyl cellulose derivative or about 0 , 01 - 1.5 g of an aqueous solution of a derivative of acrylic acid Carbopol U trez 10, which is prepared by mixing 0.01 - 1.5 g Carbopol Ultrez 10 and 0.01 - 5.5 g of purified water, followed by stirring to form a gel, the gel obtained is filled into containers intended for this purpose.