Bioavailability and Bioequivalence PDF

BIOAVAILABILITY AND BIOEQUIVALENCE Roshan Kumar Chaurasiya Chitwan Medical College 9/19/2024 1  Introduction ―Bioavailability is a term used to indicate the fractional extent to which a dose of drug reaches...

BIOAVAILABILITY AND BIOEQUIVALENCE Roshan Kumar Chaurasiya Chitwan Medical College 9/19/2024 1  Introduction ―Bioavailability is a term used to indicate the fractional extent to which a dose of drug reaches its site of action or a biological fluid from which the drug has access to its site of action.‖ (Goodman & Gillman). ―The term Bioavailability is defined as a rate & extent (amount) of absorption of unchanged drug from its dosage form.‖ 9/19/2024 2  Pharmaceutical equivalents: Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredient(s), have the same dosage form and route of administration, and are identical in strength or concentration. 9/19/2024 3  Pharmaceutical alternatives: These are drug products that contain the same active moiety but contain different chemical forms such as esters or salts of the active moiety or they may differ from the innovator‘s product in the dosage form or strength. Reference listed drug (RLD): A reference listed drug is an approved drug product to which new generic versions are compared to show that they are bioequivalent. If the size of the dose to be administered is same, then bioavailability of a drug from its dosage form depends upon 3 major factors : 1. Pharmacological factors related to physicochemical properties of the drug and characteristics of the dosage form. 2. Patient – related factors. 3. Route of administration. Within the parenteral route, intravenous injection of a drug results in 100% bioavailability as the absorption process is bypassed. However, for reason of stability and convenience, most drug are administered orally. 9/19/2024 4  The amount of drug that reaches the systemic circulation (i.e. extent of absorption) is called as systemic availability or simply availability. The term bio available fraction F, refers to the fraction of administered dose that enters the systemic circulation. Bio available dose F = --------------------------------- Administered dose To exert an optimal therapeutic action an active moiety should be delivered to its site of action in an effective concentration for the desired period. 9/19/2024 5  Objectives of bioavailability Bioavailability studies are important in the – 1. Primary stages of development of a suitable dosage form for a new drug entity to obtain evidence of its therapeutic utility. 2. Determination of influence of - excipients, - patient related factors, - possible interaction with other drugs on the efficiency of absorption. 3. Development of new formulations of the existing drugs. 4. Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage and stability on drug absorption. 5. Comparison of availability of a drug substance from different dosage forms or form the same dosage form produced by different manufacturers 9/19/2024 6  Significance of Bioavailability Drugs having low therapeutic index, e.g. cardiac glycosides, quinidine, phenytoin etc. and narrow margin of safety e.g. antiarrythmics, antidiabetics, adrenal steroids, theophylline. Drugs whose peak levels are required for the effect of drugs, e.g. phenytoin, phenobarbitone, primidone, sodium valporate, antihypertensives, antidiabetics and antibiotics. Drugs that are absorbed by an active transport, e.g. amino acid analogues, purine analogues etc. In addition, any new formulation has to be tested for its bioavailability profile 9/19/2024 7  Drugs which are disintegrated in the alimentary canal and liver, e.g. chlorpromazine etc. or those which under go first pass metabolism. Formulations that give sustained release of drug, formulations with smaller disintegration time than dissolution rate and drugs used as replacement therapy also warrant bioavailability testing. 9/19/2024 8  Components Rate of absorption – The rapidity with which the drug is absorbed. - Rapid onset : conditions like acute attack of asthma, intense acute pain - Slower onset : To prolong duration of action. To avoid adverse effects. Extent of absorption -chronic conditions like Epilepsy. 9/19/2024 9  Absolute Bioavailability ( F ) ―When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration ,is called as absolute bioavailability‖. Dose (iv) x AUC (oral) % Absorption = ------------------------------- x 100 Dose (oral) x AUC (iv) It is denoted by symbol F. Its determination is used to characterize a drug‘s inherent absorption properties from the e.v. Site. 9/19/2024 10  Relative Bioavailability ( Fr ) ―When the systemic availability of the drug after oral administration is compared with that of oral standard of same drug ( such as aqueous or non aqueous solution or a suspension ) is referred as Relative Bioavailability or comparative ‖. e.g. comparison between cap. Amox and susp. Amox It is used to characterize absorption of a drug from its formulation. It is denoted by symbol Fr. Relative Bioavailability = [AUC]test (Dose)std [AUC]std (Dose)test 9/19/2024 11 Single Dose vs Multiple Dose Studies Single dose study Advantages More common Easy less tedious Less exposure to drug. Difficult to predict steady state characteristics. 