CN119405818A

CN119405818A - A method for preparing a membrane-controlled sustained-release preparation

Info

Publication number: CN119405818A
Application number: CN202510031741.4A
Authority: CN
Inventors: 张榕; 徐慧萍; 陈中科; 张国栋
Original assignee: IVC Nutrition Corp
Current assignee: IVC Nutrition Corp
Priority date: 2025-01-09
Filing date: 2025-01-09
Publication date: 2025-02-11

Abstract

The invention discloses a preparation method of a membrane controlled sustained and controlled release preparation, which relates to the technical field of sustained and controlled release preparations, and comprises the steps of carrying out hot-melt extrusion on ethylcellulose EC, medium-chain fatty acid and monounsaturated fatty acid to obtain a mixed material, reacting with a volatile solvent, ammonia water or an ammonium compound to obtain an EC water dispersion, diluting with purified water to obtain an EC coating liquid, and coating by using a water chestnut sugar coating pot.

Description

Preparation method of membrane controlled sustained and controlled release preparation

Technical Field

The invention relates to the technical field of sustained and controlled release preparations, in particular to a preparation method of an EC film controlled sustained and controlled release preparation coated by a water chestnut sugar coating pan.

Background

The sustained and controlled release preparation is a preparation which delays the process of releasing, absorbing, distributing, metabolizing and excreting the medicine in the body by a proper method, thereby prolonging the action time of the medicine. Such formulations can be classified into sustained-release formulations and controlled-release formulations. Sustained release formulations are those which release the drug slowly in a prescribed release medium at a non-constant rate as required by the intended application. The medicine can be continuously released in a long time after the medicine is taken, so that the medicine slowly enters the body at a proper speed, the fluctuation of the peak valley of the blood concentration is small, adverse reactions caused by exceeding the range of the blood concentration can be avoided, and the medicine can be kept in the effective concentration range for a long time to maintain the curative effect.

The sustained and controlled release preparations in the market are various and can be divided into framework sustained and controlled release preparations, membrane controlled sustained and controlled release preparations, osmotic pump sustained and controlled release preparations, gastric retention preparations, crystalline sheets and the like according to different drug release mechanisms and application fields. These formulations are characterized by being suitable for different requirements. The skeleton type sustained release preparation is the most widely applied type of oral sustained and controlled release preparation due to low preparation cost and easy mass production.

Ethylcellulose (EC) is a high molecular compound with the chemical formula (C12H 22O 5) n. It is a cellulose ether prepared by reacting cellulose with an ethylating agent, typically ethyl chloride. In ethylcellulose, part of the hydroxyl groups in the cellulose chain are substituted by ethoxy groups, forming a long chain polymer with β -anhydroglucose units. Ethylcellulose has good film forming properties, acid resistance and thermal stability, and is insoluble in water, which makes it one of the most widely used water-insoluble cellulose derivatives. The molecular structure is [ C6H7O2 (OC 2H 5) 3] n. EC is insoluble in water, soluble in various organic solvents, good in thermal stability, extremely low in ash content during combustion, little in sticky feeling or astringency, capable of generating a tough film, capable of keeping flexibility at low temperature, nontoxic, extremely strong in anti-biological performance, metabolically inert, but easy to oxidize and degrade under sunlight or ultraviolet light.

Aqueous EC dispersions, i.e. aqueous ethylcellulose dispersions, are a coating material widely used in pharmaceutical formulations. The water insoluble polymer film coating material is prepared from Ethyl Cellulose (EC) and has good film forming property and hydrophobicity. This material is insoluble in water, but soluble in organic solvents such as ethanol, acetone, etc., and its semi-permeable nature makes it an effective tool for controlling drug release. One of the trade names of the EC aqueous dispersion is Surelease, which is produced by Colorcon, inc. and is widely used in the field of sustained and controlled release coatings. The Surelease is prepared by phase separation-agglomeration method or drying method in oil, which comprises dissolving EC and drug in toluene solution, gradually dripping petroleum ether as non-solvent and agglomeration phase under stirring to form microcapsule, filtering, washing, and drying to obtain final product. In addition, hydroxypropyl methylcellulose (HPMC) is often used as a porogen for aqueous EC dispersions to improve their stability and film properties. Studies have shown that suitable HPMC concentrations can significantly affect the stability of the EC aqueous dispersion and the quality of free films made from both materials. The EC water dispersion plays an important role in the coating technology, and is widely applied to sustained and controlled release preparations due to the unique physicochemical properties. For example, it can achieve taste masking and controlled release by blocking the migration of drug molecules to the surface of the coated microparticles and water molecules to the core of the microparticles.

