Research and application of the most popular slow-

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Research and application of slow-release and controlled-release pharmaceutical polymer materials (Part 2)

2.2 skeleton type (matrix type) controlled-release preparations this kind of preparations are simple to prepare, do not need the controlled-release membrane, and directly disperse the drugs in the skeleton formed by the polymer materials. The drug release rate depends on the type of skeleton materials and the diffusion rate of drugs in the materials. For example, nitroglycerin plaster with PVA and PvP as the skeleton, various slow-release tablets with HPMC and Carbopol as the skeleton materials, and mucosal Adhesive preparations with hpc/carbopol as the adhesive materials

2.2.1 the insoluble skeleton slow and controlled release system uses non-toxic plastics such as non-toxic polyvinyl chloride, polyethylene and polyoxysilane as skeleton matrix materials, adds drugs, and then uses organic solvents such as acetone as wetting agent to make soft materials, granulation and tablet pressing. These materials will not be absorbed by the body after oral administration and will be discharged from the feces unchanged. Drug release systems made of these materials are generally suitable for water-soluble drugs. For example, isosorbide nitrate and quinidine sulfate controlled-release tablets made of useful PVC are available abroad

2.2.2 hydrophilic gel skeleton slow and controlled release system uses hydrophilic polymer materials as the main auxiliary materials of tablets, such as methylcellulose, 450 yuan mono hydroxypropyl methylcellulose (K4M, K15M, k100m), Carbopol, sodium alginate, chitin, etc. these materials are characterized by swelling after hydration in the presence of water, forming a thick gel barrier around the drug release system, The drug can be released through the gel barrier by diffusion, and the release rate is delayed by the gel barrier. The hydrophilic ability of materials is the main factor to control drug release. For example, diclofenac potassium is a non steroidal anti-inflammatory and analgesic drug with a short half-life. It needs to be taken 3 ~ 4 times a day. It has strong irritation to the gastrointestinal tract and can cause gastric bleeding and gastric ulcer. It has been reported that a diclofenac potassium hydrogel matrix sustained-release tablet was developed, which used hydroxypropyl methylcellulose (hpmck4m) as the main matrix material and supplemented with other blockers to adjust the release rate. Available hydrophobic blockers include ethyl cellulose, stearic acid, enteric soluble acrylic resin, etc. Hydrophilic materials such as lactose, microcrystalline cellulose and povidone (PVP) can also be added as fillers or porogens to achieve an appropriate drug release rate. After the above excipients and drugs are mixed, they are pressed into tablets by the powder direct tablet pressing process. The human bioequivalence test shows that the preparation can reach the effective treatment concentration within half an hour after oral administration, and the drug can be slowly released within 12 hours, which can maintain the effective concentration for a long time. It only needs to be taken once or twice a day. If some waxes and fatty acid esters are added to the above materials, the specific gravity of the tablets is less than 1. After taking, they can float in gastric juice or chyme for a long time, which is conducive to the lasting release of drugs. Some pharmaceutical preparations that are mainly absorbed in the stomach or play a therapeutic role in the stomach (such as antibiotics against Helicobacter pylori) can be considered to be made into intragastric floating tablets

2.2.3 soluble skeleton slow-release system this kind of skeleton material mostly uses fat and wax substances such as beeswax, butyl stearate, etc. After oral administration, the solid fat or wax gradually dissolves in body fluid, and the drug is released from the skeleton. The release rate depends on the amount of skeleton material and its solubility. The common preparation method is to dissolve or suspend the drug in fat or wax materials while it is hot, grind it into particles after cooling, put it into capsules or press it into tablets

2.3 microcapsules and particulate controlled-release preparations can be regarded as miniaturized storehouse preparations and skeleton preparations. The size is less than 1mm, more generally only 0.1 μ M or tens of microns Water soluble or water insoluble polymer materials can be selected. With the development of polymer materials research, biodegradable polymer materials are increasingly used in microcapsules and microparticles. Polymer materials widely used include gelatin, starch, albumin, polyacrylic acid starch graft, polylactic acid, polyglycolic acid lactic acid copolymer, polyformamide, polymethylmethacrylate, polyacrylonitrile alkyl ester, ethyl cellulose, etc. In recent years, the research and application of new polymer materials have led to a new way of precise drug delivery with timing, orientation, positioning, quick effect, high efficiency and long effect. There are new slow and controlled release preparations, such as oral osmotic pump controlled release system, pulse release drug release system, pH sensitive localized drug release system, colon localized drug delivery system, etc

