TR201819752A2 - SOLID PHARMACEUTICAL COMPOSITION CONTAINING PINAVERIUM AND MEDAZEPAM - Google Patents

Abstract

The present invention relates to obtaining a stable solid oral dosage form containing pinaverium, medazepam and at least one pharmaceutically acceptable excipient.

Description

DESCRIPTION SOLID PHARMACEUTICAL COMPOSITION CONTAINING PINAVERİUM AND MEDAZEPAM The present invention includes pinaverium, medazepam, and at least one pharmaceutically acceptable It relates to obtaining a stable solid oral dosage form containing the excipient.

State of the Art Pinaverium, a quaternary ammonium derivative with selective action in the gastrointestinal tract It is an antispasmodic and musculotropic drug. It also shows weak anti-muscarinic effect. Calcium It is an antagonist, thereby preventing the entry of calcium into intestinal smooth muscle cells. It helps to restore the normal contraction process. Relieves abdominal pain and impaired improves gastrointestinal transit. It reduces the amount of acid without modifying the gastric secretion volume. and accelerates gastric emptying. It is indicated in irritable bowel syndrome.

Pinaverium was developed by Solvay Pharmaceuticals in 1975 as pinaverium bromide. licensed and marketed under the brands Dicetel and Eldicet. Chemical name 4-(2-Brrome-4,5- and its chemical structure is shown by Formula-1.

Formula-1 Medazepam is a benzodiazepine derivative. As a result of metabolism, first diazepam is formed, then It is converted to desmethyldiazepam and oxazepam. The place of gamma amino butyric acid (GABA) in the nervous system Chlorine in the membrane of nerve cells by acting on the area alpha subunit (GABA-A) It causes hyperpolarization in the neuron by increasing the entry of chloride ions through the channels. Like this It ensures that the restlessness, anxiety and tensions in the patient are reduced or eliminated.

Medazepam is disclosed with document US3243427 and is marketed under the brand Rudotel. in combination, it is marketed under the brand name Tranko-Buskas®. Chemical name 7-kI0r0-1- It is methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine and its chemical structure is shown by Formula-2- Formula-2 Indications for the current active ingredients alone, pinaverium and medazepam synergistic effect in the treatment or prevention of irritable bowel syndrome (IBS) it provides. It occurs in the enteric region and mostly due to psychosomatic problems. It will be effective in relieving gastrointestinal disorders such as abdominal pain and intestinal spasms.

In the state of the art, in the patent document EP2020234 B1, pinaverium bromide and Simethicone or dimethicone combinations have been described.

In the EP0900084 B1 patent document, it is obtained from stomach, intestines, colon and liver cells. to be used to prevent or treat the overgrowth of hepatodigestive tract cells The use of pinaverium bromide in the preparation of the product is explained.

In the TR2016/01803 Bl patent, it is used for the treatment or prevention of irritable bowel syndrome. The combination of pinaverium bromide and medazepam is indicated.

The present invention is a fixed dose combination of two active ingredients. In combinations, both the active ingredients and the excipients are chemically and It is about ensuring physical compatibility and obtaining a stable pharmaceutical product.

Therefore, the main object of the present invention is to have a stable synergistic release containing both substances. to obtain a pharmaceutical product.

Brief Description of the Invention The present invention is pinaverium, medazepam, and at least one pharmaceutically acceptable It relates to obtaining a stable solid oral dosage form containing the excipient.

Fixed dose containing active ingredients of pinaverium and medazepam used in the coating process of the core tablet during stability studies of the combination As a result of the interaction of the coating material with medazepam, the coating color pigments and with physical and chemical stability problems caused by the gradation of medazepam they met. The aim of the present invention is to obtain a stable formulation that finds a solution to this problem. is to do.

Another object of the invention is the biopharmaceutical classification (BCS] III, ie high solubility, low permeability; medazepamine biopharmaceutical classification (BCS) II, ie low solubility, solid that will provide a suitable release profile due to its high permeability obtaining the pharmaceutical composition.

