1、BIOPHARMACEUTICS & PHARMACOKINETICS,Bio lifePharmaceutics general area of study concerned with the formulation, manufacture, stability and effectiveness of pharmaceutical dosage forms.,Biopharmaceutics,study of the factors influencing the bioavailability of a drug in man and animals and the use of t
2、his information to optimize pharmacological or therapeutic activity of drug products in clinical application.,Biopharmaceutics,study of the influence of formulation on therapeutic activity of a drug product.,Biopharmaceutics,study embracing this relationship between the physical, chemical and biolog
3、ical sciences as they apply to drugs, dosage forms, and to drug action.,Biopharmaceutics,Modern biopharmaceutics is the study of the relationship of the physico-chemical properties and in vitro behavior of the drug and drug product on the delivery of the drug to the body under normal or pathologic c
4、onditions.,Drug,agent intended for use in the diagnosis, mitigation, treatment, cure or prevention of disease in man or in other animals. It may be:1. synthetic 4. biological2. semi-synthetic 5. natural3. chemical,Drug,Modern drugs are potent chemical substances that must be fabricated into a drug p
5、roduct before use. Generally, the drug is combined with other ingredients into a drug formulation, which may be a solution, tablet, capsule or suppository.,Rationale,The development of biopharmaceutic principles allowed for the rational design of drug products, which would enhance the delivery of ac
6、tive drug, and optimize the therapeutic efficacy of the drug in the patient.,Drug Product,a finished dosage form that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredient. formulation or matrix in which the drug is contained The term may also inc
7、lude a dosage form that does not contain an active ingredient intended to be used as placebo.,Drug Action,result of an interaction between the drug substance and functionally important cell receptors or enzyme systems. This response is due to the alteration in the biologic processes that were presen
8、t prior to the drug administration.,In vitro glass referring to a process or reaction carried out in a culture dish or test tube In vivo in the living organism,Effects of Biopharmaceutics,Generic equivalency Drug availability Therapeutic efficacy Drug substitution,BIOPHARMACEUTICS & PHARMACOKINETICS
9、,Effects of Biopharmaceutics,Drug product selection*drug product should be cost-effective*drug product selection should be according to the patients capability*drug product selection should be based upon the patients diagnosis,Aim,The aim of biopharmaceutics is to adjust the delivery of drug to the
10、general circulation in such a manner as to provide optimal therapeutic activity for the patient.,Aim,Biopharmaceutic studies allow drugs to be formulated rationally based on pharmaceutic properties.,Some Pharmaceutic Properties,Some drugs are intended for topical or local therapeutic action at the s
11、ite of administration. For these drugs, systemic absorption is undesirable.,Some Pharmaceutic Properties,Drugs intended for local activity generally have a direct pharmacodynamic action without affecting other body organs. These drugs may be applied topically to the skin, nose, eyes, mucous membrane
12、s, buccal cavity, throat and rectum.,Factors Affecting Biopharmaceutics,a. physical state of the drug- according to the 4 states of matterThe crystal or amorphous forms and/or the particle size of a powdered drug have been shown to affect the dissolution rate, and thus the rate of absorption, for a
13、number of drugs.,Factors Affecting Biopharmaceutics,By selective control of the physical parameters of a drug, biologic response may be optimized.,b. dosage form,- delivery system the drug could be available or administered.,b. dosage form,Each of dosage unit is designed to contain a specified quant
14、ity of medication for ease and accuracy of dosage administered.Each product is a formulation unique unto itself,Biopharmaceutic considerations often determine the ultimate dose and dosage form of a drug product.,Biopharmaceutic considerations often determine the ultimate dose and dosage form of a dr
15、ug product.For example, the dosage for a drug intended for local activity, such as a topical dosage form, is often expressed in concentration or as % of the active drug in the formulation.,The amount of drug is not specified because it is the concentration of the drug at the active site that relates
16、 to the pharmacodynamic action.,Biopharmaceutics,Biopharmaceutic studies must be performed to ensure that the dosage form does not irritate, cause an allergic response or allow systemic drug absorption.,The dosage of a drug intended for systemic absorption is given on the basis of absolute amount, s
17、uch as mg or g.,c. route of administration,each route of drug application presents special biopharmaceutic considerations in drug product design.,c. route of administration,by carefully choosing the route of drug administration and properly designing the drug product, the bioavailability of the acti
18、ve drug can vary from rapid and complete absorption to a slow, sustained rate of absorption or even virtually no absorption, depending on the therapeutic objective.,Example,The design of a vaginal tablet formulation for the treatment of a fungus infection must consider ingredients compatible with va
19、ginal anatomy and physiology.,Example,An eye medication may require special biopharmaceutic considerations including appropriate pH, isotonicity, local irritation to the cornea, draining by tears, and concern for systemic drug absorption.,1. Encompasses all possible effects observed following the ad
20、ministration of the drug in the various dosage forms.2. Encompasses all possible effects of various dosage forms on biological response3. Encompasses all possible physiological factors which may affect the drug in various dosage forms.,Scope of Biopharmaceutics,A primary concern in biopharmaceutics
