JP7331149B2 - Gel for rectal and topical administration - Google Patents

Description

The present invention relates to the field of medicine, in particular a pharmaceutical composition forming a base for a gel intended for rectal and topical administration, and the composition of said gel intended for use in the treatment of hemorrhoids and anal fissures. It relates to a 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 pharmaceuticals for rectal and topical administration, such as fat-based drugs such as gels, ointments, emulsions.

Fat-based pharmaceuticals presented in the form of ointments or emulsions for topical administration are known in the art and include nifedipine [1-3].

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

Nifedipine is a calcium antagonist and reduces the tone of the anal sphincter by inhibiting the transport of calcium ions into cells. In patients with hemorrhoids and anal fissures, reducing spasm of the anal sphincter is the primary method for reducing pain [6]. The pharmacological activity of nifedipine also modulates a reduction in the intensity of the inflammatory response [7], has regulatory effects on microcirculation [8], and prevents the development of defects in the anal canal mucosa [9].

Advantages of pharmaceuticals presented as gels, ointments, suspensions include their sustained action, presence of moistening effect, and convenience in use. For example, gels, when applied to the skin, are easily washed off by water, in contrast to ointments, making it possible to choose gels when choosing the type of drug in such cases [10 ].

Pharmaceutical compositions for treating anal fissures are known in the art [11] and include a base, an agent that reduces smooth muscle spasm, and lidocaine, wherein the base is titanium. The glycerosorbate aqua complex, smooth muscle spasm-reducing agent is nifedipine or nitroglycerin, and the composition components are contained in proportions in grams. The invention provides effective therapy at reduced active agent concentrations, reduces side effects, and shortens treatment duration.

Anal fissures are known to be caused by damage to the walls of the anal canal, such as damage from constipation. Therefore, laxatives and 0.2% nitroglycerin ointment are commonly used in prophylaxis and treatment. This ointment is now considered an important ingredient for the conservative treatment of anal fissures, because nitroglycerin relaxes the anal sphincter, thereby eliminating spasms, which are associated with ischemia. , that is, it is a pathogenic factor of anal fissure because it causes blood flow disorder. However, when using nitroglycerin ointment, only small amounts should be applied because high doses can enter the systemic bloodstream and cause headaches and dizziness [1].
2].

The use of calcium antagonists is also known in the art, such as, for example, nifedipine, diltiazem, or other drugs, used in the treatment of heart disease and recently found applicable in the treatment of anal fissures. and their principle of action is the same as that of nitroglycerin ointment,
Eliminates spasm of the anal sphincter muscle [12].

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

Methods of dissolving nifedipine in aqueous media, and pharmaceutical compositions comprising aqueous solutions of nifedipine, are known in the art [13], which methods include nifedipine, poloxamer 407,
It involves preparing an aqueous solution containing macrogol 400, poloxamer 188 at a temperature in the range of 20-37° C. to ensure dissolution of nifedipine to a concentration of 0.8-4.0 mg/g.

The method disclosed in [13] and the formulation of the corresponding pharmaceutical composition combine nifedipine and lidocaine hydrochloride as the main active substances, intended for the prevention and treatment of anal fissures, hemorrhoids, and the reduction of pain associated with these diseases. It was considered as a basis for developing a variation of the manufacturing method of the gel including as and a variation of the same gel (Patent RU2641570, [14]).

Thus, Nifedipine, Lidocaine, Poloxamer 4 according to patent RU2641570
07, Macrogol 400, Poloxamer 188, and the gel produced by that method are the closest in all their essential characteristics to the gel proposed in the present invention and its production method. , can be considered the closest prior art.

The shortcomings of the closest prior art include the following.
- the complexity and use of multiple additives in the gel manufacturing process;
- Relatively low stability of the composition, even considering that thickeners and/or stabilizers such as Cekol 2000T or Carbopol Ultrez 10 are used 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.

Provide stability of the properties achieved, transparency, maintenance of stability for a period of more than 2 years (3 years or more) and pain symptoms until their complete disappearance if anal fissures or hemorrhoids are present. ensuring reduction, promoting healing of anal fissures in various stages, relieving pain such as pain after hemorrhoidectomy,
There is a need to develop pharmaceutical methods and formulations that contain less adjuvant than the prototype and that will provide the necessary bioavailability through dissolution of the active agent in aqueous media.

It is an object of the present invention to prepare gel compositions containing nifedipine and lidocaine hydrochloride as active substances, each variant of which is characterized by stable gel-like properties, transparency, stability of properties for more than two years. provide maintenance and their use makes it possible to ensure a reduction to complete disappearance of the clinical symptoms of hemorrhoids, healing of anal fissures, reduction of pain syndromes including after hemorrhoidectomy, both active substances and adjuvants is optimal and the dissolution of the active substance in the aqueous medium ensures the necessary bioavailability.

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

The technical effect achieved by the present group is to improve the stability and transparency of the gel-like properties while maintaining the pharmacological properties of the medicaments.

The above objects and technical effects are a method of manufacturing a gel for rectal and topical administration comprising:
(a) 1.0 to 19.0 parts by mass of poloxamer 407, 0.01 to 10.0 parts by mass of poloxamer 188, and 1.0 to 30.0 parts by mass of water are mixed to form an aqueous solution 1; to manufacture;
(b) dissolving 1.5 to 3.2 parts by weight of lidocaine hydrochloride in 1.0 to 30.0 parts by weight of water to produce an aqueous solution 2;
(c) mixing 0.25-0.55 parts by weight of nifedipine and 0.01-34.0 parts 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) adding 0.01 to 0.072 parts by weight of methylparaben (Nipagin) and 0.01 to 0.032 parts by weight of propylparaben (Nipazole) to the mixture prepared in the previous step;
(g) adding 1.0 to 19.0 parts by weight of poloxamer 407 to the mixture prepared in the previous step and stirring until homogeneous;
(h) adding a pH adjuster to the mixture produced in the previous step to adjust the pH value;
including
Each step of steps (a) to (h) is a homogeneous mass
with vigorous stirring for at least 5 minutes to obtain
Step (a) is performed at a temperature of 8-17° C., 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)
is carried out at a temperature of 8-17°C;
In step (h), the pH value of the mixture is adjusted to a value in the range of 3.5-7.5;
step (f) of adding nipagin and nipazole may precede step (b);
The viscosities of the gels produced in this way range from 3 to 75 Pa s.
achieved by a method.