Detailed Description of the Invention The present invention includes pinaverium, medazepam, and at least one pharmaceutically acceptable with coating material providing stability in a solid pharmaceutical composition containing excipient The solid pharmaceutical composition described herein is in the form of tablets or capsules containing the coating. coated tablet, film-coated tablet, multi-layered tablet (such as double-layered, triple-layered tablet), in the mouth disintegrating tablet, mini tablet, sugar pellet, buccal tablet, sublingual tablet, coated granule, coated bead system, tablets in tablets, tablets inside, immediate-release tablets, modified-release tablets. can be selected but not limited to that. The present invention is preferably in the form of film-coated tablets.

For the production of the formulation subject to the invention, the dry matter in the state of the art mixing, dry granulation and/or wet granulation can be used. Preferred production method dry mix.

The term "pinaverium" as used herein is referred to as pinaverium or pharmaceutically acceptable. a salt, hydrate, solvate, ester and/or polymorph thereof is indicated. Preferred pinaverium bromide. The composition of the present invention is pinaverium bromide in the range of 10-500 mg. includes. Preferably 50 mg and 100 mg.

The term "medazepam" as used herein means medazepam or pharmaceutically acceptable A salt, hydrate, solvate, ester, polymorph or derivatives thereof is indicated. present invention The subject composition contains medazepam in the range of 5-100 mg. Preferably 10 mg and 20 mg.

In the present invention, the active ingredient of pinaverium bromide is d90 with a particle size of less than 200 mm, preferably below 100 nm, more preferably below 25 nm. Medazepam d90 particle size value The expression "size" denotes the particle diameter at which the particles are 90% by volume. d90 A measurement with known values, for example laser diffraction, which is one of the known measurement methods. It can be measured in the device (eg malvern Mastersizer). Measurements on the laser diffraction device made using the method.

The stable solid pharmaceutical composition of the present invention is pinaverium bromide, medazepam and contains at least one pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients included in the composition of the invention; filling material (diluent), binder, dispersant, glidant, lubricant (lubricant), coating material. can be selected.

The terms "filler" and "diluent" used in the present invention are interrelated. used interchangeably. Suitable fillers (diluentidibasic calcium phosphate, calcium carbonate, calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, sugar, mannitol, such as cellulose, lactose, maltose, fructose, sucrose, glucose, dextrose, dextrate and so on, sugar alcohol, methylcellulose polymers, such as erythritol, lactylol, maltitol, xylitol, sorbitol and the like, microcrystalline cellulose silicified microcrystalline cellulose and other cellulose derivatives, starches or modified starches (potato starch, wheat starch, corn starch, rice starch, pre-gelatinized corn starch), magnesium carbonate, magnesium oxide and a mixture of these can be selected, but not limited to that. Preferred filler (diluent) microcrystalline cellulose and lactose.

In the present invention, the "binder" is hydroxypropyl methyl cellulose, low substituted hydroxypropyl cellulose, natural and synthetic gums (acacia, tragacanth, sodium alginate, celluloses), hydroxymethyl cellulose, hydroxypropyl cellulose, starch (such as corn starch and pre-gelatinized starch), gelatin, sugars (sucrose, Glucose, dextrose, lactose and sorbitol), wax, synthetic materials such as polyvinylpyrrolidone (povidone) polymers can be selected from ethylcellulose, hydroxyethylcellulose, polyethylene oxide and mixtures thereof, but not angry about it.

In the present invention, "glidant" is colloidal silicon dioxide, aluminum silicate, magnesium silicate, may be selected from powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof, but not angry with it. The preferred glidant is colloidal silicon dioxide.

In the present invention, “lubricant” is sodium oleate, sodium stearate, sodium benzoate, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acids, zinc stearate, polyethylene glycol, glyceryl behenate, talc, sodium laurii sulfate, sodium benzoate, hydrogenated castor oil and their It can be selected from among the mixtures, but is not limited to this. Preferred lubricant magnesium stearate and talc.

