JP2022521444A - Gel for rectal and topical administration - Google Patents

Abstract

INDUSTRIAL APPLICABILITY, the present invention relates to a pharmaceutical composition, which forms a base of a gel intended mainly for the prevention and / or treatment of anal fissure, hemorrhoids and related medical conditions and reduction of pain sensation after hemorrhoid resection. And methods of making gels. In particular, the present invention relates to the formulation, production method and use of a gel containing nifedipine and lidocaine hydrochloride. The technical effect is achieved by the production of a gel formulation containing nifedipine and lidocaine hydrochloride. Each variant stabilizes gel-like properties, provides transparency and maintains property stability for more than 3 years, the use of which is to reduce hemorrhoids to complete disappearance of clinical symptoms, cure anal fissures, It enables management of pain including after hemorrhoid resection. All of the inventions presented are industrially applicable and tested in laboratory conditions to show that they can be practiced and are widely applicable in the pharmaceutical industry.

Description

The present invention relates to the field of medicine, in particular, pharmaceutical compositions forming a base for gels intended for rectal and topical administration, and said gels intended for use in the treatment of hemorrhoids and anal fissures. Regarding the manufacturing method. The main active substances used in the proposed invention are nifedipine and lidocaine hydrochloride.

One of the real trends in medicine is the development of new medicines for rectal and topical administration, such as fat-based drugs such as gels, ointments and emulsions.

Fat-based medicinal products presented in the form of ointments or emulsions for topical administration are known in the art, some of which include nifedipine [1-3].

Research aimed at this point is currently ongoing. Thus, the mechanism of action of nifedipine allows it to be used in the treatment of various diseases requiring vasorelaxant activity, and can also be used, for example, in proctology [4, 5].

Nifedipine is a calcium channel blocker that reduces the tone of the anal sphincter by blocking the intracellular transport of calcium ions. In patients with hemorrhoids and anal fissures, reducing spasticity of the anal sphincter is the primary method for reducing pain sensation [6]. The pharmacological activity of nifedipine also regulates the reduction in inflammatory response intensity [7], has a regulatory effect on microcirculation [8], and prevents the development of defects in the anal canal mucosa [9].

The advantages of medicinal products provided as gels, ointments, suspensions include their long-lasting effect, the presence of a moisturizing effect, and convenience in use. For example, when applied to the skin, the gel is easily washed away with water, as opposed to an ointment, allowing the gel to be selected when selecting the type of drug in such cases [10]. ].

Pharmaceutical compositions for treating anal fissure are known in the art [11], which include a base, a drug that reduces smooth muscle spasms, and lidocaine, wherein the base is titanium. The glycerosolvate aqua complex, the agent that reduces smooth muscle spasms, is nifedipine or nitroglycerin, and the composition component is contained in a fixed proportion in grams. The invention provides effective treatment at reduced concentrations of active substance, reduces side effects and shortens the duration of treatment.

It is known that the cause of anal fissure is damage to the anal canal wall such as damage due to constipation. Therefore, laxatives and 0.2% nitroglycerin ointments are commonly used for prophylaxis and treatment. This ointment is currently considered an important ingredient for the conservative treatment of anal fissures because nitroglycerin relaxes the anal sphincter muscles, thereby removing the spasm, which is ischemia. That is, it is a pathogenic factor for the development of anal fissure because it causes impaired blood flow. However, when using nitroglycerin ointment, only small doses should be applied, as high doses can enter the bloodstream throughout the body and cause headaches and dizziness [12].

The use of calcium channel blockers is also known in the art, for example nifedipine, diltiazem, or other agents used in the treatment of heart disease and recently found to be applicable in the treatment of anal fissure. And their principle of action is the same as that of nitroglycerin ointment, which eliminates anal fissure muscle spasms [12].

When nifedipine is used in gel formulations for rectal and topical administration, the preparation of nifedipine-containing pharmaceutical compositions in an aqueous medium is due to the hydrophobic behavior of nifedipine as an active agent, which is the dissolution of nifedipine in an aqueous medium. It is necessary to take into account the fact that it has some specificity due to.

Methods of dissolving nifedipine in an aqueous medium and pharmaceutical compositions containing an aqueous solution of nifedipine are known in the art [13], wherein the method comprises 20 to 20 aqueous solutions containing nifedipine, poloxamer 407, macrogol 400, poloxamer 188. Includes preparation at temperatures in the range of 37 ° C. to ensure dissolution of nifedipine to concentrations of 0.8-4.0 mg / g.

The method disclosed in [13] and the formulation of the corresponding pharmaceutical composition are intended to prevent and treat anal fissure, hemorrhoids, and reduce the pain sensation associated with these diseases, with nifedipine and lidocaine hydrochloride as the major active agents. It was considered as a basis for developing a modification of the method for producing a gel containing and a variant of the gel (patent RU2641570, [14]).

Accordingly, a method for producing a gel comprising nifedipine, lidocaine, poloxamer 407, macrogol 400, poloxamer 188 according to the patent RU2641570, and the gel produced by that method have been proposed in the present invention in all of their essential features. It is the closest to the gel and its manufacturing method and can be considered the closest prior art.

The shortcomings of the closest prior art include:
-Complexity and use of numerous additives in the process of making gels;
-Relatively low stability of the composition, even considering the use of thickeners and / or stabilizers such as Chemol 2000T or Carbopol Ultrez 10 in the composition.

Further clinical studies have shown that therapeutic results can be obtained with the use of other gel-forming adjuvants, both in formulation and amount.