According to preferred embodiments, the above technical effects are also achieved by:
- during step (e) or before step (g), 0.01 to 10.0 parts by weight of low molecular weight polyethylene glycol are added to the mixture;
- low molecular weight polyethylene glycols are selected from polyethylene glycol 400 and polyethylene glycol 600;
- the pH adjuster is selected from sodium hydroxide and hydrochloric acid;
- the total time for carrying out steps (a) to (h) of the preparation of the gel is no more than 4-6 hours;
- the method further comprises step (i) of checking the quality of the produced gel;
- step (i) comprises measuring at least one of the following:
- the content of lidocaine hydrochloride is 0.25-0.55% and the content of nifedipine is 1.5-3.2%;
- the content of identified lidocaine impurities is 0.1% or less;
- The total content of 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 gel component produced is 100 microns or less;
- the pH value is in the range of 3.5 to 7.5;
- The gel viscosity is 3 to 75 Pa s;
• The microbiological purity corresponds to the category of non-sterile medicinal product according to the valid edition of the Official Pharmacopeia (State Pharmacepeia).

Objects and technical effects also provide a gel for rectal and topical administration to prevent and/or treat anal fissures, hemorrhoids and related disorders, reduce pain after hemorrhoidectomy, and the methods described above. and contains nifedipine, lidocaine hydrochloride, poloxamer 188, low-molecular-weight polyethylene glycol, nipagin, nipazole, poloxamer 407, a pH adjuster and purified water in the following component ratios by mass %. be.
Nifedipine 0.25-0.55
Lidocaine hydrochloride 1.5-3.2
Poloxamer 407 1.0-19.0
Poloxamer 188 0.01-10.0
Low molecular polyethylene glycol 0.01-34.0
Nipagin 0.01-0.072
Nipazole 0.01-0.032
pH adjuster pH 3.5 to 7.5 Purified water 100.0

According to preferred embodiments, the above technical effects are also achieved by:
- low molecular weight polyethylene glycols are selected from polyethylene glycol 400 and polyethylene glycol 600;
- the pH adjuster is selected from sodium hydroxide and hydrochloric acid;
- The gel has the following proportions of ingredients per gram of final pharmaceutical product.
Lidocaine hydrochloride hydrate 0.0213 g
Nifedipine 0.0030 g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Nipagin 0.0007 g
Nipazole 0.0003 g
Sodium hydroxide or hydrochloric acid To make pH 7.0 Purified water To make 1.0 g

The objectives and technical effects are also achieved by administering the above gel for reducing clinical symptoms of hemorrhoids to their complete disappearance, healing anal fissures and reducing post-hemorrhoidectomy pain syndrome.

Aims and technical effects are also a method of manufacturing a gel for rectal and topical administration comprising:
(i) 1.0 to 19.0 parts by mass of poloxamer 407, 0.01 to 10.0 parts by mass of poloxamer 188, and 1.0 to 30.0 parts by mass of water are mixed to form an aqueous solution 1; manufacturing;
(ii) dissolving 1.5 to 3.2 parts by weight of lidocaine hydrochloride in 1.0 to 30.0 parts by weight of water to produce an aqueous solution 2;
(iii) mixing 0.25-0.55 parts by weight of nifedipine and 0.01-34.0 parts by weight of low-molecular-weight polyethylene glycol to prepare solution 3;
(iv) Solution 2, Solution 3, 0.01-0.072 parts by weight of methylparaben (Nipagin) and 0.01-0.032 parts by weight of propylparaben (Nipazole), so as to produce a homogeneous solution. combining with;
(v) combining the solution prepared in the previous step with Solution 1 while stirring;
(vi) 1.0 to 19.0 parts by weight of Poloxamer 407 in the mixture prepared in the previous step;
followed by stirring until homogeneous;
(vii) adding a pH adjuster to the mixture produced in the previous step to adjust the pH value;
Each step of steps (i)-(vii) is performed at least 5 times so as to obtain a homogeneous mass.
with vigorous stirring for 1 minute;
Step (i) is carried out at a temperature of 8-17°C, at a pressure of 1-80% below atmospheric pressure, without exposure to light; steps (ii) and (iii) at a temperature of 18-25°C. performed; step (iv
) and (v) are carried out 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 a method.

According to preferred embodiments, the above technical effects are also achieved by:
- low molecular weight polyethylene glycols are selected from polyethylene glycol 400 and polyethylene glycol 600;
- the pH adjuster is selected from sodium hydroxide and hydrochloric acid;
- the total time for performing gel manufacturing steps (i)-(vii) is no more than 4-6 hours;
- the method further comprises a step (viii) of checking the quality of the produced gel;
- step (viii) comprises measuring at least one of the following:
- the content of lidocaine hydrochloride is 0.25-0.55% and the content of nifedipine is 1.5-3.2%;
- the content of identified lidocaine impurities is 0.1% or less;
- The total content of 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 gel component produced is 100 microns or less;
- the pH value is in the range of 3.5 to 7.5;
- The gel viscosity is 3 to 75 Pa s;
• Microbiological purity corresponds to the category of non-sterile medicinal products according to the valid edition of the official pharmacopoeia.

The purpose and technical effect is a gel for rectal and topical administration to provide prevention and/or treatment of anal fissures, hemorrhoids and their associated diseases, reduction of pain after hemorrhoidectomy,
nifedipine, lidocaine hydrochloride, poloxamer 188, low-molecular-weight polyethylene glycol, nipagin, nipazole, poloxamer 407, pH adjuster, and purified water, produced by the above method, and containing the following component ratios in mass %: achieved.
Nifedipine 0.25-0.55
Lidocaine hydrochloride 1.5-3.2
Poloxamer 407 1.0-19.0
Poloxamer 188 0.01-10.0
Low molecular polyethylene glycol 0.01-34.0
Nipagin 0.01-0.072
Nipazole 0.01-0.032
pH adjuster pH 3.5 to 7.5 Purified water 100.0

According to preferred embodiments, the above technical effects are also achieved by:
- low molecular weight polyethylene glycols are selected from polyethylene glycol 400 and polyethylene glycol 600;
- the pH adjuster is selected from sodium hydroxide and hydrochloric acid;
- The gel has the following proportions of ingredients per gram of final pharmaceutical product.
Lidocaine hydrochloride hydrate 0.0213 g
Nifedipine 0.0030 g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Nipagin 0.0007 g
Nipazole 0.0003 g
Sodium hydroxide or hydrochloric acid To make pH 7.0 Purified water To make 1.0 g

The objects and technical effects are also achieved by using the gel described above to reduce the clinical symptoms of hemorrhoids to their complete disappearance, heal anal fissures, and reduce pain syndrome after hemorrhoidectomy. .

