Preparation method of film-controlled sustained and controlled release preparation

Abstract

The invention discloses a preparation method of a membrane-controlled sustained and controlled release preparation, and relates to the technical field of sustained and controlled release preparations, ethyl cellulose EC, medium-chain fatty acid and monounsaturated fatty acid are subjected to hot melt extrusion to obtain a mixed material, the mixed material reacts with a volatile solvent, ammonia water or an ammonium compound to obtain an EC aqueous dispersion, and purified water is added for dilution to obtain an EC coating solution; a water chestnut sugar-coating pot is used for coating, and the prepared EC film-controlled sustained and controlled release preparation has excellent controlled release performance and good appearance characteristics, can gradually and slowly release effective components of medicines, is stable in release curve, remarkably improves the use effect of the medicines and the compliance of patients, and has important application value and market prospect.

Description

Technical Field

[0001] The invention relates to the technical field of sustained-release preparations, and in particular to a method for preparing an EC film-controlled sustained-release preparation coated with water chestnut sugar coating pan. Background Art

[0002] Sustained-release preparations are preparations that delay the release, absorption, distribution, metabolism and excretion of drugs in the body through appropriate methods, thereby extending the duration of drug action. Such preparations can be divided into two types: sustained-release preparations and controlled-release preparations. Sustained-release preparations refer to the slow, non-constant release of drugs in a prescribed release medium according to preset requirements. Its main feature is that it can continuously release drugs for a long time after administration, allowing the drugs to slowly enter the body at an appropriate rate, thereby reducing the "peak and valley" fluctuations in blood drug concentrations, avoiding adverse reactions caused by exceeding the therapeutic blood drug concentration range, and being able to maintain the effective concentration range for a long time to maintain efficacy.

[0003] There are many types of sustained-release preparations on the market. According to different drug release mechanisms and application fields, they can be divided into the following categories: skeleton-type sustained-release preparations, membrane-controlled sustained-release preparations, osmotic pump-type sustained-release preparations, gastric retention preparations, crystalline tablets, etc. These dosage forms have their own characteristics and are suitable for different needs. Skeleton-type sustained-release preparations have become the most widely used type of oral sustained-release preparations due to their low preparation cost and easy large-scale production.

[0004] Ethyl cellulose (EC) is a polymer compound with a chemical formula of (C12H22O5)n. It is a cellulose ether obtained by reacting cellulose with an ethylating agent (usually ethyl chloride). In ethyl cellulose, some hydroxyl groups in the cellulose chain are replaced by ethoxy groups to form a long-chain polymer with β-anhydroglucose as a unit. Ethyl cellulose 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. Its molecular structure is [C6H7O2(OC2H5)3]n. EC is insoluble in water, soluble in various organic solvents, has good thermal stability, has extremely low ash content when burned, rarely has a sticky or astringent feeling, can form a tough film, can still maintain flexibility at low temperatures, is non-toxic, has extremely strong anti-biological properties, and is metabolically inert, but is prone to oxidative degradation under sunlight or ultraviolet light.

[0005] EC aqueous dispersion, also known as ethylcellulose aqueous dispersion, is a coating material widely used in pharmaceutical preparations. It is a water-insoluble polymer film coating material made of ethyl cellulose (EC) with good film-forming and hydrophobic properties. This material is insoluble in water, but soluble in organic solvents such as ethanol and acetone, and its semipermeability makes it an effective tool for controlling drug release. One of the trade names of EC aqueous dispersion is Surelease®, which is produced by Colorcon and is widely used in the field of sustained-release coating. Surelease® is prepared by methods such as phase separation-coacervation or oil drying, which include dissolving EC and drugs in toluene solution, gradually adding petroleum ether as a non-solvent and coacervation phase under stirring conditions, thereby forming microcapsules, and filtering, washing, and drying to obtain the final product. In addition, hydroxypropyl methylcellulose (HPMC) is often used as a pore-forming agent for EC aqueous dispersion to improve its stability and membrane properties. Studies have shown that the appropriate HPMC concentration can significantly affect the stability of EC aqueous dispersion and the quality of free films prepared from these two materials. EC aqueous dispersions not only play an important role in coating technology, but are also widely used in sustained-release preparations due to their unique physical and chemical properties. For example, they can achieve taste masking and sustained-release functions by blocking drug molecules from moving to the surface of coated particles and water molecules from moving to the core of particles.

[0006] EC membrane-controlled sustained-release preparations are preparations that use ethyl cellulose (EC) as a coating material to control the release rate, time, and location of the active ingredient. This technology mainly achieves the slow release of drugs by forming a semipermeable membrane or microporous membrane on the surface of the preparation. The working principle of EC membrane-controlled sustained-release preparations is based on the diffusion behavior of the active ingredient molecules in the polymer and the osmotic pressure difference in the membrane cavity. When the active ingredient enters the gastrointestinal tract, due to the characteristics of the EC membrane, it will gradually dissolve and release the drug in the liquid environment. In addition, the thickness and material selection of the EC membrane have a significant effect on the release rate of the active ingredient, so the drug release behavior can be optimized by adjusting these parameters.