It provides the stability, transparency, and stability of the properties achieved for a period of more than 2 years (3 years or more), and if anal fissures or hemorrhoids are present, the pain symptoms until their complete disappearance. Ensuring reduction, promoting healing of anal fissures at various stages, relieving pain such as pain after hemorrhoid resection, lower adjuvant content than prototype, required biology by dissolution of active substance in aqueous medium There is a need to develop methods and formulations of medicines that will provide bioavailability.

An object of the present invention is to produce a gel composition containing nifedipine and lidocaine hydrochloride as active substances, each of which has stable gel-like properties, transparency and stability of properties over 2 years. Providing maintenance, their use makes it possible to ensure reduction to complete elimination of clinical symptoms of hemorrhoids, healing of anal fissures, reduction of pain syndromes, including after hemorrhoid resection, both active substances and adjuvants. The content of the active substance is optimal, and the required bioavailability is ensured by dissolving the active substance in an aqueous medium.

A further object of the present invention is a method for producing a gel containing nifedipine and lidocaine hydrochloride, in which the required bioavailability is ensured by dissolving the active substance in an aqueous medium, and a thickener and / or It is to develop a method that can provide stable gel-like properties of the final gel and enhance the stability of the composition without the use of stabilizers.

The technical effect achieved by the group of inventions is to improve the stability and transparency of gel-like properties while preserving the pharmacological properties of the drug.

The above objectives and technical effects are methods of producing gels for rectal and topical administration.
(A) 1.0 to 19.0% by weight of poloxamer 407, 0.01 to 10.0% by weight of poloxamer 188, and 1.0 to 30.0% by weight of water are mixed to prepare an aqueous solution 1. To manufacture;
(B) Dissolving 1.5 to 3.2% by weight of lidocaine hydrochloride in 1.0 to 30.0% by weight of water to produce aqueous solution 2;
(C) Mixing 0.25 to 0.55% by weight of nifedipine with 0.01 to 34.0% by weight of low molecular weight polyethylene glycol to prepare Solution 3;
(D) Combining solution 2 and solution 3 to produce a homogeneous solution;
(E) Combining the solution obtained in the previous step with solution 1 while stirring;
(F) To add 0.01-0.072% by weight of methylparaben (nipagin) and 0.01-0.032% by weight of propylparaben (nipazole) to the mixture produced in the previous step;
(G) Add 1.0 to 19.0% by weight of poloxamer 407 to the mixture produced in the previous step, and stir until homogeneous.
(H) To adjust the pH value by adding a pH adjuster to the mixture produced in the previous step.
Including
Each of the steps (a) to (h) is carried out with vigorous stirring for at least 5 minutes so as to obtain a homogeneous mass (homogenous mass);
Step (a) is performed at a temperature of 8-17 ° C. and a pressure of 10-99 kPa without exposure to light; steps (b) and (c) are performed at a temperature of 18-25 ° C.; (D) and (e) are carried out at a temperature of 8 to 17 ° C.;
In step (h), the pH value of the mixture is adjusted to a value in the range of 3.5-7.5;
The step (f) of adding nipagin and nipazole may be performed before the step (b);
The viscosity of the gel thus produced is in the range of 3 to 75 Pa · s.
Achieved by the method.

According to the preferred embodiment, the above technical effects are also achieved by:
-During step (e) or prior to step (g), 0.01-10.0 wt% low molecular weight polyethylene glycol is added to the mixture;
-Small molecule polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600;
-The pH regulator is selected from sodium hydroxide and hydrochloric acid;
-The total time for performing the steps (a) to (h) for producing the gel is 4 to 6 hours or less;
-The method further comprises step (i) of checking the quality of the gel produced;
-Step (i) includes at least one overall measurement of:
The content of lidocaine hydrochloride is 0.25 to 0.55% and the content of nifedipine is 1.5 to 3.2%;
-The content of the identified lidocaine impurities is 0.1% or less;
-The total content of the identified nifedipine impurities is 2.5% or less;
-The content of a single unidentifiable impurity is 0.2% or less;
-The particle size of the produced gel component is 100 microns or less;
-The pH value is in the range of 3.5-7.5;
-Gel viscosity is 3 to 75 Pa · s;
Microbiological purity corresponds to the category of non-sterile drugs by the effective edition of the Official Pharmacopoeia.

The objective and technical effect is also a gel for rectal and topical administration, which provides prevention and / or treatment of anal fissure, hemorrhoids and related diseases, reduction of pain sensation after hemorrhoid resection, the methods described above. Achieved by the development of a gel produced in, containing nifedipine, lidocaine hydrochloride, poroxamar 188, low molecular weight polyethylene glycol, nipagin, nipazole, poroxamar 407, pH adjuster and purified water in the following component ratios by weight: To.
Nifedipine 0.25-0.55
Lidocaine Hydrochloride 1.5-3.2
Poloxamer 407 1.0-19.0
Poloxamer 188 0.01-10.0
Small Molecule Polyethylene Glycol 0.01-34.0
Nipagin 0.01-0.072
Nipazole 0.01-0.032
Acidity regulator To be pH 3.5-7.5 Purified water to be 100.0

According to the preferred embodiment, the above technical effects are also achieved by:
-Small molecule polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600;
-The pH regulator is selected from sodium hydroxide and hydrochloric acid;
-The gel has the following component ratios per gram of final pharmaceutical product.
Lidocaine hydrochloride hydrate 0.0213g
Nifedipine 0.0030g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Nipagin 0.0007g
Nipazole 0.0003g
Sodium hydroxide or hydrochloric acid so that the pH is 7.0 and the amount of purified water is 1.0 g.

