4. Dosage Form Design: Biop4. Dosage Form Design: Biopharmaceutic and Pharmacokharmaceutic and Pharmacok

inetic Considerationsinetic Considerations

Contents Contents

I.I. General principles of drug General principles of drug absorptionabsorption

II.II. Dissolution and drug absorptionDissolution and drug absorption

III.III. Bioavailability and Bioavailability and bioequivalencebioequivalence

IV.IV. Routes of drug administrationRoutes of drug administration

V.V. Fate of drug after absorptionFate of drug after absorption

VI.VI. Pharmacokinetic principles Pharmacokinetic principles

Biopharmaceutics Biopharmaceutics is the area of study is the area of study embracing the relationship between embracing the relationship between the physical, chemical, and biologicathe physical, chemical, and biological sciences as they apply to drugs, dosl sciences as they apply to drugs, dosage forms, and to drug action.age forms, and to drug action.

（生物药剂学（生物药剂学是围绕物理学、化学和生物科是围绕物理学、化学和生物科学及它们关于药物、剂型和药物作用相互学及它们关于药物、剂型和药物作用相互关系的研究领域。）关系的研究领域。）

For a drug to exert its biological effect,For a drug to exert its biological effect, it must be it must be

transported by the body fluids, transported by the body fluids, traverse the required biological membrane traverse the required biological membrane

barriers,barriers, escape widespread distribution to unwanteescape widespread distribution to unwante

d areas,d areas, endure metabolic attack, endure metabolic attack, （经受代谢改变）（经受代谢改变） penetrate in adequate concentration to the penetrate in adequate concentration to the

sites of action,sites of action, interact in a specific fashion,interact in a specific fashion, causing an alteration of cellular function.causing an alteration of cellular function.

The area of study which elucidates the The area of study which elucidates the time course of drug concentration in time course of drug concentration in the blood and tissues is termed the blood and tissues is termed pharmacokinetics.pharmacokinetics.

It is the study of the kinetics of It is the study of the kinetics of absorption, distribution, metabolism absorption, distribution, metabolism and excretion and excretion (ADME)(ADME) of drugs and of drugs and their corresponding their corresponding pharmacologic, pharmacologic, therapeutic, or toxic responsetherapeutic, or toxic response in in animals and man.animals and man.

Pharmacokinetics also may be applied Pharmacokinetics also may be applied in the study of in the study of interactions between interactions between drugs.drugs.

I. General principles of drug I. General principles of drug absorptionabsorption

Body membranes are generally Body membranes are generally classified as three main types:classified as three main types:

- those composed of several layers of those composed of several layers of cells, as the skin,cells, as the skin,

- those composed of a single layer of those composed of a single layer of cells, as the intestinal epithelium,cells, as the intestinal epithelium,

- those of less than one cell in those of less than one cell in thickness, as the membrane of a thickness, as the membrane of a single cell. single cell.

In most instances a drug In most instances a drug substance must pass more than substance must pass more than one of these membrane types one of these membrane types before it reaches its site of before it reaches its site of action. action.

Drugs are thought to penetrate Drugs are thought to penetrate these biologic membranes in two these biologic membranes in two general ways:general ways:

1) by passive diffusion1) by passive diffusion

2) through specialized transport 2) through specialized transport mechanismsmechanisms

1) Passive diffusion1) Passive diffusion

Passive diffusionPassive diffusion is used to describe is used to describe the passage of (drug) molecules the passage of (drug) molecules through a membrane which through a membrane which behaves inertly in that it does not behaves inertly in that it does not actively participate in the process.actively participate in the process.

Drugs absorbed according to this Drugs absorbed according to this method are said to be passively method are said to be passively absorbed.absorbed.

The absorption process is driven by tThe absorption process is driven by the he concentration gradientconcentration gradient existing ac existing across the membrane, with the passage ross the membrane, with the passage of drug molecules occurring primariof drug molecules occurring primarily from the side of high drug concently from the side of high drug concentration. ration.

Fick’s first law: the rate of diffusion or Fick’s first law: the rate of diffusion or transport across a membrane (dc/dt) is transport across a membrane (dc/dt) is proportional to the difference in drug coproportional to the difference in drug concentration on both sides of the membrncentration on both sides of the membrane.ane.

-dc/dt=P(C-dc/dt=P(C11-C-C22))

in which Cin which C11 and C and C22 refer to the drug conc refer to the drug concentrations on each side of the membranentrations on each side of the membrane and P is a permeability coefficient or ce and P is a permeability coefficient or constant.onstant.

For practical purposes the value of CFor practical purposes the value of C11--CC2 2 may be taken simply as that of Cmay be taken simply as that of C11 an and the equation written in the standard d the equation written in the standard form for a first order rate equation:form for a first order rate equation:

-dc/dt=PC-dc/dt=PC11

Absorption site C1

BloodC2

Biologic membrane

The gastrointestinal absorption of The gastrointestinal absorption of most drugs from solution occurs in most drugs from solution occurs in this manner in accordance with first this manner in accordance with first order kinetics in which the rate is order kinetics in which the rate is dependent on drug concentration. dependent on drug concentration.

The magnitude of the permeability The magnitude of the permeability constant, depends on constant, depends on

the diffusion coefficient of the drugthe diffusion coefficient of the drug the thickness and area of the the thickness and area of the

absorbing membraneabsorbing membrane the permeability of the membrane the permeability of the membrane

to the particular drug.to the particular drug.

Because of the Because of the lipoid naturelipoid nature of the of the cell membrane, it is highly permeable cell membrane, it is highly permeable to to lipid soluble substances.lipid soluble substances.

Because biologic cells are also Because biologic cells are also permeated by permeated by water and lipid-water and lipid-insolubleinsoluble substances, it is thought substances, it is thought that the membrane also contains that the membrane also contains water-filled pores or channelswater-filled pores or channels that that permit the passage of these types of permit the passage of these types of substances.substances.

As water passes in bulk across a As water passes in bulk across a porous membrane, any dissolved porous membrane, any dissolved solute molecularly small enough solute molecularly small enough to traverse the pores passes in by to traverse the pores passes in by filtration.filtration.

