Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0031—Rectum, anus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
  • A61P23/02—Local anaesthetics

Definitions

• the inventions relate to the field of pharmaceutics, namely to pharmaceutical compositions that form the basis of gels for rectal and external use, as well as to methods for producing these gels intended for use in the treatment of hemorrhoids and anal fissures, the main active ingredients used in the proposed inventions are nifedipine and lidocaine hydrochloride.
• One of the topical areas of pharmaceuticals is the creation of new dosage forms for rectal and external use, including dosage forms on a fat basis, for example, gels, ointments, emulsions.
• nifedipine makes it possible to successfully use it for various diseases requiring a vasodilator action, including in proctology [4, 5].
• Nifedipine being a calcium channel blocker, prevents the transport of calcium ions into cells and thereby reduces the tone of the anal sphincter. Reducing spasticity of the anal sphincter is the main way to reduce pain in patients with hemorrhoids and anal fissure [6].
• the pharmacological activity of nifedipine also causes a decrease in the intensity of the inflammatory reaction [7], has a modulating effect on microcirculation [8], and prevents the development of defects in the mucous membrane of the anal canal [9].
• a medicinal composition for the treatment of anal fissures which includes a base, a drug that reduces spasms of smooth muscle muscles, lidocaine, contains an aqua complex of titanium glycerosolvate as a base, and nife as a drug that reduces spasms of smooth muscle muscles dipin or nitroglycerin, and the components in the composition are contained in a certain ratio in grams.
• the invention provides effective treatment with a decrease in the concentration of active substances, a decrease in side effects, and a decrease in the duration of treatment.
• nitroglycerin ointment 0.2% which is currently considered one one of the important components of the conservative treatment of anal fissure, since nitroglycerin relaxes the muscles of the anal sphincter, relieving its spasm, which is one of the pathogenetic factors in the development of fissures, since it leads to ischemia, that is, to impaired blood flow ...
• nitroglycerin ointment it is necessary to use a small amount of it, since in large doses it can be absorbed into the systemic circulation and cause headaches and dizziness [12].
• calcium channel blockers including, for example, nifedipine, diltiazem or other drugs that are used in the treatment of heart disease, and have recently found their application in the treatment of anal fissure, the principle of which is the same as that of nitroglycerin ointment - they relieve spasm of the anal sphincter [12].
• nifedipine When using nifedipine in a gel for rectal and external use, it is necessary to take into account the fact that, due to the hydrophobicity of such an active substance as nifedipine, the creation of pharmaceutical compositions of nifedipine in an aqueous medium, including gels, has some peculiarities caused by dissolution nifedipine in the aquatic environment.
• a method for dissolving nifedipine in an aqueous medium and a pharmaceutical composition containing a solution of nifedipine in an aqueous medium includes preparing an aqueous solution containing go nifedipine, poloxamer 407, macrogol 400, poloxamer 188 at a temperature of 20-37 ° C, which ensures the dissolution of nifedipine to a concentration of about 0.8-4.0 mg / g.
• the method for preparing a gel including nifedipine, lidocaine, poloxamer 407, macrogol 400, poloxamer 188, as well as the gel obtained by the above method according to patent RU2641570 are the closest to the gel proposed in the present invention in terms of their essential features. and the method for its production, and can be selected as a prototype.
• composition relatively low stability of the composition, even taking into account the presence of thickeners and / or stabilizers in the composition, such as Cekol 2000 T or Carbapol Ultrez 10).
• the objective of the present invention is to obtain such a gel composition, including nifedipine and lidocaine hydrochloride as active substances, each version of which would ensure the stability of the gel-like properties, transparency, preservation of the stability of properties for more than two years, the use of which would provide a reduction in the clinical symptoms of hemorrhoids, up to until their complete elimination, healing of anal fissures, relief of pain syndrome, including after hemorrhoidectomy, in which the content of both active and excipients would be optimal, and the required bioavailability would be ensured by dissolving the active substances in the aquatic environment.