9/19/2024 12 Multiple dose study Advantages Accurate. Easy to predict the peak & valley characteristics of drug. Few blood samples required. Ethical. Small inter subject variability. Better evaluation of controlled release formulations. Can detect non linearity in pharmacokinetics. Higher blood levels ( d/t cumulative effect ). Eliminates the need for long wash out period between doses. Disadvantages Poor subject compliance. Tedious , time consuming. More drug exposure. More difficult and costly. 9/19/2024 13 9/19/2024 14  Plasma Level- Time Studies Most common type of human bioavailability studies. Based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action. The method is based on the assumption of 2 dosage forms that exhibit super imposable plasma level time profiles in a group of subject should result in identical therapeutic activity. With single dose study, the method requires collection of serial blood samples for a period of 2 to 3 biological half lives after drug administration, their analysis for drug concentration and making a plot of concentration versus corresponding time of sample collection to obtain the plasma level – time profile. With i.v. Dose, sampling should start within 5 minutes of drug administration and subsequent samples taken at 15 minute intervals. 9/19/2024 15 Bioavailability (the rate and extent of drug absorption) is generally assessed by the determination of following three parameters. They are.. Cmax (Peak plasma concentration) tmax(time of peak) Area under curve 9/19/2024 16 9/19/2024 17 Cmax: (Peak plasma drug concentration) Maximum concentration of the drug obtained after the administration of single dose of the drug. Expressed in terms of μg/ml or mg/ml. tmax: (Time of peak plasma conc.) Time required to achieve peak concentration of the drug after administration. Gives indication of the rate of absorption. Expressed in terms of hours or minutes. 9/19/2024 18 9/19/2024 19 9/19/2024 20 9/19/2024 21 PLANIMETER: Instrument for mechanically measuring the area under the curve. Measures area by tracing outline of curve. Disadvantage: Degree of error is high due to instrumental & human error. COUNTING THE SQUARE : Total no. of squares enclosed in the curve is counted. Area of each square determined using relationship: AREA=(height) (width) 9/19/2024 22 9/19/2024 23 9/19/2024 24 9/19/2024 25  Urinary Excretion Studies Urinary excretion of unchanged drug is directly proportional to plasma concentration of drug. Thus, even if a drug is excreted to some extent (at least 10 to 20%) in the urine, bioavailability can be determined. eg: Thiazide diuretics, Sulphonamides. Method is useful when there is lack of sufficiently sensitive analytical technique to measure drug concentration. Noninvasive method, so better patient compliance. 9/19/2024 26 9/19/2024 27 9/19/2024 28 9/19/2024 29 9/19/2024 30  BIOEQUIVALENCE STUDIES It is a relative term which denotes that the drug substance in two or more identical dosage forms, reaches the systemic circulation at the same relative rate and to the same relative extent i.e. their plasma concentration-time profiles will be identical without significant statistical differences. When statistically significant differences are observed in the bioavailability of two or more drug products, bio- inequivalence is indicated. Chemical Equivalence: It indicates that two or more drug products contain the same labeled chemical substance as an active ingredient in the same amount. 9/19/2024 31  Pharmaceutical Equivalence: This term implies that two or more drug products are identical in strength, quality, purity, content uniformity and disintegration and dissolution characteristics; they may however differ in containing different excipients. Therapeutic Equivalence: This term indicates that two or more drug products that contain the same therapeutically active ingredient elicit identical pharmacological effects and can control the disease to the same extent. 9/19/2024 32  Types of Bioequivalence Studies In vivo, or In vitro. 9/19/2024 33  In vivo Bioequivalence Studies The following sequence of criteria is useful in assessing the need for in vivo studies: 1. Oral immediate release products with systemic action Indicated for serious conditions requiring assured response Narrow therapeutic margin Pharmacokinetics complicated by absorption < 70% or absorption window, nonlinear kinetics, presystemic elimination > 70% Unfavourable physiochemical properties, e.g. low solubility, metastable modifications, instability, etc. Documented evidence for bioavailability problems No relevant data available, unless justification by applicant that in vivo study is not necessary. 