Aqueous pores vary in size from Aqueous pores vary in size from membrane to membrane and thus membrane to membrane and thus in their individual permeability in their individual permeability characteristics for certain drugs characteristics for certain drugs and other substances.and other substances.

The majority of drugs today are weaThe majority of drugs today are weak organic acids or bases. Cell membk organic acids or bases. Cell membranes are more permeable to the ranes are more permeable to the uniunionized formsonized forms ofof drugs drugs than to their ithan to their ionized forms.onized forms.

The degree of a drug’s ionization deThe degree of a drug’s ionization depends both on the pH of the solution pends both on the pH of the solution in which it is presented to the biologiin which it is presented to the biologic membrane and on the pKa.c membrane and on the pKa.

Henderson-Hasselbalch equationHenderson-Hasselbalch equationFor an acid:For an acid:pH=pKa+logpH=pKa+logionized conc.(salt)ionized conc.(salt)//uniounio

nized conc.(acid)nized conc.(acid)For a base:For a base:pH=pKa+logpH=pKa+logunionized conc.(base)unionized conc.(base)/ / ionized conc.(salt)ionized conc.(salt)

2) Specialized transport 2) Specialized transport mechanismsmechanisms

This type of transport is thought to involve This type of transport is thought to involve membrane components that may be membrane components that may be enzymenzymes or some other type of agentes or some other type of agent capable of fo capable of forming a complex with the drug at the surfacrming a complex with the drug at the surface membrane, after which the complex movee membrane, after which the complex moves across the membrane where the drug is res across the membrane where the drug is released, with the carrier returning to the orileased, with the carrier returning to the original surface.ginal surface.（这种类型的转运认为需要涉及一些生物膜的成分，（这种类型的转运认为需要涉及一些生物膜的成分，可能是酶或其他能与药物在膜表面结合成复合物的可能是酶或其他能与药物在膜表面结合成复合物的物质。复合物能移动到膜的另一侧并释放出药物，物质。复合物能移动到膜的另一侧并释放出药物，载体则重新回到膜的表面。）载体则重新回到膜的表面。）

This type of transfer seeThis type of transfer seems to ms to accountaccount for those s for those substances, many naturalubstances, many naturally occurring as ly occurring as amino acamino acids and glucose,ids and glucose, that are that are too lipid-insoluble to distoo lipid-insoluble to dissolve in the boundary ansolve in the boundary and too large to flow or filtd too large to flow or filter through the pores.er through the pores. （这种转运方式可以用来解（这种转运方式可以用来解释某些物质的转运，如许多释某些物质的转运，如许多天然存在的氨基酸和葡萄糖，天然存在的氨基酸和葡萄糖，有些是脂溶性很小在生物膜有些是脂溶性很小在生物膜中不能溶解或分子很大不能中不能溶解或分子很大不能通过膜上的孔道。）通过膜上的孔道。）

Active transportActive transport denotes a process of the s denotes a process of the solute or drug being moved across the memolute or drug being moved across the membrane against a concentration gradient, thbrane against a concentration gradient, that is, from a solution of lower concentratioat is, from a solution of lower concentration to one of a higher concentration or, if thn to one of a higher concentration or, if the solute is an ion, against an electrochemie solute is an ion, against an electrochemical potential gradient.cal potential gradient.

（主动转运是指溶质或药物穿过生物膜的转运的过（主动转运是指溶质或药物穿过生物膜的转运的过程是逆浓度梯度进行，即从低浓度向高浓度转运程是逆浓度梯度进行，即从低浓度向高浓度转运或当溶质是离子时逆电化学电势梯度转运。）或当溶质是离子时逆电化学电势梯度转运。）

Many large moleMany large molecules and particlcules and particles can not enter es can not enter cells via passive cells via passive or active mechaor active mechanisms. However, nisms. However, some may enter, some may enter, as yet, by a procas yet, by a process known as ess known as enendocytosis(docytosis( 内吞内吞 ))..

In In phagocytosis (phagocytosis ( 吞噬吞噬 )) (cell eating), larg (cell eating), large particles suspended in the extracellulae particles suspended in the extracellular fluid are engulfed and either transportr fluid are engulfed and either transported into cells or are destroyed within the ed into cells or are destroyed within the cell. This is a very important process for cell. This is a very important process for lung phagocytes and certain liver and splung phagocytes and certain liver and spleen cells. leen cells.

Pinocytosis (Pinocytosis ( 胞饮胞饮 )) (cell drinking) is a si (cell drinking) is a similar process but involves the engulfing milar process but involves the engulfing of liquids or very small particles that are of liquids or very small particles that are in suspension within the extracellular flin suspension within the extracellular fluid. uid.

II. Dissolution and drug II. Dissolution and drug absorptionabsorption

The process by which a drug particle dissolves The process by which a drug particle dissolves is termed is termed dissolution. dissolution.

The dissolution of a substance may be describeThe dissolution of a substance may be described by the modified d by the modified Noyes-Whitney equation:Noyes-Whitney equation:dc/dt=kS(cdc/dt=kS(css-c-ctt))

in which in which dc/dtdc/dt is the rate of dissolution is the rate of dissolutionkk is the dissolution rate constant is the dissolution rate constantSS is the surface area of the dissolving solid, is the surface area of the dissolving solid,CCss is the saturation concentration of drug in the diffusi is the saturation concentration of drug in the diffusion layeron layerCCtt is the concentration of the drug in the dissolution m is the concentration of the drug in the dissolution medium at time tedium at time t

The equation reveals that the The equation reveals that the dissolution rate of a drug may be dissolution rate of a drug may be increased byincreased by

- increasing the surface area of the increasing the surface area of the drug,drug,

- increasing the solubility of the drug increasing the solubility of the drug in the diffusion layer,in the diffusion layer,

- factors embodied in the dissolution factors embodied in the dissolution rate constant, k, including the rate constant, k, including the intensity of agitation of the solvent,intensity of agitation of the solvent,

- the diffusion coefficient of the the diffusion coefficient of the dissolving drug.dissolving drug.

1) Surface area1) Surface area

When a drug particle is reduced to a laWhen a drug particle is reduced to a larger number of smaller particles, the rger number of smaller particles, the ttotal surface areaotal surface area created is increased. created is increased.