In the present invention, "dispersive" cross-linked polyvinylpyrrolidone (eg crospovidone, polypiliplasdon XL®, kollidon CL®), corn starch and dried sodium starch glycolate, starches such as pregelatinized starch; gums such as alginic acid, sodium alginate, guar gum, croscarmellose sodium, microcrystalline cellulose and salts, carboxymethyl cellulose, low substituted cellulose products such as hydroxypropyl cellulose and mixtures thereof, but with not angry. The preferred dispersant is crospovidone and pregelatinized starch.

Solid pharmaceutical containing active ingredients of pinaverium and medazepam During the stability studies of the composition, in the finished product, in the coating process of the core tablet As a result of the interaction of the coating material used with medazepam, the coating color pigments and physical and chemical problems caused by the color gradation of medazepam. they met. In other words, in solid pharmaceutical composition containing pinaverium and medazepam As a result of the interaction of the coating material with medazepam, the coating color pigments and It was observed that the color of medazepam gave dye to the primary packaging material used.

The term "color pigments" as used herein refers to the coloring matter of the coating material. is being done. Yellow, red, orange, blue, green, white, transparent or a mixture of these can be selected but not limited to that.

First of all, it is possible that this problem may be caused by the permeability of the packaging material. PVC/PE/PVDC packaging material used with lower permeability It was replaced with aluminum foil and again the same problem was encountered. Seeing the same problem HDPE bottle with a higher moisture barrier was used as the primary packaging material. but again with the same problem. On top of that, the inventors in the pharmaceutical composition They conducted research to determine whether there is a problem caused by the coating material.

In this context, pinaverium bromide, medazepam and at least pharmaceutically acceptable of a solid pharmaceutical composition containing one excipient with different coating materials. Formulation development studies have been carried out. Sample studies on coating material It is shown in Table-1. These examples are for illustrative purposes only and do not cover the scope of protection. should not be evaluated in an annoying way.

Table 1: Compositions Containing Different Coating Agents (mg) Contents D01 D02 DO3 D04 DOS D06 colloidal 1 1 1 1 1 1 silicon dioxide silicified cellulose Crospovidone ' - - - 2.5 2.5 starch The contents of the coating materials are also stated below.

Coating-1 Polyvinyl alcohol based, orange colored Coating-2 Wax red color Coating-3 Polyvinyl alcohol based, red Coating-4 Hydroxypropyl methyl cellulose based Coating-5 Acrylic acid derivatives The above-mentioned compositions are as specified below using the same method. they are produced: Microcrystalline cellulose and colloidal silicon dioxide are sieved together. It is transferred to the mixer. Top it with pinaverium bromide, medazepam, pregelatinized starch, lactose and preferably crospovidone. is added. Talc is added to this mixture and mixed. Then magnesium stearate is added The final mixture is obtained and the tablet is pressed. Film coating process by preparing coating solution is performed.

In the D01, DOZ and D03 trials, there was a significant discoloration at the beginning. has been observed. For this reason, it is recommended that polyvinyl alcohol and wax-based coating materials are used in pinaverium and It is not suitable for use in solid pharmaceutical compositions containing medazepam.

In the formulations of D04 and DOS trials, color distortions were detected at the beginning. has not been made. Therefore, the physical and chemical Stability of the compositions of the D04 and D5 trials has been checked. As a result of the stability data, the compositions of the D04 and DOS trials were both severe. It has been determined that both color distortions and impurities are out of the limit. Achieved Stability data are explained in Table 2 below.

Table 2: Impurity Profile of D04 and D05 D04 D05 Beginning 6. Month25 oC 6.Month40°C Beginning 6. Month 25 0C 6.Month40°c Maximum unknown 0.70) benzophenone Total impurity *RRT: Relative Retention Time *T.E.: Not detected Surprisingly, however, the inventors found a product containing acrylic acid or its derivatives. both color and impurity when coating the solid pharmaceutical composition with the coating material They found that their problem was solved. Baseline and stability data of the study It is explained in Table 3.