A method of preparing gels for rectal and topical administration is to mix poloxamer 407 and poloxamer 188 with water to form aqueous solution no. 1. Next, lidocaine hydrochloride was dissolved in water to form solution no. 2 is prepared. Next, nifedipine and low-molecular-weight polyethylene glycol are mixed to form mixture no. Prepare 3. Next, combine the prepared solutions—solution no. 2 and solution no. 3; and the homogenous solution produced is mixed with Solution No. 3 while stirring. Combine with 1. The mixing operation is carried out in a magnetic mixer or an overhead mixer or in a mixer for viscous liquids for 5 minutes or longer so as to obtain a homogeneous mass. Homogenization is carried out at a temperature below 15° C. and in a vacuum of 10-99 kPa. After making a homogeneous mixture, add Nipagin, Nipazole, and the remaining amount of Poloxamer 407 and stir until homogeneous. Nipagin and Nipazole are solution no. 1, solution N
o. 1 as solution no. 2 and no. 3 before combining with the combined solution, or solution no. 2 and no. 3 may be added.

In a preferred embodiment of the invention, the step of preparing solution 1 is carried out at a temperature of 8-17°C,
It is performed at a pressure of 99 kPa and 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 Improve system stability. Solutions 2 and 3 are prepared at temperatures ranging from 18-25°C.
These solutions are mixed at a temperature of 8-17°C.

Using an aqueous solution of sodium hydroxide or hydrochloric acid in preparing the final mixture (gel),8
A pH value of 3.5-7.5 is adjusted in the temperature range of ~17°C. While doing this, the viscosity of the product is monitored and should be in the range of 3-75 Pa·s.

The proposed gels for rectal and topical administration in the proposed embodiments are highly effective for eliminating symptoms of chronic anal fissures and external hemorrhoids, and for reducing post-hemorrhoidectomy pain.

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

When producing the gel of the present invention, instead of poloxamer 407, blocks of ethylene oxide and propylene oxide having a polyoxyethylene block content of 20 to 40 % by mass or less, which are equivalent block copolymers Copolymer (proxanol
anols)) may be used.

It should be noted that there is a significant difference between the gel manufacturing method of the present invention and the closest prior art or the method disclosed in patent RU2606858. Since the corresponding intermediate poloxamer compound is of thermoreversible structure, i.e. exhibits a thermotropic phase transition at a certain temperature, thereby reducing the viscosity of the poloxamer intermediate product, the gel at that temperature is
It is a poloxamer micelle network that 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 shorten the time required for the production process (to 4-6 hours), and by first producing a micellar suspension, the rheological structure of the produced gel can be improved, As a result, the gel can be degassed faster, producing a more stable gel morphology and, most importantly, an improved gel stability compared to the prototype. Since the ingredients used are insensitive to pH changes until the gel structure is fully balanced, final neutralization was chosen directly on the final unpackaged gel, excluding all intermediate pH adjustments. be done. This significantly reduces the time of the manufacturing process (3-5 hours).

Illustrative embodiments are described below, but these embodiments are not intended to be inclusive of all possible embodiments of the invention and are not intended to limit the claimed invention.

Exemplary Embodiments of the Invention and Example 1 thereof
A method of preparing a gel for rectal and topical administration is to prepare aqueous solution no.
1. Next, 1.5 parts by mass of lidocaine hydrochloride was dissolved in 1.0 parts by mass of water to obtain solution No. 2 is prepared. Then, 0.25 parts by mass of nifedipine and 0.01 parts by mass of polyethylene glycol 400 were mixed to form a mixture No. Prepare 3. then
Solution no. 2 as solution no. 3, which gives a homogeneous solution, which is called solution no. Combine with 1 while stirring. All mixing operations are performed in an overhead mixer for 15 minutes to ensure a homogeneous mass. A mixture of 0.01 parts by weight of nipagin and 0.01 parts by weight of nipazole and the remaining amount of poloxamer 407 (0.3 parts by weight ) was mixed with stirring while adding solution no. 2 and no. Add 3 to the combination.

Solution no. The preparation of 1 takes place in the absence of light at a temperature of 8° C. and subatmospheric pressure (99.0 kPa). Solution no. 2 and No. 3 is prepared at a temperature of 18°C. The solutions are mixed at a temperature of 8°C.

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

Table 1 shows examples of gels produced by the above method.

Example 2
A method of making a gel for rectal and topical administration comprises 12.0 parts by weight of poloxamer 407 and 1
0.0 part by mass of poloxamer 188 and 30.0 parts by mass of water were mixed to form an aqueous solution No. 1
including manufacturing Next, 3.2 parts by mass of lidocaine hydrochloride was dissolved in 30.0 parts by mass of water to obtain solution No. 2 is prepared. Then, 0.55 parts by mass of nifedipine and 34.0 parts by mass of polyethylene glycol 400 were mixed to form a mixture No. Prepare 3. then
Solution no. 2 and solution no. 3, thereby producing a homogeneous solution, which is called 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 parts by weight of Nipagin and 0.03 parts by weight of Nipazole and the remaining amount of Poloxamer 407 (0.5
parts by mass ) were added to solution No. 1 while stirring. 2 and no. Add 3 to the combination.

Solution no. The operation for the preparation of Part 1 is carried out at a temperature of 17° C., sub-atmospheric pressure (80 kPa) and without exposure to light (in a dark glass vessel). Solution no. 2 and no. 3 is 25
Prepared at a temperature of °C. The solutions are mixed at a temperature of 17°C.