[0007] Water chestnut sugar coating machine is mainly used for the production of sugar coating for pills and tablets in the pharmaceutical industry. It can also be used for rolling, mixing and polishing spherical or granular materials in the food, light industry and chemical industry. EC membrane-controlled sustained-release preparations coated with water chestnut sugar coating pans have many advantages, such as increasing the stability of preparations, improving appearance and recognition, reducing the stimulation of irritating drugs to the human body when released in large quantities at the same time, etc., so as to achieve better effects and safety, and have a green, efficient and stable production method. In short, EC membrane-controlled sustained-release preparations, as an advanced drug delivery system, provide a more efficient sustained-release solution by precisely controlling drug release.

[0008] A Chinese patent publication with publication number CN118078770A discloses "an efficient automatic sugar coating process for ibuprofen tablets", comprising the following steps: preparing an inner coating liquid and an outer coating liquid; first coating the inner coating liquid on the tablets through a coating pan to form tablets with an inner coating; and then coating the outer coating liquid on the tablets with the inner coating; the inner coating liquid includes talcum powder, and the outer coating liquid includes talcum powder and titanium dioxide.

[0009] The Chinese patent publication number CN101843613B discloses "a vitamin EC chewable tablet with high stability and a preparation method thereof", which discloses a vitamin EC chewable tablet with high stability and a preparation method thereof, belonging to the field of pharmaceutics. The chewable tablet is composed of vitamin E and vitamin C, and also contains a filler, a binder, a glidant, a stabilizer and a flavoring agent. In the preparation process, the powder coating technology is used to coat the vitamin C, so that the obtained chewable tablet has high stability, high safety, and is easy to transport and store, but dust is generated, which is easy to pollute the environment.

[0010] It can be seen from the above-mentioned patent disclosure that the existing EC membrane-controlled preparations usually adopt ordinary coating technology. The coating materials and methods have certain limitations in drug release control and cannot achieve an ideal drug release curve. At the same time, traditional preparations also have shortcomings in appearance, taste and stability. The existing technology has the following disadvantages: (1) Unsatisfactory release control: Traditional sustained-release preparations are difficult to achieve the expected effect in terms of drug release rate and duration, and cannot achieve long-term stable release; (2) Poor appearance and taste: Traditional preparations have uneven coating, unstable color, and often have unpleasant odors; (3) Poor safety and compliance: Traditional preparations may cause toxic side effects or allergic reactions during use, and have poor safety and patient compliance; (4) Low production efficiency and insufficient stability make it difficult to cope with special circumstances of transportation, storage and production. Summary of the invention

[0011] The object of the present invention is to solve the above technical problems and provide a method for preparing an EC membrane-controlled sustained-release preparation coated with water chestnut sugar coating pan.

[0012] In order to achieve the above technical objectives and meet the above technical requirements, the technical solution adopted by the present invention is: a method for preparing a membrane-controlled sustained-release preparation, comprising 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, preparation of coating solution: 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, and then diluting with purified water to obtain an EC coating solution; 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.

[0013] Preferably, the medium-chain fatty acid includes one or more of medium-chain triglycerides (MCT) and lauric acid.

[0014] Preferably, the monounsaturated fatty acid includes one or more of oleic acid, palmitoleic acid, trans-oleic acid, ricinoleic acid and erucic acid.

[0015] Preferably, the volatile solvent includes one or more of ethanol and ether.

[0016] Preferably, the ammonia water or ammonium compound includes one or more of ammonia water, ammonium sulfate, ammonium chloride and ammonium nitrate.

[0017] Preferably: 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, 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.

[0018] A membrane-controlled sustained-release preparation coated with a water chestnut sugar coating pan is prepared by adopting the preparation method of the membrane-controlled sustained-release preparation. The coated preparations include tablets, soft capsules and pellets.

[0019] Compared with the traditional structure, the invention has the following beneficial effects: 1. The present invention has high stability, and the prepared EC membrane-controlled sustained-release preparation has excellent controlled-release performance and good appearance characteristics, can gradually and slowly release the active ingredients of the drug, and has a smooth release curve, which significantly improves the drug's use effect and patient compliance, and has important application value and market prospects.

[0020] 2. The present invention adopts a new coating liquid formula and uses it to prepare tablets, soft capsules, micropills, etc., which reduces the adverse effects such as peak-valley effect brought by ordinary preparations, can reduce gastric acid stimulation, and reduce the number of times of taking.

