1、Biopharmaceutics (Biopharmacy) Chapter 1 Introduction Branches of pharmaceutics Physical pharmaceutics Industry pharmaceutics Biopharmaceutics Clinical pharmaceutics I. Concept Study on the process of absorption, distribution, metabolism and excretion of drug and its dosage form in vivo. to state a
2、relationship between the factor of biology and dosage form and the pharmacologic effect of drug to provide scientific basis for evaluation of quality of the drug preparation and design and use of drug products rationally 1. Factors of dosage form Type of drug Physical and chemical properties of drug
3、 Dosage form and administration of drug The nature of excipients and additives and the dose of drug The technological process and operation conditions of preparation Incompatibility and interaction between drugs Type of drug i.e. ester, salt, complex, derivative and so on e.g. The solubility of sodi
4、um tolbutamide (甲磺丁脲钠甲磺丁脲钠)is better than that of tolbutamide. The pharmacologic effect is either. Physical and chemical properties of drug i.e. diameter of particle, crystal form, solubility, dissolution rate and so on Dissolution is the process by which a chemical or drug becomes dissolved in a so
5、lvent Lots of facts have proved that the dissolution rate of tablets influences the absorption and clinical therapeutic effect. At the present, the pharmacopeia of China and many other countries all have requirement of dissolution rate for solid preparations such as tablets or capsules. e.g. convent
6、ion tablets micronized tablets solid dispersion (pills) Griseofulvin (灰黄霉素灰黄霉素) Dosage form and administration of drug i.e. tablets, capsules, injections, transdermal therapeutic system (TTS) and so on. e.g. the therapeutic effect of injections is faster than that of tablets. Because the former was
7、absorbed rapidly to the blood systemic circulation. The nature of excipients and additives and the dose of drug e.g. The fillers of phenytoin sodium (苯妥英钠苯妥英钠)capsules, calcium sulphate or lactose The technological process and operation conditions of preparation e.g. Preparation for chloramphenicol
8、palmitate, heating is effective and formulating in cold solvent is ineffective. Incompatibility and interaction between drugs e.g. SMZ + TMP: antibacterial effect is enhanced Warfarin + butazolidn : bleeding (side effect) 2. Biological factor Differences in race, sex and age Differences in physiolog
9、ic and pathological conditions 3. Pharmacologic effect of drug Therapeutic effect Side effect and Toxicity II. Differences from relative subjects Pharmacology Study on the mode of action and mechanism of drugs in vivo. Biochemistry Study on the biochemical process of drugs in vivo. III. History of b
10、iopharmaceutics the main action of a drug depends on its chemical structure pharmacologic effect of a drug related not only to its chemical structure but also to dosage form and biologic factors Dissolution rate is a quality index in vitro Bioavailability is a quality index in vivo The founder in fo
11、reign country Kruger Thiemer, E. Nelson, J.G. Wagner, J. Levy, M. Gibaldi, T. L. Loo, 内藤俊一内藤俊一, 村田敏村田敏 郎郎, 野上寿野上寿, 褂见喜一等。褂见喜一等。 In our country, China Pharmaceutical University conducted a training class of biopharmaceutics in 1978. IV. Experiment design of biopharmaceutics Theory basis Experimental
12、process Experiment Animal Theory basis Pharmacokinetics study on the transport law of drug in vivo by means of the fundamentals of kinetics and mathematics Experimental process Analyze blood concentration urine concentration metabolite concentration concentration in tissue, organ and fluid Determina