After the final solution (gel) has been produced, the pH value is adjusted to 7.5 with aqueous sodium hydroxide at a temperature of 17°C. While doing this, monitor the product viscosity, which should be between 3 and 75
It should be in the range of Pa·s.

Table 2 shows examples of gels produced by the above method.

Example 3 Preparation of Gel A method for preparing a gel for rectal and topical administration comprises 7.0 parts by weight of poloxamer 407;
0 parts by mass of poloxamer 188 and 25.0 parts by mass of water were mixed to form an aqueous solution No. 1. Then, a mixture of 0.03 parts by weight of nipagin and 0.02 parts by weight of nipazole was added to solution no. Add to 1. Next, 3.2 parts by mass of lidocaine hydrochloride was added to 15.0
Solution 2 is prepared by dissolving in 1 part by mass of water. and 0.55 parts by mass of nifedipine and 17
. 0 parts by mass of polyethylene glycol 400 was mixed to obtain mixture No. Prepare 3. Then solution no. 2 as solution no. 3 to form a homogenous solution, which was added to solution no. Combine with 1 while stirring. All mixing operations are
Mixing is done with a mixer for viscous liquids for 15 minutes so that a homogeneous mass is obtained. The remaining amount of poloxamer 407 (0.3 parts by weight ) is added to the prepared solution with stirring.

Solution no. Operations for the preparation of 1 are carried out at a temperature of 12° C., a pressure of 10.0 kPa, and without exposure to light. Solution no. 2 and no. 3 is prepared at a temperature of 20°C. The solutions are mixed at a temperature of 12°C.

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

Table 3 shows examples of gels produced by the above method.

Example 4
A method of making a gel for rectal and topical administration comprises 10.5 parts by weight of poloxamer 407 and 5
. 0 parts by mass of poloxamer 188 and 35.0 parts by mass of water were mixed to form an aqueous solution No. 1. Next, solution 2 is prepared by dissolving 3.2 parts by mass of lidocaine hydrochloride in 15.0 parts by mass of water. Then, 0.40 parts by mass of nifedipine and 17.0 parts by mass of polyethylene glycol 600 were mixed to form a mixture No. Prepare 3. Then solution No.
. 2 as solution no. 3 to form a homogenous solution, which is added to solution no. Combine with 1 while stirring. All mixing operations were carried out for 15 minutes to obtain a homogeneous mass.
It is carried out with stirring in a mixer for viscous liquids. 0.05 parts by weight of nipagin and 0.0
A mixture of 32 parts by weight of Nipazole and the remaining amount of Poloxamer 407 (4.5 parts by weight ) are added with stirring to the homogeneous mixture produced.

Solution no. Operations for the production of 1 are carried out at a temperature of 15° C., a pressure of 50.0 kPa, and without exposure to light. Solution no. 2 and no. 3 is prepared at a temperature of 22°C. The solutions are mixed at a temperature of 15°C.

After the final solution (gel) has been produced, the pH value is adjusted to 7.5 using aqueous sodium hydroxide at a temperature between 8°C and 17°C. While doing this, monitor the product viscosity, which is 3
It should be in the range of ~75 Pa·s.

Table 4 shows examples of gels produced by the above method.

Example 5 Stability Study of Produced Gels The extended stability period of the proposed formulations is confirmed by the data shown in Table 5 (average of 5 measurements).

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 the impurities remain within acceptable limits, thus proving formulation stability up to at least 3 years. can be improved.

Example 6
A method of making a gel for rectal and topical administration comprises 0.7 parts by weight of poloxamer 407 and 0.7 parts by weight of poloxamer 407.
01 parts by mass of poloxamer 188 and 1.0 parts by mass of water were mixed to form an aqueous solution No. 1. Next, 1.5 parts by mass of lidocaine hydrochloride is dissolved in 1.0 parts by mass of water to prepare Solution 2. Then, 0.25 parts by mass of nifedipine and 0.01 parts by mass of polyethylene glycol 400 were mixed to form a mixture No. Prepare No. 3. Then solution No.
. 2 to solution no. 3 was combined with a mixture of 0.01 parts by weight of nipagin and 0.01 parts by weight of nipazole to form a homogeneous solution, which was added to 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 carried out at a temperature of 8° C. and vacuum. The remaining amount of poloxamer 407 (0.3 parts by weight ) is added to the prepared solution with stirring.

Solution no. The preparation of 1 is carried out in the absence of light at a temperature of 8° C. and a pressure of 99.0 kPa below atmospheric pressure. No. 2 and no. A solution of 3 is prepared at a temperature of 18°C. The solutions are mixed at a temperature of 8°C.

After preparation of the final solution (gel), the pH value is adjusted to 4.5 at a temperature of 8° C. with aqueous sodium hydroxide solution. While doing this, monitor the product viscosity, which should be between 3 and 75P
It should be in the range of a·s.

Exemplary gels produced by the method described above are shown in Table 6.

Example 7
A method of making a gel for rectal and topical administration comprises 12.0 parts by weight of poloxamer 407 and 1
0.0 part by mass of poloxamer 188 and 30.0 parts by mass of water were mixed to form an aqueous solution No. 1
including manufacturing Next, solution 2 is prepared by dissolving 3.2 parts by mass of lidocaine hydrochloride in 30.0 parts by mass of water. Then, 0.55 parts by mass of nifedipine and 34.0 parts by mass of polyethylene glycol 400 were mixed to form a mixture No. Prepare 3. Then solution N
o. 2 to solution no. 3 was combined with a mixture of 0.072 parts by weight of nipagin and 0.03 parts by weight of nipazole to form a homogeneous solution, which was added to solution no. Combine with 1 while stirring. The mixing operation is carried out with stirring in a magnetic mixer for 5 minutes in order to obtain a homogeneous mass. The remaining amount of poloxamer 407 (0.5 parts by weight ) is added to the prepared solution with stirring.

Solution no. The preparation of 1 takes place at a temperature of 17° C. and a pressure of 80 kPa below atmospheric pressure without exposure to light (in a dark glass vessel). Solution no. 2 and no. 3 is prepared at a temperature of 25°C. The solutions are mixed at a temperature of 17°C.