Objectives and technical benefits are also achieved by administration of the gels to reduce the clinical manifestations of hemorrhoids until they are completely eliminated, to cure anal fissures, and to reduce pain syndrome after hemorrhoid resection.

Objectives and technical effects are also methods of making gels for rectal and topical administration:
(I) Aqueous solution 1 is prepared by mixing 1.0 to 19.0% by weight of poloxamer 407, 0.01 to 10.0% by weight of poloxamer 188, and 1.0 to 30.0% by weight of water. To manufacture;
(Ii) Dissolving 1.5 to 3.2% by weight of lidocaine hydrochloride in 1.0 to 30.0% by weight of water to produce aqueous solution 2;
(Iii) Mixing 0.25 to 0.55% by weight of nifedipine with 0.01 to 34.0% by weight of low molecular weight polyethylene glycol to prepare Solution 3;
(Iv) Solution 2, solution 3, 0.01-0.072% by weight of methylparaben (nipagin) and 0.01-0.032% by weight of propylparaben (nipazole) to produce a homogeneous solution. In combination with;
(V) Combining the solution produced in the previous step with solution 1 with stirring;
(Vi) Add 1.0 to 19.0 wt% poloxamer 407 to the mixture produced in the previous step, followed by stirring until homogeneous;
(Vii) Containing the addition of a pH regulator to the mixture produced in the previous step to adjust the pH value.
Each step (i)-(vii) is carried out with vigorous stirring for at least 5 minutes to obtain a homogeneous mass;
Step (i) is performed at a temperature of 8-17 ° C., a pressure 1-80% lower than atmospheric pressure, without exposure to light; steps (ii) and (iii) are performed at a temperature of 18-25 ° C. Performed; Steps (iv) and (v) are performed at a temperature of 8-17 ° C .;
In step (vi), the pH value of the mixture is adjusted to a value in the range of 3.5-7.5;
The viscosity value of the gel obtained by this method is in the range of 3 to 75 Pa · s.
Achieved by the method.

According to the preferred embodiment, the above technical effects are also achieved by:
-Small molecule polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600;
-The pH regulator is selected from sodium hydroxide and hydrochloric acid;
-The total time for performing the gel manufacturing steps (i) to (vii) is 4 to 6 hours or less;
-The method further comprises a step (viii) of checking the quality of the gel produced;
-The step (viii) includes at least one measurement of the whole of:
The content of lidocaine hydrochloride is 0.25 to 0.55% and the content of nifedipine is 1.5 to 3.2%;
-The content of the identified lidocaine impurities is 0.1% or less;
-The total content of the identified nifedipine impurities is 2.5% or less;
-The content of a single unidentifiable impurity is 0.2% or less;
-The particle size of the produced gel component is 100 microns or less;
-The pH value is in the range of 3.5-7.5;
-Gel viscosity is 3 to 75 Pa · s;
-Microbiological purity corresponds to the category of non-sterile drugs according to the valid version of the official Pharmacopoeia.

The purpose and technical effect is a gel for rectal and topical administration, which provides prevention and / or treatment of anal fissure, hemorrhoids and related diseases, reduction of pain sensation after hemorrhoid resection, manufactured by the method described above. It is also achieved by the development of a gel comprising nifedipine, lidocaine hydrochloride, poroxamer 188, low molecular weight polyethylene glycol, nipagine, nipazole, poroxamer 407, pH adjuster and purified water in the following component ratios by weight.
Nifedipine 0.25-0.55
Lidocaine Hydrochloride 1.5-3.2
Poloxamer 407 1.0-19.0
Poloxamer 188 0.01-10.0
Small Molecule Polyethylene Glycol 0.01-34.0
Nipagin 0.01-0.072
Nipazole 0.01-0.032
Acidity regulator To be pH 3.5-7.5 Purified water to be 100.0

According to the preferred embodiment, the above technical effects are also achieved by:
-Small molecule polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600;
-The pH regulator is selected from sodium hydroxide and hydrochloric acid;
-The gel has the following component ratios per gram of final pharmaceutical product.
Lidocaine hydrochloride hydrate 0.0213g
Nifedipine 0.0030g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Nipagin 0.0007g
Nipazole 0.0003g
Sodium hydroxide or hydrochloric acid so that the pH is 7.0 and the amount of purified water is 1.0 g.

Objectives and technical benefits are also achieved by using the above gels to reduce the clinical symptoms of hemorrhoids until they are completely eliminated, to heal anal fissures, and to reduce pain syndrome after hemorrhoid resection. ..

For rectal and topical administration, the method for producing the gel is to mix poloxamer 407 and poloxamer 188 with water to obtain an aqueous solution No. Includes manufacturing 1. Next, the lidocaine hydrochloride was dissolved in water and the solution No. 2 is prepared. Next, nifedipine and low-molecular-weight polyethylene glycol were mixed to obtain Mixture No. 3 is prepared. Next, combine the prepared solutions-Solution No. 2 and solution No. Combined with 3; and while stirring the produced homogeneous solution, solution No. Combine with 1. The mixing operation is carried out in a magnetic mixer or an overhead mixer or in a viscous liquid mixer for 5 minutes or more so that a homogeneous mass is obtained. Homogenization is performed at a temperature of 15 ° C. or lower in a vacuum of 10 to 99 kPa. After making a homogeneous mixture, add nipagin, nipazole, and the remaining amount of poloxamer 407 and stir until homogeneous. Nipagin and Nipazole are described in Solution No. No. 1 is the solution No. 1 is the solution No. 2 and No. Before combining with the liquid in which 3 is combined, or the solution No. 2 and No. May be added together with 3.