For drug substances that are For drug substances that are poorly or poorly or slowly solubleslowly soluble, this generally results in , this generally results in an an increase in the rate of dissolutionincrease in the rate of dissolution..

Micronized powdersMicronized powders consist of drug pa consist of drug particles reduced in size to about 5 microrticles reduced in size to about 5 microns and smaller.ns and smaller.

2) Crystal or amorphous 2) Crystal or amorphous drug formdrug form

The The amorphous or crystallineamorphous or crystalline character of a drug substance may character of a drug substance may be of considerable importance to be of considerable importance to

its ease of formulation and its ease of formulation and handlinghandling

Its chemical stabilityIts chemical stability Its biological activityIts biological activity

Certain medical agents may be Certain medical agents may be produced to exist in either a produced to exist in either a crystalline or an amorphous state.crystalline or an amorphous state.

The amorphous form of a chemical iThe amorphous form of a chemical is usually s usually more solublemore soluble than the cryst than the crystalline form. e.g. novobiocin, chloraalline form. e.g. novobiocin, chloramphenicol palmitate.mphenicol palmitate.

Crystalline forms of drugs may be usCrystalline forms of drugs may be used because of greater stability than ted because of greater stability than the corresponding amorphous forms, he corresponding amorphous forms, e.g. the crystalline forms of penicillie.g. the crystalline forms of penicillin G.n G.

3) Salt forms3) Salt forms

The dissolution rate of a salt form The dissolution rate of a salt form of a drug is generally quite different of a drug is generally quite different from that of the parent compound.from that of the parent compound.

Sodium and potassium salts of weak Sodium and potassium salts of weak organic acids and hydrochloride organic acids and hydrochloride salts of weak organic bases salts of weak organic bases dissolve much more readily than do dissolve much more readily than do the respective free acids or bases.the respective free acids or bases.

4) Other factors4) Other factors

The state of hydration of a drug The state of hydration of a drug molecule can affect its solubility molecule can affect its solubility and pattern of absorption.and pattern of absorption.

Usually the anhydrous form of an Usually the anhydrous form of an organic molecules is more organic molecules is more readily soluble than the hydrated readily soluble than the hydrated form.form.

III. Bioavailability and III. Bioavailability and bioequivalencebioequivalence

The bioavailabilityThe bioavailability describes the rate describes the rate and extent to which an active drug inand extent to which an active drug ingredient or therapeutic moiety is absgredient or therapeutic moiety is absorbed from a drug product and becoorbed from a drug product and becomes available at the site of drug actiomes available at the site of drug action.n.

The bioequivalenceThe bioequivalence refers to the com refers to the comparison of bioavailabilities of differeparison of bioavailabilities of different formulations, drug products, or bnt formulations, drug products, or batches of the same drug product.atches of the same drug product.

Graphically, bioavailability of a Graphically, bioavailability of a drug is portrayed by a drug is portrayed by a concentration-time curve of the concentration-time curve of the administered drug in an administered drug in an appropriate tissue system.appropriate tissue system.

Bioavailability dataBioavailability data are used to are used to determinedetermine

1)1) the amount or proportion of drug the amount or proportion of drug absorbed from a formulation or absorbed from a formulation or dosage form,dosage form,

2)2) the rate at which the drug was the rate at which the drug was absorbed,absorbed,

3)3) the duration of the drug’s presence the duration of the drug’s presence in the biologic fluid or tissue,in the biologic fluid or tissue,

4)4) the relationship between drug blood the relationship between drug blood level and clinical efficacy and level and clinical efficacy and toxicity. toxicity.

1) Blood concentration-1) Blood concentration-time curvetime curve

2) Parameters for 2) Parameters for assessment and comparison assessment and comparison

of bioavailabilityof bioavailability Peak height (CPeak height (Cmaxmax)) concentrationconcentration is th is th

e maximum drug concentration obsee maximum drug concentration observed in the blood plasma or serum forved in the blood plasma or serum following a dose of the drug. llowing a dose of the drug.

For conventional dosage forms, as taFor conventional dosage forms, as tablets and capsules, the Cblets and capsules, the Cmaxmax will usual will usually occur at only a single time point, rly occur at only a single time point, referred to as Teferred to as Tmaxmax..

Time of peak (TTime of peak (Tmaxmax),), maximum level maximum level of drug in the bloodof drug in the blood

This parameter reflects the rate of drThis parameter reflects the rate of drug absorption from a formulation. It ug absorption from a formulation. It is the rate of drug absorption that detis the rate of drug absorption that determines the time needed for the miniermines the time needed for the minimum effective concentration to be remum effective concentration to be reached and thus for the initiation of thached and thus for the initiation of the desired pharmacologic effect.e desired pharmacologic effect.

Area under the serum Area under the serum concentration time curve (AUC)concentration time curve (AUC)

The AUC of a concentration-time The AUC of a concentration-time plot is considered representative plot is considered representative of the total amount of drug of the total amount of drug absorbed into the circulation absorbed into the circulation following the administration of a following the administration of a single dose of that drug.single dose of that drug.

The smaller the AUC, the less The smaller the AUC, the less drug absorbed. drug absorbed.

The fraction (F) (or bioavailability) of The fraction (F) (or bioavailability) of an orally administered drug may be caan orally administered drug may be calculated by comparison of the AUC aftlculated by comparison of the AUC after oral administration with that obtaier oral administration with that obtained after intravenous administration:ned after intravenous administration:

F=(AUC)F=(AUC)oraloral/(AUC)/(AUC)intravenousintravenous

In practice, it would be rare for a drug In practice, it would be rare for a drug to be completely absorbed into the cirto be completely absorbed into the circulation following oral administration.culation following oral administration.

Many drugs undergo the Many drugs undergo the first-pass first-pass effecteffect resulting in some degree of resulting in some degree of metabolic degradation before metabolic degradation before entering the general circulation.entering the general circulation.