13、tion of bioavailability Analysis methods Ultraviolet spectrometry ( UV ) Fluoro spectrophotometry Nuclear magnetic resonance spectroscopy Flame photometer Thin-layer chromatography (TLC) Isotope label method Experiment Animal Mammilla (哺乳动物哺乳动物) includes rat (mice), rabbit, dog, pig, row, monkey and
14、 so on Human body V. Research Work Dissolution rate and Bioavailability of solid dosage Design sustained-release and controlled- release preparations dependence of physiological function The fate of particles delivery system in systemic circulation. New administration way and method Dissolution rate
15、 and Bioavailability of traditional Chinese medicine preparations Research method of biopharmaceutics LOGO Drug Absorption Chapter 2 LOGO I. Concept and content A transport process of active drug from administration sites to the systemic circulation. LOGO II. Gastrointestinal Absorption LOGO 1.Natur
16、e of the epithelial cell membrane 膜的组成膜的组成 膜的基本骨架膜的基本骨架 膜的性质膜的性质 Cell Membrane Proteins Lipid - polar head-group Lipid - Neutral hydrocarbon chain Extracellular Cytosol LOGO 膜的组成膜的组成 类脂、蛋白质和少量多糖类脂、蛋白质和少量多糖 LOGO 膜的基本骨架膜的基本骨架 由流动的液态类脂双分子层所由流动的液态类脂双分子层所 组成组成 脂质分子的极性部分向外，非脂质分子的极性部分向外，非 极性部分向内，外侧为蛋白质极性部分
17、向内，外侧为蛋白质 覆盖，膜上含有细孔，水分子覆盖，膜上含有细孔，水分子 能自由通过能自由通过 LOGO 膜上的蛋白质，具有生理功能，根据其在脂质双膜上的蛋白质，具有生理功能，根据其在脂质双 分子层的不同位置可分为：分子层的不同位置可分为： 外在性蛋白，如外在性蛋白，如ATP酶、己糖激酶等酶、己糖激酶等 内在性蛋白内在性蛋白,如细胞色素如细胞色素C、药物的受体、特异、药物的受体、特异 性载体等性载体等 LOGO 膜的性质膜的性质 选择性的屏障，生命所需要的物质如，选择性的屏障，生命所需要的物质如，AA、糖类、脂肪、糖类、脂肪 酸等易通过酸等易通过 细胞膜的分子间及蛋白质的分子内存在细微含水孔道
18、细胞膜的分子间及蛋白质的分子内存在细微含水孔道 为半渗透性膜，具有半透膜和双电层的性质，水和脂溶为半渗透性膜，具有半透膜和双电层的性质，水和脂溶 性物质可通过，高度解离的分子和大分子如蛋白质和蛋性物质可通过，高度解离的分子和大分子如蛋白质和蛋 白结合的药物不能通过。白结合的药物不能通过。 LOGO Henderson Hasselbalch Equation For weak acids -to describe the relationship between pKa and pH For weak bases LOGO 2Passage of drugs across cell membr
19、anes Passive Diffusion Active Transport Facilitated diffusion Vesicular Transport Pore (Convective) Transport Ion Pair Formation and Transport + - Cell Diffusion Neutral Molecules Charged Molecules + - - + - + + - Bulk Flow Ion Pair Endocytosis Carrier Mediated (active and facilitated) + - Mechanism
20、s of transport across membranes LOGO Passive Diffusion（被动扩散） Passive diffusion is a process by which molecules spontaneously diffuse from a region of higher conc. to a region of lower conc. LOGO 药物的细胞转运途径：被动扩散药物的细胞转运途径：被动扩散 LOGO Ficks law of diffusion dQ/dt = DAK (CGI- CP) /h dQ/dt = rate of diffusi
21、on（扩散速度） D = diffusion coefficient（扩散系数） K = partition coefficient（分配系数） A = surface area of membrane（膜的表面积） h = membrane thickness（膜的厚度） CGI- CP = difference between the conc. of drug in the gastrointestinal tract and in the plasma （药物在胃肠道与血液之间的差异） LOGO PH-partition hypotheses describes the relatio
22、nship of the rate of drug transport with the extent of ionization and lipid soluble property of drug LOGO Active Transport（主动转运） Active transport is a transport process of drug against a concentration gradientthat is, from regions of low drug conc. to regions of high conc. LOGO LOGO 一些机体必需的物质如，氨基一些机
23、体必需的物质如，氨基 酸，单糖，酸，单糖，Na+, K+及某些及某些 维生素等的吸收通过此方式完维生素等的吸收通过此方式完 成。成。 主动转运：钠、钾泵排放主动转运：钠、钾泵排放 LOGO Characteristics It is an energy-consuming system. It is a specialized process requiring a carrier. Drug of similar structure may compete for sites of absorption on the carrier. Because only a certain amoun
24、t of carrier is available, all the absorption sites on the carrier may become saturated if the drug conc. gets very high. LOGO 被动转运与主动转运比较被动转运与主动转运比较 LOGO Facilitated diffusion（促进扩散或易化扩散） Facilitated diffusion is also a carrier-mediated transport system, differing from active transport in that the d
25、rug moves along a conc. gradient LOGO 非脂溶性或亲水性药物如，非脂溶性或亲水性药物如，L- 赖氨酸赖氨酸,D-木糖木糖,葡萄糖等葡萄糖等 通通 过此方式转运。过此方式转运。 LOGO Characteristics This system does not require energy input. Because this system is carrier mediated, it may be saturated. Competition kinetics for drugs of similar structure. LOGO Vesicular