In a preferred embodiment of the invention, the step of producing solution 1 is carried out at a temperature of 8 to 17 ° C. and a pressure of 10 to 99 kPa, without exposure to light (or in a dark glass container). As we have unexpectedly found, this technical solution makes it possible to reduce the bubble content, resulting in the absence of air oxygen and the reduced potential of the redox reaction. Improve system stability. Solutions 2 and 3 are prepared at temperatures in the range of 18-25 ° C. These solutions are mixed at a temperature of 8-17 ° C.

When producing the final mixture (gel), an aqueous solution of sodium hydroxide or hydrochloric acid is used to adjust the pH value to 3.5-7.5 in the temperature range of 8-17 ° C. While doing this, the viscosity of the product is monitored, but the viscosity of the product should be in the range of 3 to 75 Pa · s.

The proposed gels for rectal and topical administration in the proposed embodiments are very effective in eliminating the symptoms of chronic anal fissure and external hemorrhoids and reducing pain sensation after hemorrhoid resection.

The proposed technique can improve the stability of the gel composition and does not require thickeners or stabilizers.

When producing the gel of the present invention, instead of poloxamer 407, a block of ethylene oxide and propylene oxide having a polyoxyethylene block content of 20 to 40% by weight or less, which is an equivalent block copolymer. Copolymers (proxanols) may be used.

It should be noted that there is a significant difference between the gel production method of the present invention and the nearest prior art or the method disclosed in patent RU2606858. In order to reduce the viscosity of the intermediate product of poloxamer by exhibiting a thermotropic phase transition at a certain temperature, that is, the corresponding intermediate poloxamer compound has a thermoreversible structure, the gel at that temperature is poloxamer. It is a micellar network and is converted into a simple liquid micellar suspension by maintaining a temperature regimen in the range of 8 ° C to 17 ° C. This makes it possible to significantly reduce the time required for the manufacturing process (to 4 to 6 hours), and by first producing a micelle suspension, the rheological structure of the produced gel can be improved. As a result, the gel can be degassed faster, a more stable gel form can be produced, and most importantly, the stability of the gel is improved as compared with the prototype. The ingredients used are insensitive to pH changes until the gel structure is perfectly balanced, so direct final neutralization was selected for the unwrapped final gel, excluding all intermediate pH adjustments. Will be done. This significantly reduces the manufacturing process time (3-5 hours).

Hereinafter, exemplary embodiments will be described, but these embodiments do not include all possible embodiments of the present invention and do not limit the claimed invention.

An exemplary embodiment of the present invention and Example 1 thereof.
The method for producing a gel for rectal and topical administration is to mix 0.7% by weight of poloxamer 407, 0.01% by weight of poloxamer 188, and 1.0% by weight of water to obtain an aqueous solution No. Includes manufacturing 1. Next, 1.5% by weight of lidocaine hydrochloride was dissolved in 1.0% by weight of water, and the solution No. 2 is prepared. Then, 0.25% by weight of nifedipine and 0.01% by weight of polyethylene glycol 400 were mixed to obtain Mixture No. 3 is prepared. Then, the solution No. No. 2 is the solution No. Combined with No. 3, a homogeneous solution was obtained, which was referred to as Solution No. 3. Combine with 1 while stirring. All mixing operations are performed in an overhead mixer for 15 minutes to obtain a homogeneous mass. A mixture of 0.01% by weight nipagin and 0.01% by weight nipazole and the remaining amount of poloxamer 407 (0.3% by weight) were stirred with solution No. 2 and No. Add to the combination of 3.

Solution No. The production of No. 1 is carried out at a temperature of 8 ° C., a pressure lower than the atmospheric pressure (99.0 kPa), and without light. Solution No. 2 and No. 3 is prepared at a temperature of 18 ° C. The solution is mixed at a temperature of 8 ° C.

After producing the final solution (gel), the pH value is adjusted to 4.5 at a temperature of 8 ° C. using an aqueous sodium hydroxide solution. While doing this, monitor the viscosity of the product, but the viscosity should be in the range of 3 to 75 Pa · s.

Table 1 shows an example of the gel produced by the above method.

Example 2
The method for producing a gel for rectal and topical administration is to mix 12.0% by weight of poloxamer 407, 10.0% by weight of poloxamer 188, and 30.0% by weight of water to obtain an aqueous solution No. Includes manufacturing 1. Next, 3.2% by weight of lidocaine hydrochloride was dissolved in 30.0% by weight of water, and the solution No. 2 is prepared. Then, 0.55% by weight of nifedipine and 34.0% by weight of polyethylene glycol 400 were mixed to obtain Mixture No. 3 is prepared. Then, the solution No. 2 and solution No. 3 and this are combined to produce a homogeneous solution, which is then referred to as Solution No. Combine with 1 while stirring. All mixing operations are performed with stirring in a magnetic mixer for 5 minutes to obtain a homogeneous mass. A mixture of 0.072% by weight nipagin and 0.03% by weight nipazole and the remaining amount of poloxamer 407 (0.5% by weight) were mixed with solution No. 2 and No. Add to the combination of 3.

Solution No. The operation of preparing the 1st liquid is carried out at a temperature of 17 ° C., a pressure lower than the atmospheric pressure (80 kPa), and without exposure to light (in a dark glass container). Solution No. 2 and No. 3 is prepared at a temperature of 25 ° C. The solution is mixed at a temperature of 17 ° C.

After producing the final solution (gel), the pH value is adjusted to 7.5 at a temperature of 17 ° C. using an aqueous sodium hydroxide solution. While doing this, the product viscosity is monitored, but the viscosity should be in the range of 3 to 75 Pa · s.