• the object of the present invention is to provide such a method for preparing a gel comprising nifedipine and lidocaine hydrochloride, in which the required bioavailability would be ensured by dissolving the active substance in an aqueous medium and which would ensure the stability of the gel-like properties of the final gel without the use of thickeners and / or stabilizers. , and which would provide increased stability of the composition.
• the technical result to be achieved by this group of inventions is to increase the stability and stability of gel-like properties, as well as transparency, while maintaining the pharmacological properties of the drug.
• each of stages (a) - (h) is carried out with vigorous stirring for at least 5 minutes until a homogeneous mass is obtained;
• step (a) is carried out at a temperature of 8-17 ° C, at a pressure of 10 to 99 kPa and without access to light; stages (b) and (c) are carried out at a temperature of 18-25 ° C; steps (d) and (e) are carried out at a temperature of 8-17 ° C;
• step (h) the pH value of the mixture is adjusted to a value in the range from 3.5 to 7.5;
• step (e) of adding nipagin and nipazole may be carried out before step (b);
• the viscosity of the gel obtained by the said method is in the range from 3 to 75 Pa-s.
• the specified technical result is also achieved in that:
• stage (e) 0.01-10.0 mass parts of low molecular weight polyethylene glycol are added to the mixture;
• polyethylene glycol 400 is selected from polyethylene glycol 400 and polyethylene glycol 600;
• the substance that corrects the pH is selected from sodium hydroxide and hydrochloric acid;
• the above method further includes the step (s) of quality control of the obtained gel
• step (s) includes the definition of at least one of the following set:
• microbiological purity according to the current edition of the State Pharmacopoeia corresponds to the category of non-sterile medicinal products.
• a gel for rectal and external use which provides the prevention and / or treatment of anal fissures and hemorrhoids and related diseases, a decrease in pain after hemorrhoidectomy, obtained by the above method, including nifedipine, lidocaine hydrochloride, poloxamer 188, low molecular weight polyethylene glycol, nipagin, nipazole, poloxamer 407, a substance that corrects the pH value, and purified water, at a ratio of ingredients, wt%:
• the specified technical result is also achieved in that:
• polyethylene glycol 400 is selected from polyethylene glycol 400 and polyethylene glycol 600;
• the substance that corrects the pH is selected from sodium hydroxide and hydrochloric acid;
• the said gel has the following ratio of ingredients per 1 g of the finished medicinal product:
• lidocaine hydrochloride monohydrate 0.0213 g
• the problem is also being solved, and the technical result is achieved by using the aforementioned gel to reduce the clinical symptoms of hemorrhoids, up to their complete elimination, healing of anal fissures, relief of pain syndrome after hemorrhoid dectomy.
• each of steps (i) - (vii) is carried out with vigorous stirring for at least 5 minutes until a homogeneous mass is obtained;
• step (i) is carried out at a temperature of 8-17 ° C, at a pressure of 1-80% below atmospheric and without access to light; stages (n) and (w) are carried out at a temperature of 18-25 ° C; steps (iv) and (v) are carried out at a temperature of 8-17 ° C;
• step (vi) the pH value of the mixture is adjusted to a value in the range from 3.5 to 7.5;
• the viscosity of the gel obtained by the said method is in the range from 3 to 75 Pa-s.
• the specified technical result is also achieved in that:
• polyethylene glycol 400 is selected from polyethylene glycol 400 and polyethylene glycol 600;
• the substance that corrects the pH is selected from sodium hydroxide and hydrochloric acid;
• the above method further includes the step (viii) quality control of the obtained gel
• step (viii) includes identifying at least one of the following:
• microbiological purity according to the current edition of the State Pharmacopoeia corresponds to the category of non-sterile medicinal products.
