Author: qihuafeng Currently, oral pharmaceutical formulations is still one of the main forms of administration. In-depth study of new oral dosage forms to improve drug efficacy and reduce adverse reactions is not only an urgent need for clinical pharmacy research, but also important in the economic benefits of medical research and pharmaceutical industry. The sustained-release preparation can provide a suitable blood concentration to the human body within a predetermined period of time as needed, reducing the number of administrations and obtaining a good therapeutic effect. Its important feature is that it can maintain the blood concentration of the human body for a long time, rather than falling faster than the ordinary preparation, so that the phenomenon of "bee valley" which occurs in the frequent administration of common preparations can be avoided, and the safety of the medicine can be avoided. Sex, effectiveness and adaptability have improved. Because of the reduced number of medications, patients are greatly facilitated, especially those who have been on medication for a long time. With the deepening of the drug delivery system and the administration site, the preparation technology and the development and development of new varieties of the sustained release preparation are promoted. In recent years, oral sustained-release dosage forms have developed rapidly, such as sustained release water pills, various skeleton sustained release preparations, coated sustained release preparations, sustained release capsules, sustained release medicine films, resin drug sustained release preparations, and liquid sustained release preparations. Oral sustained-release preparations are generally controlled by the characteristics of dissolution, diffusion, penetration and ion exchange of the drug. In many cases, it is mainly through the selection of appropriate excipients, using the formulation technology to achieve the purpose of delaying the release of drugs. The design of sustained-release pharmaceutical preparations should consider the effects of the physical and chemical properties of the drug itself, such as the type of crystal form, the solubility of the drug, the partition coefficient, the stability of the drug in the digestive juice, the binding rate of absorption in the body to plasma proteins, the PKA value of the drug and the organism. The relationship between membrane permeability and the like. At the same time, the effects of physiological factors on the performance of sustained-release dosage forms should also be considered: absorption, distribution, metabolism of drugs, sustained release time of drugs, therapeutic index and disease status. There are more than ten kinds of general sustained release dosage forms, such as sustained release preparation of skeleton type, sustained release preparation of coating, sustained release water pellet, sustained release microcapsule, multi-layer sustained release tablet, sustained release capsule, magnetic sustained release preparation, and sustained release of pharmaceutical resin. Formulations and sustained release drug films. Skeletal sustained-release tablets are one of the types of oral sustained-release preparations currently used in clinical practice. According to the different skeleton materials used, it can be divided into insoluble skeleton sustained release tablets, wax skeleton sustained release tablets, hydrophilic gel skeleton sustained release tablets and mixed material skeleton sustained release tablets. Insoluble skeleton sustained-release tablets, which are made of a polymer material which is insoluble in water or extremely water-soluble, and a non-toxic plastic as a skeleton material. Commonly used insoluble framework materials are: ethyl cellulose, polyethylene, polypropylene, polysiloxane and polyoxyethylene. In order to adjust the release rate, electrolytes (such as sodium oxide, potassium oxide or sodium sulfate), sugars (such as lactose, fructose, sucrose or mannitol) and hydrophilic gels (such as hydroxypropylmethyl) may be added to the formulation. Cellulose, sodium carboxymethylcellulose or scutellaria, etc.). The waxy skeleton sustained-release tablet is a tablet made of a drug such as an inert fat or a wax as a skeleton material. Commonly used waxy skeleton materials are: beeswax, hydrogenated vegetable oil, synthetic wax, butyl stearate, stearic acid, carnauba wax, glyceryl stearate, propylene glycol-stearate and stearyl alcohol. Commonly used backbone porogens are polyvinylpyrrolidone, microcrystalline cellulose, polyethylene glycol-1500, -1400, -600 and water-soluble surfactants. The hydrophilic gel skeleton sustained release tablet is made of a hydrophilic high molecular polymer as a skeleton material. Hydrophilic gel matrix material can be divided into four types of 1 cellulose derivatives (methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyl Methylcellulose