1 thinner (filler)
Sucrose, dextrin and starch are traditional thinners, but sucrose is hygroscopic. Patients with diabetes, obesity, hypertension, coronary heart disease and dental caries should not take it for a long time. The solubility of dextrin and starch is not ideal. Pharmacists have done a lot of research to develop high performance diluents.
1.1 Lactose is easily soluble in water, stable in nature, non-hygroscopic, and does not chemically react with most drugs. It has little effect on the determination of main drug content and is a good diluent. For example, the ratio of Zuijia auxiliaries of compound cypress granules is extract powder: lactose = 8:2; the ratio of excipients of Qingyan Xiaoyan granules is β-cyclodextrin: dextrin: lactose = 1:3:5 . For the first time, the Chinese Pharmacopoeia 2000 edition contained four types of lactose-type granules.
1.2 mannitol, xylitol, chitosan, disaccharide antiviral particles of the adjuvant dextrin changed to mannitol, can be dissolved in hot and cold water, clinical observation found that changing the excipient does not affect the efficacy, the need to control sugar The patient who entered was given an option. The research on shuangchun granules showed that the preparations with soluble mannitol, xylitol and completely water-insoluble chitosan were not good, while the bismuth sugar was soluble in water and had certain water adsorption capacity and dissolution rate. Slower, whether it is mixed with extract powder or starch, it has good granulation effect. As a result, Zuijia's recipe is extract powder: double sugar: starch = 10:3:2. Among the excipients, sucrose, lactose, mannitol, xylitol, and disaccharide have the functions of flavoring. In addition, soluble starch or water-soluble dextrin is used as a diluent, which is more soluble than starch.
2 Wetting agents and adhesives
2.1 Such excipients can make the fine powder of the medicine moist and bond, so as to make qualified granules, factors such as the type, concentration and mixing uniformity of the powder should be considered in use.
2.2 Ethanol is a semi-polar wetting agent. When the raw material contains more extracts, it is easy to agglomerate with water. Therefore, different concentrations of ethanol are commonly used as wetting agents. For example, compound cypress granules use 50% ethanol as the wetting agent, the amount of alcohol is 4% of the extract powder, and Yinao Anshen granules use 37.6% ethanol as the wetting agent, so that the yield of qualified particles reaches 94.52%. The concentration of ethanol used in Bushen Zhuanggu Granules is 60%. Guan Yuzhu et al. found that the alcohol concentration directly affected the appearance of the granules when the anti-sensing granules were studied. When the alcohol concentration was lower than 85%, the particles were dark in color and softened and agglomerated when the wet granules were dried. When the alcohol concentration was 90% The particles are made light in color and easy to dry. The author also had similar findings when developing Pingzhi granules. Therefore, when using ethanol as a wetting agent, it is necessary to control its concentration and dosage, and stir rapidly to immediately granulate and reduce volatilization.
2.3 Polyvinylpyrrolidone (PVP) is a synthetic polymer with stable properties and soluble in water or alcohol. It was introduced as a blood volume supplement in the 1940s. Since the 1970s, this product has been used as tablets and granules. Adhesives, the United States Pharmacopoeia 19-23 version has been successively included. Foreign products include Plasdobe from the US ISP and Kollidon from BASF in Germany. PVPK30 has good solubility and stability, and has good adhesion and disintegration to many varieties. It is widely used in western medicine preparations and is also used in traditional Chinese medicine preparations. Wei Fengling et al. used 10% PVPK30 as a binder preparation to prepare 70% alcohol extract particles of Radix Puerariae and the like. Liu Ligen et al. prepared a swallowed Shuanghuanglian granule with 3% PVP ethanol solution as binder. In addition, sodium carboxymethylcellulose (CMC-Na), low-substituted hydroxypropylcellulose (L-HPC), polyethylene glycol (PEG), and the like are also tried as binders for granules of traditional Chinese medicine.