Table 2 shows an example of the gel produced by the above method.

Example 3 Gel production The method for producing a gel for rectal and topical administration is to mix 7.0% by weight poloxamer 407, 5.0% by weight poloxamer 188, and 25.0% by weight water in an aqueous solution No. .. Includes manufacturing 1. Then, a mixture of 0.03% by weight nipagin and 0.02% by weight nipazole was added to Solution No. Add to 1. Next, 3.2% by weight of lidocaine hydrochloride is dissolved in 15.0% by weight of water to prepare Solution 2. Then, 0.55% by weight nifedipine and 17.0% by weight polyethylene glycol 400 were mixed to obtain Mixture No. 3 is prepared. Then, the solution No. No. 2 is the solution No. Combined with 3 to form a homogeneous solution, which was combined with Solution No. 1 containing nipagin and nipazole. Combine with 1 while stirring. All mixing operations are performed with stirring in a viscous liquid mixer for 15 minutes to obtain a homogeneous mass. The remaining amount (0.3 wt%) of poloxamer 407 is added to the prepared solution with stirring.

Solution No. The manufacturing operation of 1 is carried out at a temperature of 12 ° C. and a pressure of 10.0 kPa without exposure to light. Solution No. 2 and No. 3 is prepared at a temperature of 20 ° C. The solution is mixed at a temperature of 12 ° C.

After producing the final solution (gel), the pH value is adjusted to 6.5 at a temperature of 12 ° C. using an aqueous sodium hydroxide solution. While doing this, the product viscosity is monitored, but the viscosity should be in the range of 3 to 75 Pa · s.

Table 3 shows an example of the gel produced by the above method.

Example 4
The method for producing a gel for rectal and topical administration is to mix 10.5% by weight of poloxamer 407, 5.0% by weight of poloxamer 188, and 35.0% by weight of water to obtain an aqueous solution No. Includes manufacturing 1. Next, 3.2% by weight of lidocaine hydrochloride is dissolved in 15.0% by weight of water to prepare Solution 2. Then, 0.40% by weight of nifedipine and 17.0% by weight of polyethylene glycol 600 were mixed to obtain Mixture No. 3 is prepared. Then, the solution No. No. 2 is the solution No. Combine with No. 3 to form a homogeneous solution, which is referred to as Solution No. Combine with 1 while stirring. All mixing operations are performed with stirring in a viscous liquid mixer for 15 minutes to obtain a homogeneous mass. A mixture of 0.05% by weight nipagin and 0.032% by weight nipazole and the remaining amount of poloxamer 407 (4.5% by weight) are added to the produced homogeneous mixture with stirring.

Solution No. The manufacturing operation of 1 is carried out at a temperature of 15 ° C. and a pressure of 50.0 kPa without exposure to light. Solution No. 2 and No. 3 is prepared at a temperature of 22 ° C. The solution is mixed at a temperature of 15 ° C.

After producing the final solution (gel), the pH value is adjusted to 7.5 at a temperature of 8 ° C to 17 ° C using an aqueous sodium hydroxide solution. While doing this, monitor the product viscosity, but the viscosity should be in the range of 3 to 75 Pa · s.

Table 4 shows an example of the gel produced by the above method.

Example 5 Examination of the stability of the produced gel The extension of the stability period of the proposed formulation is confirmed by the data shown in Table 5 (mean measurement of 5 times).

Thus, the proposed method, in contrast to the prototype, does not change the content of related impurities and the amounts of lidocaine and nifedipine, and keeps the impurities within acceptable limits, thus providing pharmaceutical stability for at least 3 years. Can be improved.

Example 6
The method for producing a gel for rectal and topical administration is to mix 0.7% by weight of poloxamer 407, 0.01% by weight of poloxamer 188, and 1.0% by weight of water to obtain an aqueous solution No. Includes manufacturing 1. Next, 1.5% by weight of lidocaine hydrochloride is dissolved in 1.0% by weight of water to prepare two solutions. Then, 0.25% by weight of nifedipine and 0.01% by weight of polyethylene glycol 400 were mixed to obtain Mixture No. Prepare No. 3. Then, the solution No. No. 2 is the solution No. 3 and a mixture of 0.01% by weight nipagin and 0.01% by weight nipazole were combined to form a homogeneous solution, which was referred to as Solution No. Combine with 1 while stirring. The mixing operation is carried out with stirring in an overhead mixer for 15 minutes to obtain a homogeneous mass. Homogenization is performed at a temperature of 8 ° C. and in vacuum. The remaining amount (0.3% by weight) of poloxamer 407 is added to the produced solution with stirring.

Solution No. The production of No. 1 is carried out at a temperature of 8 ° C., a pressure of 99.0 kPa lower than the atmospheric pressure, and no light. No. 2 and No. The solution of 3 is prepared at a temperature of 18 ° C. The solution is mixed at a temperature of 8 ° C.

After producing the final solution (gel), the pH value is adjusted to 4.5 at a temperature of 8 ° C. using an aqueous sodium hydroxide solution. While doing this, the product viscosity is monitored, but the viscosity should be in the range of 3 to 75 Pa · s.

An exemplary gel produced by the above method is shown in Table 6.

