RU2025122C1 - Compound with regulated liberation of active substance - Google Patents

Abstract

FIELD: chemical and pharmaceutical industry. SUBSTANCE: active substance comprises ketoprophenstearic acid, paracetamol stearic acid, diltiazemparaffin; lipophil compounds - stearic acid, paraffin, hardening component ethyl cellulose or copolymer of methacrylic acid. EFFECT: constant liberation of active substance for a long time. 2dwg, 2 cl

Description

 The invention relates to the pharmaceutical industry, in particular, relates to a membrane coating for the controlled release of an active ingredient, which may be a pharmaceutical agent, a synthetic or extractive type veterinary agent, and to preparations containing said coated active ingredient.

 In the pharmaceutical field, the manufacture of microgranules with a constant release of the agent is known.

 The preparation process includes applying the active substance to spherical cores, the diameter of which is in the range from 0.2 to 2 mm, using a special binding agent, or the spherical cores of the active substance can be prepared with or without a binding agent. A semi-permeable membrane is then applied, which allows the drug agent to diffuse over a controlled period of time, or it breaks down within a clearly defined period of time, releasing the drug agent.

 The commonly used membrane, described in several patents, consists of liquor, copolymers of methacrylic acid, ethyl cellulose, ethyl cellulose phthalate, hydroxypropyl methyl cellulose, cellulose acetate phthalate and the like. The membranes mentioned and currently used are also made of natural material, in particular liquor, as a result of which their composition is uncertain. Thus, the amounts of material used to obtain an identical coating vary significantly from one case to another, therefore creating permanent problems. For this reason, from one batch of raw materials to another, production is fraught with technological difficulties and it is often impossible to achieve the same release mode.

 Moreover, it is very difficult to achieve a zero-order isolation or isolation over an adjustable period of time, determined by the need for the drug.

 In the field of pharmacology, the goal is to create compositions with continuous release to achieve a 12-hour therapeutically active level in the blood with sequential dosing by twice daily administration to the body or a 24-hour level in the blood by introducing one capsule per day into the body. To achieve such results, the release of the drug substance must be more or less slowed down in accordance with the half-life characteristics of each drug.

 It has now been established that varying the amount of applied membrane material or the ratios between the two components allows for constant release for 4-6 to 18-22 hours or more, as shown in FIG. 1, ketoprofen [a membrane of ethyl cellulose and stearic acid] and, as shown in FIG. 2, diltiazem hydrochloride [membrane of paraffin-methacrylic acid copolymers].

 This technological flexibility makes it possible to choose the most acceptable excretion mode in laboratory conditions in order to ensure in vivo in the blood such a level that gives a pharmaceutical effect for the desired period of time.

 Several tests performed showed very good reproducibility from one batch of starting material to another and good stability. Membranes made of synthetic materials with a clearly defined molecular composition, reported by International Pharmacopeas, are characterized by high purity, as shown by the results of analytical tests.

 These new membranes (like paraffin) by their very nature have very low chemical affinity for the products that they cover. Due to this, very good compatibility must exist between the membrane and the product that it covers, so very high time stability can be achieved.

 Thus, the invention relates to both semipermeable and degradable membranes, either from lipophilic compounds only, or from a mixture of these compounds with a suitable curing agent. More specifically, the invention relates to a membrane coating for pharmaceutical, cosmetic, veterinary synthetic and extractive substances and to preparations manufactured using them.

 In another embodiment, the invention also provides a method for manufacturing said preparations, the implementation of which provides for applying to a pill of inert material a first coating layer from a therapeutically active compound and then applying to this layer a second layer consisting of either only one lipophilic substance or mixtures thereof with a curing agent.

 In the preparations of the invention, inert pills according to a preferred embodiment should be made of sucrose and starch.

The following substances are used as materials for lipophilic membranes:
AND). Fatty acids containing from 12 to 20 carbon atoms, in particular malmitic acid and / or paraffinic acids (see USP XXI, p. 1584).

Compounds used for curing action are selected from the class:
B) Herculous ethyl cellulose with 44.5-50% ethoxy groups.

 C) Oxypropyl methylcellulose (Dow Chemicals type Premium with a viscosity of 50 to 4000 cP).

 D) Oxyethyl cellulose (varieties Hercules Natrosol with a viscosity of 180 to 250 cP).

 E) Oxypropyl cellulose (Hercules Klusel varieties with a viscosity of 150 to 6500 cP).

 F) Oxypropyl methylcellulose phthalate (Shinetsu Chemicals, Tokyo).

 G) Methyl cellulose (Dow-Chemkal-Methocel Premium grades with a viscosity of 15 to 4000 cP, according to the Henkel Wiskontran instrument).

