Application technology of oral solid preparation medicinal excipients

Foreword: Pharmaceutical excipients include various excipients and additives, which are important components of pharmaceutical preparations. A pharmaceutical preparation is a general term for a "state" in which a drug is present at the time of medical administration, that is, a "dosage form". It has been compatible with the drug substance and the auxiliary material, and is processed by the formulation technology to be a type of medical product that can be directly applied to the patient. The administration of the drug to the body requires a suitable pharmaceutical dosage form, which can impart the necessary physical or physical chemistry and biological properties of the pharmaceutical dosage form to suit the medical application and ensure therapeutic effects. The dosage form is a complex physical and chemical system composed of drugs and excipients. The location and method of administration and the quality of the product have a great influence on the appearance, strength, speed and duration of the drug. The active drug in the dosage form is a substantial part of the body that determines the overall direction of action. The excipients ensure that the drug is selectively transported to the tissue site in a certain procedure to prevent the drug from being inactivated before being released from the subject, and to release the drug at a certain speed and time in a certain part of the body. All of these factors, combined with appropriate dosing regimens, ensure a certain concentration of drug in the corresponding tissues and body fluids and achieve the desired therapeutic effect. Therefore, the dosage form consisting of suitable excipients has a positive and critical role in the practical application and efficacy of the drug. In order to meet the needs of the continuous development of medical services, formulation production has been developed with the development of dosage forms, excipients and processes. In particular, the development and application of new excipients in recent years have greatly promoted the innovation of dosage forms and new formulations. According to incomplete statistics, nearly one thousand kinds of excipients are actually used in the research and production of preparations at home and abroad, indicating that the research and development and application of excipients have become an important part of the production of modern preparations. In order to make the drug bioavailable, stable, safe and compliant with a wide range of people, it is inseparable from medical requirements, such as excipients, production processes and advanced equipment. Pharmaceutical excipients are the necessary foundation for the development of pharmaceuticals. The rapid development of foreign pharmaceutical preparations is inseparable from the development and rational application of excipients. Therefore, the development and application of a good excipient is more than the development of a new drug variety. Because the rational application of a new auxiliary material can correspond to a large number of dosage forms, a large number of new products, and the quality of a batch of products can be integrated with international products, the economic and social benefits brought about by it cannot be estimated. Under the premise that the development of new drugs is relatively slow and people continue to develop new uses of old drugs, drug research and development has entered the era of preparation, and the Drug Delivery System (DDS) is the main theme of this era. 1 Development and application of oral pharmaceutical excipients at home and abroad World pharmaceutical excipients With the development of polymer materials, the formulation forms are endless, the preparation process and equipment are continuously improved, and the pharmaceutical excipients are also developing rapidly. Currently applied to various dosage forms including slow release formulations, microcapsules, microspheres, inclusions, etc., film coating materials, pharmaceutical carrier materials, solid dispersion carrier materials, surfactants, immediate release preparation materials, gel materials Additives, transdermal absorption materials, mucosal preparation materials and other accessories dozens of types of thousands of varieties. In particular, specialized institutions for research and development of new excipients in developed countries have emerged to develop new materials with various properties. Foreign pharmaceutical excipients include polyethylene glycol series, carbopol series, polyvinylpyrrolidone series, polyoxyethylene alkyl ether series, polyacrylic resin series, polylactide series, polyoxyethylene alkanoate series, etc. Molecular polymer adjuvant; xanthan gum, cyclodextrin, pullulan and other biosynthetic polysaccharide excipients; pregelatinized starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, cellulose series and other semi-synthetic excipients; Plant extracting auxiliary materials such as alginic acid, red alginic acid and carrageenan; and animal extracting auxiliary materials such as chitin and chitin. The variety of excipients has increased dramatically, for example, more than 1,000 kinds of oral pharmaceutical excipients (excluding