Example 7
The method for producing a gel for rectal and topical administration is to mix 12.0% by weight of poloxamer 407, 10.0% by weight of poloxamer 188, and 30.0% by weight of water to obtain an aqueous solution No. Includes manufacturing 1. Next, 3.2% by weight of lidocaine hydrochloride is dissolved in 30.0% by weight of water to prepare Solution 2. Then, 0.55% by weight of nifedipine and 34.0% by weight of polyethylene glycol 400 were mixed to obtain Mixture No. 3 is prepared. Then, the solution No. No. 2 is the solution No. 3 and a mixture of 0.072% by weight nipagin and 0.03% by weight nipazole were combined to form a homogeneous solution, which was referred to as Solution No. Combine with 1 while stirring. The mixing operation is carried out with stirring in a magnetic mixer for 5 minutes so that a homogeneous mass is obtained. The remaining amount (0.5% by weight) of poloxamer 407 is added to the produced solution with stirring.

Solution No. The production of No. 1 is carried out at a temperature of 17 ° C. and a pressure of 80 kPa lower than the atmospheric pressure without exposure to light (in a dark glass container). Solution No. 2 and No. 3 is prepared at a temperature of 25 ° C. The solution is mixed at a temperature of 17 ° C.

After producing the final solution (gel), the pH value is adjusted to 7.5 at a temperature of 17 ° C. using an aqueous sodium hydroxide solution. While doing this, monitor the product viscosity, but the viscosity should be in the range of 3 to 75 Pa · s.

An exemplary gel produced by the above method is shown in Table 7.

Example 8
The method for producing a gel for rectal and topical administration is to mix 7.0% by weight poloxamer 407, 5.0% by weight poloxamer 188, and 25.0% by weight water to obtain an aqueous solution No. Includes manufacturing 1. Next, 3.2% by weight of lidocaine hydrochloride is dissolved in 15.0% by weight of water to prepare Solution 2. Then, 0.55% by weight of nifedipine and 17.0% by weight of polyethylene glycol 400 were mixed to obtain Mixture No. 3 is prepared. Then, the solution No. No. 2 is the solution No. 3 was combined with a mixture of 0.03% by weight nipagin and 0.02% by weight nipazole 0.02% by weight to form a homogeneous solution, which was referred to as Solution No. Mix with 1 while stirring. The mixing operation is carried out with stirring in a viscous liquid mixer for 15 minutes to obtain a homogeneous mass. The remaining amount (0.3% by weight) of poloxamer 407 is added to the produced solution with stirring.

Solution No. Production of 1 is carried out at a temperature of 12 ° C. and a pressure of 10.0 kPa, which is lower than atmospheric pressure, without exposure to light. Solution No. 2 and No. 3 is prepared at a temperature of 20 ° C. The solution is mixed at a temperature of 12 ° C.

After producing the final solution (gel), the pH value is adjusted to 6.5 at a temperature of 12 ° C. using an aqueous sodium hydroxide solution. While doing this, monitor the product viscosity, but the viscosity should be in the range of 3 to 75 Pa · s.

An exemplary gel produced by the above method is shown in Table 8.

Example 9
The method for producing a gel for rectal and topical administration is to mix 10.5% by weight of poloxamer 407, 5.0% by weight of poloxamer 188, and 35.0% by weight of water to obtain an aqueous solution No. Includes manufacturing 1.

Next, 3.2% by weight of lidocaine hydrochloride is dissolved in 15.0% by weight of water to prepare Solution 2. Then, 0.40% by weight of nifedipine and 17.0% by weight of polyethylene glycol 600 were mixed to obtain Mixture No. 3 is prepared. Then, the solution No. No. 2 is the solution No. 3 and a mixture of 0.05% by weight nipagin and 0.032% by weight nipazole were combined to form a homogeneous solution, which was referred to as Solution No. Mix with 1 while stirring. The mixing operation is carried out with stirring in a viscous liquid mixer for 20 minutes to obtain a homogeneous mass. The remaining amount (4.5% by weight) of poloxamer 407 is added to the produced solution with stirring.

Solution No. The production of No. 1 is carried out at a temperature of 15 ° C. and a pressure of 50.0 kPa without light. Solution No. 2 and No. 3 is prepared at a temperature of 22 ° C. The solution is mixed at a temperature of 15 ° C.

After producing the final solution (gel), the pH value is adjusted to 7.5 at a temperature of 8 to 17 ° C. using an aqueous sodium hydroxide solution. While doing this, monitor the product viscosity, but the viscosity should be in the range of 3 to 75 Pa · s.

An exemplary gel produced by the above method is shown in Table 9.

Example 10 Examination of the stability of the produced gel The extension of the stability period of the proposed formulation is confirmed by the data shown in Table 10 (mean measurement of 5 times).

Therefore, the proposed method can increase the pharmaceutical stability up to at least 3 years because the content of related impurities and the amount of lidocaine and nifedipine do not change, in contrast to the nearest prior art.

Example 11 Analysis results of quality indicators of the formulations manufactured in Examples 1 to 4 and 6 to 9

Example 12 Examination of the efficacy of the proposed formulations produced in Examples 1-4 and 6-9, in vivo experiments.
The efficacy of the gels of the proposed formulations produced in Examples 1-4 and 6-9 was tested in rats.

The gel was administered around the anus of an anal fissure model rat twice a day for 14 days. Administration of the gel made it possible to completely eliminate the morphological changes typical of anal fissure. That is, complete healing was achieved in 95% of the rats tested. In the control group using a gel base containing no active substances of nifedipine and lidocaine, the proportion of animals with reduced anal fissure symptoms was 15%.

The gel was administered to the perianal and rectum of acute hemorrhoid model rats twice daily for 14 days. Hemorrhoidal symptoms were completely abolished in 92.5% of the animals by administration of the gel, whereas hemorrhoidal symptoms were completely alleviated in 45% of the animals in the control group treated with the gel base.