The EC film controlled sustained and controlled release preparation is a preparation which uses Ethyl Cellulose (EC) as a coating material and controls the release rate, time and position of active ingredients. The technology mainly realizes the slow release of the medicine by forming a layer of semi-permeable membrane or microporous membrane on the surface of the preparation. The working principle of the EC membrane controlled release preparation is based on the diffusion behavior of active ingredient molecules in a polymer and the osmotic pressure difference in a membrane cavity. When the active ingredient enters the gastrointestinal tract, it gradually dissolves and releases the drug in a liquid environment due to the characteristics of the EC film. Furthermore, the thickness of the EC film and the choice of material have a significant impact on the rate of release of the active ingredient, and thus the release behaviour of the drug can be optimised by adjusting these parameters.

The water chestnut sugar coating machine is mainly used for sugar coating production of Chinese medicinal pills and tablets in the pharmaceutical industry, and can also be used for rolling, mixing and polishing spherical or granular materials in the food, light industry and chemical industry. The EC film controlled sustained-release preparation coated by the water chestnut sugar coating pan has various advantages, such as increasing the stability of the preparation, improving the appearance and the identification, reducing the stimulation of the stimulation medicine released in a large amount to the human body at the same time, and the like, so as to achieve better effect and safety, and can have a green, efficient and stable production mode. In a word, the EC membrane controlled sustained and controlled release preparation is used as an advanced drug delivery system, and provides a more efficient sustained release scheme by accurately controlling drug release.

The Chinese published patent application No. CN118078770A discloses an efficient automatic sugar coating process of ibuprofen tablets, which comprises the following steps of preparing inner coating liquid and outer coating liquid, coating the inner coating liquid on tablets through a coating pot to form tablets with inner coating, and coating the outer coating liquid on the tablets with inner coating, wherein talcum powder is contained in the inner coating liquid, and talcum powder and titanium dioxide are contained in the outer coating liquid.

The Chinese published patent with publication number CN101843613B discloses a vitamin EC chewable tablet with high stability and a preparation method thereof, and belongs to the field of pharmacy. The chewable tablet consists of vitamin E and vitamin C, and also comprises a filler, an adhesive, a glidant, a stabilizer and a flavoring agent. The vitamin C is coated by adopting the powder coating technology in the preparation process, so that the prepared chewable tablet has high stability and safety, is convenient to transport and store, but has dust generation and is easy to pollute the environment.

As can be seen from the above-mentioned published patent application, the conventional EC film-controlled preparation generally adopts a common coating technology, and the coating materials and methods have certain limitations in drug release control, so that an ideal drug release profile cannot be achieved. Meanwhile, the conventional formulations have drawbacks in appearance, taste and stability. The prior art has the following defects that (1) the release control is not ideal, the traditional sustained and controlled release preparation is difficult to achieve the expected effect in the drug release speed and duration time, and cannot achieve stable release for a long time, (2) the traditional preparation is poor in appearance and taste, is uneven in coating, unstable in color and often has bad smell, (3) the traditional preparation is poor in safety and compliance, and can possibly cause toxic and side effects or allergic reaction in the use process, and is poor in safety and patient compliance, (4) the production efficiency is not high, and the preparation is not stable enough, so that the special situations of transportation, storage and production are difficult to deal with.

Disclosure of Invention

The invention aims to solve the technical problems and provides a preparation method of an EC film controlled sustained and controlled release preparation coated by a water chestnut sugar coating pan.

In order to achieve the technical aim and meet the technical requirements, the technical scheme adopted by the invention is that the preparation method of the membrane controlled sustained and controlled release preparation comprises the following steps:

Step one, preparing raw materials, wherein the raw materials comprise 5-10% of ethylcellulose EC, 1-3% of medium-chain fatty acid, 0.5-2% of monounsaturated fatty acid, 50-60% of volatile solvent, 25-35% of ammonia water or ammonium compound and 5-15% of purified water in percentage by weight;

Step two, coating liquid preparation, namely feeding a mixture of ethyl cellulose EC, medium-chain fatty acid and monounsaturated fatty acid into a hot-melt extruder, obtaining a mixed material through hot-melt extrusion, reacting the mixed material with a volatile solvent, ammonia water or an ammonium compound to obtain an EC water dispersion, and diluting the EC water dispersion with purified water to obtain an EC coating liquid;

And thirdly, preparing the preparation, namely adding substances to be coated into a water chestnut sugar coating pot at 25-35 ℃, controlling the solid content of coating liquid slurry to be 10-20%, controlling the slurry flow rate to be 1.8-2.5rpm and the rotating speed of the water chestnut sugar coating pot to be 15-20rpm, and coating to obtain the sustained and controlled release preparation.