3. The following is a brief introduction to the oral pulse release drug delivery system and colon specific drug delivery system

3.1 oral pulse release drug delivery system generally speaking, the slow-release preparation releases the drug at the first-order speed, and the controlled-release preparation releases the drug at the zero order speed, which can maintain the stable blood drug concentration for a long time and ensure the long-term effect of the drug. However, during the treatment period, the sustained-release preparations of some drugs can reduce the efficacy and increase the side effects, especially the drugs with large first pass effect, such as levodopa and propoxyphene sustained-release preparations, will increase the degradation amount, and then reduce the bioavailability of the drugs. In addition, the long-term stimulation of the interaction between drugs and receptors inactivates them, resulting in drug resistance, thereby reducing the efficacy. If nitroglycerin is used to control the forming shrinkage: 0 7% release plaster can maintain a certain blood drug concentration for a long time, which is easy to produce drug resistance and is not conducive to the treatment of angina pectoris. With the development of chronobiology, chronopharmacology and chronopharmacology, it has been found that human body, tissues and cells have periodic rhythm differences in drug sensitivity. For example, the effects of corticosteroids, anti asthma, cardiovascular and anti rheumatism drugs are often affected by diurnal fluctuations. 80% of asthma occurs when they get up, so they hope that the drugs will take effect in the morning when they are taken at bedtime. Essential hypertension has the highest blood pressure before getting up in the morning, gradually decreases in the afternoon, and the lowest at bedtime. Therefore, antihypertensive drugs do not need to maintain a constant blood concentration for 24 hours. In this case, a new time controlled drug delivery system - pulse drug delivery system came into being. This kind of preparation can release drugs regularly and quantitatively according to the biological rhythm change characteristics of the human body and the physiological and therapeutic needs. In recent years, it has been widely valued by researchers at home and abroad who slightly tilt back the metal ruler and many pharmaceutical companies. The ideal pulse type drug delivery system is the multiple pulse controlled-release preparation. At present, the oral pulse release system is mainly the two pulse controlled-release preparation, in which the first dose of the drug can be replaced by the rapid release preparation. At present, more research is focused on the pulse type drug delivery system with the missing first dose, which is also called timed release preparation or timed release preparation. According to different preparation technologies, pulse controlled-release systems can be divided into osmotic pump pulse drug delivery system, coated pulse drug delivery system and timed pulse plug capsule. For example, in a "timed blasting" system, the core is sucrose particles, and the core is wrapped with the model drug diclofenac sodium; Then hydroxypropyl methylcellulose was used as a binder to wrap the disintegrated substance low substituted hydroxypropyl cellulose outside the drug layer; The outermost layer is coated with an insoluble coating material with a porogen, such as ethyl cellulose. The system does not release the drug immediately after dosing, but has an obvious time lag. The drug release starts at an interval of about 2 hours, and the drug release is complete 3 ~ 4 hours after release. After the coated pellets enter the gastrointestinal tract, the gastrointestinal fluid can enter the swelling and disintegration layer through the controlled-release membrane. At this time, the hydrophilic gel material will undergo hydration and swelling to produce a certain swelling pressure. It will take a certain time for the polymer material from swelling to dissolution. When the swelling pressure and expansion must pay attention to the model and the volume is large enough, the coating membrane will rupture. At this time, the drug will be released in a burst manner to form a pulse release. If the gastric acid secretion of human body has a peak at about 10 p.m., famotidine pulse controlled release capsule is designed to release the second dose of drug 10 ~ 14 hours after taking the drug, so that the drug has two drug release peaks in the body. In the case of oral administration once a day, it can also effectively control gastric acid secretion

3.2 colon specific drug delivery system colon specific drug delivery system is one of the most studied targeted drug delivery technologies in recent years. Colonic drug release is of great significance for the treatment of colonic diseases and increasing the total gastrointestinal absorption of drugs. With the development of biotechnology, the varieties of protein and peptide drugs are gradually increasing. These drugs are easy to be degraded by the gastrointestinal enzyme system. However, in the colon segment, there are fewer enzyme systems and lower activity, which is an ideal site for oral absorption of protein and peptide drugs. The commonly used colon localization techniques include the time controlled release type designed based on the transit time of gastrointestinal tract, the pH controlled release type designed based on the characteristics of high pH in colon, and the decomposition of specific polymer materials (such as colloidal calcium, α- Starch) designed colon specific drug delivery system, etc

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