In addition, In addition, factors of drug product factors of drug product formulationformulation, , drug dissolutiondrug dissolution, , chemical and physical interactions chemical and physical interactions with the gastrointestinal contentswith the gastrointestinal contents, , gastric emptying timegastric emptying time, , intestinal intestinal motilitymotility, and others contribute to , and others contribute to the incomplete absorption of an the incomplete absorption of an administered dose of a drug.administered dose of a drug.

3) Bioequivalence of drug 3) Bioequivalence of drug productsproducts

Pharmaceutical equivalentsPharmaceutical equivalents are drug products that c are drug products that contain ontain identical amountsidentical amounts of the of the identical active drug identical active drug ingredientingredient, i.e., the same salt or ester of the same th, i.e., the same salt or ester of the same therapeutic moiety, erapeutic moiety, in identical dosage formsin identical dosage forms, but , but not not necessarily containing the same inactive ingredientsnecessarily containing the same inactive ingredients,, and that meet the and that meet the identical compendial or other appidentical compendial or other applicable standard of identitylicable standard of identity, strength, quality, and pu, strength, quality, and purity, including potency and, where applicable, conterity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolutint uniformity, disintegration times, and/or dissolution rates.on rates.（制剂等效指包含等量同种活性药物成分的药品，即：有相（制剂等效指包含等量同种活性药物成分的药品，即：有相同治疗效应的相同盐或酯的形式，相同剂型。但并不一定包同治疗效应的相同盐或酯的形式，相同剂型。但并不一定包含相同的非活性成分，具有相同的外观或其他相应的性质如含相同的非活性成分，具有相同的外观或其他相应的性质如规格、质量、纯度，包括效价、含量均匀性、崩解时间和溶规格、质量、纯度，包括效价、含量均匀性、崩解时间和溶出速率。）出速率。）

Pharmaceutical alternativesPharmaceutical alternatives are drug products that are drug products that contain contain the identical therapeutic moiety, or its precthe identical therapeutic moiety, or its precursorursor, , but not necessarily in the same amount or dobut not necessarily in the same amount or dosage form or as the same salt or estersage form or as the same salt or ester. Each such pr. Each such product individually meets oduct individually meets either the identical or its oeither the identical or its own respective compendialwn respective compendial or other applicable stand or other applicable standard of identity, strength, quality, and purity, includiard of identity, strength, quality, and purity, including potency and, where applicable, content uniformng potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.ity, disintegration times, and/or dissolution rates.

（制剂替代品指含有相同治疗效果的组成部分或它的前体药（制剂替代品指含有相同治疗效果的组成部分或它的前体药物，不需要相同剂量、相同剂型、相同的盐或酯的形式。每物，不需要相同剂量、相同剂型、相同的盐或酯的形式。每种药品符合同样的或各自的外观和其他相应的性质如规格、种药品符合同样的或各自的外观和其他相应的性质如规格、质量、纯度，包括效价，含量均匀性、崩解时间和溶出速质量、纯度，包括效价，含量均匀性、崩解时间和溶出速率。率。 ))

Bioequivalent drug productsBioequivalent drug products are pharmac are pharmaceutical equivalents or pharmaceutical alteeutical equivalents or pharmaceutical alternatives whose rate and extent of absorptirnatives whose rate and extent of absorption do not show a significant difference whon do not show a significant difference when administered at the same molar dose of en administered at the same molar dose of the therapeutic moiety under similar expthe therapeutic moiety under similar experimental conditions, either single dose or erimental conditions, either single dose or multiple dose.multiple dose.(( 生物等效性药品指在相同的试验条件下，单次生物等效性药品指在相同的试验条件下，单次或多次给予相同治疗剂量的药物，其吸收的速率或多次给予相同治疗剂量的药物，其吸收的速率和程度没有显示显著性差异的制剂等效品或制剂和程度没有显示显著性差异的制剂等效品或制剂替代品。）替代品。）

Therapeutic equivalentsTherapeutic equivalents has been has been used to indicate pharmaceutical used to indicate pharmaceutical equivalents which, when equivalents which, when administered to the same administered to the same individuals in the same dosage individuals in the same dosage regimens, will provide essentially regimens, will provide essentially the same therapeutic effect. the same therapeutic effect.

IV. Routes of drug IV. Routes of drug administrationadministration

Drugs may be administered by a Drugs may be administered by a variety of dosage forms and variety of dosage forms and routes of administration.routes of administration.

One of the fundamental One of the fundamental considerations in dosage form considerations in dosage form design is whether the drug is design is whether the drug is intended for intended for local or systemic local or systemic effectseffects..

Local effectsLocal effects are achieved from are achieved from direct application of the drug to direct application of the drug to the desired site of action, such as the desired site of action, such as the eye, nose, or skin.the eye, nose, or skin.

Systemic effectsSystemic effects result from the result from the entrance of the drug into the entrance of the drug into the circulatory system and its circulatory system and its subsequent transport to the subsequent transport to the cellular site of its action.cellular site of its action.

The difference in drug absorThe difference in drug absorption between dosage forms iption between dosage forms is a function of the s a function of the formulatioformulation and the route of administran and the route of administrationtion..

A problem associaA problem associated with the oralted with the oral a administration of a dministration of a drug is that once adrug is that once absorbed through tbsorbed through the lumen of the gahe lumen of the gastrointestinal tracstrointestinal tract into the portal vet into the portal vein, the drug may pin, the drug may pass directly to the ass directly to the liver and undergo liver and undergo the first-pass effecthe first-pass effect.t.

The bioavailable fraction is determinThe bioavailable fraction is determined by the fraction of drug that is absoed by the fraction of drug that is absorbed from the gastrointestinal tract arbed from the gastrointestinal tract and the fraction that escapes metabolind the fraction that escapes metabolism during its first pass through the lism during its first pass through the liver.ver.

f=fraction of drug absorbedf=fraction of drug absorbedfraction fraction escaping first-pass metabolismescaping first-pass metabolism

The flow of blood through the The flow of blood through the liver can be decreased under liver can be decreased under certain conditions.certain conditions.

Consequently, the Consequently, the bioavailability of those drugs bioavailability of those drugs that undergo a first-pass effect that undergo a first-pass effect then would be expected to then would be expected to increase, e.g. cirrhotic patients.increase, e.g. cirrhotic patients.