[0021] 3. Compared with other preparation methods, the present invention adopts hot melt extrusion to prepare EC coating liquid, which reduces the operation time and production cost, and avoids the quality problems caused by post-processing and storage. The coating liquid is prepared in two phases, and no additional powder is required, which avoids dust generation and protects the environment; the prepared sugar coating layer does not crack or bump, has high integrity, and has high quality, which can greatly improve the compliance of people who are not easy to take medicine.

[0022] 4. The present invention uses a water chestnut sugar coating pan for coating, which has simple process operation, good reproducibility, high productivity, high finished product yield, beautiful appearance, light yellow surface of the preparation, light sweet taste, and moisture-proof and taste-masking effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the dissolution curve of vitamin C in Example 1; Figure 2 This is the dissolution curve of vitamin C in Example 2; Figure 3 This is the dissolution curve of vitamin B2 in Example 3. DETAILED DESCRIPTION

[0024] The present invention will be further described below.

[0025] Embodiment 1: A method for preparing a membrane-controlled sustained-release preparation comprises the following steps: (1) Raw material preparation: Multivitamin tablets, select ethyl cellulose EC, medium chain triglyceride MCT, oleic acid, ethanol, ammonium sulfate, etc. as coating materials, add purified water; (2) Preparation of coating solution: 8% ethyl cellulose EC, 1% medium chain triglyceride MCT, and 1% oleic acid were mixed in proportion, and the mixture was sent to a hot melt extruder. The extrusion temperature (130°C) and speed were adjusted to make the materials evenly mixed and extruded. After the extruded material was cooled, it was mixed with 60% ethanol and 25% ammonium sulfate in proportion, and reacted at 105°C for 8 hours to obtain EC water dispersion, which was diluted with purified water to obtain a fine and uniform coating layer. (3) Preparation of preparations: Using a water chestnut sugar coating pan, add the material to be coated at 28-35°C, control the solid content of the coating liquid slurry at 15%, the slurry flow rate at 2.2rpm, and the water chestnut sugar coating pan speed at 15rpm to coat and obtain a sustained-release preparation. The surface of the preparation is light yellow, with a light sweet taste, achieving moisture-proof and taste-masking effects.

[0026] (4) Drug release test: Vitamin C was selected as the dissolution test item in Example 1, and the dissolution test was carried out according to the United States Pharmacopoeia (USP). <2040> The detection method determines the dissolution value of vitamin C in the above-mentioned multi-dimensional sustained-release tablets, the rotation speed: 75 rpm, the dissolution medium: 900 mL 0.1N HCl (0.1 equivalent concentration hydrochloric acid), the labeled amount of vitamin C in Example 1 is 0.2 g / tablet, and the vitamin C dissolution value of 1h / 2h / 3h / 4h is detected.

[0027] calculate:

[0028] Where: C: concentration of iodine titrant, mol / l; V: volume of iodine titrant consumed, ml; W: labeled amount of active ingredient, g.

[0029] The test data (coating solid weight gain 4%) is shown in Table 1: Table 1 Dissolution data of Example 1 (unit: %)

[0030] Note: The data in the table are the dissolution values ​​at corresponding time points obtained from the dissolution experiment of the same sample (6 tablets at a time).

[0031] Vitamin C dissolution curve Figure 1 As shown, the results show that the preparation can gradually and slowly release the active ingredient of the drug within 4 hours, and the release curve is stable.

[0032] Embodiment 2: A method for preparing a membrane-controlled sustained-release preparation comprises the following steps: (1) Raw material preparation: Select vitamin C as the active ingredient of the drug and prepare it into soft capsules. Select ethyl cellulose EC, medium chain triglyceride MCT, oleic acid, ether, ammonia water, etc. as coating materials, other excipients (such as sweeteners, moisture-proof agents, etc.), and add purified water; (2) Preparation of coating solution: 5% ethyl cellulose EC, 3% medium chain triglyceride MCT, and 2% oleic acid were mixed in proportion, and the mixture was sent to a hot melt extruder. The extrusion temperature (130°C) and speed were adjusted to make the materials evenly mixed and extruded. After the extruded material was cooled, it was mixed with 55% ether and 30% ammonia water in proportion, and other auxiliary materials were added. The mixture was reacted at 100°C for 8 hours to obtain EC aqueous dispersion, which was diluted with purified water to form a fine and uniform coating layer. (3) Preparation of preparations: Using a water chestnut sugar coating pan, add the material to be coated at 25-30°C, control the solid content of the coating liquid slurry at 15%, the slurry flow rate at 1.8rpm, and the rotation speed of the water chestnut sugar coating pan at 18rpm to obtain a sustained-release preparation.

[0033] The surface of the preparation is light yellow and has a light sweet taste, achieving moisture-proof and taste-masking effects.