• the problem is also solved, and the technical result is achieved by creating a gel for rectal and external use, which ensures the prevention and / or treatment of anal fissures and hemorrhoids and related diseases, reduction of pain after hemorrhoidectomy, obtained by the above method, including nifedipine, lidocaine hydrochloride , poloxamer 188, low molecular weight polyethylene glycol, nipagin, nipazole, poloxamer 407, a substance that corrects the pH value, and purified water, with a ratio of ingredients, wt%: nifedipine 0.25-0.55
• the specified technical result is also achieved in that:
• polyethylene glycol 400 is selected from polyethylene glycol 400 and polyethylene glycol 600;
• the substance that corrects the pH is selected from sodium hydroxide and hydrochloric acid;
• the said gel has the following ratio of ingredients per 1 g of finished th medicinal product:
• lidocaine hydrochloride monohydrate 0.0213 g
• the problem is also solved, and the technical result is achieved by using the aforementioned gel to reduce the clinical symptoms of hemorrhoids, up to their complete elimination, healing of anal fissures, relief of pain syndrome after hemorrhoid dectomy.
• a method for producing a gel for rectal and external use includes obtaining an aqueous solution No. 1 by mixing Poloxamer 407 and Poloxamer 188 with water. Next, a solution N ° 2 is prepared by dissolving lidocaine hydrochloride in water. Next, mix N ° 3 is prepared by mixing nifedipine and low molecular weight polyethylene glycol. Then the obtained solutions are combined - solution N ° 2 with solution N ° 3, a homogeneous solution is obtained, which is combined with stirring with solution N ° l. All mixing operations are carried out on a magnetic stirrer or overhead stirrer, or in a mixer for viscous liquids until a homogeneous mass is obtained, but not less than 5 minutes.
• Homogenization is carried out at a temperature ⁇ 15 ° C and a vacuum of 10 to 99 kPa. After obtaining a homogeneous mixture, add nipagin and nipazole, the remaining amount of Poloxamer 407 and mix until smooth. Nipagin and nipazole can also be added to solution No. 1 before being combined with the combined solution of No. 2 and No. 3 or together with the combined solution.
• the step of obtaining solution 1 is carried out at a temperature of 8-17 ° C at a pressure of 10 to 99 kPa and in the absence of illumination (or in a container made of dark glass).
• This technological re- The change allows the content of air bubbles to be reduced, which in turn increases the stability of the system due to the lack of oxygen in the air and a decrease in the potential for redox reactions.
• Solutions 2 and 3 are prepared at a temperature of 18-25 ° C. The solutions are mixed at a temperature of 8-17 ° C.
• the pH value is adjusted to the intervals of 3.5-7.5 with an aqueous solution of sodium hydroxide or an aqueous solution of hydrochloric acid at a temperature of 8-17 ° C.
• the viscosity of the product is controlled, which should be in the range from 3 to 75 Pa-s.
• the proposed gel for rectal and external use in all of the presented variants provides high efficiency in eliminating the symptoms of chronic anal fissure, external hemorrhoids, reducing pain after hemorrhoid dectomy.
• the proposed technology improves the stability of the gel composition and does not require thickeners and / or stabilizers.
• a method for producing a gel for rectal and external use includes obtaining an aqueous solution of Ml by mixing 0.7 parts by weight of Poloxamer 407 with 0.01 parts by weight of Poloxamer 188 and 1.0 parts by weight of water.
• a solution M2 is prepared by dissolving 1.5 parts by weight of lidocaine hydrochloride in 1.0 parts by weight of water.
• mixture 3 is prepared by mixing 0.25 parts by weight of nifedipine and 0.01 parts by weight of polyethylene glycol 400.
• solution 2 is combined with solution M3, a homogeneous solution is obtained, which is combined with a solution of Ml while stirring. All mixing operations are carried out with stirring on an overhead stirrer until a homogeneous mass is obtained for 15 minutes.
• a mixture of 0.01 parts by weight of nipagin and 0.01 parts by weight of nipazole, the remaining amount of Poloxamer 407 (0.3 parts by weight) is added to the combined solution of M2 and 3 with stirring.
• the operation to obtain the Ml solution is carried out at a temperature of 8 ° C at a pressure below atmospheric (99.0 kPa) and in the absence of illumination.
• Solutions M2 and M3 are prepared at a temperature of 18 ° C.
• Mixing of solutions is carried out at a temperature of 8 ° C.
• the pH value is adjusted to 4.5 with an aqueous solution of sodium hydroxide at a temperature of 8 ° C.
• the viscosity of the product is controlled, which should be in the range from 3 to 75 Pa s.