2. Non-oral immediate release products. 3. Modified release products with systemic action. 9/19/2024 34  In vitro Bioequivalence Studies If none of the above criteria is applicable, comparative in vitro dissolution studies will suffice. In vitro studies, i.e. dissolution studies can be used in lieu of in vivo bioequivalence under certain circumstances, called as biowaivers (exemptions) – 1. The drug product differs only in strength of the active substance it contains, provided all the following conditions hold – Pharmacokinetics are linear The qualitative composition is the same The ratio between active substance and the excipients is the same, or (in the case of small strengths) the ratio between the excipients is the same Both products are produced by the same manufacturer at the same production site A bioavailability or bioequivalence study has been performed with the original product Under the same test conditions, the in vitro dissolution rate is the same. 9/19/2024 35  Bioequivalence Experimental Study Design 1. Completely randomised designs In a completely randomised design, all treatments (factor levels) are randomly allocated among all experimental subjects. Method of randomisation Label all subjects with the same number of digits, for e.g., if there are 20 subjects, number them from 1 to 20. Randomly select non-repeating random numbers (like simple randomisation) with among these labels for the first treatment, and then repeat for all other treatments. Advantages 1) The design is extremely easy to construct. 2) It can accommodate any number of treatments and subjects. 3) The design is easy and simple to analyse even though the sample sizes might not be the same for each treatment. 9/19/2024 36  Disadvantages 1) Although the design can be used for any number of treatments, it is best suited for situations in which there are relatively few treatments. 2) All subjects must be as homogeneous as possible. Any extraneous sources of variability will tend to inflate the random error term, making it difficult to detect differences among the treatment (or factor level) mean responses. 9/19/2024 37  2. Randomised block designs First, subjects are sorted into homogeneous groups, called blocks and the treatments are then assigned at random within the blocks. Method of Randomisation Subjects having similar background characteristics are formed as blocks. Then treatments are randomised within each block, just like the simple randomisation. Randomisations for different blocks are done independent of each other. Advantages 1) With effective and systematic way of grouping, it can provide substantially more precise results than a completely randomised design of comparable size. 2) It can accommodate any number of treatments or replications. 3) Different treatments need not have equal sample size. 4) The statistical analysis is relatively simple. The design is easy to construct 9/19/2024 38  Disadvantages 1) Missing observations within a block require more complex analysis. 2) The degrees of freedom of experimental error are not as large as with a completely randomised design. 9/19/2024 39 3. Repeated measures, cross-over and carry-over designs This is essentially a randomised block design in which the same subject serves as a block. The same subject is utilized for each of the treatments under study. Since we take repeated measures on each subject we get the design name ―repeated measures design. The study may involve several treatments or a single treatment evaluated at different points in time. The administration of two or more treatments one after the other in a specified or random order to the same group of patients is called a crossover design or change- over design. The drawback of crossover studies is the potential for distortion due to carry-over, that is, residual effects from preceding treatments. To prevent carry-over effects, one must always allow for a wash-out period during which most of the drug is eliminated from the body – generally about 10 elimination half-lives. Example: clinical trials to monitor safety and side effects. 9/19/2024 40 Method of Randomisation Complete randomisation is used to randomise the order of treatments for each subject. Randomisations for different subjects are independent of each other. Advantages 1) They provide good precision for comparing treatments because all sources of variability between subjects are excluded from the experimental error. 2) It is economic on subjects. This is particularly important when only a few subjects can be utilized for the experiments. 