[0034] (4) Drug release test: Vitamin C was selected as the dissolution test item in Example 2, and the dissolution test was carried out according to the United States Pharmacopoeia (USP). <2040> The detection method determines the dissolution value of vitamin C in the above-mentioned vitamin C sustained-release tablets, the rotation speed is 75 rpm, the dissolution medium is 900 mL 0.1N HCl (0.1 equivalent concentration hydrochloric acid), the labeled amount of vitamin C in Example 2 is 0.5 g / tablet, and the vitamin C dissolution value of 1h / 2h / 3h / 4h is detected.

[0035] The calculation formula is the same as that in Example 1.

[0036] The test data (coating solid weight gain 4%) is shown in Table 2: Table 2 Dissolution data of Example 2 (unit: %)

[0037] Note: The data in the table are the dissolution values ​​at corresponding time points obtained from the dissolution experiment of the same sample (6 tablets at a time).

[0038] Vitamin C dissolution curve Figure 2 As shown, the results show that the preparation can gradually and slowly release vitamin C within 4 hours, and the release curve is smooth.

[0039] Embodiment 3: A method for preparing a membrane-controlled sustained-release preparation comprises the following steps: (1) Raw material preparation: Select B vitamins as the active ingredients of the drug, prepare the original tablets, select ethyl cellulose EC, lauric acid, oleic acid, ethanol, ammonium nitrate, etc. as coating materials, and other excipients (such as sweeteners, moisture-proofing agents, etc.); add purified water; (2) Preparation of coating solution: 10% ethyl cellulose EC is mixed with 3% lauric acid and 2% oleic acid in proportion, and the mixture is fed into a hot melt extruder. The extrusion temperature (130°C) and speed are adjusted to make the materials uniformly mixed and extruded. After the extruded material is cooled, it is mixed with 50% ethanol and 25% ammonium nitrate in proportion, and reacted at 100°C for 8 hours to obtain EC aqueous dispersion, which is diluted with purified water to obtain a fine and uniform coating layer. (3) Preparation of preparations: Using a water chestnut sugar coating pan, add the material to be coated at 28-32° C., control the solid content of the coating liquid slurry at 15%, the slurry flow rate at 1.8 rpm, and the rotation speed of the water chestnut sugar coating pan at 20 rpm to obtain a sustained-release preparation.

[0040] The surface of the preparation is light yellow and has a light sweet taste, achieving moisture-proof and taste-masking effects.

[0041] (4) Drug release test: Vitamin B2 was selected as the dissolution test item in Example 3, and the dissolution test was carried out according to the United States Pharmacopoeia (USP). <2040> The detection method determines the dissolution value of vitamin B2 in the above-mentioned B complex sustained-release tablets, rotation speed: 75 rpm, dissolution medium: 900 mL 0.1N HCl (0.1 equivalent concentration hydrochloric acid), the labeled amount of vitamin B2 in Example 3 is 20 mg / tablet, and the dissolution value of vitamin B2 is detected for 1h / 2h / 3h / 4h.

[0042] calculate:

[0043] Where: C 样 :The concentration of the sample solution is calculated by checking the standard curve based on the peak area of ​​the sample solution, mg / ml; W 样 : Labelled amount of active ingredient, mg.

[0044] The test data (coating solid weight gain 4%) are shown in Table 3: Table 3 Dissolution data of Example 3 (unit: %)

[0045] Note: The data in the table are the dissolution values ​​at corresponding time points obtained from the dissolution experiment of the same sample (6 tablets at a time).

[0046] Vitamin B2 dissolution curve Figure 3 As shown, the results show that the preparation can gradually and slowly release B vitamins within 4 hours, and the release curve is smooth.

[0047] The above embodiments of the present invention are merely examples to clearly illustrate the present invention, but are not intended to limit the protection scope of the present invention. All equivalent technical solutions also belong to the scope of the present invention. The patent protection scope of the present invention should be defined by the claims.

Claims

1. A method for preparing a membrane-controlled sustained-release preparation, characterized in that: The following steps are involved: 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 the membrane-controlled sustained-release preparation according to claim 1, characterized in that: The medium-chain fatty acids include one or more of medium-chain triglycerides (MCT) and lauric acid.

3. The method for preparing the membrane-controlled sustained-release preparation according to claim 1, characterized in that: The monounsaturated fatty acids include one or more of oleic acid, palmitoleic acid, trans-oleic acid, ricinoleic acid, and erucic acid.

4. The method for preparing the membrane-controlled sustained-release preparation according to claim 1, characterized in that: The volatile solvent includes one or more of ethanol and ether.

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

6. The method for preparing the membrane-controlled sustained-release preparation according to claim 1, 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. 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: The film-controlled sustained-release preparation is prepared by the preparation method of claim 1, and the coated preparations include tablets, soft capsules, and pellets.

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