Preferably, the medium chain fatty acid comprises one or more of medium chain triglyceride MCT and lauric acid.

Preferably, the monounsaturated fatty acid comprises one or more of oleic acid ‌, ‌ palmitoleic acid ‌, trans-oleic acid, ricinoleic acid and erucic acid.

Preferably, the ‌ volatile solvents include one or more of ethanol and diethyl ether.

Preferably, the ammonia water or the ammonium compound comprises one or more of ammonia water, ammonium sulfate, ammonium chloride and ammonium nitrate.

In the second step, the mixed material is fed into a hot melt extruder, the extrusion temperature is 120-140 ℃, so that the materials are uniformly mixed and extruded for molding, the extruded material is cooled and then mixed with volatile solvent, ammonia water or ammonium compound according to a certain proportion, and the mixture reacts for 8 hours at 95-120 ℃ to form a fine and uniform coating layer.

A film-controlled sustained-release preparation coated with corm Eleocharitis sugar-coating pan is prepared by the preparation method of the film-controlled sustained-release preparation, and the coated preparation comprises tablets, soft capsules and micropills.

Compared with the traditional structure, the invention has the beneficial effects that:

1. The invention has high stability, and the prepared EC membrane controlled sustained and controlled release preparation has excellent controlled release performance and good appearance characteristics, can gradually and slowly release the active ingredients of the medicine, has stable release curve, remarkably improves the use effect of the medicine and the compliance of patients, and has important application value and market prospect.

2. The invention adopts a novel coating liquid formula, and uses the novel coating liquid formula to prepare tablets, soft capsules, micropills and the like, thereby reducing adverse effects such as peak-valley effect and the like caused by common preparations, and reducing gastric acid irritation and administration times.

3. Compared with other preparation methods, the method for preparing the EC coating liquid by adopting the hot-melt extrusion method reduces the operation time and the production cost and avoids the quality problems in the post-treatment and storage processes. The coating liquid is prepared in two phases, no powder is required to be additionally scattered, dust is avoided, the environment is protected, the prepared sugar coating layer is not cracked or bumped, the integrity is high, the quality of the sugar coating layer is high, and the compliance of people who are not easy to take medicine can be greatly improved.

4. The invention uses the water chestnut sugar coating pot to coat, has simple process operation, good reproducibility, high production rate, high yield of finished products, beautiful appearance, light yellow surface of the preparation, light sweet taste and moisture-proof and taste-masking effects.

Drawings

FIG. 1 is a graph showing the dissolution of vitamin C in example 1;

FIG. 2 is a graph showing the dissolution of vitamin C in example 2;

fig. 3 is a graph showing the dissolution of vitamin B2 in example 3.

Detailed Description

The present invention will be further described below.

Example 1A method for preparing a membrane controlled sustained and controlled release preparation comprises the following steps:

(1) The preparation method comprises the steps of preparing a multi-vitamin tablet, selecting ethyl cellulose EC, medium chain triglyceride MCT, oleic acid, ethanol, ammonium sulfate and the like as coating materials, and adding purified water;

(2) And (3) preparing a coating liquid:

Mixing 8% ethyl cellulose EC with 1% medium chain triglyceride MCT and 1% oleic acid in proportion, feeding the mixture into a hot melt extruder, uniformly mixing and extruding the materials by adjusting the extrusion temperature (130 ℃) and the extrusion speed, cooling the extruded materials, mixing the extruded materials with 60% ethanol and 25% ammonium sulfate in proportion, reacting for 8 hours at 105 ℃ to obtain an EC water dispersion, and diluting with purified water to obtain a fine and uniform coating layer;

(3) Preparation:

And (3) adding substances to be coated into a water chestnut sugar coating pot at the temperature of 28-35 ℃, controlling the solid content of coating liquid slurry to be 15%, controlling the slurry flow rate to be 2.2rpm and the rotating speed of the water chestnut sugar coating pot to be 15rpm, and coating to obtain the sustained and controlled release preparation. The preparation has light yellow surface, light sweet taste, and dampproof and taste masking effects.