1) Oral route1) Oral route

The oral route is considered the most The oral route is considered the most natural, uncomplicated, convenient, natural, uncomplicated, convenient, and safeand safe means of administering drugs. means of administering drugs.

DisadvantagesDisadvantages Slow drug responseSlow drug response Chance of irregular absorption of drugsChance of irregular absorption of drugs The amount or type of food present within The amount or type of food present within

the gastrointestinal tractthe gastrointestinal tract The destruction of certain drugs by the acid The destruction of certain drugs by the acid

reaction of the stomach or by reaction of the stomach or by gastrointestinal enzymes.gastrointestinal enzymes.

Dosage forms applicableDosage forms applicable

Drugs are administered by the Drugs are administered by the oral route in a variety of oral route in a variety of pharmaceutical forms.pharmaceutical forms.

The most popular are The most popular are tabletstablets, , capsulescapsules, , suspensions suspensions and and various pharmaceutical various pharmaceutical solutionssolutions..

Capsules are solid dosage forms in Capsules are solid dosage forms in which the drug substance and which the drug substance and appropriate pharmaceutical adjuncts appropriate pharmaceutical adjuncts as fillers are enclosed in either a hard as fillers are enclosed in either a hard or a soft “shell”, generally composed or a soft “shell”, generally composed of a form of gelatin.of a form of gelatin.

Drug material are released from Drug material are released from capsules faster than from tablets. capsules faster than from tablets.

Suspensions are preparations of Suspensions are preparations of finely divided drugs held in finely divided drugs held in suspension throughout a suitable suspension throughout a suitable vehicle. vehicle.

Suspensions are taken orally Suspensions are taken orally generally employ an aqueous vehicle.generally employ an aqueous vehicle.

Nearly all suspensions must be Nearly all suspensions must be shaken before use because they tend shaken before use because they tend to settle.to settle.

Suspension are a useful means to Suspension are a useful means to administer large amounts of solid administer large amounts of solid drugs that would be inconveniently drugs that would be inconveniently taken in tablet or capsule form.taken in tablet or capsule form.

Drugs administered in aqueous Drugs administered in aqueous solution are absorbed much more solution are absorbed much more rapidly than those administered rapidly than those administered in solid form, because the in solid form, because the processes of disintegration and processes of disintegration and dissolution are not required.dissolution are not required.

Among the solutions frequently Among the solutions frequently administered orally are administered orally are elixirselixirs, , syrups and solutions.syrups and solutions.

Absorption Absorption Absorption of drugs after oral administratioAbsorption of drugs after oral administratio

n may occur at the various body sites betwen may occur at the various body sites between the mouth and rectum. en the mouth and rectum.

The higher up a drug is absorbed along the lThe higher up a drug is absorbed along the length of the alimentary tract, the more rapiength of the alimentary tract, the more rapid will be its action, a desirable feature in mod will be its action, a desirable feature in most instances.st instances.

The differences in the chemical and physicaThe differences in the chemical and physical nature among drug substances, a given drul nature among drug substances, a given drug may be better absorbed from one site than g may be better absorbed from one site than from another within the alimentary tract.from another within the alimentary tract.

Oral cavity

Oral or sublingual

Gastrointestinal tract

2) Rectal route2) Rectal route

Some drugs are administered Some drugs are administered rectally for their rectally for their local effectslocal effects and and others for their others for their systemic effectssystemic effects..

Drugs given rectally may be Drugs given rectally may be administered as administered as solutions, solutions, suppositories, or ointmentssuppositories, or ointments..

Suppositories are Suppositories are defined as solid defined as solid bodies of various bodies of various weights and shapes weights and shapes intended for intended for introduction into a introduction into a body orifice where body orifice where they soften, melt, they soften, melt, or dissolve, release or dissolve, release their medication, their medication, and exert their and exert their drug effects.drug effects.

应用范围： Rectal administration for systemic act

ion may be preferred for those drugs destroyed or inactivated by the environments of the stomach and intestines.

The administration of drugs by the rectal route may also be indicated when the oral route is precluded because of vomiting or when the patient is unconscious or incapable of swallowing drugs safety without choking.

3) Parenteral route3) Parenteral route The three primary routes of parenteral The three primary routes of parenteral

administration are subcutaneous, intradministration are subcutaneous, intramuscular, and intravenous although tamuscular, and intravenous although there are others such as intracardiac ahere are others such as intracardiac and intraspinal.nd intraspinal.

使用范围：使用范围： Drugs destroyed or inactivated in the gDrugs destroyed or inactivated in the g

astrointestinal tract or too poorly absoastrointestinal tract or too poorly absorbed to provide satisfactory response rbed to provide satisfactory response may be parenterally administered. may be parenterally administered.

The parenteral route is also preferreThe parenteral route is also preferred when rapid absorption is essential, d when rapid absorption is essential, as in emergency situations.as in emergency situations.

The parenteral route of administratiThe parenteral route of administration is especially useful in treating paton is especially useful in treating patients who are uncooperative, unconsients who are uncooperative, unconscious, or otherwise unable to accept cious, or otherwise unable to accept oral medication.oral medication.

Dosage forms applicableDosage forms applicable Pharmaceutically, Pharmaceutically, injectable preparatinjectable preparat

ionsions are usually either sterile suspensi are usually either sterile suspension or solutions of a drug substance in on or solutions of a drug substance in water or in a suitable vegetable oil.water or in a suitable vegetable oil.

Drugs in solution act more rapidly thaDrugs in solution act more rapidly than drugs in suspension, with an aqueoun drugs in suspension, with an aqueous vehicle providing faster action in eacs vehicle providing faster action in each instance than an oleaginous vehicle.h instance than an oleaginous vehicle.

Dosage forms applicableDosage forms applicable Subcutaneous Injections (Subcutaneous Injections ( 皮 下 注 射皮 下 注 射 ))

(sc)(sc) Intramuscular Injection (Intramuscular Injection ( 肌肉注射肌肉注射 ) (i) (i

m)m) Intravenous Injections (Intravenous Injections ( 静脉注射静脉注射 )(iv))(iv) Intradermal Injections (Intradermal Injections ( 皮内注射皮内注射 ) (i) (i

d)d)

4) Epicutaneous route4) Epicutaneous routeDrugs are administered topically, Drugs are administered topically, or applied to the skin, for their or applied to the skin, for their action at the site of application action at the site of application or for systemic drug effects.or for systemic drug effects.