 H) Copolymers of methacrylic acid (Rum Pharma G.M.b.x company) Eudragit E, L, S, RS, RL, E30D, L30D, RL30D, RS30D - types.

 K) Cellulose acetate phthalate (Kodak company).

 L) Polyethylene glycol (varieties Hoechst PEG mol. M. From 300 to 35000).

 M) Polyvinyl acetate (PVA) (Colorcon UK), Canada Packers Chemicals, Canada).

 N) Polyvinylpyrrolidone (PVP) (Kollidon product from BASF with k values from 10 to 95).

 O) Oxybutyl cellulose (Dow Chemicals, with a viscosity of 12,000 cP).

 P) Sodium carboxymethyl cellulose (Henkel Dehydazol product, with a viscosity of 400-15000 cP).

 Q) Polyvinyl Acetophthalate (PVAF) (Colorcon, UK, Canada Packers Chemicals, Canada).

 All of these curing agents are preferably dissolved in ethanol, acetone, methylene chloride or other organic solvents at room temperature or at a temperature that corresponds to the boiling point of the solvent used. In this way, solutions with a concentration of 0.1% to saturation can be prepared. These hardeners can be dissolved either individually or in mixtures with each other in all proportions.

 Lipophilic substances are dissolved in these solvents or they are melted. They can be used individually or in a mixture with each other in molten or dissolved form.

 Tests that were carried out using one stearic acid as the membrane on theophylline showed faster release compared to that achieved using the same amount of stearic acid, but with the addition of hydroxypropyl methylcellulose. The addition of curing agents to lipophilic compounds allows for a more flexible and less rapid release over a controlled period of time. In order to obtain stronger mechanically and more resistant membranes, lipophilic compounds should be mixed in a solution with curing agents when possible, or applied in alternating layers.

 In this case, the preferred ratio between the lipophilic compound and the curing agent is from 0.1 to 100% for the lipophilic compound and from 0.9 to 99.9% for the hardener. The application of membranes on microcapsules or other material to be coated is performed to achieve slow release of the coated material, protection of the stomach, separation of incompatible substances, weakening of chemical reactivity, physical separation, simplification of manipulations, elimination of unpleasant odor and taste, and increase durability. A molten or solubilized membrane is applied to the material to be coated with a high pressure pump to separate into microdrops.

The specified procedure is carried out in a coating bath made of stainless steel with a variable rotation speed of 3 to 40 rpm depending on the diameter in combination with a fluidized bed apparatus (uni-glatt) or quick mixers, in particular the type of apparatus Reading or the like. The process of evaporation of the solvents used in this procedure is carried out in thermostatic dryers or in vacuum at a temperature of from 30 to 45 ^about C.

 Lipophilic compounds individually or in a mixture with each other and with the possible addition of curing agents can also be used in combination with spray drying or spray cooling technology.

 EXAMPLE 1. On 19 kg of neutral pills that contained 75 wt.% Sucrose and 25 wt.% Starch and which were placed in a stainless steel coating bath, 53.5 kg of ketoprofen were applied together with an alcohol solution. (ethanol) with a concentration of 20 wt.% polyethylene glycol mol. m 4000. After drying, applied 4.5% by weight of an alcoholic solution of ethyl cellulose (with ethoxy groups from 44.5 to 50%) and 7.5% stearic acid with the addition of 2.70 kg of talc.

 After drying, the product contained 2.23 kg of stearic acid and 1.33 kg of ethyl cellulose. Tests on the release mode, which was carried out in accordance with USP XXI, apparatus NO 1 at 150 rpm./min using 900 ml of juice with a pH value of 7.2, gave the results shown in FIG. 1, curve D. Curves A to C were obtained using preparations that included increased amounts of membrane material. Using the aforementioned preparation, capsules can be made which contain from 50 to 250 mg of ketoprofen.

EXAMPLE Example 2 82.00 kg of paracetamol were placed in a Lödige mixer type mixer, and under stirring conditions of temperature 50-60 ^{° C} was added 12.40 kg of stearic acid (NF XVI, p. 1611), melted and mixed with 25.00 kg of a 10% by weight ethanol solution of ethyl cellulose with a content of ethoxy groups from 44.5 to 50%.

The entire mass was stirred for 10-15 minutes and then dried in a thermostatic chamber at a temperature of 35-45 ^C. The granulate thus prepared is characterized by a taste-masked so that it can be used either in monodose bags or in other pharmaceutical forms. This granulate was mixed with 3.00 kg of magnesium stearate and thus tablets were prepared which contained 200 mg to 1 g of paracetamol each.