(4) Drug release test:

Vitamin C is selected as a dissolution investigation item of the embodiment 1, the dissolution value of the vitamin C in the multi-dimensional sustained-release tablet is measured according to a method of USP <2040> detection, the rotating speed is 75rpm, the dissolution medium is 900ml of 0.1N HCl (0.1 equivalent concentration hydrochloric acid), the marking amount of the vitamin C of the embodiment 1 is 0.2 g/tablet, and the vitamin C dissolution value of 1h/2h/3h/4h is detected.

And (3) calculating:

Wherein, C is the concentration of iodine titration solution and mol/l;

V, the volume of the consumed iodine titration solution is ml;

W is the marked amount of the functional components and g.

The test data (4% weight gain of the coated solids) are shown in table 1:

TABLE 1 elution data (unit:%)

Note that the data in the table are dissolution value data at the corresponding time points obtained by performing dissolution experiments (6 particles at a time) on the same sample.

The dissolution curve of vitamin C is shown in figure 1, and the result shows that the preparation can gradually and slowly release the active ingredients of the medicine within 4 hours, and the release curve is stable.

Example 2A method for preparing a membrane controlled sustained and controlled release preparation comprises the following steps:

(1) The preparation method comprises selecting vitamin C as medicinal active ingredient, preparing into soft capsule, selecting ethyl cellulose EC, medium chain triglyceride MCT, oleic acid, diethyl ether, ammonia water, etc. as coating material, adding other adjuvants (such as sweetener, dampproof agent, etc.), and adding purified water;

(2) And (3) preparing a coating liquid:

Mixing 5% ethyl cellulose EC, 3% medium chain triglyceride MCT and 2% oleic acid in proportion, feeding the mixture into a hot melt extruder, uniformly mixing and extruding the materials by adjusting the extrusion temperature (130 ℃) and the speed, cooling the extruded materials, mixing the extruded materials with 55% diethyl ether and 30% ammonia water in proportion, adding other auxiliary materials, reacting for 8 hours at 100 ℃, obtaining an EC water dispersion, and diluting with purified water to form a fine and uniform coating layer;

(3) Preparation:

And (3) adding substances to be coated into a water chestnut sugar coating pot at 25-30 ℃, controlling the solid content of coating liquid slurry to be 15%, controlling the slurry flow rate to be 1.8rpm and the rotating speed of the water chestnut sugar coating pot to be 18rpm, and coating to obtain the sustained and controlled release preparation.

The preparation has light yellow surface, light sweet taste, and dampproof and taste masking effects.

(4) Drug release test:

vitamin C was selected as a dissolution test item in example 2, and the dissolution value of vitamin C in the above-mentioned sustained-release tablet of vitamin C was measured according to the method of U.S. pharmacopoeia USP <2040>, the rotation speed was 75rpm, the dissolution medium was 900ml of 0.1N HCl (0.1 equivalent concentration hydrochloric acid), the labeled amount of vitamin C in example 2 was 0.5 g/tablet, and the dissolution value of vitamin C was measured for 1h/2h/3h/4 h.

The calculation formula is the same as in example 1.

The test data (4% weight gain of the coated solids) are shown in table 2:

TABLE 2 elution data (unit:%)

The vitamin C dissolution curve is shown in figure 2, and the result shows that the preparation can gradually and slowly release vitamin C in 4 hours, and the release curve is stable.

Example 3A method for preparing a membrane controlled sustained and controlled release preparation comprises the following steps:

(1) The preparation method comprises selecting vitamin B as medicinal active ingredient, preparing into tablet, selecting ethyl cellulose EC, lauric acid, oleic acid, ethanol, ammonium nitrate, etc. as coating material, and other adjuvants (such as sweetener, dampproof agent, etc.);

(2) And (3) preparing a coating liquid:

Mixing 10% ethyl cellulose EC, 3% lauric acid and 2% oleic acid in proportion, feeding the mixture into a hot-melt extruder, uniformly mixing and extruding the materials by adjusting the extrusion temperature (130 ℃) and the extrusion speed, cooling the extruded materials, mixing the extruded materials with 50% ethanol and 25% ammonium nitrate in proportion, reacting for 8 hours at 100 ℃ to obtain an EC water dispersion, and diluting with purified water to obtain a fine and uniform coating layer;

(3) Preparation:

And (3) adding substances to be coated into a water chestnut sugar coating pot at 28-32 ℃, controlling the solid content of coating liquid slurry to be 15%, controlling the slurry flow rate to be 1.8rpm and the rotating speed of the water chestnut sugar coating pot to be 20rpm, and coating to obtain the sustained and controlled release preparation.