After the final solution (gel) has been produced, the pH value is adjusted to 7.5 with aqueous sodium hydroxide at a temperature of 17°C. While doing this, monitor the product viscosity, which ranges from 3 to 75P.
It should be in the range of a·s.

Exemplary gels produced by the method described above are shown in Table 7.

Example 8
A method for preparing a gel for rectal and topical administration comprises 7.0 parts by weight of poloxamer 407;5.
0 parts by mass of poloxamer 188 and 25.0 parts by mass of water were mixed to form an aqueous solution No. 1. Next, solution 2 is prepared by dissolving 3.2 parts by mass of lidocaine hydrochloride in 15.0 parts by mass of water. Then, 0.55 parts by mass of nifedipine and 17.0 parts by mass of polyethylene glycol 400 were mixed to form a mixture No. Prepare 3. Then solution no.
2 to solution no. 3 with a mixture of 0.03 parts by weight of nipagin and 0.02 parts by weight of nipazole to form a homogeneous solution, which is added to 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 residual amount of poloxamer 407 (0
. 3 parts by mass ) are added with stirring.

Solution no. The preparation of 1 is carried out at a temperature of 12° C. and a pressure of 10.0 kPa below atmospheric pressure without exposure to light. Solution no. 2 and no. 3 is prepared at a temperature of 20°C. solution is 1
Mix at a temperature of 2°C.

After preparing the final solution (gel), the pH was adjusted with aqueous sodium hydroxide at a temperature of 12°C.
Adjust the value to 6.5. While doing this, monitor the product viscosity, which ranges from 3 to 75
It should be in the range of Pa·s.

Exemplary gels produced by the method described above are shown in Table 8.

Example 9
A method of making a gel for rectal and topical administration comprises 10.5 parts by weight of poloxamer 407 and 5
. 0 parts by mass of poloxamer 188 and 35.0 parts by mass of water were mixed to form an aqueous solution No. 1.

Next, solution 2 is prepared by dissolving 3.2 parts by mass of lidocaine hydrochloride in 15.0 parts by mass of water. Then, 0.40 parts by mass of nifedipine and 17.0 parts by mass of polyethylene glycol 600 were mixed to form a mixture No. Prepare 3. Then solution no. 2 to solution no.
3 was combined with a mixture of 0.05 parts by weight of nipagin and 0.032 parts by weight of nipazole to form a homogeneous solution, which was added to 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 of poloxamer 407 (4.5 parts by weight ) is added to the prepared solution with stirring.

Solution no. The preparation of 1 is carried out at a temperature of 15° C. and a pressure of 50.0 kPa in the absence of light. Solution No.
. 2 and no. 3 is prepared at a temperature of 22°C. The solutions are mixed at a temperature of 15°C.

After the final solution (gel) has been produced, the pH value is adjusted to 7.5 with aqueous sodium hydroxide at a temperature of 8-17°C. While doing this, monitor the product viscosity, which ranges from 3 to
It should be in the range of 75 Pa·s.

Exemplary gels produced by the method described above are shown in Table 9.

Example 10 Stability Study of Produced Gels The extended stability period of the proposed formulations is confirmed by the data shown in Table 10 (average of 5 measurements).

Thus, the proposed method, in contrast to the closest prior art, improves the formulation stability by at least 3 as the content of relevant impurities and the amounts of lidocaine and nifedipine remain unchanged.
It can be increased up to a year.

Example 11 Results of quality index analysis of formulations produced in Examples 1-4 and 6-9

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

The gel was administered around the anus of the anal fissure model rats twice a day for 14 days. Administration of the gel made it possible to completely eliminate the morphological changes typical of anal fissures. complete cure was achieved in 95% of the rats tested. In the control group using gel base without nifedipine and lidocaine actives, the percentage of animals with reduced anal fissure symptoms was 15%.

The gel was administered perianally and rectally to acute hemorrhoid model rats twice daily for 14 days. Administration of the gel completely eliminated hemorrhoidal symptoms in 92.5% of the animals, whereas 45% of the animals in the control group treated with the gel base completely relieved hemorrhoidal symptoms.

The efficacy of gel administration to reduce pain after hemorrhoidectomy was indirectly evaluated in rats. Anal sphincter spasm is known to be the major cause of pain after surgical removal of hemorrhoids. Therefore, alleviation of pain sensation in hemorrhoid model rats was evaluated as a stable recovery of anorectal manometry indices toward initial levels. The gel is perianal and rectal, 2 per day.
dose for 14 days. Gel administration allowed the anorectal manometry index to return to initial levels in 100% of the animals, whereas a complete recovery of the index was 17.0 in the control group treated with the gel base.
Only observed in 5% of animals. Furthermore, all gel formulations produced by the above method showed similar efficacy in vivo.

The above exemplary variations of the proposed gels and methods for making them illustrate all possible embodiments of the proposed invention, but are not exhaustive.

A technical effect was achieved by manufacturing variations of gel formulations for rectal and topical administration containing nifedipine and lidocaine hydrochloride, each variation providing gel-like properties of stability, transparency, and at least 3 Maintain stable characteristics for years. By administration of the gel variant,
Reduction to complete disappearance of clinical symptoms of hemorrhoids, healing of anal fissures, reduction of pain syndromes including after hemorrhoidectomy is possible. It also expands the range of gels with different properties.

In addition, a technical effect was achieved by developing a method for manufacturing a gel containing nifedipine and lidocaine hydrochloride for rectal and topical administration, showing stability of gel-like properties, transparency, and stable properties for at least 3 years. maintenance is ensured.

The pharmaceutical composition of the present invention, which is the base of the gel, and the method for producing the gel are mainly intended for the prevention and/or treatment of anal fissures, hemorrhoids and related diseases, and the reduction of pain after hemorrhoidectomy. The present invention relates to formulations, methods of manufacture and uses of gels containing nifedipine and lidocaine hydrochloride as main active substances.

The proposed gel showed high efficacy in eliminating symptoms of chronic anal fissures, external hemorrhoids and reducing pain until their elimination when used for rectal or topical administration in all presented variants made by the proposed method. Guarantee.