3 disintegrant
Due to the high viscosity of traditional Chinese medicine extracts, in order to improve the disintegration degree and release degree of traditional Chinese medicine granules, especially sugar-free granules, it is often necessary to add starch as a disintegrating agent. At present, the best disintegrators are:
3.1 CMS-Na is an ionic starch derivative and is a multi-purpose pharmaceutical excipient. The foreign trade name is Primojel. It has been included in the 21st edition of the United States Pharmacopoeia and the 1995 edition of the Chinese Pharmacopoeia. It is an excellent disintegrant, a colloidal solution dispersed in water into a network structure, insoluble in ethanol and ether, and has good wettability and swelling. It can absorb 30 parts of its dry volume of water, and the volume can be increased by 200-300 times after water swelling, and the particles themselves do not break. The degree of swelling is 3 to 5 times that of starch, and the swelling property is superior to that of microcrystalline cellulose, and it is preferably used as a disintegrating agent for the alcohol extract of traditional Chinese medicine. Wei Fengling et al. used the alcohol extract: CMS-Na=1:1.33 when preparing 70% ethanol extract granules such as radix puerariae.
3.2 Microcrystalline cellulose (Avicel, MCC) is a tablet filler and disintegrant that has been applied since the 1960s. It has good performance and is especially suitable as a stabilizer for suspension granules. Originally only PH101 and PH102 are available. In recent years, PH103, PH105, PH301, PH302, R91 and Emocel have been newly launched. MCC can greatly reduce the hygroscopicity of the particles and increase the stability of the drug. For example, the Zuijia forming excipient of Bushen Zhuanggu Granule is MCC: soluble starch=1:4; the economical formula of anti-inductive granule is extract powder: dextrin: starch: MCC=5:1:2:2.
3.3 Effervescent disintegrants are generally a mixture of NaHCO3 and organic acids (such as: citric acid, tartaric acid, citric acid, fumaric acid, etc.), when they meet water, they react with acid and alkali to produce CO2 and effervescent. Disintegration. For example, Hawthorn Effervescent Granules use citric acid and NaHCO3 as effervescent to dissolve them quickly in water. In order to avoid direct contact of NaHCO3 with acid and increase stability, NaHCO3 can be encapsulated by polyethylene glycol microcapsule encapsulation. In addition, the micro-powder silica gel can absorb up to 39% of water, and can still maintain a non-sticky flowable state. Adding granules can prevent agglomeration; hydroxypropyl starch has good disintegration, and Zui is suitable as an excipient for spray granulation; soluble Starch and water-soluble dextrin can increase the disintegration effect of granules.
4 inclusion agent
It is a new type of excipient, which can contain volatile oil and bitter ingredients. It can be used as a solid powder to reduce or eliminate the odor and bitterness of the drug, reduce side effects and irritation, and improve solubility and stability. However, among the 11 kinds of Chinese medicine granules containing volatile oil contained in the 2000 edition of the Chinese Pharmacopoeia, all the volatile oils were added by spraying, and no inclusion technique was used, which may be related to the high cost of the existing inclusion technology. The current inclusion agents mainly include α-cyclodextrin (α-CD), β-cyclodextrin (β-CD) and N-LOK modified starch, and the application of β-CD is more. It has been reported that the volatile oil of Rhododendron chinense is encapsulated with α-CD, so that the rhododendron oil is powdered, which basically covers up its strong odor, and can be made into granules, tablets, etc.; after the improvement of cold-clearing granules by β-CD inclusion Compared with the pharmacopoeia process: the volatile oil has a low loss rate, the method is simple, and the storage performance is good. After the β-CD inclusion of Yinqiao detoxification particles, the volatile oil component is better preserved and the stability is improved. N-LOK is a new type of low viscosity modified starch. It is a white powder, odorless and tasteless. It is easy to disperse in water and has good emulsifying function. Chen Lulin and other studies on three kinds of volatile oil inclusions such as Forsythia suspensa showed that the N-LOK ratio of β-CD inclusion efficiency increased by 2 to 2.5 times, the total yield was 2% to 3%, and the volatile oil inclusion was prepared by N-LOK. The utility model has the advantages of good inclusion effect, low dosage, low cost, simple process, direct spray drying, and is suitable for industrial production.