• a method for preparing a gel for rectal and external use includes obtaining an aqueous solution No. 1 by mixing 12.0 mass parts of Poloxamer 407 with 10.0 mass parts of Poloxamer 188 and 30.0 mass parts in.
• a solution of N ° 2 is prepared by dissolving 3 , 2 parts by weight of lidocaine hydrochloride in 30.0 parts by weight of water.
• a mixture of N ° 3 is prepared by mixing 0.55 mass parts of nifedipine and 34.0 mass parts of polyethylene glycol 400.
• solution N ° 2 is combined with solution N ° 3, a homogeneous solution is obtained, which is combined with a solution of N ° l.
• solution No. 1 The operation to obtain solution No. 1 is carried out at a temperature of 17 ° C at a pressure below atmospheric (80 kPa) and in the absence of access to light (in a dark glass dish).
• Solutions N ° 2 and N ° 3 are prepared at 25 ° C. The solutions are mixed at a temperature of 17 ° C.
• the value is corrected pH up to 7.5 with an aqueous solution of sodium hydroxide at a temperature of 17 ° C.
• the viscosity of the product is controlled, which should be in the range from 3 to 75 Pa s.
• a method for producing a gel for rectal and external use includes obtaining an aqueous solution No. 1 by mixing 7.0 parts by weight of Poloxamer 407 with 5.0 parts by weight of Poloxamer 188 and 25.0 parts by weight of water. Then a mixture of 0.03 parts by weight of nipagin and 0.02 parts by weight of nipazole is added to solution No. 1. Next, solution N ° 2 is prepared by dissolving 3.2 parts by weight of lidocaine hydrochloride in 15.0 parts by weight of water. Next, mixture No. 3 is prepared by mixing 0.55 mass parts of nifedipine and 17.0 mass parts of polyethylene glycol 400. Next, solution No. 2 is combined with solution No.
• a homogeneous solution is obtained, which is combined with stirring with the solution Nsl containing nipagin and nipazole. All mixing operations are carried out with stirring in a mixer for viscous liquids until a homogeneous mass is obtained. 15 minutes, the remaining amount of Poloxamer 407 (0.3 parts by weight) is added to the resulting solution with stirring.
• solution No. 1 The operation to obtain solution No. 1 is carried out at a temperature of 12 ° C at a pressure of 10.0 kPa and in the absence of illumination.
• Solutions N ° 2 and J s3 are prepared at 20 ° C. Mixing of solutions is carried out at a temperature of 12 ° C.
• the pH value is adjusted to 6.5 with an aqueous solution of sodium hydroxide at a temperature of 12 ° C.
• the viscosity of the product is controlled, which should be in the range from 3 to 75 Pa s.
• a method for producing a gel for rectal and external use includes preparing an aqueous solution No. 1 by mixing 10.5 parts by weight of Poloxamer 407 with 5.0 parts by weight of Poloxamer 188 and 35.0 parts by weight of water.
• a solution N ° 2 is prepared by dissolving 3.2 parts by weight of lidocaine hydrochloride in 15.0 parts by weight of water.
• mix N ° 3 is prepared by mixing 0.40 mass parts of nifedipine and 17.0 mass parts of polyethylene glycol 600.
• solution No. 2 is combined with solution No. 3, a homogeneous solution is obtained, which is combined with stirring with solution No. l.
• solution No. 1 The operation to obtain solution No. 1 is carried out at a temperature of 15 ° C at a pressure of 50.0 kPa and in the absence of illumination.
• Solutions N ° 2 and N ° 3 are prepared at 22 ° C. Mixing of solutions is carried out at a temperature of 15 ° C.
• the pH value is adjusted to 7.5 with an aqueous solution of sodium hydroxide at a temperature of 8-17 ° C.
• the viscosity of the product is controlled, which should be in the range from 3 to 75 Pa-s.
• HPLC is a method for the determination of substances by high performance liquid chromatography.
• the proposed method allows increasing the stability of the composition up to at least three years, due to the fact that the content of related impurities, the quantitative content of lidocaine and nifedipine, in contrast to the prototype, do not change, and the impurities remain within acceptable limits.
