First, the development direction of sustained and controlled release pharmaceutical preparations
A new development direction of sustained and controlled release preparations abroad is put forward, that is, the goal is to prolong the action time of drugs, facilitate medication, stabilize the blood concentration and reduce side effects, so as to improve the curative effect of patients in disease state. Such as nifedipine osmotic tablets and diltiazem hydrochloride sustained-release capsules, etc., due to the advanced sustained-release technology, they have achieved ideal medicinal properties. Therefore, the problems that should be considered when developing new sustained and controlled release preparations include:
1. Can this preparation improve the therapeutic value? That is, can the preparation reach the required release speed (unsteady release), release time (non-prolonged release time) and release site or target? 2. How does the preparation meet the above requirements? That is, are the above drug release products optimized? Is the correlation between pharmacokinetics and pharmacodynamics obtained through pharmacodynamic and pharmacological experiments, especially in disease state? 3. Is the dosage form and process selected for this preparation the most suitable for the above characteristics? Whether it includes the comprehensive consideration of pharmacoeconomics, the convenience of medication and the formulation of dosage plan.
The important progress made according to this goal is the timed pulse sustained release system developed according to the time pharmacology of disease treatment. For example, the designed metoprolol sustained-release pulse preparation is administered 1 time within 24 hours and 10 at night. After 6 hours, the drug begins to release slowly, reaching the maximum blood drug concentration at 8:00- 12 in the morning, and then maintaining the effective blood drug concentration until the second administration. This is undoubtedly superior to the general sustained-release preparation in treating migraine with the highest frequency of attack in the morning. Verapamil hydrochloride osmotic pump tablets also adopted a similar design idea, using computer programs to control the timed release of drugs. However, as far as the properties of most sustained-release and new social release preparations at home and abroad are concerned, this goal is far from being achieved. Many development and research work did not involve and solve the above problems, especially the latter two problems did not attract enough attention. The development of sustained-release and controlled-release preparations puts forward high requirements for the depth of research and development, which increases the difficulty, cost and cycle of research and development to a certain extent, but high-quality products will inevitably achieve greater social and economic benefits. Nifedipine osmotic pump tablets and diltiazem hydrochloride sustained-release capsules are the top four varieties in new drugs and new systems.
Second, the choice of oral sustained and controlled release drugs
With the in-depth understanding of things and the progress of preparation technology, the selection of oral sustained-release preparations has broken through some previous principles in recent years. 1, many drugs with strong first-pass effect have been developed into slow-release and controlled-release preparations, such as propranolol and metoprolol, and some of them have been included in Pharmacopoeia. In the past, it was thought that the slow release and absorption of these drugs in the gastrointestinal tract could increase their metabolism in the liver, but there were few reports on the relative bioavailability of these sustained and controlled release preparations. 2. Semi-old drugs, such as carbamazepine and felodipine, have sustained-release preparations, the main purpose of which is to reduce side effects, and there is no report of accumulation. Drugs with short half-life are often inconvenient to take after being developed into sustained-release tablets or capsules, but sustained-release granules, sustained-release dry suspensions and other dosage forms can solve this problem. The half-life of nitroglycerin is very short, and the purpose of sustained release is achieved by developing oral patches. Due to the loose oral mucosa cortex, drugs, especially macromolecular drugs, have the permeability of traps. Oral mucosal drug delivery is becoming one of the important development directions of some peptides and protein pharmaceutical preparations. 3. From the treatment point of view, long-term low-dose antibiotic treatment is easy to produce bacterial resistance, so it is not recommended to make such drugs into sustained-release preparations. At present, gentamicin sulfate sustained-release tablets have been approved to treat inflammation caused by Liu You bacteria in China, and were listed in China Pharmacopoeia in 2000. Cefalexin enteric-coated sustained-release capsules and cefradine sustained-release tablets have been marketed. The conflict between the design of this kind of sustained-release preparation and the therapeutic point of view, whether it is easy to produce tolerance when maintaining the effective inhibitory concentration for a long time and the tolerance mechanism of different antibiotics deserve further study. 4. Some addictive drugs are made into sustained-release preparations to adapt to special medical applications. In order to reduce the spasm of patients and facilitate medication, morphine, codeine, narcotine and other narcotic drugs were developed into sustained-release preparations.
Thirdly, the relationship between sustained release time and gastrointestinal absorption site.