specifications and models). According to incomplete statistics, more than 300 kinds of new accessories have been developed in the past 10 years, and there are many varieties, many models and all specifications. For example, acrylic resin has dozens of different specifications and types of products. Polyethylene glycol has 33 different specifications, which can fully adapt to the needs of developing new formulations and new formulations, which has effectively promoted the development of the pharmaceutical industry. The advanced countries in the pharmaceutical industry pay special attention to the application research of new excipients, closely combine with the actual production, serve the development of new formulations and new varieties, and improve the quality of products. The main contents include: (1) Studying the physical and chemical properties of new excipients and how they are suitable for the development and production of preparations. (2) Combining oral production equipment and preparation technology to study the compatibility characteristics of excipients and drugs, and obtain the formula of Zuijia auxiliary materials. (3) Carry out research on compatibility between excipients, and combine with the actual production of various countries to design Zuijia composite excipients, such as microcrystalline cellulose and lactose, microcrystalline cellulose and sodium carboxymethyl cellulose. The development trend of pharmaceutical excipients in developed countries is specialized in production, serialized varieties, scientific application, and promoted by multinational companies in all aspects. At present, there are dozens of foreign companies in China that have offices in the country to promote and exchange domestic pharmaceutical preparation plants. This provides new kinds of excipients for domestic preparations, so that foreign medicinal materials that have been registered and listed in China and gradually not produced in China are gradually applied to Chinese medicine. The preparation of the enterprise has improved the current lack of domestic excipients and promoted the further development of the domestic pharmaceutical industry. The application of pharmaceutical excipients in China has a long history. As early as 1766 BC, the world's early pharmaceutical preparations - decoctions were created with water as solvent. Animal glue, honey, starch, vinegar, vegetable oil and animal oil were used as pharmaceutical ingredients. . In 1980, oral solid adjuvants began to be used, including starch, powdered sugar, dextrin, lactose, magnesium stearate and the like. Due to the small variety of excipients, the preparation has the following problems: 1. Poor quality (appearance, hardness, disintegration, dissolution, bioavailability, and poor efficacy). 2. Limit the development of new formulations of new formulations for solid formulations. 3. The traditional accessories are incomplete in specifications and unstable in quality (such as fineness, purity, heavy metals, etc.). Therefore, after the 1980s, under the leadership and support of the State Administration of Medicine, national research institutes, colleges and universities, and production enterprises joined forces to test pharmaceutical auxiliary materials, and applied and promoted new auxiliary materials. Shanghai Pharmaceutical Industry Research Institute first developed a large number of oral solid pharmaceutical excipients, microcrystalline cellulose, calcium sulfate, cellulose acetate cellulose acetate, hydroxypropyl methyl cellulose, direct compression mixed materials, acrylic resin series five products , Polyether F68, etc.; Shanghai Glucose Factory produced corn    谆矸勰 谆矸勰 挥 蜓粢┭ 蜓粢┭ 嚎 嚎 嚎 嚎 嗽そ夯矸郏绰迳 嗽そ夯矸郏绰迳 嗽そ夯矸郏绰迳 嗽そ夯矸郏绰迳 嗽そ夯矸郏绰迳 盗 盗 盗 盗 盗 盗 盗 盗 盗 盗 盗 盗Э(5)苏崽invading the leg of the (宋兀一宋兀úǎT逅崮 fatigue?/SPAN>β-cyclodextrin, cetyl alcohol , octadecyl alcohol, edible aluminum lake, titanium dioxide, stevia and so on, a total of dozens of new accessories are on the market. In particular, the premixing of film coating materials (Shanghai Pharmaceutical Industry Research Institute Pu Li Membrane Preparation Materials Technology Co., Ltd., Ailiyi Company, etc.) led to the application of film coating technology, and various oral solid preparation products improved the quality of sugar coatings. The problem of adhesion, mold, large pieces, a large number of applications of talcum powder, quality decline, etc. caused a large proportion of returns. Due to the large-scale promotion of film coating technology, it has greatly promoted new varieties, new processes and new dosage forms, resulting in huge economic and social benefits. However, how to closely combine the application research of new excipients with actual production, to serve new varieties of new formulations, and to improve product quality, has become an important direction for the development of pharmaceutical excipients. The development trend of pharmaceutical excipients is “production specialization”, “variety serialization” and “application scientificization”. This is the significance of research and development of new excipients. 