• a method for producing a gel for rectal and external use includes obtaining an aqueous solution No. 1 by mixing 0.7 parts by weight of Poloxamer 407 with 0.01 parts by weight of Poloxamer 188 and 1.0 parts by weight of water. Next, a solution of N ° 2 is prepared by dissolving 1.5 parts by weight of lidocaine hydrochloride in 1.0 parts by weight of water. Next, a mixture of N ° 3 is prepared by mixing 0.25 mass parts of nifedipine and 0.01 mass parts of polyethylene glycol 400.
• solution N ° 2 is combined with a solution of N ° 3, as well as with a mixture of 0.01 mass parts of nipagin and 0.01 parts by weight of nipazole, a homogeneous solution is obtained, which is combined with stirring with a solution of No. 1. All mixing operations are carried out with stirring on an overhead stirrer until a homogeneous mass is obtained for 15 minutes. 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 resulting solution with stirring.
• solution No. 1 The operation to obtain solution No. 1 is carried out at a temperature of 8 ° C at a pressure below atmospheric (99.0 kPa) and in the absence of illumination.
• Solutions M ° 2 and N ° 3 are prepared at a temperature of 18 ° C.
• the solutions are mixed at a temperature of 8 ° C.
• the pH value is adjusted to 4.5 with an aqueous solution of sodium hydroxide at a temperature of 8 ° C.
• the viscosity of the product is controlled, which should be in the range from 3 to 75 Pa s.
• An example of a gel obtained by the above method is shown in Table
• a method for producing a gel for rectal and external use includes preparing an aqueous solution No. 1 by mixing 12.0 parts by weight of Poloxamer 407 with 10.0 parts by weight of Poloxamer 188 and 30.0 parts by weight of water. Next, a solution N ° 2 is prepared by dissolving 3.2 parts by weight of lidocaine hydrochloride in 30.0 parts by weight of water. Next, a mixture of N ° 3 is prepared by mixing 0.55 mass parts of nifedipine with 34.0 mass parts of polyethylene glycol 400.
• solution N ° 2 is combined with a solution of N ° 3, as well as with a mixture of 0.072 mass parts of nipagin and 0.03 mass parts nipazole, a homogeneous solution is obtained which is combined with stirring with solution No. 1. All mixing operations are carried out with stirring on a magnetic stirrer until a homogeneous mass is obtained for 5 minutes. The remaining amount of Poloxamer 407 (0.5 parts by weight) is added to the resulting solution with stirring.
• solution N ° 1 is carried out at a temperature of 17 ° C at a pressure below atmospheric (80 kPa) and in the absence of access to light (in dishes dark glass).
• Solutions N ° 2 and N ° 3 are prepared at 25 ° C. The solutions are mixed at a temperature of 17 ° C.
• the pH value is adjusted to 7.5 with an aqueous solution of sodium hydroxide at a temperature of 17 ° C.
• the viscosity of the product is controlled, which should be in the range from 3 to 75 Pa s.
• a method for producing a gel for rectal and external use includes obtaining an aqueous solution No. 1 by mixing 7.0 parts by weight of Poloxamer 407 with 5.0 parts by weight of Poloxamer 188 and 25.0 parts by weight of water. Next, a solution N ° 2 is prepared by dissolving 3.2 parts by weight of lidocaine hydrochloride in 15.0 parts by weight of water. Next, a mixture of No. 3 is prepared by mixing 0.55 mass parts of nifedipine and 17.0 mass parts of polyethylene glycol 400. Then, solution No. 2 is combined with a solution of No.
• solution No. 1 The operation to obtain solution No. 1 is carried out at a temperature of 12 ° C at a pressure below atmospheric (10.0 kPa) and in the absence of illumination.
• Solutions N ° 2 and N ° 3 are prepared at 20 ° C. Mixing of solutions is carried out at a temperature of 12 ° C.
• the pH value is adjusted to 6.5 with an aqueous solution of sodium hydroxide at a temperature of 12 ° C.
• the viscosity of the product is controlled, which should be in the range from 3 to 75 Pa s.