All the inventions presented are industrially applicable, have been tested in laboratory conditions, can be implemented in practice and will be widely used in the pharmaceutical industry.
<Appendix>
Item 1
A method of making a gel for rectal and topical administration comprising:
(a) 1.0 to 19.0 parts by mass of poloxamer 407, 0.01 to 10.0 parts by mass of poloxamer 188, and 1.0 to 30.0 parts by mass of water are mixed to form an aqueous solution 1; manufacturing;
(b) dissolving 1.5 to 3.2 parts by weight of lidocaine hydrochloride in 1.0 to 30.0 parts by weight of water to produce an aqueous solution 2;
(c) mixing 0.25-0.55 parts by weight of nifedipine and 0.01-34.0 parts 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) adding 0.01 to 0.072 parts by weight of methylparaben (Nipagin) and 0.01 to 0.032 parts by weight of propylparaben (Nipazole) to the mixture prepared in the previous step;
(g) adding 1.0 to 19.0 parts by weight of Poloxamer 407 to the mixture prepared in the previous step and stirring until homogeneous;
(h) adding a pH adjuster to the mixture produced in the previous step to adjust the pH value;
including
Each of steps (a)-(h) is performed with vigorous stirring for at least 5 minutes to obtain a homogeneous mass;
Step (a) is performed at a temperature of 8-17° C., 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 performed at a temperature of 8-17°C;
In step (h), the pH value of the mixture is adjusted to a value in the range of 3.5-7.5;
step (f) of adding nipagin and nipazole may precede step (b);
The viscosity of the gel obtained by the method is in the range of 3 to 75 Pa s.
Method.
Item 2
Item 1. The method according to item 1, characterized in that 0.01 to 10.0 parts by mass of low-molecular-weight polyethylene glycol is added to the solution or mixture during step (e) or before step (g).
Item 3
Item 3. Method according to item 1 or 2, characterized in that the low molecular weight polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600.
Item 4
2. Process according to paragraph 1, characterized in that the pH adjusting agent is selected from sodium hydroxide and hydrochloric acid.
Item 5
Item 2. The method according to Item 1, wherein the total time for performing the steps (a) to (h) for producing the gel is 4 to 6 hours or less.
Item 6
2. The method of paragraph 1, further comprising step (i) of checking the quality of the produced gel.
Item 7
7. The method of paragraph 6, wherein step (i) comprises measuring at least one of the following parameters:
- the content of lidocaine hydrochloride is 0.25-0.55% and the content of nifedipine is 1.5-3.2%;
- the content of identified lidocaine impurities is 0.1% or less;
- the total content of identified nifedipine impurities is not more than 2.5%;
- the content of a single unidentifiable impurity is 0.2% or less;
- the particle size of the produced gel is less than or equal to 100 microns;
- pH ranges from 3.5 to 7.5;
- the gel viscosity is in the range from 3 to 75 Pa.s;
- The microbiological purity corresponds to the category of non-sterile medicinal products according to the valid edition of the official pharmacopoeia.
Item 8
A gel for rectal and topical administration, which provides prevention and/or treatment of anal fissures, hemorrhoids and related diseases, reduction of pain after hemorrhoidectomy, by the method of any one of paragraphs 1-7 A gel produced and containing nifedipine, lidocaine hydrochloride, poloxamer 188, low-molecular-weight polyethylene glycol, nipagin, nipazole, poloxamer 407, a pH adjuster and purified water in the following component ratios in % 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
Low molecular polyethylene glycol 0.01-34.0
Nipagin 0.01-0.072
Nipazole 0.01-0.032
pH adjuster pH 3.5 to 7.5
Purified water so that it becomes 100.0
Item 9
Item 9. The gel according to Item 8, wherein the low molecular weight polyethylene glycol is polyethylene glycol 400 or polyethylene glycol 600.
Item 10
9. Gel according to clause 8, characterized in that the pH adjusting agent is selected from sodium hydroxide and hydrochloric acid.
Item 11
9. Gel according to paragraph 8, characterized in that the gel has the following ratios of ingredients per gram of final pharmaceutical product:
Lidocaine hydrochloride hydrate 0.0213 g
Nifedipine 0.0030 g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Nipagin 0.0007 g
Nipazole 0.0003 g
Sodium hydroxide or hydrochloric acid to pH 7.0
Purified water so that it becomes 1.0 g
Item 12
Use of a gel according to any one of paragraphs 8 to 11 for reducing clinical symptoms of hemorrhoids to their complete disappearance, healing anal fissures and reducing post-hemorrhoidectomy pain syndrome.
Item 13
A method of making a gel for rectal and topical administration comprising:
(i) 1.0 to 19.0 parts by mass of poloxamer 407, 0.01 to 10.0 parts by mass of poloxamer 188, and 1.0 to 30.0 parts by mass of water are mixed to form an aqueous solution 1; manufacturing;
(ii) dissolving 1.5 to 3.2 parts by weight of lidocaine hydrochloride in 1.0 to 30.0 parts by weight of water to produce an aqueous solution 2;
(iii) mixing 0.25-0.55 parts by weight of nifedipine and 0.01-34.0 parts by weight of low-molecular-weight polyethylene glycol to prepare solution 3;
(iv) Solution 2, Solution 3, 0.01-0.072 parts by weight of methylparaben (Nipagin) and 0.01-0.032 parts by weight of propylparaben (Nipazole), so as to obtain a homogeneous solution; combining;
(v) combining the solution obtained in the previous step with Solution 1 while stirring;
(vi) adding 1.0 to 19.0 parts by weight of poloxamer 407 to the mixture prepared in the previous step and further stirring until homogeneous;
(vii) adding a pH adjuster to the mixture produced in the previous step to adjust the pH value;
including
Each of steps (i)-(vii) is performed with vigorous stirring for at least 5 minutes to obtain a homogeneous mass;
Step (i) is carried out at a temperature of 8-17°C, at a pressure of 1-80% below atmospheric pressure, without exposure to light; steps (ii) and (iii) at a temperature of 18-25°C. steps (iv) and (v) are carried out 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 ranges from 3 to 75 Pa s,
Method.
Item 14
14. Method according to paragraph 13, characterized in that the low molecular weight polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600.
Item 15
14. Method according to paragraph 13, characterized in that the pH adjusting agent is selected from sodium hydroxide and hydrochloric acid.
Item 16
Item 14. A method according to item 13, characterized in that the total time for performing steps (i) to (vii) for producing the gel is 4 to 6 hours or less.
Item 17
14. The method of paragraph 13, further comprising a step (viii) of checking the quality of the produced gel.
Item 18
18. The method of paragraph 17, wherein step (vii) comprises measuring at least one of the following parameters:
- the content of lidocaine hydrochloride is 0.25-0.55% and the content of nifedipine is 1.5-3.2%;
- the content of identified lidocaine impurities is 0.1% or less;
- has a content of identified nifedipine impurities not greater than 2.5%;
- the content of a single unidentifiable impurity is 0.2% or less;
- the particle size of the produced gel is less than or equal to 100 microns;
- pH ranges from 3.5 to 7.5;
- the gel viscosity is in the range from 3 to 75 Pa.s;
- The microbiological purity corresponds to the category of non-sterile medicinal products according to the valid edition of the official pharmacopoeia.
Item 19
19. A method according to any one of paragraphs 13 to 18, wherein the gel for rectal and topical administration provides prevention and/or treatment of anal fissures and hemorrhoids and related diseases, reduction of pain after hemorrhoidectomy. and comprising nifedipine, lidocaine hydrochloride, poloxamer 188, low-molecular-weight polyethylene glycol, nipagin, nipazole, poloxamer 407, a pH adjuster, and purified water in the following component ratios by weight percent:
Nifedipine 0.25-0.55
Lidocaine hydrochloride 1.5-3.2
Poloxamer 407 1.0-19.0
Poloxamer 188 0.01-10.0
Low molecular polyethylene glycol 0.01-34.0
Nipagin 0.01-0.072
Nipazole 0.01-0.032
pH adjuster pH 3.5 to 7.5
Purified water so that it becomes 100.0
Item 20
Item 20. The gel according to item 19, characterized in that the low molecular weight polyethylene glycol is polyethylene glycol 400 or polyethylene glycol 600.
Item 21
20. Gel according to paragraph 19, characterized in that the pH adjusting agent is selected from sodium hydroxide and hydrochloric acid.
Item 22
20. Gel according to paragraph 19, characterized in that the gel has the following ratios of ingredients per gram of final pharmaceutical product:
Lidocaine hydrochloride hydrate 0.0213 g
Nifedipine 0.0030 g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Nipagin 0.0007 g
Nipazole 0.0003 g
Sodium hydroxide or hydrochloric acid to pH 7.0
Purified water so that it becomes 1.0 g
Item 23
Use of a gel according to any one of paragraphs 19 to 22 for reducing clinical symptoms of hemorrhoids to their complete disappearance, healing anal fissures and reducing post-hemorrhoidectomy pain syndrome.