and sodium carboxymethylcellulose, etc. 2 non-cellulosic polysaccharides (such as glucose, chitin, chitosan and galactomannan) 34 natural gum (pectin, sodium alginate, alginic acid) Potassium, agar, horn, etc., locust bean gum, claw gum and scutellaria, etc.) 4 vinyl polymer or acrylic polymer (such as polyvinyl alcohol and polyhydroxyethylene 934) mixed material skeleton sustained release tablets It is prepared by mixing a drug with two or more of the above-mentioned insoluble waxy and hydrophilic gel skeleton materials. The coated sustained release preparation is a coating of granules, pellets or tablets, etc., using one or more mixed coating materials. The slow-dissolving waxy coated sustained-release preparation is a medicinal wax with different thicknesses for various kinds of drug-containing pellets or granules, so as to obtain a preparation time of different lengths. Commonly used coating materials are agar wax, stearic acid, hydrogenated cottonseed oil and carnauba wax. The microporous film coated sustained-release preparation is coated with a microporous film. The commonly used microporous coating materials are ethyl cellulose, cellulose acetate, polyethylene, polypropylene, polylactic acid, polyglycolic acid, polylactic acid-polyethanol. Acid copolymers, high purity polyhydrogenethylene, polycarbonate, epoxy resins, polyamides, acetal polymers, polyesters, polyurethanes, polyimides, and polystyrene derivatives, etc. Soluble substances (such as micronized sugar powder, etc.) or other soluble polymer materials (such as polyethylene glycol and methyl cellulose) are added to the membrane material solution as a porogen for the membrane to adjust the release rate. The gastric-soluble film-coated sustained-release preparation is prepared using a gastric-soluble film coating material. Commonly used are hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylacetal diethylaminoacetic acid and dimethylaminoethyl methacrylate-neutral methacrylate copolymer. The enteric film-coated sustained-release preparation is prepared by using a film coating material which is insoluble in gastric juice and soluble in intestinal juice, and has previously used cellulose such as "CAP", "MCP", and "CATHP". The composite film coating sustained-release preparation is a composite film coating liquid formed by mixing various film materials in a solvent to coat a drug, such as a sodium carbonate-de-vinyl chitosan polyelectrolyte, ethyl cellulose. Mixed with water-soluble coating materials, etc. The multi-layer coating film sustained-release preparation is coated with two or more layers of pharmaceutical preparations (such as granules, pellets or tablets) in different concentrations of the same coating material solution or different coating material solutions. Membrane, commonly used gastric-soluble cellulose derivatives are hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose; gastric-soluble polyethylene derivatives are polyvinylpyrrolidone, PVP - vinyl acetate copolymer, polyvinyl acetal-diethylaminoacetic acid copolymer and diethylaminoethyl methacrylate-methyl methacrylate copolymer; enteric cellulose derivative with phthalic acid acetic acid Cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate, etc.; enteric acrylic acid derivative with methacrylic acid Ester-methacrylic acid copolymer and the like. The gastric-soluble coating materials commonly used in the sustained-release pellets are: gum arabic, stomach-soluble acrylic resin, cellulose derivatives (such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), gelatin, Hydrogenated castor oil, glycerides, polyethylene glycol, waxy. Enteric coating materials include anionic acrylic resin, hydroxypropyl methylcellulose phthalate and shellac. The sustained-release microcapsules are obtained by coating solid or liquid drug particles on a surface with a polymer substance or a copolymer to form a semi-permeable or sealed coating layer. The commonly used wrapping materials are: gelatin which is easily soluble in water, peach gum, and nail. Cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and polyethylene glycol, water-insoluble ethylcellulose, nylon and methacrylate copolymers, methacrylic acid soluble in acidic media Dimethylaminoethyl ester-neutral methacrylate copolymer, etc., anionic polymer methacrylic acid copolymer soluble in alkaline medium, cellulose acetate phthalate, hydroxypropyl methyl phthalate And phthalic acid vinyl acetate and the like. Multi-layer sustained-release tablets, modern multi-layer tablet machines open a new way for the preparation technology of sustained-release preparations. These machines compress two or three layers of granules having different release rates into tablets. One of the layers is relatively rigid so that the integrity of the dosage form is maintained most of the time the tablet is passed through the intestine. Commonly used auxiliary materials