Transcript chapter 6
6. Capsules Characters 1) orally, conveniently carried, readily identified, and easily taken 2) compared with equivalent doses of a liquid medication, accurate dosing, most tasteless when swallowed 3) readily identified 4) Prescribing flexibility (a variety of dosage strengths) 5) from a pharmaceutic standpoint, solid dosage forms are • efficiently and productively manufactured • packaged and shipped by manufacturers at lower cost and with less breakage than comparable liquid forms • more stable, have a longer shelf-life than their liquid counterparts. I. Capsules 1. Hard gelatin capsules 2. Soft gelatin capsules 3. Compendial requirements for capsules 4. Official and commercially available capsules 5. Inspecting, counting, packaging, and storing capsules Capsules are solid dosage forms in which medicinal agents and/or inert substances are enclosed in a small shell of gelatin. Gelatin capsule shells may be hard or soft, depending on their composition. 1. Hard gelatin capsules • Hard gelatin capsule shells are used in most commercial medicated capsules. • The empty capsule shells are made of gelatin, sugar, and water. • They can be clear, colorless, and essentially tasteless; or they may be colored with various dyes. • Most commercially available medicated capsules contain combinations of colorants and opaquants to make them distinctive, many with caps and bodies of different colors. • Gelatin is obtained by the partial hydrolysis of collagen obtained from the skin, white connective tissue, and bones of animals. • It is desirable to maintain hard gelatin capsules in an environment free from excessive humidity or dryness. • Many capsules are packaged along with a small packet of a desiccant material to protect against the absorption of atmospheric moisture. The desiccant materials most used are dried silica gel, clay, and activated charcoal. • A number of methods have been developed to track the passage of capsules and tablets through the gastrointestinal tract to map their transit time and drug release patterns. • Among these is gamma scintigraphy, a noninvasive procedure that entails use of a gamma ray-emitting radiotracer incorporated into the formulation with a gamma camera coupled to a data recording system. When scintigraph is combined with pharmacokinetic studies, the resultant pharmacoscintographic evaluation provides information about the transit and drug release patterns of the dosage form as well as the rate of drug absorption from the various regions of the gastrointestinal tract. This method is particularly useful in (a) determining whether a correlation exists between in vitro and in vivo bioavailability for immediate-release products, (b)assessing the integrity and transit time of enteric coated tablets through the stomach en route to the intestines, (c) drug and dosage form evaluation in new product development. 1) The manufacture of hard gelatin capsule shells • Hard gelatin capsule shells are manufactured in two sections, the capsule body and a shorter cap. • The shells are produced industrially by the mechanical dipping of pins or pegs of the desired shape and diameter into a temperature-controlled reservoir of melted gelatin mixture. • The pegs submerged to the desired depth and maintained for the desired period to achieve the proper length and thickness of coating. • The pegs are slowly lifted from the bath and the gelatin dried by a gentle flow of temperature- and humidity-controlled air. • When dried, each capsule part trimmed mechanically to the proper length and removed from the pegs, and the capsule bodies and caps are joined together. 空胶囊的制备工艺： • 溶胶 蘸胶 干燥 拔壳 切割 整理 • 一般由自动化生产线完成，生产环境洁 净度应达10000级，温度1025C，相对 湿度3545%。 2) Capsule sizes • Empty gelatin capsules are manufactured in various lengths, diameters, and capacities. • The size selected for use is determined by the amount of fill material to be encapsulated. • The density and compressibility of the fill will largely determine to what extent it may be packed into a capsule shell. 