In order to facilitate drug use and strengthen patient compliance, it is an important trend to develop sustained-release and controlled-release varieties with daily dosage of/kloc-0. Such as thiazides, theophylline, nifedipine, felodipine, ketoprofen, pseudoephedrine, isosorbide dinitrate, chlorpheniramine, naproxen, tramadol, diclofenac sodium, etc. , with products or patents managed 1 times within 24 hours. The average retention time of pharmaceutical preparations in gastrointestinal tract is generally 8- 12 hours, and the retention time in colon can be as long as 30 hours. It is considered that pellets, microcapsules and microspheres with multi-dose units have uniform drug release and high safety, which is convenient for the production of photocopying preparations Because it is easy to be retained by the folds of gastrointestinal mucosa, the retention time is extended to about 16 hours, which is beneficial to absorption. As a 24-hour administration method, it is a better preparation form. There are not many varieties of sustained-release microparticle preparations independently developed in China, and there are even fewer varieties that are administered 24 hours 1 time. Although its technology and equipment requirements are higher than tablets, there are many equipment and technologies for producing particles or particle preparations at home and abroad, which can be produced by coating pot, boiling bed, extrusion-spheronization centrifugal granulation and so on. Microparticle preparation is also the development direction of oral drug delivery system for peptides and protein drugs, which is worth further development.
The residence time of gastrointestinal preparation is related to the rhythm of gastrointestinal peristalsis and also changes with diet. However, the absorption ability of drugs in stomach, duodenum, small intestine and large intestine varies greatly, and the absorption degree below large intestine is very poor. Although there may be a long residence time, there may not be the same effective absorption at different times. Therefore, it is necessary to develop sustained-release preparations, especially sustained-release preparations once a day 1 time, fully study the permeability characteristics in various intestinal segments, and increase the absorption of drugs in large intestine, ileum and colon segments or increase the release time in stomach to increase the absorption in small intestine segments. In order to achieve this goal, people have developed a large number of methods, materials and technologies, such as adding absorption enhancers to gastric retention, colon release and pulse release, using viscous and swelling excipients with small or large specific gravity as carriers of gastric retention drugs, and using PH sensitive materials, electrolyte sensitive materials, intestinal enzyme degradation materials, quantitative swelling and disintegration materials to realize colon release or pulse release. However, many of these studies have not yet reached the practical application stage. At present, some slow-release varieties of 1 day 1 time mainly focus on ensuring the drug dosage and slow-release elimination of 1 day. Drugs with small dosage, long half-life, suitable solubility and good total intestinal absorption are more likely to achieve 24-hour sustained release effect, and the blood drug concentration is relatively stable. The FDA also recently approved PROZAC, a weekly oral sustained-release capsule for the treatment of depression.
4. Convenient administration is one of the important purposes of developing sustained and controlled release preparations.
According to the definition of American Pharmacopoeia, sustained and controlled release preparations have characteristics that ordinary preparations can't provide, such as reducing the number of times of administration, which can improve the compliance of patients. Liquid oral sustained-release preparation not only has this advantage, but also can facilitate children, the elderly and patients with dysphagia to take medicine and improve the bad taste. Convenient medication does not mean that this kind of preparation is a simple dosage form or process change, but in fact it usually contains novel design ideas and innovative or innovative production processes. There are many patents for liquid sustained and controlled release preparations. Mesafen sustained-release syrup based on ion exchange resin has been marketed, and other products and products under development include phenylpropanolamine, diclofenac sodium, codeine, narcotine, chlorpheniramine, pseudoephedrine and tramadol hydrochloride. Pennekinetic plans to study more than 100 similar varieties, and has developed about 15. When ion exchange resin is used as sustained-release drug carrier, it is necessary to combine impregnation and coating controlled-release technology to keep it stable in ionic aqueous liquid for a long time without drug leakage. Some sustained-release particles or microcapsules can also be directly made into suspension, such as ramobili microcapsule suspension and coated granular syrup of ibuprofen, theophylline and other drugs. The saturated aqueous solution of the drug is used as a dispersion medium to prevent the drug from diffusing from the particles to the water phase. This kind of preparation contains a part of quick-release dosage, which is more suitable for poorly soluble drugs. Other processes or technologies are actually products prepared temporarily before taking, such as particles prepared by multi-layer coating or adsorption technology, microcapsules, microspheres, sustained-release emulsions, gel preparations and so on prepared by various methods.