 Tests on the selection mode, conducted in accordance with USP XXI, apparatus No. 2 at a rotation speed of 50 rpm./min using 900 ml of juice at a pH of 5.8 gave the following selection results: for 1 h - 22.8%, for the 4th hour - 54.6%, for the 8th hour - 98.3%.

 The release rate was increased or decreased by proportionally varying the amount of applied membrane material. It must be borne in mind that instead of a mixer such as a Ledig mixer, a pseudo-boiling layer or a bath for coating with a pseudo-boiling layer can be used and with an identical membrane comparable results can be achieved.

 PRI me R 3. During the process similar to that described in example 2, but with the application of only 10% of the membrane, tablets were prepared, which were characterized by a very rapid release. After additional coating on the tablets in a stainless steel bath using 10 to 20% of the membrane material, the following release mode was achieved: for the 1st h - 10-25%, for the 4th h - 40-80%, for 8 h - 70-100%.

 PRI me R 4. During the process similar to that described in example 1, 34.40 kg of inert granules (sizes from 0.7 to 1 mm) were applied 49.50 kg of propanol-hydrochloride together with 11.00 kg of 20% by weight of ethanol solution of polyvinylpyrrolidone (k-30 value).

The membranes were applied in the form of successive layers with a total mass of 8.10 kg of paraffin, pre-melted and diluted to 40% concentration with methylene chloride at a temperature of 30-45 ^o C.

Copolymers of methacrylic acid (Rum Pharma company), types Eudragit E and RS, were applied in an acetone solution. The following amounts were applied:
Eudragit RS - 0.60 kg; Eudragit E - 0.30 kg
4.80 kg of talc were added in the process of applying successive layers.

In the process of testing for the selection mode, conducted in accordance with USP XXI, apparatus No. 1 at a rotation speed of 100 rpm using 900 ml of juice with a pH of 1.2 for the first hour and 7.5 for the fourth and eighth hours received the following results:
For the 1st hour - 13.3%, for the 4th hour - 47.2%, for the 8th hour - 82.8%.

 After the introduction of a capsule containing 160 mg of propanol hydrochloride into the body, in vivo tests showed an active pharmacologically active blood concentration for 24 hours, as well as the well-known Inderal LA drug, which is commercially available in Switzerland, England, etc. Using the described composition, capsules can be prepared, each of which contains from 40 to 250 mg of propanal hydrochloride.

 PRI me R 5. During the process similar to that described in example 4, but using the composition of the following percentage composition in terms of dried microspheres,%: Diltiazem hydrochloride 43.6 Neutral granules (part size 0.7-1 mm) 22, 5 Paraffin (USP XXI, p. 1584) 13.0 Polyvinylpyrrolidinone (USP XXI, p. 1584) 8.8 Eudragit E (Rum Pharma) 2.1 Eudragit RS (Rum Pharma) 0.8 Talc 9.2 prepared a preparation, the analysis of which, carried out in accordance with USP XXI, apparatus N 1, at a rotation speed of 100 rpm./min and using 800 ml of 0.10N. hydrochloric acid, gave the results shown in FIG. 2, curve D. Other curves were obtained by increasing to reduce the amount of membrane material compared to that indicated. These various release rates were guaranteed by very good reproducibility.

 Using this drug, you can prepare capsules, each of which contains from 50 to 250 mg of diltiazem.

 PRI me R 6. 69.30 kg of neutral microbeads (granule sizes: 0.9-1.1 mm) were placed in a stainless steel bath and 23.00 kg of isosorbide-5-mononitrate were applied to them after dissolution in 20 00 kg of acetone and 45.00 kg of methylene chloride, with 0.95 kg of ethyl cellulose dissolved in the same solution (ethoxy content: 44.5-50%).

 After drying, a membrane was applied from an ethanol solution. The dried microbeads contained 6.05 kg of ethyl cellulose, 0.655 kg of stearic acid (NF XVI, p. 1611) and 85 g of talc.

 The analysis, carried out in accordance with USP XXI, apparatus No. 2, at a rotation speed of 100 rpm and using 1000 ml of juice with a pH value of 7.5 gave the following isolation results: for the first hour - 29.7%, for 4th hour - 70.4%, for the 8th hour - 88.7%.

 Studies on 8 volunteers using 50 milligram capsules compared with the well-known Elantam Long, available in West Germany, showed very high bioequivalence with a dosage of one capsule per day.

 Using this preparation, capsules can be prepared, each of which contains from 20 to 120 mg of isosorbide-5-mononitrate.