hydroxymethyl cellulose, calcium phosphate, lactose, kaolin, mannitol, starch sucrose, glucose and the like. Sustained-release capsules are usually prepared by adding small pellets, granules, beads and microcapsules of different thickness to the coating, adding them into an appropriate amount of hard plastic shell, or dissolving or suspending the drug in different solvents or different The auxiliary material skeleton material is mixed and filled into the rubber pellets. Corn gelatin and shellac are also coated with auxiliary materials such as microcrystalline cellulose. The drug-resin sustained-release preparation was studied by oral ion exchange principle to study oral sustained-release and controlled-release preparations. Commonly used auxiliary materials such as ethyl cellulose. The magnetic sustained-release preparation is guided by an external magnetic field to cause the preparation to be sucked in the lesion area or the cancerous area of ​​the digestive tract, and then the drug is released slowly. The participle material used in the oral preparation is non-toxic to the human body and has high magnetic permeability. Pure iron such as carbon-based iron, magnetite, orthoferrate, γ-ferric oxide, iron-nickel alloy, iron-aluminum alloy and iron-cobalt alloy. The commonly used auxiliary materials can be made of a high molecular polymer such as ethyl cellulose, polyvinyl acetate, methacrylic acid or methyl methacrylate. The preparation should also be thoroughly mixed with an appropriate amount of polyvinylpyrrolidone and magnesium stearate. The sustained release drug film is prepared by dissolving the drug in a polymer film material. Commonly used water-soluble membrane materials are polyvinyl alcohol, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sodium alginate, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and o-benzene-formic acid acetate fiber. Prime. Insoluble in water is ethyl cellulose, cellulose acetate, ethylene-vinyl acetate copolymer, and the like. Biodegradable membrane materials are polylactic acid and polyglycolic acid-ethylene glycol. There are many excipients for preparing sustained release preparations from above. Existing excipients that may be used in the production of commodities can be classified into the following 40 types: natural products and simple extracts such as carnauba wax, cetyl wax, corn gelatin, agar, sodium alginate, gelatin, shellac, pectin, claws. Ear gum, carrageenan, locust bean gum, tragacanth and cholesterol. Cellulose derivatives are ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxyl Propylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, and sodium carboxymethylcellulose. Acrylic resin is dimethylaminoethyl methacrylate-neutral methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, trimethylammonium methacrylate- Acrylate copolymer, trimethylammonium methacrylate-methacrylate copolymer and acrylic acid-methacrylate. The vinyl polymers are polyvinyl phthalate, polyvinylpyrrolidone, polyvinyl alcohol, polystyrene, polyhydroxyethylene and polyhydrogenethylene. Others include stearyl alcohol, glycerol-stearate, nylon, chitin, chitosan, diethyl phthalate, dioctyl phthalate, stearic acid, glucose, polyethylene. Alcohol, polypropylene and polysiloxane. Here are a few examples to further understand the use of excipients in these sustained release formulations. Example 1 waxy skeleton sustained-release tablets: using carnauba wax as the skeleton material, polyethylene glycol 1500, -4000, -6000 as the skeleton pore-forming agent (addition amount is generally 10-25%), using melting method and solvent The theophylline sustained release tablets were prepared by evaporation. The pore-forming polyethylene glycol can increase the release rate of the sustained-release tablets, and the sustained-release preparation prepared by the melt method can release the drug faster than the solvent evaporation method. A zero-order release rate is achieved within the first 7 hours of dissolution, depending on the amount of porogen-inducing agent added. In Example 2, the theophylline sustained release tablet can also be pressed with ethyl cellulose. Theophylline has been used in bronchial asthma for more than 40 years. In recent years, studies on pharmacokinetics and pharmacodynamics have shown that theophylline is effective in preventing and treating the symptoms of chronic asthma. Oral theophylline needs to be taken orally three times. The drug affects sleep during nighttime attack, and the plasma concentration of theophylline treatment is narrow (5-20kg/ml). The elimination rate and the half-reduction period are also different from person to person. The blood concentration after frequent administration. It is prone to "peak and valley" phenomenon, leading to side effects such as headache, nausea, vomiting, dizziness, insomnia, upper abdominal pain, fever, rapid heartbeat, cramps and allergies. Theophylline