According to statistics, the more kinds of drugs prescribed by doctors, the worse the patient's compliance, the higher the drug leakage rate, the worse the treatment effect, and the longer the treatment time, the greater the actual medical expenditure. Many compound preparations are popular with patients, not because of the synergistic effect between drugs or better curative effect, but mainly because they are convenient to use and reduce the drug leakage rate. From the standpoint of improving patient compliance, improving curative effect and reducing cost, we should vigorously develop compound preparations commonly used in clinic. In the treatment of acute, severe and acute diseases, it is emphasized that the individualization of medication represents the characteristics of things, while for many long-term, chronic and general diseases, over-the-counter drugs, conventional drugs and compound drugs represent the characteristics of things. Neither aspect can be ignored. In Europe, America, Japan and other advanced countries, there are not only a large number of common compound preparations, but also many compound sustained-release preparations, such as compound levodopa and compound carbidopa sustained-release tablets, compound pseudoephedrine sustained-release tablets (including paracetamol), compound nifedipine sustained-release capsules (including aminoacyllol or metoprolol), compound nisoldipine sustained-release tablets and compound dipyridamole sustained-release capsules (including aspirin). Also under study are compound salbutamol osmotic pump tablets (containing terbutaline), compound propranolol (containing hydrochlorothiazide), compound felodipine sustained-release capsules (containing anllol or enalapril), compound terfenadine (containing pseudoephedrine), compound loratadine (containing pseudoephedrine), compound verapamil (containing Terrado pril) and compound theophylline (containing salbutamol). Most preparations only control the release of one drug, such as nifedipine, felodipine and salbutamol. While other drugs exist in the preparation as immediate release components. Some quick-release drugs generally have a long half-life or only need to be administered 1 time a day.
Pharmacoeconomics and innovation in the development of sustained-release and controlled-release preparations
Undoubtedly, the development of sustained-release preparations has strong economic benefits, such as prolonging the second choice of drug release preparations, and the fillers are generally sustained-release matrix particles or sustained-release pellets. The new extrusion-centrifugal pelletizing technology with convenient production and high output has been popularized, which has replaced the coating process of suspension pelletizing to some extent. In addition, sustained-release capsules filled with small tablets and sustained-release capsules filled with pellets and small tablets are also on the market. Hydrogel skeleton technology and insoluble polymer coating technology are commonly used in sustained-release tablets, because there is not much difference between them in process flow and equipment. Multilayer sustained-release tablets or core-coated sustained-release tablets are also easy to realize industrial production, and are especially suitable for compound preparations. Osmotic pump requires high technical conditions for production, including the application of new equipment, and the production efficiency is relatively low. In addition, due to patent restrictions, there are only a few varieties at present. However, as an innovative technology, it breaks the patent restrictions of the skeleton technology and coating technology, and uses a completely different release mechanism to guide the development of new preparations, so it is easier to achieve sustained release. Compared with matrix tablets or film-coated tablets, although the cost is relatively high, it also has its unique competitive advantages. There is a similar situation in the controlled release of ion exchange resin and polymer mixed melt extrusion molding. There are innovations in technology, mechanical equipment and drug release mechanism, and the cost will increase. However, with the establishment of high-tech platform, long-term benefits will inevitably increase. The innovation of sustained and controlled release preparation includes two aspects: the first development of sustained and controlled release preparation; On the other hand, the second development of the same drug with different sustained and controlled release dosage forms, different innovative technologies or different release characteristics and therapeutic characteristics is a common phenomenon in the new varieties of sustained and social release approved by the FDA of the United States, especially the innovation of the latter, which is a mechanism to encourage innovation after the patent expires. There are few innovative sustained-release and controlled-release preparations with independent intellectual property rights in China. The reason is that developers pay more attention to the immediate economic benefits and are keen on imitation to achieve the purpose of short-term and quick release, which seriously hinders the innovation of dosage form, technology and release mechanism. The relatively high investment, time consumption and technical difficulty in developing new sustained-release and controlled-release preparations discourage developers. Animal pharmacokinetics may only be a requirement of this development. In order to achieve an ideal sustained-release effect in vivo, it may be necessary to conduct a lot of research on gastrointestinal permeability, pharmacokinetics and pharmacodynamics to determine a reasonable design basis.