• a method for producing a gel for rectal and external use includes preparing an aqueous solution No. 1 by mixing 10.5 parts by weight of Poloxamer 407 with 5.0 parts by weight of Poloxamer 188 and 35.0 parts by weight of water. Next, a solution N ° 2 is prepared by dissolving 3.2 parts by weight of lidocaine hydrochloride in 15.0 parts by weight of water. Next, a mixture of No. 3 is prepared by mixing 0.40 mass parts of nifedipine and 17.0 mass parts of polyethylene glycol 600. Next, solution No. 2 is combined with a solution of No.
• solution No. 1 The operation to obtain solution No. 1 is carried out at a temperature of 15 ° C at a pressure of 50.0 kPa and in the absence of illumination.
• Solutions N ° 2 and N ° 3 are prepared at 22 ° C. Mixing of solutions is carried out at a temperature of 15 ° C.
• the pH value is adjusted to 7.5 with an aqueous solution of sodium hydroxide at a temperature of 8-17 ° C.
• the viscosity of the product is controlled, which should be in the range from 3 to 75 Pa-s.
• HPLC is a method for the determination of substances by high liquid chromatography.
• the proposed method makes it possible to increase the stability of the composition up to at least three years, due to the fact that the content of related impurities, the quantitative content of lidocaine and nifedipine, in contrast to the prototype, do not change.
• Example 11 The results of the analysis of the quality indicators of the compositions obtained in examples 1-4 and 6-9.
• Example 12 Study of the effectiveness of the gel formulations obtained in examples 1-4 and 6-9, in experiments in vivo
• the gel was applied perianally, twice a day for fourteen days, to rats with an anal fissure model.
• the use of the gel made it possible to completely eliminate the morphological changes characteristic of the anal fissure, that is, to achieve complete healing in 95% of the tested rats.
• the proportion of animals with resolution of anal fissure symptoms was 15%.
• the gel was applied perianally and rectally, twice a day for fourteen days, to rats with an acute hemorrhoid model.
• the use of the gel made it possible to completely eliminate the manifestations of hemorrhoids in 92.5% of animals, while in the control group receiving treatment with a gel base, complete resolution of the manifestations of hemorrhoids was achieved in 45% of animals.
• the effectiveness of the gel in reducing pain after hemorrhoidectomy was evaluated indirectly in rats. It is known that the main cause of pain after surgery to remove hemorrhoids is spasm of the anal sphincter. Therefore, the resolution of pain sensations in rats with a hemorrhoid model was assessed as a stable recovery of the anorectal manometry index to the initial level.
• the gel was applied perianally and rectally, twice a day for fourteen days. The use of the gel made it possible to return the anorectal manometry indicator to the initial level in 100% of the animals, whereas in the control group receiving treatment with the gel base, the complete recovery of the indicator was observed only in 17.5% of the animals. Moreover, all gel formulations obtained by the above described methods showed the same efficacy in vivo.
• the technical result was achieved by obtaining options for the composition of the gel for rectal and external use, including nifedipine and lidocaine hydrochloride, each version of which ensures the stability of gel properties, transparency, preservation of stability of properties for a period of at least 3 years, the use of gel options allows to reduce clinical symptoms of hemorrhoids, up to their complete elimination, healing of anal fissure and relief of pain syndrome, including after hemorrhoid dectomy, increases the assortment list of gels with different helium properties.
• the proposed pharmaceutical compositions which constitute the basis of gels, a method for the production of gels, are intended mainly for the prevention and / or treatment of anal fissures, hemorrhoids and related diseases, for reducing pain after hemorrhoidectomy.
• the inventions relate to compositions and methods of preparation, as well as to the use of gels comprising nifedipine and lidocaine hydrochloride as the main active ingredients.
• the proposed gel in all the variants presented, obtained by the proposed method, provides, when used for rectal or external use, high efficiency in eliminating the symptoms of chronic anal fissure, external hemorrhoids, reducing pain, up to their elimination.
• L-type calcium channel blockers modulate the microvascular hyperpermeability induced by plateletactivating factor in vivo” H J Vase Surg, 1995; 22: 723-39.

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