Drug absorption via the skin is Drug absorption via the skin is enhanced enhanced

if the drug substance is in if the drug substance is in solution,solution,

if it has a favorable lipid/water if it has a favorable lipid/water partition coefficient,partition coefficient,

if it is a non-electrolyte.if it is a non-electrolyte.

Drugs that are aDrugs that are absorbed enter thbsorbed enter the skin by way of e skin by way of the pores, sweat the pores, sweat glands, hair folliglands, hair follicles, sebaceous cles, sebaceous glands, and otheglands, and other anatomic strucr anatomic structures of the skitures of the skin’s surface.n’s surface.

Among the few drugs currently emplAmong the few drugs currently employed topically to the skin surface for oyed topically to the skin surface for percutaneous absorption and systempercutaneous absorption and systemic action areic action are

nitroglycerin (antianginal), nitroglycerin (antianginal), nicotine (smoking cessation), nicotine (smoking cessation), estradiol (estrogenic hormone), estradiol (estrogenic hormone), clonidine (antihypertensive), clonidine (antihypertensive), scopolamine (antinausea/antimotion scopolamine (antinausea/antimotion

sickness).sickness).

Drugs applied to the skin for their loDrugs applied to the skin for their local action include cal action include

antiseptics,antiseptics, antifungal agents,antifungal agents, anti-inflammatory agents,anti-inflammatory agents, local anesthetic agents,local anesthetic agents, skin emollients,skin emollients, protectants against environmental cprotectants against environmental c

onditions.onditions.

5) Ocular, oral, and nasal 5) Ocular, oral, and nasal routesroutes

Ophthalmic solutions and Ophthalmic solutions and suspensions are sterile aqueous suspensions are sterile aqueous preparations with other preparations with other quantities essential to the safety quantities essential to the safety and comfort of the patient.and comfort of the patient.

Ophthalmic ointments must be Ophthalmic ointments must be sterile, and also free of sterile, and also free of grittiness.grittiness.

Nasal preparatioNasal preparations are usually solns are usually solutions or suspensutions or suspensions administereions administered by drops or as a d by drops or as a fine mist from a nfine mist from a nasal spray contaiasal spray container.ner.

V. Fate of drug after V. Fate of drug after absorptionabsorption

After absorption into the general After absorption into the general circulation from any route of circulation from any route of administration, a drug may become administration, a drug may become bound to blood proteins and delayed bound to blood proteins and delayed in its passage into the surrounding in its passage into the surrounding tissues.tissues.

Many drug substances may be highly Many drug substances may be highly bound to blood protein and others bound to blood protein and others little-bound.little-bound.

The degree of drug binding to plasma prThe degree of drug binding to plasma proteins is usually expressed as a percentaoteins is usually expressed as a percentage or as a fraction (ge or as a fraction () of the bound conc) of the bound concentration (Centration (Cbb) to the total concentration ) to the total concentration (C(Ctt), bound plus unbound (C), bound plus unbound (Cuu) drug:) drug: =C=Cbb/(C/(Cuu+C+Cbb)=C)=Cbb/C/Ctt

Drugs having an alpha value of greater tDrugs having an alpha value of greater than han 0.90.9 are considered highly bound (90 are considered highly bound (90%); those drugs with an alpha value of le%); those drugs with an alpha value of less than ss than 0.20.2 are considered to be little pr are considered to be little protein bound. otein bound.

Bound drug is neither exposed to the boBound drug is neither exposed to the body’s detoxication (metabolism) processdy’s detoxication (metabolism) processes nor is it filtered through the renal gloes nor is it filtered through the renal glomeruli.meruli.

Bound drug is therefore referred to as thBound drug is therefore referred to as the e inactive portioninactive portion in the blood, and unbo in the blood, and unbound drug, with its ability to penetrate celund drug, with its ability to penetrate cells, is termed the ls, is termed the active blood portionactive blood portion. .

The bound portion of drug serves as The bound portion of drug serves as a a drug reservoir or a depotdrug reservoir or a depot, from , from which the drug is released as the which the drug is released as the free form when the level of free drug free form when the level of free drug in the blood no longer is adequate to in the blood no longer is adequate to ensure protein saturation.ensure protein saturation.

For this reason a drug that is For this reason a drug that is highly highly protein boundprotein bound may remain in the may remain in the body body for longer periods of timefor longer periods of time and and require require less frequent dosage less frequent dosage administrationadministration than another drug than another drug that may be only slightly protein that may be only slightly protein bound and may remain in the body bound and may remain in the body for only a short period of time.for only a short period of time.

A drug’s binding to blood A drug’s binding to blood proteins may be affected by the proteins may be affected by the simultaneous presence of a simultaneous presence of a second (or more) drugs.second (or more) drugs.

The additional drugs may result The additional drugs may result in drug effects or durations of in drug effects or durations of drug action quite dissimilar to drug action quite dissimilar to that found when each is that found when each is administered alone.administered alone.

1. Drug metabolism1. Drug metabolism

Biotransformation is a term used to Biotransformation is a term used to indicate the chemical changes that indicate the chemical changes that occur with drugs within the body as occur with drugs within the body as they are metabolized and altered by they are metabolized and altered by various biochemical mechanismsvarious biochemical mechanisms..

The process of biotransformation is The process of biotransformation is commonly referred to as the commonly referred to as the “detoxification” or “inactivation” “detoxification” or “inactivation” process.process.

The biotransformation of a drug The biotransformation of a drug results in its conversion to one or more results in its conversion to one or more compounds that arecompounds that are

more water soluble,more water soluble, more ionized,more ionized, less capable of being stored in fat less capable of being stored in fat

tissue,tissue, less able to penetrate cell membranes,less able to penetrate cell membranes, less active pharmacologically,less active pharmacologically, less toxic and is more readily excreted.less toxic and is more readily excreted.