(4) Drug release test:

vitamin B2 was selected as a dissolution test item in example 3, and the dissolution value of vitamin B2 in the above-mentioned sustained-release tablets of group B was measured according to the method of U.S. Pharmacopeia USP <2040>, the rotation speed was 75rpm, the dissolution medium was 900ml of 0.1N HCl (0.1 equivalent concentration hydrochloric acid), the labeled amount of vitamin B2 in example 3 was 20 mg/tablet, and the dissolution value of vitamin B2 was measured for 1h/2h/3h/4 h.

And (3) calculating:

Wherein, C _Sample is that the concentration of the sample solution is calculated by checking a standard curve of the peak area of the sample solution, and mg/ml;

W _Sample the marked amount of the effective components, mg.

The test data (4% weight gain of the coated solids) are shown in table 3:

TABLE 3 elution data (unit:%)

The dissolution curve of vitamin B2 is shown in figure 3, and the result shows that the preparation can gradually and slowly release vitamin B in 4 hours, and the release curve is stable.

The foregoing embodiments of the present invention are merely illustrative of the present invention and are not intended to limit the scope of the present invention, and all equivalent technical solutions are also included in the scope of the present invention, which is defined by the claims.

Claims

1. A method for preparing a membrane-controlled sustained-release preparation, characterized in that it comprises the following steps:

Step 1, raw material preparation: the raw materials include ethyl cellulose EC, medium-chain fatty acids, monounsaturated fatty acids, volatile solvents, ammonia water or ammonium compounds, and purified water. By weight percentage, the content of each component is: ethyl cellulose EC 5-10%, medium-chain fatty acids 1-3%, monounsaturated fatty acids 0.5-2%, volatile solvents 50-60%, ammonia water or ammonium compounds 25-35%, and purified water 5-15%;

Step 2, coating liquid preparation: feeding a mixture of ethyl cellulose EC, medium-chain fatty acids, and monounsaturated fatty acids into a hot melt extruder, obtaining a mixed material through hot melt extrusion, and reacting with a volatile solvent, ammonia water or an ammonium compound to obtain an EC aqueous dispersion, which is then diluted to obtain an EC coating liquid;

Step 3, preparation of preparation: using a water chestnut sugar coating pan, add the material to be coated at 25-35°C, control the solid content of the coating liquid slurry at 10-20%, the slurry flow rate at 1.8-2.5rpm, and the rotation speed of the water chestnut sugar coating pan at 15-20rpm, and perform coating to obtain a sustained-release preparation.

2. The method for preparing a membrane-controlled sustained-release preparation according to claim 1, wherein the medium-chain fatty acid comprises one or more of medium-chain triglycerides (MCT) and lauric acid.

3. The method for preparing a membrane-controlled sustained-release preparation according to claim 1, wherein the monounsaturated fatty acid comprises one or more of oleic acid, palmitoleic acid, trans-oleic acid, ricinoleic acid, and erucic acid.

4. The method for preparing a membrane-controlled sustained-release preparation according to claim 1, wherein the volatile solvent comprises one or more of ethanol and ether.

5. The method for preparing a membrane-controlled sustained-release preparation according to claim 1, characterized in that the ammonia water or ammonium compound comprises one or more of ammonia water, ammonium sulfate, ammonium chloride, and ammonium nitrate.

6. The method for preparing a membrane-controlled sustained-release preparation according to claim 1 is characterized in that: in step 2, the mixed material is fed into a hot-melt extruder at an extrusion temperature of 120-140° C. so that the materials are evenly mixed and extruded to form, and after the extruded material is cooled, it is mixed with a volatile solvent, ammonia water or an ammonium compound in proportion, and reacted at 95-120° C. for 8 hours to form a fine and uniform coating layer.

7. A membrane-controlled sustained-release preparation coated with water chestnut sugar coating pan, characterized in that: it is prepared by the preparation method of the membrane-controlled sustained-release preparation as described in claim 1, and the coated preparations include tablets, soft capsules, and pellets.