3) Preparation of filled hard gelatin capsules • Developing and preparing the formulation and selecting the size capsule • Filling the capsule shells • Capsule sealing (optional) • Cleaning and polishing the filled capsules 4) Developing the formulation and selection of capsule size In developing a capsule formulation, the goal is to prepare a capsule with • accurate dosage, • good bioavailability, • ease of filling and production, stability, and elegance. • In dry formulations, the active and inactive components must be blended thoroughly to ensure a uniform powder mix for the fill. • A diluent or filler (lactose, microcrystalline cellulose and starch) may be added to the formulation to produce the proper capsule fill volume. • Disintegrants (pregelatinized starch, croscarmellose 交 联 羟 甲 纤 维 素 , and sodium starch glycolate 羟 基 乙 酸 淀 粉 钠 ) are frequently included in a capsule formulation to assist the breakup and distribution of the capsule’s contents in the stomach. • To achieve uniform drug distribution, it is advantageous if the density and particle size of the drug and nondrug components are similar. • The addition of a lubricant or glidant such as fumed silicon dioxide, magnesium stearate, calcium stearate, stearic acid, or talc (about 0.25-1%) to the powder mix enhances flow properties. • A surface-active agent, such as sodium lauryl sulfate（硫酸月桂醇钠）, is used to facilitate wetting by the gastrointestinal fluids. • Gelatin aqueous gelatin resulting capsules are unsuitable for liquids because water softens and distorts the capsules, in leakage of the contents. • A liquid may be mixed with an inert powder to make a wet mass or paste, which may then be placed in capsules in the usual manner. • Eutectic mixtures of drugs, or mixtures of agents that have a propensity to liquefy when admixed, may be mixed with a diluent or absorbent to separate the interacting agents and to absorb any liquefied material that may form. 药物的填充 胶囊内容物的配方研究 1）粉末的流动性 粉末流动性会影响到装量的准确性，流动 性差针晶或引湿性粉末，可加适量润滑剂、 助流剂。用量0.1%. 2）粉末的分散与湿润 疏水性药物遇体液时会结块，加惰性亲水 性辅料如甲基纤维素，可增加药物的分散 与湿润性，从而提高生物利用度。 3）药物的释放 难溶性药物，粒径减少可增加药物的溶出。 但有些药物粒径小的粉末由于空隙小，液体 不易渗入。加表面活性剂或亲水性辅料，加 速药物的溶出。 4）液体、半固体药物的填装 - 用于填充液体或半固体类药物的胶囊应采用 锁口胶囊； - 液体药物以可选用适当的辅料，制成糊状物， 用泵压法填充。 选择辅料的基本原则是： 1）不与主药发生物理、化学变化； 2）与主药混合后具有较好的流动性； 3）遇水后具有一定分散性，不会粘结成团而 影响药物的溶出。 The selection of the capsule size • Hard gelatin capsules are used to encapsulate between about 65 mg and 1 g of powdered material. • The smallest capsule (No. 5) may be expected to hold 65 mg of powder or more, depending on the characteristics of the powder substance. An example of commercially available capsule: • Active ingredient: tetracycline hydrochloride 250 mg • Filler: lactose • Lubricant/glidant: magnesium stearate • Capsule colorants: FD&C Yellow No. 6 • Capsule opaquant: Titanium dioxide 5) Filling hard capsule shells 填充药物有手工法和自动填充机法两种： 1）手工填充法 药尘飞扬严重，装量误差大，生产效率低。 2）自动填充机法： a. 螺旋钻压进药物 b. 栓塞上下往复将药物压进 c. 药粉自由流动，要求物料具有良好的流动 性，常需制粒才能达到。 d. 由捣棒在填充管内先将药物压成一定量后 再填充于胶囊中，适用于聚集性较强的针 状结晶或吸湿性药物。 6) Capsule sealing • Sealed with gelatin • Sealed through a heat welding process that fuses the capsule cap to the body through the double wall thickness at their juncture • Utilized a melting-point-lowering liquid wetting agent in the contact areas of the capsule’s cap and body and then thermally bonds the two parts using low temperatures (40-45C). 7) Cleaning and polishing capsules • On a small scale, capsules may be cleaned individually or in small numbers by rubbing them with a clean gauze or cloth. • On a large scale, many capsule-filling machines are affixed with a cleaning vacuum that removes any extraneous material from the capsules as they exit the equipment. 2. Soft gelatin capsules • Soft gelatin capsules are made of gelatin to which glycerin or a polyhydric alcohol such as sorbitol has been added. • Soft gelatin capsules, which contain more moisture than hard capsules, may have a preservative, such as methylparaben and/or propylparaben, to retard microbial growth. • Soft gelatin capsules may be oblong, oval, or round. 软胶囊剂的主要特点有： - 装量均匀准确 - 软胶囊完全密封，其厚度可防氧进入； 挥发性药物，遇空气容易变质的药物 - 适合盛装难以压片或贮存中会变形的低熔 点固体药物 - 药物溶解或分散在可与水混溶的溶剂或油 状液体后再装胶囊，这样药物分散面大， 生物利用度也高。 