5 sweetener
Due to various sucrose deficiency, the Ministry of Health requested lowering the sugar content of medicines in 1988. Therefore, it is inevitable to develop new sweeteners and sugar-free granules. The Chinese medicine sugar-free granules have not been included in the 1995 edition of the Chinese Pharmacopoeia, while the 2000 edition has contained 11 species, which shows that its development is fast. Sweeteners are developing from synthetic sweeteners to functional natural sweeteners. The main sweeteners are:
5.1 Stevia sugar sweetness is 200-300 times that of sucrose, the price is 30 times that of sucrose, it has bitterness or odor (especially when it exceeds 15%), it is stable to heat, acid and alkali, and it has good safety. It has been approved. Medicinal. The amount of the solution preparation is generally 0.07%.
5.2 Protein sugar, aspartame, is a proteinaceous compound containing aspartic acid and phenylalanine. The sweetness is 180-300 times that of sucrose, the price is 80 times that of sucrose, the sweetness is good, it is not resistant to high temperature, it will be destroyed when it exceeds 120 degrees Celsius, the safety is good, the metabolism does not require insulin to participate, and the medicinal application has been approved. The dosage is from 0.01% to 0.6%.
5.3 The sweetness of xylitol is equivalent to that of sucrose. The price is 6-7 times that of sucrose. The taste is good, the safety is good, and the metabolism does not require insulin to participate. Large dosage and high cost.
5.4 The main component of high fructose is fructose and glucose. It is a nutritive new sweetener. The sweetness depends on the amount of fructose (the fructose is 1.5 times that of sucrose). The taste is good, the safety is good, and the metabolism is not. Insulin is required to participate. Large dosage.
5.5 Sodium cyclamate is a chemical compound. It is divided into sodium cyclamate, which is 50 times sweeter than sucrose. The taste is similar to that of metal. The cost is low and the dosage is limited, generally not exceeding 0.1%. In summary, the traditional Chinese medicine sugar-free granules should be sweetened with stevia or protein sugar. The new preparation for the treatment of fatty liver, the sugar-free type Pingzhi granule, which is prepared by the Institute, uses stevioside as a sweetener, and the effect is ideal.
6 coating agent
Film coating technology has been widely used in tablets. In recent years, it has also been used in traditional Chinese medicine granules. Its advantages are: (1) can significantly improve moisture resistance; (2) mask bitter taste or bad taste; (3) have strong irritation to the stomach or in the stomach The drug that is easily destroyed can be enteric coated and made into a swallowing granule, which avoids the side effects of the drug and improves the curative effect.
At present, the film coating materials of traditional Chinese medicine granules mainly include: HPMC, PEG, acrylic resin and the like. HPMC is soluble in cold water and polar organic solvent, non-irritating, stable to light and heat, has good water absorption and polar organic solvent, no irritation, stable to light and heat, good water swelling and film forming. According to the different methoxy and hydroxypropyl groups, there are 1828, 2208, 29069, 2910 and other models. After the Banlangen granules are coated with stomach-soluble acrylic resin, the dosage is small, the dosage is accurate and easy to swallow. The new Xuedan granules are coated with HPMC and PEG and compared with the IV acrylic resin to improve the solubility and moisture resistance. Amber stone particles coated with 60RT50HPMC ensure the quality during storage and transportation; Shuanghuanglian particles coated with HPMC and PEG masked the bitter taste and easy to swallow, improving stability.
7 Outlook
Excipients are the general term for all additional materials except drugs, which are the material basis for the preparation and the necessary materials for the production of the preparation. The development of new excipients can produce new preparations and drive the improvement of the quality of old products, and can achieve significant social and economic benefits.
All countries in the world attach great importance to the development of new excipients. China's pharmaceutical excipients industry is relatively weak. There is no industrial system of excipients. The excipients are loosely produced and not matched with products. The quality of excipients is poor and unstable. The varieties available for selection are limited. . Without the advanced auxiliary industry, China's traditional Chinese medicine products cannot compete with foreign products, and the quality cannot be improved. Therefore, the key to the development of traditional Chinese medicine granules is: (1) China should establish its own auxiliary material industrial system, develop more suitable new auxiliary materials, and preferably the compatibility ratio of composite auxiliary materials; (2) New technologies and new equipment should be continuously applied to traditional Chinese medicine granules. To further improve the biopharmaceutical properties of traditional Chinese medicine granules; (3) to develop the development of traditional Chinese medicine unilateral and compound swallowing granules, swallowable granules are easier to swallow than tablets and capsules, and blister-type granules The ratio does not require a lot of water, and the patient is easy to accept.
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