Literature

Claims (20)

A method of making a gel for rectal and topical administration comprising:
(a) mixing a first portion of poloxamer 407 , 0.01-10.0 parts by weight of poloxamer 188, and 1.0-30.0 parts by weight of water to produce an aqueous solution 1;
(b) dissolving 1.5 to 3.2 parts by weight of lidocaine hydrochloride in 1.0 to 30.0 parts by weight of water to produce an aqueous solution 2;
(c) mixing 0.25-0.55 parts by weight of nifedipine and 0.01-34.0 parts by weight of low-molecular-weight polyethylene glycol to prepare solution 3;
(d) combining aqueous solution 2 and solution 3 to produce a homogeneous solution;
(e) combining the solution obtained in the previous step with the aqueous solution 1 while stirring;
(f) adding 0.01 to 0.072 parts by weight of methylparaben and 0.01 to 0.032 parts by weight of propylparaben to the mixture prepared in the previous step;
(g) adding a second portion of Poloxamer 407 to the mixture prepared in the previous step and stirring until homogeneous;
(h) adding a pH adjuster to the mixture produced in the previous step to adjust the pH value;
including
Each of steps (a)-(h) is performed with vigorous stirring for at least 5 minutes to obtain a homogeneous mass;
Step (a) is performed at a temperature of 8-17° C., 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 performed at a temperature of 8-17°C;
In step (h), the pH value of the mixture is adjusted to a value in the range of 3.5-7.5;
The viscosity of the gel obtained by the method is in the range of 3 to 75 Pa s,
the total amount of the first portion and the second portion of Poloxamer 407 is 1.0 to 19.0 parts by weight ;
Method. A method of making a gel for rectal and topical administration comprising:
(a) mixing a first portion of poloxamer 407 , 0.01-10.0 parts by weight of poloxamer 188, and 1.0-30.0 parts by weight of water to produce an aqueous solution 1;
(b) dissolving 1.5 to 3.2 parts by weight of lidocaine hydrochloride in 1.0 to 30.0 parts by weight of water to produce an aqueous solution 2;
(c) mixing 0.25-0.55 parts by weight of nifedipine and 0.01-34.0 parts by weight of low-molecular-weight polyethylene glycol to prepare solution 3;
(d) combining aqueous solution 2 and solution 3 to produce a homogeneous solution;
(e) combining the solution obtained in the previous step with the aqueous solution 1 while stirring;
(g) adding a second portion of Poloxamer 407 to the mixture prepared in the previous step and stirring until homogeneous;
(h) adding a pH adjuster to the mixture produced in the previous step to adjust the pH value;
including
Each of steps (a)-(h) is performed with vigorous stirring for at least 5 minutes to obtain a homogeneous mass;
Step (a) is performed at a temperature of 8-17° C., 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 performed at a temperature of 8-17°C;
In step (h), the pH value of the mixture is adjusted to a value in the range of 3.5-7.5;
further comprising, prior to step (b), adding 0.01 to 0.072 parts by weight of methylparaben and 0.01 to 0.032 parts by weight of propylparaben to the mixture produced in the previous step;
The viscosity of the gel obtained by the method is in the range of 3 to 75 Pa s,
the total amount of the first portion and the second portion of Poloxamer 407 is 1.0 to 19.0 parts by weight ;
Method. 3. The method according to claim 1 or 2, characterized in that during step (e) or before step (g), 0.01-10.0 parts by weight of low-molecular-weight polyethylene glycol is added to the solution or mixture. Method. Process according to any one of claims 1 to 3, characterized in that the low-molecular-weight polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600. 3. Process according to claim 1 or 2, characterized in that the pH adjuster is selected from sodium hydroxide and hydrochloric acid. The method according to claim 1 or 2, characterized in that the total time for performing steps (a) to (h) of gel production is 6 hours or less . 3. Method according to claim 1 or 2, characterized in that it further comprises a step (i) of checking the quality of the produced gel. 8. A method according to claim 7, characterized in that step (i) comprises measuring at least one of the following parameters :
- the content of identified lidocaine impurities is not more than 0.1% by weight;
- the total content of identified nifedipine impurities is not more than 2.5% by weight;
- the content of a single unidentifiable impurity is less than or equal to 0.2% by weight;
- the particle size of the produced gel is less than or equal to 100 microns;
- pH ranges from 3.5 to 7.5;
- The gel viscosity is in the range of 3 to 75 Pa·s. A gel for rectal and topical administration to prevent and/or treat anal fissures, hemorrhoids and related disorders, reduce pain after hemorrhoidectomy, wherein the gel contains nifedipine, lidocaine hydrochloride, poloxamer 188 , low-molecular-weight polyethylene glycol, methylparaben, propylparaben, poloxamer 407, pH adjuster and purified water in the following component ratios in mass %:
Nifedipine 0.25-0.55
Lidocaine hydrochloride 1.5-3.2
Poloxamer 407 1.0-19.0
Poloxamer 188 0.01-10.0
Low molecular polyethylene glycol 0.01-34.0
Methylparaben 0.01-0.072
Propylparaben 0.01-0.032
pH adjuster pH 3.5 to 7.5 Purified water 100.0 10. Process according to claim 9, characterized in that the gel has the following ratios of ingredients per gram of final pharmaceutical product:
Lidocaine hydrochloride hydrate 0.0213 g
Nifedipine 0.0030 g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Methylparaben 0.0007g
Propylparaben 0.0003g
Sodium hydroxide or hydrochloric acid To make pH 7.0 Purified water To make 1.0 g 11. The method according to claim 9 or 10, wherein the gel is for reducing clinical symptoms of hemorrhoids to their complete disappearance, healing anal fissures and reducing pain syndrome after hemorrhoidectomy. A method of making a gel for rectal and topical administration comprising:
(i) mixing a first portion of poloxamer 407 , 0.01-10.0 parts by weight of poloxamer 188, and 1.0-30.0 parts by weight of water to produce an aqueous solution 1;
(ii) dissolving 1.5 to 3.2 parts by weight of lidocaine hydrochloride in 1.0 to 30.0 parts by weight of water to produce an aqueous solution 2;
(iii) mixing 0.25-0.55 parts by weight of nifedipine and 0.01-34.0 parts by weight of low-molecular-weight polyethylene glycol to prepare solution 3;
(iv) combining aqueous solution 2, solution 3, and 0.01-0.072 parts by weight of methylparaben and 0.01-0.032 parts by weight of propylparaben, so as to obtain a homogeneous solution;
(v) combining the solution obtained in the previous step with the aqueous solution 1 while stirring;
(vi) adding a second portion of Poloxamer 407 to the mixture prepared in the previous step and stirring until homogeneous;
(vii) adding a pH adjuster to the mixture produced in the previous step to adjust the pH value;
including
Each of steps (i)-(vii) is performed with vigorous stirring for at least 5 minutes to obtain a homogeneous mass;
Step (i) is carried out at a temperature of 8-17°C, at a pressure of 1-80% below atmospheric pressure, without exposure to light; steps (ii) and (iii) at a temperature of 18-25°C. steps (iv) and (v) are carried out 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,
the total amount of the first portion and the second portion of Poloxamer 407 is 1.0 to 19.0 parts by weight ;
Method. 13. Process according to claim 12, characterized in that the low molecular weight polyethylene glycol is selected from polyethylene glycol 400 and polyethylene glycol 600. 13. Process according to claim 12, characterized in that the pH adjuster is selected from sodium hydroxide and hydrochloric acid. 13. A method according to claim 12, characterized in that the total time for performing steps (i)-(vii) of the preparation of the gel is 6 hours or less . 13. The method of claim 12, further comprising a step (viii) of checking the quality of the produced gel. 17. A method according to claim 16, characterized in that step (viii) comprises measuring at least one of the following parameters :
- the content of identified lidocaine impurities is not more than 0.1% by weight;
- the content of identified nifedipine impurities is not more than 2.5% by weight;
- the content of a single unidentifiable impurity is less than or equal to 0.2% by weight;
- the particle size of the produced gel is less than or equal to 100 microns;
- pH ranges from 3.5 to 7.5;
- The gel viscosity is in the range of 3 to 75 Pa·s. A gel for rectal and topical administration to prevent and/or treat anal fissures and hemorrhoids and related disorders, reduce pain after hemorrhoidectomy, wherein the gel contains nifedipine, lidocaine hydrochloride, poloxamer 188, low-molecular-weight polyethylene glycol, methylparaben, propylparaben, poloxamer 407, pH adjuster, and purified water in the following component ratios by weight percent:
Nifedipine 0.25-0.55
Lidocaine hydrochloride 1.5-3.2
Poloxamer 407 1.0-19.0
Poloxamer 188 0.01-10.0
Low molecular polyethylene glycol 0.01-34.0
Methylparaben 0.01-0.072
Propylparaben 0.01-0.032
pH adjuster pH 3.5 to 7.5 Purified water 100.0 19. Process according to claim 18, characterized in that the gel has the following ratios of ingredients per gram of final pharmaceutical product:
Lidocaine hydrochloride hydrate 0.0213 g
Nifedipine 0.0030 g
Poloxamer 188 0.0500g
Poloxamer 407 0.1750g
Polyethylene glycol 400 0.3000g
Methylparaben 0.0007g
Propylparaben 0.0003g
Sodium hydroxide or hydrochloric acid To make pH 7.0 Purified water To make 1.0 g 20. The method according to claim 18 or 19, wherein the gel is for reducing the clinical symptoms of hemorrhoids to their complete disappearance, healing anal fissures and reducing pain syndrome after hemorrhoidectomy.