1) Preparation of soft gelatin capsules Soft gelatin capsules may be prepared • by the plate process, using a set of molds to form the capsules. • by the rotary（旋转） or reciprocating（往返 式） die processes by which they are produced, filled, and sealed in a continuous operation. • Most soft gelatin capsules are prepared by the rotary die process. By the plate process, 1) A warm sheet of plain or colored gelatin is placed on the bottom plate of the mold and the liquid-containing medication is evenly poured on it. 2) A second sheet of gelatin is carefully placed on top of the medication and the top plate of the mold is put into place. 3) Pressure is then applied to the mold to form, fill, and seal the capsules simultaneously 4) The capsules are removed and washed with a solvent harmless to the capsules. By the rotary die process, 1) Liquid gelatin flowing from an overhead tank is formed into two continuous ribbons by the rotary die machine and brought together between twin rotating dies. 2) At the same time, metered fill material is injected between the ribbons precisely at the moment that the dies form pockets of the gelatin ribbons. 3) These pockets of fill-containing gelatin are sealed by pressure and heat and then severed from the ribbon. 4) Use of ribbons of two different colors results in bicolored capsules. The reciprocating die process is similar to the rotary process in that ribbons of gelatin are formed and used to encapsulate the fill, but it differs in the actual encapsulating process. 1) The gelatin ribbons are fed between a set of vertical dies that continually open and close to form rows of pockets in the gelatin ribbons. 2) These pockets are filled with the medication and are sealed, shaped, and cut out of the films. 3) As the capsules are cut from the ribbons, they fall into refrigerated tanks which prevent the capsules from adhering to one another. 软胶囊剂的生产工艺 1、滴制法： 系将明胶溶液与油状药物通过滴丸机的喷 头使夹层内的两种液体按不同速度喷出， 这样，外层明胶液将定量的内层油状液包 裹后，滴入另一种不相混溶的冷却液中， 明胶液在冷却液中因表面张力作用而形成 球形，并逐渐凝固成球形软胶囊剂。 滴制法制备软胶囊剂的生产工艺流程： （1）胶液的准备 明胶 加热至7080C 水和甘油 混匀 熔融 保温过滤 保温12小时 待用 （2）药液的提取或炼制 （3）制胶丸 将药液明胶液经滴丸机特制的喷头滴入冷却液中， 由收集器收集而成。 ①明胶的处方 明胶:甘油:水为1:(0.30.4):(0.71.4)为宜。 ②液体的密度 一定的沉降速度和足够的冷却成型时间 制备鱼肝油胶丸时，药液:胶液:冷却液 =0.9g/ml:1.12g/ml:0.86g/ml。 ③温度 胶液和药液均应保持在60C，喷头处应 保持在80C，冷却液为1317C。 （4）整丸与干燥 纱布 室温冷风干燥 制得的胶丸 3035C烘干 水份达到12%15% 石油醚洗涤两次 95%乙醇洗涤一次 （5）检查与包装 2、压制法 将明胶、甘油、水等溶解后制成胶皮，再 将药物置于两块胶皮之间，用钢模压制而 成。 2) Utilization of soft gelatin capsules • Soft gelatin capsules are prepared to contain a variety of liquid, paste, and dry fills. • Liquids that may be encapsulated into soft gelatin capsules include the following: - water-immiscible volatile and nonvolatile liquids such as vegetable and aromatic oils, aromatic and aliphatic hydrocarbons, chlorinated hydrocarbons, ethers, esters, alcohols and organic acids. - water-miscible, nonvolatile liquids, such as polyethylene glycols, and nonionic surface active agents as polysorbate 80. - water-miscible and relatively nonvolatile compounds, as propylene glycol and isopropyl alcohol, depending on factors as concentration used and packaging conditions. • Liquids are not suitable for soft gelatin capsules. These materials include - water above 5% - low molecular weight water-soluble and volatile organic compounds such as alcohols, ketones, acids, amines, and esters. 3. Compendial requirements for capsules 1) Requirements for added substances - Harmless - Do not impair the product’s bioavailability, therapeutic efficacy or safety - Do not interfere with requisite compendial assays and tests - Do not exceed the minimum amounts required to provide their intended effect 2) Containers for dispensing capsules The container may be required to be tight, well-closed, and light resistant. 3) Disintegration tests for capsules The capsules are placed in the basket rack assembly, which is immersed 30 times per minute into a thermostatically controlled fluid at 37C. The capsules disintegrate completely into a soft mass. 4) Dissolution test for capsules The dissolution test for capsules uses the same apparatus, dissolution medium, and test as that for uncoated and plain coated tablets. 