26、Transport（胞饮作用或囊泡转运） Vesicular Transport is a process of engulfing particles or dissolved materials by the cell. LOGO Pinocytosis and phagocytosis are forms of vesicular transport that differ by the type of material ingested. 一些高分子物质如蛋白质、 甘油三酸酯等通过此方式 转运。 LOGO Pinocytosis （胞饮）（胞饮）refers to the engulf
27、ment of small solutes or fluid Phagocytosis （吞噬）（吞噬） refers to the engulfment of larger particles or macromolecules generally by macrophages LOGO Pore (Convective) Transport微孔(传递)转运 Very small molecules (such as urea, water, and sugars) are able to rapidly cross cell membranes as if the membrane con
28、tained channels or pores. 水、乙醇、尿素等通过此方式转运 LOGO Ion Pair Formation and Transport(离子对转运) When highly ionized or charged molecules linked up with an oppositely charged ion, an ion pair is formed in which the overall charge of the pair is neutral. The neutral complex diffuses more easily by passive diff
29、usion across the membrane. LOGO 季铵盐、磺酸、吗啡衍生物等季铵盐、磺酸、吗啡衍生物等 通过此方式转运。通过此方式转运。 LOGO 3.Influence Factors for Drug Absorption Anatomic and Physiologic factors Pharmaceutical factors (剂 型因素) LOGO Anatomic and Physiologic factors pH and surface area of absorption Gastric Emptying Rate （胃空（胃空 速率）速率） Effect
30、of Food Intestinal Motility (小肠运动小肠运动) Perfusion of the Gastrointestinal tract (胃肠道胃肠道 的血液灌注的血液灌注) LOGO pH and surface area of absorption Stomach (胃) provides a small surface area of absorption. The fasting pH is about 2 to 6. In the presence of food, the pH is about 1.5 to 2 Duodenum（十二指肠） provides
31、 a large surface area because of the presence of villi and microvilli. The pH is about 5 to 6. LOGO Ileum (回肠) is the terminal part of the small intestine. The pH is about 7. Colon (结肠) lacks microvilli and is very limited in drug absorption. The pH in this region is about 7. Rectum (大肠) is limited
32、in drug absorption. The pH is about 7 to 8. 胃肠道生理因素对药物吸收的影响 LOGO 被动扩散的药物可以在消化道的各被动扩散的药物可以在消化道的各 个部分包括舌下、口腔、胃肠道、个部分包括舌下、口腔、胃肠道、 直肠等部位吸收。给药后，药物吸直肠等部位吸收。给药后，药物吸 收的最佳部位是小肠上部和十二指收的最佳部位是小肠上部和十二指 肠。这是由于十二指肠的绒毛和微肠。这是由于十二指肠的绒毛和微 绒毛特征提供了巨大的吸收面，此绒毛特征提供了巨大的吸收面，此 外，十二指肠具有丰富的毛细血管外，十二指肠具有丰富的毛细血管 网，有助于维持肠腔与血液循环之网，有
33、助于维持肠腔与血液循环之 间的浓度梯度。间的浓度梯度。 LOGO Gastric Emptying Rate （胃空速率） 胃内容物从幽门向小肠的排出称为胃排空。胃内容物从幽门向小肠的排出称为胃排空。 Gastric Emptying Rate is the content emptied by stomach per time.（单位时间内胃内容物的排出量称为胃空速率。）（单位时间内胃内容物的排出量称为胃空速率。） LOGO Factors of affecting emptying time (rate)（影响胃空速率的因素）（影响胃空速率的因素） 空腹与饱腹空腹与饱腹 食物的组成与性质食
34、物的组成与性质 药物因素药物因素 LOGO Effect of Food 食物除影响胃空速率外还从以下方面食物除影响胃空速率外还从以下方面 影响药物吸收：影响药物吸收： 食物消化使胃肠道液体减少食物消化使胃肠道液体减少 食物存在使胃液粘度增大食物存在使胃液粘度增大 食物成分影响肠道食物成分影响肠道pH和药物溶解和药物溶解 度度 LOGO Intestinal Motility (小肠运动) Peristaltic movement of small intestine (小小 肠的蠕动，约为肠的蠕动，约为1-2cm/min) mix the contents of the duodenum,
35、bring the drug particles into intimate contact the mucosal cell. LOGO Perfusion of the Gastrointestinal tract (胃肠道的血液灌注) Blood circulation receives about 98% of drug. Lymph circulation receives about 2% of drug (some lipophilic drug). LOGO Pharmaceutical factors (剂型因素) particle size crystalline form
36、s ionizable salt of drug dosage form formulation ingredients technological process and operation conditions drug in product disintegration solid particle drug in solution drug in body LOGO Disintegration Disintegration is a process in which solid drug product disintegrates into small particles LOGO
37、Dissolution Dissolution is the process by which a chemical or drug becomes dissolved in a solvent. LOGO The overall rate of drug dissolution may be described by the Noyes- Whitney equation: dC/dt = DAK (Cs C)/h D= diffusion rate constant A = surface area of the particle Cs= conc. of drug in the stag