There are four principal chemical reactiThere are four principal chemical reactions involved in the metabolism of drugs:ons involved in the metabolism of drugs:

oxidationoxidation reductionreduction hydrolysishydrolysis conjugationconjugation

Other metabolic processes, including mOther metabolic processes, including methylation, and acylation conjugation reethylation, and acylation conjugation reactions, occur with certain drugs to fostactions, occur with certain drugs to foster elimination.er elimination.

Several examples of biotransformations Several examples of biotransformations occuring within the body are as follows:occuring within the body are as follows:

AcetaminophenAcetaminophen Acetaminophen glucAcetaminophen glucuronideuronide

AmoxapineAmoxapine 8-hydroxy-amoxapine8-hydroxy-amoxapine

ProcainamideProcainamide p-Aminobenzoic acidp-Aminobenzoic acid

NitroglycerinNitroglycerin 1-2and 1-3 dinitroglycerol1-2and 1-3 dinitroglycerol

conjugation

oxidation

hydrolysis

reduction

It is important to mention that It is important to mention that several factors influence drug several factors influence drug metabolism.metabolism.

species differencesspecies differences age of the patientage of the patient diet diet presence of disease statespresence of disease states

2. Excretion of drugs2. Excretion of drugs

The kidney plays the dominant role The kidney plays the dominant role by eliminating drugs via the urine.by eliminating drugs via the urine.

Drug excretion with the feces is Drug excretion with the feces is also important, especially for drugs also important, especially for drugs that are poorly absorbed and that are poorly absorbed and remain in the gastrointestinal tract remain in the gastrointestinal tract after oral administration. after oral administration.

Exit through the bile is significant only Exit through the bile is significant only when the drug’s reabsorption from thwhen the drug’s reabsorption from the gastrointestinal tract is minimal. e gastrointestinal tract is minimal.

The lungs provide the exit for many volThe lungs provide the exit for many volatile drugs through the expired breath.atile drugs through the expired breath.

The sweat glands, saliva, and milk play The sweat glands, saliva, and milk play only minor roles in drug elimination.only minor roles in drug elimination.

VI. Pharmacokinetic VI. Pharmacokinetic PrinciplesPrinciples

Pharmacokinetic analysis utilizes Pharmacokinetic analysis utilizes mathematical modelsmathematical models to simplify or to simplify or simulate the disposition of the drug simulate the disposition of the drug in the body.in the body.

The principal assumption is that the The principal assumption is that the human body may be represented by human body may be represented by one or more compartmentsone or more compartments in which in which a drug resides in a dynamic state for a drug resides in a dynamic state for a short period of time.a short period of time.

The simplest pharmaThe simplest pharmacokinetic model is thcokinetic model is the single compartmene single compartment open-model system. t open-model system.

This model depicts tThis model depicts the body as one comphe body as one compartment characterizeartment characterized by a certain volumd by a certain volume of distribution (Ve of distribution (Vdd) ) that remains constanthat remains constant.t.

For drugs whose For drugs whose distribution distribution follows first-order, follows first-order, one-compartment one-compartment pharmacokinetics, pharmacokinetics, a plot of the a plot of the logarithm of the logarithm of the concentration of concentration of drug in the plasma drug in the plasma (or blood) versus (or blood) versus time will yield a time will yield a straight line. straight line.

The equation that describes the plasma The equation that describes the plasma decay curve is decay curve is

CCpp=C=C00ee-Kelt-Kelt

where where KKelel is the first-order rate of eli is the first-order rate of elimination of the drug from the body, mination of the drug from the body,

CCpp is the concentration of the drug at t is the concentration of the drug at time equal to t, ime equal to t,

CC00 is the concentration of drug at time is the concentration of drug at time equal to zero.equal to zero.

LogCLogCpp = LogC = LogC00-K-Kelel/2.303(t)/2.303(t)

Most drugs administered orally can Most drugs administered orally can be adequately described using a one-be adequately described using a one-compartment model.compartment model.

Drugs administered by Drugs administered by rapid intraverapid intravenous infusionnous infusion are usually described are usually described by a two-compartment or three comby a two-compartment or three compartment model system.partment model system.

In the two-In the two-compartment compartment system, a drug system, a drug enters intoenters into and is and is instantaneously instantaneously distributed distributed throughout the throughout the central central compartment.compartment.

Its subsequent Its subsequent distribution into the distribution into the second or peripheral second or peripheral compartment is compartment is slower.slower.

The central coThe central compartment is umpartment is usually considersually considered to include thed to include the e bloodblood, , the extthe extracellular spacracellular spacee, and , and organs worgans with good blood ith good blood perfusionperfusion, e.g., , e.g., lungs, liver, kidlungs, liver, kidneys, heart.neys, heart.

Note the initial Note the initial steep decline of steep decline of the plasma drug the plasma drug concentration concentration curve. curve.

This typifies the This typifies the distribution of distribution of the drug from the the drug from the central central compartment to compartment to the peripheral the peripheral compartment.compartment.

A semi-A semi-logarithmic plot logarithmic plot of the plasma of the plasma concentration concentration versus timeversus time after after rapid intravenous rapid intravenous injection of a injection of a drug which is best drug which is best described by a described by a two-compartment two-compartment model system can model system can often be resolved often be resolved into two linear into two linear components.components.

The slope of the feathered line (-a/2.30The slope of the feathered line (-a/2.303) and the extrapolated line (-b/2.303) a3) and the extrapolated line (-b/2.303) and the intercepts, A and B, are determind the intercepts, A and B, are determined.ned.

CCpp=Ae=Ae-at-at+Be+Be-bt-bt

This is a bi-exponential equation which This is a bi-exponential equation which describes the two-compartment system.describes the two-compartment system.

1. Half life1. Half life The half-life (TThe half-life (T1/21/2) of a drug describes ) of a drug describes

the time required for a drug’s blood or the time required for a drug’s blood or plasma concentration to decrease by plasma concentration to decrease by one half.one half.

The biological half-life of a drug in the The biological half-life of a drug in the blood may be determined graphically blood may be determined graphically off of a pharmacokinetic plot of a off of a pharmacokinetic plot of a drug’s blood-concentration time plot, drug’s blood-concentration time plot, typically after intravenous typically after intravenous administration to a sample population.administration to a sample population.