5) Weight variation The uniformity of dosage units may be demonstrated by determining weight variation and/or content uniformity. - hard capsules - Soft capsules HARD CAPSULES: • Ten capsules are individually weighed and the contents removed. • The emptied shells are individually weighed and the net weight of the contents calculated by subtraction. • From the results of an assay performed as directed in the indidual monograph, the content of active ingredient in each of the capsules is determined. SOFT CAPSULES: • The gross weight of 10 intact capsules is determined individually. • Each capsule is cut open with a scissors or a sharp open blade, and the contents removed by washing with a suitable solvent. • The solvent is allowed to evaporate at room temperature over a period of about 30 minutes, taking precautions to avoid uptake or loss of moisture. • The individual shells are weighed and the net contents calculated. • From the results of the assay directed in the individual monograph, the content of active ingredient in each of the capsules is determined. 6) Content uniformity - The amount of active ingredient, determined by assay, is within the range of 85% to 115% of the label claim for 9 of 10 dosage units assayed, with no unit outside the range of 70% to 125% of label claim. - Additional tests are prescribed when two or three dosage units are outside of the desired range but within the stated extremes. 7) Content labeling requirement All official capsules must be labeled to express the quantity of each active ingredient in each dosage unit. 8) Stability testing Stability testing of capsules is performed to determine - the intrinsic stability of the active drug molecule, - the influence of environmental factors as - temperature, - humidity, - light, - formulative compounds - the containers/closure system. The battery of • stress testing, • long-term stability • and accelerated stability tests help determine the appropriate conditions for storage and the product’s anticipated shelf-life. 9) Moisture permeation test The degree and rate of moisturepenetration of containers are determined - by packaging the dosage unit together with a color-revealing desiccant pellet, - exposing the packaged unit to known relative humidity over a specified time, - observing the desiccant pellet for color change (indicating absorption of moisture) - comparing the pre- and post-weight of the packaged unit. 胶囊剂的质量检查与包装贮存 1、质量检查 胶囊剂的质量应符合《中国药典》2005 年版二部附录I “制剂通则”项下对胶囊 剂的要求： 1）外观 胶囊剂外观应整洁，不得有粘结、变形、 渗漏或囊壳破裂现象，并应无异臭。 2） 装量差异 胶囊剂装量差异，应符合下列规定 平均装量 装量差异限度 0.30g 以下 10% 0.30g 及0.30g以上 7.5% 检查法 • 取供试品20粒，分别精密称定重量后，倾出内 容物（不得损失囊壳），硬胶囊用小刷或其他 适宜用具试净，软胶囊用乙醚等易挥发性溶剂 洗净，置通风处使溶剂自然挥尽，再分别精密 称定囊壳重量，求出每粒内容物的装量与平均 装量。 • 每粒的装量与平均装量相比较，超出装量差异 限度的不得多于2粒，并不得有一粒超出限度 一倍。 • 凡规定检查含量均匀度的胶囊剂，可不进行装 量差异的检查。 3）崩解时限 • 取供试品6粒，按《中国药典》2005年版 二部附录XA进行崩解时限检查（如胶囊 浮于液面，可加挡板）。 • 硬胶囊应在30min内全部崩解，软胶囊应 在1h内全部崩解。 • 如有一粒不能完全崩解，应另取6粒复试， 均应符合规定。 2）包装和储存 • 一般来说，高温、高湿（相对湿度60%） 对胶囊剂可产生不良的影响，不仅会使 胶囊吸湿、软化、变粘、膨胀、内容物 结团，而且会造成微生物滋生。 • 一般应选用密封性能良好的玻璃容器、 透湿系数小的塑料容器和泡罩式包装， 在<25C、相对湿度<60%的干燥阴凉处， 密闭贮藏。 4. Official and commercially available capsules • There are approximately 200 officially recognized medications in capsule form in the USP. • However commercially, there are many fold this number of capsule products available from various manufactures for various drugs and in various dosage strengths. 5. Inspecting, packaging and storing capsules • Capsules produced on a small or large scale should be uniform in appearance. • Visual or electronic inspection should be undertaken to detect any flaws in the integrity and appearance of the capsules. • Capsules are packaged in glass or in plastic containers, some containing packets of a desiccant to prevent the absorption of excessive moisture. • Capsules should be stored in tightly capped containers in a cool, dry place. Questions 1．How to manufacture the hard gelatin capsules？ 2．How to select the hard gelatin capsule sizes？ 3．Describe the preparation of filled hard gelatin capsules? 4．How to prepare soft gelatin capsules? 5．How many compendial requirements for capsule？simply describe them.