2 The choice of pharmaceutical excipients in oral solid preparations can be roughly divided into fillers, binders, disintegrators, lubricants, glidants, pressurizers, effervescent agents, and surfactants according to the different functions of the excipients used in solid preparations. Agents, film formers, toners, flavoring agents, preservatives, dispersing agents, fragrances, and the like. To make the desired solid preparation, reasonable choice of pharmaceutical excipients requires comprehensive consideration from the following aspects: 2.1 It is necessary to understand the performance, function, quality specifications, stability, incompatibility, etc. of pharmaceutical excipients. It has application content. Such as the hygroscopicity of the excipients, compatibility with drugs, fluidity, solubility, viscosity, etc. 2.2 It is necessary to understand the nature of the drug (physical chemistry, biology, etc.). Such as the polymorphic form of the drug, sensitivity to heat, humidity, light, pH, solubility, stability in vitro and in vivo. 2.3 Selection of pharmaceutical excipients according to the process of formulation research and development These preparation processes mainly include direct compression, wet granulation, dry pressing, fluidized bed granulation, coating, spray granulation and the like. Different production processes require the selection of suitable excipients. 2.4 The dose of the drug is generally divided into high dose and low dose. For high doses, such as some tablets, the problem usually is that the high dose of the drug and the necessary excipients make the film too large and do not meet the requirements. This requires the selection of superior excipients to reduce the amount of excipients. . For low doses, the uniformity of the trace drug in the formulation is a big problem. According to reports, Germany's JRS new product PROSOLV can better solve this problem. PROSOLV is a patented new high-functionality excipient that combines microcrystalline cellulose with colloidal silica to provide good flow, compressibility and drug dispersion. It produces a good content uniformity. Sexual small tablets. This product has been approved by the FDA, EU and Japanese drug review authorities. 2.5 Dosage forms such as tablets, capsules, granules, powders, pellets, dropping pills, etc. 2.6 Drug release characteristics such as immediate release, sustained release, controlled release (timing, positioning). According to the above requirements, then comprehensive consideration of the selection of reasonable excipients, prescription processes and other programs. However, understanding the performance of excipients and thinking about application development are the primary conditions. For example, lactose, which is generally used as a filler for tablets and capsules, has many other uses. There are three forms of lactose: alpha-anhydrous, alpha-monohydrate (also known as alpha lactose), beta-anhydrous (also known as beta lactose). BP lactose is α-monohydrate, and NF refers to both forms of anhydrous. Commercial lactose is mainly alpha-monohydrate. Spray dried lactose contains a portion of the amorphous material. Beta lactose is slightly sweeter and more soluble than alpha, and is only anhydrous. Hygroscopicity: Monohydrate lactose is slightly affected by air humidity at room temperature. The anhydrous lactose can be changed to monohydrate lactose at a relative humidity of 70%. Anhydrous lactose contains about 1% of water, 0.1%-0.2% of adsorbed water, while monohydrated lactose contains about 5% of crystal water, 0.1% of adsorbed water, and drying at 80 °C can only remove adsorbed water. Its application is: 2.6.1 Solid preparation: As a filler and excipient, the compressibility is good, and the fine granules can be used for wet granulation. 2.6.2 Used as an adsorbent to make the poorly soluble drug adsorb to lactose, dissolve it in the solvent, and increase the dissolution and bioavailability of the drug. 2.6.3 Lactose can be colored into a fine powder and then compressed to stabilize the color of the tablet. 2.6.4 Dry pressing process using anhydrous lactose. 2.6.5 Film coating. 2.6.6 Freeze-dried products. HPMC is also available in a variety of sizes and viscosities, and its application functions are quite different. Low viscosity (5 cps, 15 cps, 50 cps) HPMC can be used as a binder for film-coated film formers and tablets, in amounts of 2-10% and 2-5%, respectively. High viscosity (4000 cps, 15000 cps, etc.) HPMC can be used as a sustained release material to retard the release of water-soluble drugs; used as a thickener for eye drops and artificial tears, in an amount of 0.45-1.0%; colloidal protective agent to prevent Production of coalesced particles and gels; as an emulsifier for gels and ointments; suspensions and stabilizers; adhesives in plastic bandages. Due to different drug varieties, various dosage forms can be prepared, various models can be selected, and different solvents can be formulated into different concentrations. The use of the auxiliary materials can be continuously innovated, and the performance can be fully utilized to improve the quality of the preparation. 