The effectiveness of gel administration to reduce pain sensation after hemorrhoid resection was indirectly evaluated in rats. Anal sphincter spasms are known to be the main cause of cramps after surgical removal of hemorrhoids. Therefore, the relief of pain in the hemorrhoid model rat was evaluated as a stable recovery of the anal-rectal manometry index toward the initial level. The gel was administered perianal and rectum twice daily for 14 days. Gel administration allowed the anal-rectal manometry index to return to initial levels in 100% of animals, but complete recovery of the index was observed only in 17.5% of animals in the gel-based controlled control group. .. In addition, all gel formulations produced by the above method showed similar efficacy in vivo.

The above exemplary variants of the proposed gels and the methods for producing them illustrate, but not all, all possible embodiments of the proposed invention.

The technical effect was achieved by producing variants of the gel formulation for rectal and topical administration containing nifedipine and lidocaine hydrochloride, each variant providing stability, transparency of gel-like properties and at least 3 Maintain stable characteristics for years. Administration of a variant of the gel can reduce the clinical symptoms of hemorrhoids to complete disappearance, cure anal fissures, and reduce pain syndromes, including after hemorrhoid resection. It also expands the range of gels with different properties.

In addition, the technical effect was achieved by developing a method for producing gels for rectal and topical administration, including nifedipine and lidocaine hydrochloride, with stability, transparency and stable properties of gel-like properties for at least 3 years. Maintenance is ensured.

The pharmaceutical composition of the present invention and the method for producing a gel, which is the base of the gel, are mainly intended for the prevention and / or treatment of anal fissure, hemorrhoids and related diseases, and reduction of pain sensation after hemorrhoid resection. The present invention relates to the formulation, production method, and use of a gel containing nifedipine and lidocaine hydrochloride as main active substances.

The proposed gel is highly effective in eliminating symptoms of chronic anal fissure, external hemorrhoids and pain sensation until their elimination when used for rectal or topical administration in all presented variants made by the proposed method. Guarantee.

All the inventions presented will be industrially applicable, tested in laboratory conditions, practically feasible and will be widely used in the pharmaceutical industry.

Literature

Claims (23)