38、nant layer C = conc. of drug in the bulk solvent, K = oil /water partition coefficient h = thickness of the stagnant layer. LOGO The rate of dissolution, (dc/dt)(1/A) is the amount of drug dissolved per unit area per time. LOGO Influence factors for dissolution rate Physicochemical Nature of the Dru
39、g particle size degree of aqueous solubility crystalline forms Formulation Factors Eg. Various excipients in a drug product In Vitro Dissolution Testing （略）（略） LOGO Particle size( 粒径 ) The effective surface area of a drug may be increased enormously with a reduction in the particle size. Eg. Griseof
40、ulvin (灰黄霉素灰黄霉素) LOGO Crystalline forms (晶型) Polymorphs(多晶型多晶型) Amorphous(无定型无定型) Solvates (溶剂化物溶剂化物) LOGO Polymorphs(多晶型) The drug exists in more than one of the crystalline form. They have identical chemical structure but have different physical properties such as hardness, melting point, solubili
41、ty, dissolution rate. LOGO Crystalline forms (晶型) Polymorphs(多晶型多晶型) Amorphous(无定型无定型) Solvates (溶剂化物溶剂化物) LOGO Amorphous(无定型) There are no stable appearance and apparent melting points, and a disorder in inner particles. Eg. chloramphenicol palmitate LOGO Crystalline forms (晶型) Polymorphs(多晶型多晶型) A
42、morphous(无定型无定型) Solvates (溶剂化物溶剂化物) LOGO Solvates (溶剂化物) Some drugs interact with solvent to form a crystal called solvate (药物结晶时与溶媒形药物结晶时与溶媒形 成的分子复合物成的分子复合物) Hydrous and anhydrous LOGO Ionizable salt of drug（盐型） Generally, the ionizable salt of the drug is more water soluble than the free acid or
43、free base. LOGO Dosage form Dosage form is a release system of drug. Absorption: for oral dosage form, Solutions Suspensions Powders Capsules Tablets Coated tablets LOGO Formulation Ingredients (处方成分) Excipients: the inactive components in a drug product and are often needed to produce a drug produc
44、t with homogeneity（均一性）（均一性） and stability（稳定性）。（稳定性）。 LOGO Questions ? What are the two rate- limiting steps possible in the oral absorption of a solid drug product? Which one would apply to a soluble drug? Which one the pharmacist could alter? Give examples. LOGO ? What is the physiologic transpor
45、t mechanism for the absorption of most drugs from the GI tract? What area of the GI tract is most favorable for the absorption of drugs? Why? LOGO ? What type of oral dosage form general yields the greatest amount of systemically available drug in the least amount of time? LOGO III. Oral cavity abso
46、rption LOGO 1. Anatomic and Physiologic Characteristics of oral mucosa LOGO Although surface area of oral cavity is limited, oral gingival(牙龈牙龈) and sublingual (舌下舌下) mucosa are formed a large capillary network. The oral epithelium is essentially lipophilic, the intercellular space(细胞细胞 间隙间隙)which i
47、s narrow and tortuous(弯弯 曲的曲的) is relatively hydrophilic LOGO After administration, drug is passed to internal jugular vein(颈内静脉颈内静脉) to go into blood systemic circulation. 1-2L saliva is secreted by oral cavity every day. Its average pH is about 6, general drugs are not decomposed. LOGO 2. Drug abs
48、orption in oral cavity LOGO Increase pH of saliva is benefit to absorption of weak base drugs, but not for weak acid drugs. Eg. Benzedrine(苯丙胺苯丙胺). Normally, lipophilic drugs are readily transported to oral mucosa and their mechanism of transport belongs mainly to passive diffusion. LOGO Drug absorb
49、ed through the oral mucosa will no pass through the liver before distribution. So, there was no first-pass effect during absorption. Eg. Nitroglycerin(硝酸甘油硝酸甘油), compare conventional tablets to sublingual tablets. First-pass effect extensive intestinal metabolism extensive hepatic metabolism eg: clonazepam chlorpromazine eg: isoproterenol meperidine pentazocine morphine LOGO 3. Classification of the Oral Mucosal Drug Delivery System: Solution in the from of mouthwashes or sprays Tablets (Nitroglycerin: sublingual tablets) Bioadhe