PRI me R 7. During the process similar to that described in example 6, but using in this case, the composition of the following percentage composition,%:
Phenylpropanololamine Hydrochloride 31.6
Neutral granules (with sizes 0.7-1 mm) 56.5
Polyvinylpyrrolidone (with k = 30) 2.0
Ethyl cellulose (with ethoxy groups 44.5-50%) 7.7
Stearic acid (NF XVI, p. 1611) 0.7 Talc 1.5 prepared a preparation, the analysis of which in accordance with USP XXI, apparatus No. 1, at a rotation speed of 100 rpm using 500 ml of distilled water gave the following results: for the 1st hour - 51.8%, for the 2nd hour - 72.2%, for the 4th hour - 96.4%.

 In percentage terms, the selection mode was similar to the selection mode for the well-known drug Dexatrin, which is commercially available in Switzerland and the United States. Using the above preparation, capsules can be made, each of which contains from 10 to 150 mg of the product.

 EXAMPLE 8. 40.0 kg of diacerein were applied to 33.0 kg of neutral microbeads prepared similarly to Example 1 using a binder, which is a solution containing 10.20 kg of polyethylene glycol 4000 and 40.00 kg of ethanol. After drying in a solution, a membrane was applied using 42.20 kg of ethanol, 2.20 kg of ethyl cellulose (with an ethoxy content of 44.5-50.0%) and 0.500 kg of stearic acid. The tests were carried out in accordance with USP XXI apparatus N 2 at a rotation speed of 100 rpm. / min and using 900 ml of juice with a pH value of 7.5, to which was added 0.05 wt.% product Tuin 80, receiving the following results: for the 1st h - 47%, for the 4th h - 73%, for the 8th hour - 88%, for the 12th hour - 94%.

 PRI me R 9. 93.00 kg of theophylline was placed in a granulator together with a solution that contained 3.50 kg of polyvinylpyrrolidone with a value of k = 30 and 14.00 kg of ethanol. After drying, the granulate was sieved, leaving only fractions with a granule size of 500 to 800 microns. Fractions with more or less finely dispersed granules were passed through a micron colloid mill and a bath for coating the selected cores using a binder solution containing 3.50 kg of polyvinylpyrrolidone with values of k = 30 and 28.00 kg of ethanol.

 After drying, 10.00 kg of microbeads were applied with a solution that contained 0.84 kg of ethyl cellulose (with a concentration of ethoxy groups of 44.5-50.0%) and 84 g of stearic acid in 16.00 kg of ethanol.

 The test to determine the mode of selection, conducted in accordance with USP XXI, apparatus No. 1, at a rotation speed of 125 rpm and using 900 ml of distilled water, gave the following results: for 1 hour - 12.7%, for 2 -th hour - 22.5%, for the 4th hour - 37.6%, for the 6th hour - 49.1%, for the 8th hour - 58.2%, for the 12th hour - 71, 0%, for the 16th hour - 82.3%.

 PRI me R 10. On 10.00 kg of microgranules prepared by granulation as described in example 9, a solution was applied, which included 0.40 kg of hydroxypropyl methylcellulose (50 cP) and 0.40 kg of stearic acid.

 The test, carried out similarly to that described in example 9, gave the following results: for the 1st hour - 7.6%, for the 2nd hour - 21.9%, for the 4th hour - 45.5%, for the 6th h - 61.4%, for the 8th hour - 72.1%, for the 12th hour - 86.5%, for the 16th hour - 93.9%.

 PRI me R 11. On 10.00 kg of microgranules prepared by granulation as described in example 9, applied a solution that included 0.35 kg of methacrylic acid copolymer (product of Eudragit RS and 0.35 kg of stearic acid in 3.50 kg of acetone and 3.50 kg of ethanol.

 The test to determine the selection mode, conducted similarly to that described in example 9, gave the following results: for the 1st hour - 24.5%, for the 2nd hour - 47.1%, for the 4th hour - 71.5%, for the 6th hour - 82.1%, for the 8th hour - 87.8%, for the 12th hour - 94.0%.

Claims (1)

1. COMPOSITION WITH A REGULATED ISOLATION OF AN ACTIVE SUBSTANCE, including an active substance, a membrane of a lipophilic compound and a curing component, characterized in that the active substance is a soluble compound selected from ketoprofen, paracetamol, propranolol, diltiazem, isosonitrol 5 ketoprofenstearic acid, paracetamol stearic acid, diltiazemparaffin and diacerhein, with the following components, wt.%:
Active substance 4 - 22
Lipophilic compound 0.7 - 29.8
Curing component 0.3 - 26.3
2. The composition according to claim 1, characterized in that, as a lipophilic compound, the composition contains stearic acid, paraffin, a curing component - ethyl cellulose, a methacrylic acid copolymer.

Images