Table 3: Impurity Profile of the D06 Trial Limit Start Angle 0% RH 7y5 RH o Benzophenone 0.3% The object of the present invention is pinaverium, medazepam and at least pharmaceutically acceptable It is a solid pharmaceutical composition containing one excipient, characterized by acrylic acid or its derivatives. is covered with a coating material containing Containing acrylic acid or its derivatives subject to the invention coating material ethylacrylate-methylmethacrylate copolymer, methacrylic acid divinyl benzene copolymer, amino methacrylate copolymer, aminoalkyl methacrylate copolymer, butylated methacrylate copolymer and can be selected from a mixture of these, but is not limited to them. Preferably butylated in this invention methacrylate copolymer is used.

In a preferred embodiment of the invention, by total tablet weight i. 8-50% by weight pinaverium bromide, ii. 1.5-10% by weight medazepam, iii. 20-90% filler by weight, IV. 1-15% dispersant by weight, V. 0.5-4% by weight lubricant, vi.0.5-3% glidant by weight vii. 0-10% binder by weight It is a pharmaceutical composition containing, and its feature is that it is coated with an acrylic-based coating material.

The pharmaceutical composition production method in the present invention is dry mix.

In another preferred embodiment of the invention, by total tablet weight i. 8-50% by weight pinaverium bromide, ii. 1.5-10% by weight medazepam, iii. 20-90% by weight microcrystalline cellulose and lactose as fillers, 1-15% by weight of crospovidone and pregelatinized starch as iv. v. 0.5-4% talc and magnesium stearate by weight as lubricants vi. 0.5-3% by weight silicon dioxide as glidant, It is a solid pharmaceutical composition containing a butylated methacrylate copolymer-based coating. is covered with substance.

While obtaining a stable suitable pharmaceutical composition, the dissolution characteristics of both agents must be determined. It has also been taken into account that it provides an appropriate release profile because it is different. inventors obtained a pharmaceutical composition with trial D06 that is both stable and maintains adequate release.

Table-5 and Table-6 of “Medazepam and Pinaverium Bromide” in three different dissolution media (pH dissolution results are shown.

Table-4: Dissolution results of Medazepam in different dissolution media (%) pH 4.5 Acetate Buffer pH 6.8 Phosphate Buffer 0.1 N HCl Reference DOG Reference D06 Reference D06 Table 5: Dissolution results of Pinaverium Bromide in different dissolution media (0%) pH 4.5 Acetate Buffer pH 6.8 Phosphate Buffer 0.1 N HCl

Claims (9)

REQUESTS 1. It is a solid pharmaceutical composition containing pinaverium, medazepam and at least one pharmaceutically acceptable excipient, characterized in that it is coated with a coating material containing acrylic acid or its derivatives. 2. It is a pharmaceutical composition according to claim 1 and the coating material containing acrylic acid or its derivatives is selected from ethylacrylate-methylmethacrylate copolymer, methacrylic acid divinyl-like copolymer, amino methacrylate copolymer, aminoalkyl methacrylate copolymer, butylated methacrylate copolymer and their mixture. 3. A pharmaceutical composition according to claim 1, wherein pinaverium bromide is in the range of 10-500 mg, medazepamine 5-100 mg. 4. A pharmaceutical composition according to claim 1, wherein at least one pharmaceutically acceptable excipient is a filler (diluent), dispersant, binder, glidant, lubricant (lubricant). 5. A pharmaceutical composition according to claim 4 wherein the filler is microcrystalline cellulose and lactose. 6. A pharmaceutical composition according to claim 4, wherein the dispersant is crospovidone and pregelatinized starch. 7. A pharmaceutical composition according to claim 4, wherein the glidant is colloidal Silicon dioxide. 8. A pharmaceutical composition according to claim 4, the lubricant being magnesium stearate and talc. 9. Pharmaceutical composition according to claim 1, 8-50% by weight of pinaverium bromide based on the total tablet weight of the composition, ii. 1.5-10% by weight of medazepam, iii.20-90% by weight of filler, iv. 1-15% by weight of distribution, V. 0.5-4% by weight of lubricant, vi.0.5-3% by weight of glidant vii. It is a pharmaceutical composition containing 0-10% binder by weight and its feature is that it is coated with an acrylic-based coating material.