long-acting tablets can solve this problem. The long-acting tablet of theophylline is prepared by using ethyl cellulose as the skeleton material and hydroxypropylmethylcellulose. After oral administration, the hydroxypropylmethylcellulose is gradually dissolved due to the insoluble of ethylcellulose in the gastrointestinal tract, so that the tablet is dissolved. Intricate pores are generated in the agent, and theophylline slowly diffuses into the gastrointestinal fluid through the pores. The in vitro dissolution rate test was carried out by adjusting the dosage ratio of ethyl cellulose and hydroxypropyl methylcellulose in the prescription, and the prescription was sieved out. The theophylline long-acting tablet of the reagent is administered in one dose (300 mg), the effective blood concentration is reached at 3.5 hours, and the blood concentration of 5 mg/ml or more can be maintained for 23 hours; the multi-dose is administered, and the effective blood concentration is reached in 3 hours. By the second day, the steady-state blood concentration was 13.78+0.47mg/ml. Example 3 Co-production of theophylline sustained-release tablets with acrylic acid methacrylate: After melting the polyethylene glycol-600 and ethyl cellulose, they were respectively poured into a ceramic dish on a hot plate (the temperature was controlled at 75 ° C, 85 ° C, respectively). It was mixed with 90 ° C for 10 minutes each, and an acrylic-methacrylic ester resin was added and stirred for 10 minutes. Then, theophylline was added under heat for another 10 minutes to make the drug distribution uniform. The mixture was poured hot on a glass plate, cooled and kept at 0 ° C to allow it to coagulate. Each of the condensed solids was transferred to a ceramic mortar for 15 minutes, and sieved to collect particles having a particle size of less than 420 μm. It was pressed into two tablets having a tablet weight of 200 mg, a diameter of 7.5 mm, and a hardness of 3.5 and 4.8 kg/cm, and the difference in uniformity of the whole tablet weight and hardness was not more than 5%. The in vitro dissolution test showed that the dissolution rate of the drug from the tablet was less affected by the hardness. Hardness may alter the cell density and channel curvature within the tablet backbone, thereby affecting the rate of release. A similar release rate can be obtained by solid dispersion technique granulation and drug micronization. The higher temperature (90 ° C) is used to achieve high dispersion of the drug in the polymer and to obtain a larger surface area, thus significantly increasing the rate of drug release per unit time. It can be seen that the properties of the polymer used as the framework material, the pore director, the blending mode and the temperature at which the solid dispersion is used are all important factors affecting the release rate of the sustained release preparation. Example 4 Theophylline is composed of glycerol-stearate as a skeleton material, and microcrystalline cellulose is a pore-forming agent, which can be obtained by a melt method and a solvent evaporation method. Melt method: glycerin-stearate or propylene glycol-stearate was melted on water at 65 ° C, and a mixture of theophylline and microcrystalline cellulose (has passed through a 60 mesh sieve) was slowly added while stirring. Allow it to cool slowly while continuing to stir. The coagulum was scraped off, sieved through a 14 mesh sieve, and magnesium stearate was added. Solvent evaporation method: Dissolve glycerin-stearate or propylene glycol-stearate in ethanol at 60 ° C, add a mixture of the drug and microcrystalline cellulose, stir well, and evaporate the solvent. The dry block is pulverized, granulated, and tableted. The tablets prepared by the two methods each weighed 600 mg and had a diameter of 12 mm. In vitro dissolution test showed that the sustained release tablets prepared by the two prescriptions showed a sustained release of the sustained release of the drug in a controlled period of time, and the release rate was proportional to the amount of microcrystalline cellulose and glyceryl-stearate added in the prescription. Increased and accelerated; sustained-release tablets prepared by solvent evaporation method are faster than melt-released preparations; propylene glycol-stearate is used as the matrix material, but the results are similar, but released by glycerol-stearate Slightly faster. The sustained release preparations made from the above 4 cases of theophylline with different excipients are better than the ordinary theophylline. The above four sustained-release preparations have their own advantages, which will provide a useful attempt for the future application of sustained-release preparations, lay a certain foundation for future work, and make our due contribution to the development of drugs.
HEBEI PINGLE FLOUR MACHINERY GROUP CO., LTD , https://www.plrollermill.com