3 Application of new auxiliary materials in new drug preparations The purpose of developing new materials is application. The application is the core of the development of auxiliary materials. After the development of a new auxiliary material, more research is needed on application technology to promote the development of auxiliary materials and processes and equipment. Push each other. Therefore, in the application of specific varieties, it is necessary to conduct research on the properties of materials and the compatibility of various drugs, research on excipient formulations and processes and equipment. The application of the process can promote the development of a variety of new dosage forms, especially the development of DDS formulations. 3.1 Pharmaceutical excipients and controlled release preparations In recent years, the development of polymer materials has promoted the preparation of slow-release preparations and the development of new varieties. Oral controlled release preparations have more than ten different types of sustained release dosage forms, such as skeleton type, coating type, sustained release pellets, capsules, multi-layer sustained release tablets and sustained release of pharmaceutical resins. 3.1.1 Skeletal sustained-release preparations (especially tablets) Most can be prepared by conventional production equipment and processes, with high degree of mechanization, low cost and stable quality. 3.1.1.1 Insoluble skeleton sustained-release tablets There are many methods for preparing water-insoluble skeleton sustained-release tablets. Commonly used materials are ethyl cellulose, polyethylene, acrylic resin, ethylene-vinyl acetate copolymer and the like. Since the rate of release of poorly soluble drugs from the skeleton is too slow, water-soluble drugs are more suitable for such sustained-release tablets. For example, ethyl cellulose with low viscosity grade, indomethacin and theophylline can be directly compressed after being dry mixed with a small amount of lubricant. 3.1.1.2 Erosive Skeletal Sustained Release Tablets This tablet is made into a tablet with an inert fat and wax matrix as a matrix material, and the drug is released by fat or waxy gradual dissolution, pH value, digestive enzyme pair The rate of hydrolysis of fatty acid esters has a certain effect. Commonly used materials are: beeswax, hydrogenated vegetable oil, stearic acid, polyethylene glycol, carnauba wax, glyceryl stearate, propylene glycol stearate and stearyl alcohol. Commonly used porogens are microcrystalline cellulose, PVP, PEG1500, PEG4000, PEG6000 and water-soluble surfactants. The preparation process uses a coagulation method and a water dispersion method. 3.1.1.3 Hydrophilic gel skeleton sustained-release tablets The sustained-release tablets are made of a hydrophilic polymer as a skeleton material, and the preparation method thereof is relatively simple. The drug, the skeleton material and the appropriate amount of the auxiliary material are uniformly mixed and granulated, and compressed into tablets. The prepared sustained-release tablets are orally expanded in the digestive juice of the gastrointestinal tract to form a gel, which prolongs the release time. The release of this type of drug is less affected by physiological factors of the gastrointestinal tract, pH and peristaltic velocity. Hydrophilic gel matrix materials can be classified into four categories: cellulose derivatives, non-cellulosic polysaccharides, natural gums and vinyl polymers, and acrylic polymers. 3.1.1.4 Intragastric Retention Tablets This technology allows tablets to stay in the stomach to prolong drug release time, improve drug absorption, and improve bioavailability agents. It has a skeleton release property and can be regarded as a special matrix sheet. The tablet is an oral tablet prepared from a drug and a hydrophilic colloid and other auxiliary materials, and is a hydrodynamically balanced preparation, also known as a gastric floating tablet. The gastric retention film has the following characteristics: 3.1.1.4.1 After the tablet contacts the gastric juice, it forms a gel barrier film on the surface at body temperature and expands to maintain the shape of the original tablet; 3.1.1.4.2 The composition of the tablet is favorable for Retention in the stomach; 3.1.1.4.3 The nature, dosage and excipients of the main drug can meet the requirements of in vitro and in vivo drug release requirements of the gastric retention tablets, which can be slowly dissolved and spread, and maintained in the stomach for a long time. Can reach 5-6 hours; 3.1.1.4.4 Strong drug activity, small dosage range; 3.1.1.4.5 Drugs that are stable under acidic conditions and easy to dissolve under acidic conditions, such as norfloxacin, diltiazem, etc. 3.1.1.4.6 Gastric acid secretion inhibitors, such as ranitidine, etc.; 3.1.1.4.7 Gastric treatment drugs, such as certain drugs, play a role in the treatment of gastroenteritis by inhibiting Helicobacter pylori in the gastric mucosa, such as Furazolidone; 3.1.1.4.8 Continuous absorption in the gastrointestinal tract, such as absorption of Zuijia B2 in the upper part of the small intestine; 3.1.1.4.9 Short half-life, other sustained release methods can not meet the requirements of the drug. Applicable materials are hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, etc., also combined with PVP and PVA, or HPMC, PVP and PVA, can also be used Wax-based dissolution type lightweight material.

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