The half-life can also be mathematicThe half-life can also be mathematically determined.ally determined.

KKelelt/2.303=log Ct/2.303=log C00 -logC -logCpp=log C=log C00 /C /Cpp

If it assumed that CIf it assumed that Cpp is equal to one-h is equal to one-half of Calf of C00

pp, the equation will become:, the equation will become: KKelelt/2.303= log Ct/2.303= log C00/0.5C/0.5C00=log2=log2

Thus,Thus,tt1/21/2=2.303log2/K=2.303log2/Kelel=0.693/K=0.693/Kelel

KKelel=0.693/t=0.693/t1/21/2

Data on a drug’s biologic half-life Data on a drug’s biologic half-life are useful in determining the are useful in determining the most appropriate dosage regimen most appropriate dosage regimen to achieve and maintain the to achieve and maintain the desired blood level of drug. desired blood level of drug.

Such determinations usually Such determinations usually result in such recommended result in such recommended dosage schedules for a drug, as dosage schedules for a drug, as the drug to be taken every 4 the drug to be taken every 4 hours, 6 hours, 8 hours, etc.hours, 6 hours, 8 hours, etc.

2. Concept of clearance2. Concept of clearance

The three main mechanisms by which a drug The three main mechanisms by which a drug is removed or cleared from the body includeis removed or cleared from the body include

The hepatic metabolism, i.e., hepatic clearanThe hepatic metabolism, i.e., hepatic clearance, Clce, Clhh, of a drug to either an active or inactiv, of a drug to either an active or inactive metabolite,e metabolite,

The renal excretion, i.e., renal clearance, ClThe renal excretion, i.e., renal clearance, Clrr, , of a drug unchanged in the urine,of a drug unchanged in the urine,

Elimination of the drug into the bile and subsElimination of the drug into the bile and subsequently into the intestines for excretion in fequently into the intestines for excretion in feces.eces.

In the one compartment model descrIn the one compartment model described earlier, total body clearance is tibed earlier, total body clearance is the product of the volume of distributhe product of the volume of distribution, Vion, Vdd, and the overall rate of elimin, and the overall rate of elimination, kation, kelel::

ClClBB=V=Vddkkelel

tt1/21/2=0.693V=0.693Vdd/Cl/ClBB

tt1/21/2=0.693V=0.693Vdd/(Cl/(Clhh+Cl+Clrr))

3. Dosage regimen 3. Dosage regimen considerationsconsiderations

There are two approaches to the There are two approaches to the development of dosage regimens:development of dosage regimens:

1) 1) The empirical approachThe empirical approach, which , which involves the administration of a involves the administration of a drug in a drug in a certain quantitycertain quantity, noting , noting the the therapeutic responsetherapeutic response and then and then modifying the dosage of drug and modifying the dosage of drug and the dosing interval accordingly. the dosing interval accordingly.

2) 2) The kinetic approachThe kinetic approach is based on the is based on the assumption that the therapeutic and assumption that the therapeutic and toxic effects of a drug are related to the toxic effects of a drug are related to the amount of drug in the body or to the amount of drug in the body or to the plasma concentration of drug at the plasma concentration of drug at the receptor site.receptor site.

Through careful pharmacokinetic Through careful pharmacokinetic evaluation of a drug’s absorption, evaluation of a drug’s absorption, distribution, metabolism and excretion distribution, metabolism and excretion in the body from a single dose, the in the body from a single dose, the levels of drug attained from multiple levels of drug attained from multiple dosing can be estimated.dosing can be estimated.

When one considers the development of When one considers the development of a dosage regimen, a number of factors tha dosage regimen, a number of factors that should be consideredat should be considered

1)1) Inherent activity, i.e., pharmacodynamicInherent activity, i.e., pharmacodynamics, and toxicity, i.e., toxicology of the drug.s, and toxicity, i.e., toxicology of the drug.

2)2) The pharmcokinetics of the drug, which The pharmcokinetics of the drug, which are influenced by the dosage form in whiare influenced by the dosage form in which the drug is administered to the patient,ch the drug is administered to the patient, e.g., biopharmaceutical considerations. e.g., biopharmaceutical considerations.

3) The patient to whom the drug will b3) The patient to whom the drug will be given and encompasses the clinical e given and encompasses the clinical state of the patient and how the patiestate of the patient and how the patient will be managed.nt will be managed.

4) A typical factors may influence the 4) A typical factors may influence the dosage regimen.dosage regimen.

The dosage regimen of a drug may simply The dosage regimen of a drug may simply involve the administration of a drug once involve the administration of a drug once for its desired therapeutic effect, e.g. for its desired therapeutic effect, e.g. pinworm medication, or encompass the pinworm medication, or encompass the administration of drug for a specific time administration of drug for a specific time through multiple doses.through multiple doses.

The objective of pharmacokinetic dosing The objective of pharmacokinetic dosing

is to design a dosage regimen that will is to design a dosage regimen that will continually maintain a drug’s therapeutic continually maintain a drug’s therapeutic serum or plasma concentration within the serum or plasma concentration within the drug’s therapeutic index, i.e., above the drug’s therapeutic index, i.e., above the minimum effective concentration but minimum effective concentration but below the minimum toxic level.below the minimum toxic level.

QuestionsQuestions11．．What are general principles of drug absorptionWhat are general principles of drug absorption？？22．．Write Henderson-Hasselbalch equation and exWrite Henderson-Hasselbalch equation and ex

plain it.plain it.33．．What is Noyes-Whitney equation? What is Noyes-Whitney equation? 44．．What factors could affect drug absorption?What factors could affect drug absorption?55．． Describe the routes of drug administration and Describe the routes of drug administration and

their characteristicstheir characteristics？？66．．What is biotransformationWhat is biotransformation？？What are the biocWhat are the bioc

hemical mechanisms of biotransformation?hemical mechanisms of biotransformation?77．． Explain shortly about one compartment model Explain shortly about one compartment model

and two compartment modeland two compartment model？？88．． How to develop dosage regimensHow to develop dosage regimens？？