21、is the bioavailability of drugs.,Bioavailability,refers to the measurement of the rate and extent of active drug that reaches the systemic circulation.means access to the bloodstream,Drug in the drug product,Drug in solution,Solid drug particles,Drug in the body,Drug Bioavailability Process,Pharmace
22、utic Factors Affecting Drug Bioavailability,1. type of the drug product 2. nature of excipients in the drug product 3. physico-chemical properties of the drug- measurable characteristics by which a compound interacts with other systems,Physico-Chemical Properties of the Drug,1. Particle size of a dr
23、ug in a solid dosage form 2. Particle size of a dispersed phase in an emulsion 3. Tablet disintegration 4. Tablet & capsule adjuncts 5. Tablet coating 6. Crystalline drug properties,Something to ponder.,1. Particle size of a drug in a solid dosage form,In order to affect dissolution rate based on on
24、es objective, there should be a change in particle size. particle size larger surface area to be wetted dissolution rate faster rate of absorption But for local effect, increased particle size is required,2. Particle size of the dispersed phase in an emulsion,2-phase system in which one should be un
25、iformly dispersed into another.Dispersed phase should be in small particle size so it can readily mix with dispersion medium.,3. Tablet Disintegration,Disintegration is the physical break-up of an intact dosage form to its component aggregates. Disintegration depends on the disintegrant used. Starch
26、 Microcrystalline cellulose,It was generally recognized some years ago that a solid drug product had to disintegrate into small particles and release the drug before absorption could take place. For the purpose of monitoring tablet disintegration, USP established an official disintegration test.,USP
27、 Specifications,Separate specifications are given for uncoated tablets plain coated tablets enteric coated tablets buccal tablets sublingual tablets,USP Specifications,Solid drug products exempted from disintegration tests Troches Tablets which are intended to be chewed Drug products intended for SR
28、, or prolonged or repeat action,4. Tablet & Capsule Adjuncts,Excipients added to the active ingredient to form a dosage form that is convenient for control purposes.- it should be inert, inactive, neither enhances nor diminishes the therapeutic effect of the drug,Roles/Effects of Excipients,may affe
29、ct drug absorption may increase solubility may increase retention time of drug in the GIT may act as carriers to increase diffusion across intestinal wall In contrast, most excipients may retard drug dissolution and decrease drug absorption,Different Excipients used in Tablets,1. Diluents added to i
30、ncrease the bulk/mass of the dosage form ex. Lactose, Dibasic Ca Phosphate, starch, microcrystalline cellulose 2. Binder makes the diluent adhere to the tablet to form a compact mass. Pressure is applied to make the tablets contact. Ex. Acacia, alginic acid, gelatin, povidone, etc.,Different Excipie
31、nts used in Tablets,3. Lubricant helps to have an easier transfer from one stage of manufacture to another - assist the smooth tableting process. Ex. Mag. Stearate, stearic acid, talc, hydrogenated vegetable oil excessive magnesium stearate (a hydrophobic lubricant) in the formulation may retard dru
32、g dissolution and cause slower drug absorption.,5. Tablet Coating,protection uneven coating can cause uneven release of active ingredientExample:a. enteric coatings employed to permit safe passage of tablet thru the acid environment of the stomach where certain drugs may be destroyed, to the more su
33、itable juices of the intestines where tablet dissolution safely takes place. ( shellac, cellulose acetate phthalate),b. film-coatings employed to protect the drug substance from the destructive influences of moisture, light and air throughout their period of storage or to conceal a bad or bitter tas
34、te from the taste buds of the patient. (hydroxypropylmethylcellulose)c. sugar-coatings conceal bitter taste (liquid glucose, sucrose),4. Surfactants Low conc. of surfactant = decrease surface tension = rate of dissolution? High conc. of surfactant = formation of micelles = rate of dissolution?,6. Cr
35、ystalline Drug Properties,Polymorphism refers to the arrangement of a drug in various crystal forms or Polymorphs Polymorphs have the same chemical structure but different physical properties such as: solubility, density, hardness and compression characteristics,Some polymorphic crystals may have mu
36、ch lower aqueous solubility than the amorphous forms, causing a product to be incompletely absorbed.Ex. ChloramphenicolCrystal with the LOWEST free energy is stable,Solvate Drug + solvent = crystalHydrates Drug + H2O = crystal,In general, the crystalline form of drugs are more rigid and thermodynami
37、cally more stable than the amorphous form. The crystal form with the lowest free energy is the most stable polymorph. A change in crystal form may cause problems in manufacturing the product. For example, a change in crystal structure of the drug may cause cracking in a tablet or even inability for
38、a granulation to be compressed to form a tablet.,Example,Erythromycin dehydrate dissolves faster than the monohydrate & anhydrous formless hydrated faster dissolutionAmpicillin anhydrous would have faster dissolution than trihydrate but it is less absorbed,Clathrates- cages the drug to make it more
39、stable (protective) and soluble (reacts with the solvent) e.g. gallic acid, urea, zeolite,Drugs with narrow therapeutic window,Size of dose (mg/kg) Dosing frequency (bid, tid, od),Size of the dose,Determined by: Inherent potency of the drug Dosing strengthsE.g. score in tablets for fractured dosing.
40、 Paper tablets,Dosing frequency,Dependent on: Clearance of the drug (elimination) Target plasma drug concentration (MEC) e.g. Drug with a short half-life or rapid clearance how frequent is the dosing?,Sustained release (SR) tablets,Devised to minimize fluctuating plasma concentration and good patient compliance,Route of administration,Formulation given in IM, IV and oral only changes the rate of absorption but NOT the rate of eliminationSublingual rapid onset but shorter duration of action,Maraming salamat po,