A method for producing gels for rectal and topical administration:
(A) 1.0 to 19.0% by weight of poloxamer 407, 0.01 to 10.0% by weight of poloxamer 188, and 1.0 to 30.0% by weight of water are mixed to prepare an aqueous solution 1. To manufacture;
(B) Dissolving 1.5 to 3.2% by weight of lidocaine hydrochloride in 1.0 to 30.0% by weight of water to produce aqueous solution 2;
(C) Mixing 0.25 to 0.55% by weight of nifedipine with 0.01 to 34.0% by weight of low molecular weight polyethylene glycol to prepare Solution 3;
(D) Combining solution 2 and solution 3 to produce a homogeneous solution;
(E) Combining the solution obtained in the previous step with solution 1 while stirring;
(F) To add 0.01-0.072% by weight of methylparaben (nipagin) and 0.01-0.032% by weight of propylparaben (nipazole) to the mixture produced in the previous step;
(G) Add 1.0 to 19.0% by weight of poloxamer 407 to the mixture produced in the previous step and stir until homogeneous;
(H) To adjust the pH value by adding a pH adjuster to the mixture produced in the previous step.
Including
Each of the steps (a) to (h) is carried out with vigorous stirring for at least 5 minutes so as to obtain a homogeneous mass;
Step (a) is performed at a temperature of 8-17 ° C. and a pressure of 10-99 kPa without exposure to light; steps (b) and (c) are performed at a temperature of 18-25 ° C.; (G) and (e) are carried out at a temperature of 8 to 17 ° C .;
In step (h), the pH value of the mixture is adjusted to a value in the range of 3.5-7.5;
The step (f) of adding nipagin and nipazole may be performed before the step (b);
The viscosity of the gel obtained by the above method is in the range of 3 to 75 Pa · s.
Method. The method of claim 1, wherein 0.01 to 10.0% by weight of low molecular weight polyethylene glycol is added to the solution or mixture during or prior to step (e). The method of claim 1 or 2, wherein the small molecule polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600. The method of claim 1, wherein the pH regulator is selected from sodium hydroxide and hydrochloric acid. The method according to claim 1, wherein the total time for performing the steps (a) to (h) for producing the gel is 4 to 6 hours or less. The method according to claim 1, further comprising a step (i) of checking the quality of the produced gel. 6. The method of claim 6, wherein step (i) comprises at least one measurement of all of the following parameters:
-The content of lidocaine hydrochloride is 0.25 to 0.55% and the content of nifedipine is 1.5 to 3.2%;
-The content of the identified lidocaine impurities is 0.1% or less;
-The total content of the identified nifedipine impurities is 2.5% or less;
-The content of a single unidentifiable impurity is 0.2% or less;
-The particle size of the produced gel is 100 microns or less;
-The pH is in the range of 3.5-7.5;
-Gel viscosity is in the range of 3 to 75 Pa · s;
-Microbiological purity corresponds to the category of non-sterile drugs according to the valid version of the official Pharmacopoeia. The method of any one of claims 1-7, which is a gel for rectal and topical administration, which provides prevention and / or treatment of anal fissure, hemorrhoids and related diseases, reduction of pain sensation after hemorrhoid resection. A gel comprising, nifedipine, lidocaine hydrochloride, poroxamar 188, low molecular weight polyethylene glycol, nipagin, nipazole, poroxamar 407, pH adjuster and purified water in the following component ratios by weight.
Nifedipine 0.25-0.55
Lidocaine Hydrochloride 1.5-3.2
Poloxamer 407 1.0-19.0
Poloxamer 188 0.01-10.0
Small Molecule Polyethylene Glycol 0.01-34.0
Nipagin 0.01-0.072
Nipazole 0.01-0.032
Acidity regulator To be pH 3.5-7.5 Purified water to be 100.0 The gel according to claim 8, wherein the small molecule polyethylene glycol is polyethylene glycol 400 or polyethylene glycol 600. The gel according to claim 8, wherein the pH adjuster is selected from sodium hydroxide and hydrochloric acid. The gel according to claim 8, wherein the gel has the following component ratios per 1 g of the final pharmaceutical product.
Lidocaine hydrochloride hydrate 0.0213g
Nifedipine 0.0030g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Nipagin 0.0007g
Nipazole 0.0003g
Sodium hydroxide or hydrochloric acid so that the pH is 7.0 and the amount of purified water is 1.0 g. Use of the gel according to any one of claims 8 to 11 to reduce the clinical symptoms of hemorrhoids until they are completely eliminated, heal anal fissures, and reduce pain syndrome after hemorrhoid resection. A method for producing gels for rectal and topical administration:
(I) Aqueous solution 1 is prepared by mixing 1.0 to 19.0% by weight of poloxamer 407, 0.01 to 10.0% by weight of poloxamer 188, and 1.0 to 30.0% by weight of water. To manufacture;
(Ii) Dissolving 1.5 to 3.2% by weight of lidocaine hydrochloride in 1.0 to 30.0% by weight of water to produce aqueous solution 2;
(Iii) Mixing 0.25 to 0.55% by weight of nifedipine with 0.01 to 34.0% by weight of low molecular weight polyethylene glycol to prepare Solution 3;
(Iv) To obtain a homogeneous solution, solution 2, solution 3, and 0.01 to 0.072% by weight of methylparaben (nipagin) and 0.01 to 0.032% by weight of propylparaben (nipazole). With the combination of;
(V) Combining the solution obtained in the previous step with solution 1 while stirring;
(Vi) Add 1.0 to 19.0 wt% poloxamer 407 to the mixture produced in the previous step and further stir until homogeneous;
(Vii) To adjust the pH value by adding a pH adjuster to the mixture produced in the previous step.
Including
Each step (i)-(vii) is carried out with vigorous stirring for at least 5 minutes to obtain a homogeneous mass;
Step (i) is performed at a temperature of 8-17 ° C., a pressure 1-80% lower than atmospheric pressure, without exposure to light; steps (ii) and (iii) are performed at a temperature of 18-25 ° C. Performed; Steps (iv) and (v) are performed at a temperature of 8-17 ° C .;
In step (vi), the pH value is adjusted to a value in the range of 3.5-7.5;
The final gel viscosity is in the range of 3 to 75 Pa · s,
Method. 13. The method of claim 13, wherein the small molecule polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600. 13. The method of claim 13, wherein the pH regulator is selected from sodium hydroxide and hydrochloric acid. The method according to claim 13, wherein the total time for performing the steps (i) to (vii) for producing the gel is 4 to 6 hours or less. 13. The method of claim 13, further comprising a step (viii) of checking the quality of the gel produced. 17. The method of claim 17, wherein the step (vii) comprises at least one measurement of all of the following parameters:
-The content of lidocaine hydrochloride is 0.25 to 0.55% and the content of nifedipine is 1.5 to 3.2%;
-The content of the identified lidocaine impurities is 0.1% or less;
-The content of the identified nifedipine impurities is 2.5% or less;
-The content of a single unidentifiable impurity is 0.2% or less;
-The particle size of the produced gel is 100 microns or less;
-The pH is in the range of 3.5-7.5;
-Gel viscosity is in the range of 3 to 75 Pa · s;
-Microbiological purity corresponds to the category of non-sterile drugs according to the valid version of the official Pharmacopoeia. A gel for rectal and topical administration, which provides prevention and / or treatment of anal fissure and hemorrhoids and related diseases, reduction of pain sensation after hemorrhoid resection, according to any one of claims 13-18. A gel prepared by the method and comprising nifedipine, lidocaine hydrochloride, poroxamer 188, low molecular weight polyethylene glycol, nipagine, nipazole, poroxamer 407, pH adjuster, and purified water in the following component ratios by weight.
Nifedipine 0.25-0.55
Lidocaine Hydrochloride 1.5-3.2
Poloxamer 407 1.0-19.0
Poloxamer 188 0.01-10.0
Small Molecule Polyethylene Glycol 0.01-34.0
Nipagin 0.01-0.072
Nipazole 0.01-0.032
Acidity regulator To be pH 3.5-7.5 Purified water to be 100.0 19. The gel of claim 19, wherein the small molecule polyethylene glycol is polyethylene glycol 400 or polyethylene glycol 600. 19. The gel of claim 19, wherein the pH regulator is selected from sodium hydroxide and hydrochloric acid. The gel according to claim 19, wherein the gel has the following component ratios per 1 g of the final pharmaceutical product.
Lidocaine hydrochloride hydrate 0.0213g
Nifedipine 0.0030g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Nipagin 0.0007g
Nipazole 0.0003g
Sodium hydroxide or hydrochloric acid so that the pH is 7.0 and the amount of purified water is 1.0 g. Use of the gel according to any one of claims 19 to 22 to reduce the clinical symptoms of hemorrhoids until they are completely eliminated, heal anal fissures, and reduce pain syndrome after hemorrhoid resection.