3) When the interest is in the effects of a treatment over time, it is usually desirable to observe the same subject at different points in time rather than observing different subjects at the specified points in time. Disadvantages 1) There may be an order effect, which is connected with the position in the treatment order. 2) There may be a carry-over effect, which is connected with the preceding treatment or treatments. 9/19/2024 41  4. Latin square designs Completely randomised design, randomised block design and repeated measures design are experiments where the person/subject/volunteer remains on the treatment from the start of the experiment until the end and thus are called as continuous trial. In a Latin square, however, each subject receives each treatment during the course of the experiment. A Latin square design is a two-factor design (subjects and treatments are the two factors) with one observation in each cell. Such a design is useful compared the earlier ones when three or more treatments are to be compared and carry-over effects are balanced. In a Latin square design, rows represent subjects, and columns represent treatments. 9/19/2024 42 Randomised, balanced, cross-over Latin square design are commonly used for bioequivalence studies. Advantages 1) It minimizes the inter-subject variability in plasma drug levels. 2) Minimizes the carry-over effects which could occur when a given dosage form influences the bioavailability of a subsequently administered product (intra-subject variability). 3) Minimizes the variations due to time effect. 4) Treatment effects can be studied from a small-scale experiment. This is particularly helpful in preliminary or pilot studies. 5) Makes it possible to focus more on the formulation variables which is the key to success for any bioequivalence study. Disadvantages 1) The use of Latin square design will lead to a very small number of degrees of freedom for experimental error when only a few treatments are studied. On the other hand, when many treatments are studied, the degrees of freedom for experimental error maybe larger than necessary. 2) The randomisation required is somewhat more complex than that for earlier designs considered. 9/19/2024 43  Elements of Bioequivalence Study Protocol 1. Title c. Inclusion/exclusion criteria a. Principal investigator i. Inclusion criteria b. Project number and date ii. Exclusion criteria 2. Study objective d. Restrictions/prohibitions 3. Study design 5. Clinical procedures a. Design a. Dosage and drug administration b. Drug Products b. Biological sampling schedule i. Test product(s) c. Activity of subjects ii. Reference product 6.Ethical considerations c. Dosage regimen a.Basic principles d. Sample collection schedule b. Institutional review board e. Housing c. Informed consent f. Fasting/meals schedule d. Indications for subject withdrawal g. Analytical methods e. Adverse reactions and emergency procedures 4. Study population 7. Facilities a. Subjects 8. Data analysis b. Subject selection 9/19/2024 a. Analytical validation procedure 44 b. Statistical treatment of data 9. Drug accountability 10. Appendix 9/19/2024 45  Single dose bioequivalence study and relevant statistics The in vivo bioequivalence study requires determination of relative bioavailability after administration of a single dose of test and reference formulations by the same route, in equal doses, but at different times. The reference product is generally a previously approved product, usually the innovator‗s product or some suitable reference standard. The study is performed in fasting, young, healthy, adult male volunteers to assure homogeneity in the population and to spare the patients, elderly or pregnant women from rigors of such a clinical investigation. Homogeneity in the study population permits focus on formulation factors. As for bioavailability studies, either plasma level or urinary excretion studies may be performed to assess bioequivalence between drug products. In vitro-in vivo correlation can also be established for the formulations. 9/19/2024 46 It is always easier to establish bioequivalence between existing drug products than determination of pharmacokinetics of a new drug or bioavailability of a new dosage form since — 1. The human volunteers used for the study of both products are same and all pharmacokinetic parameters can be assumed to be same for both drug formulations and there is no need to investigate nonlinearity. 2. The study protocol for all subjects is uniform, the efficiency of drug absorption from both formulations can be considered as same and thus differences in absorption pattern can be ascribed to differences in drug release from the two dosage form. 9/19/2024 47  Statistical Interpretation of Bioequivalence Data After the data has been collected, statistical methods must be applied to determine the level of significance of any observed difference in the rate and/or extent of absorption in order to establish bioequivalence between two or more drug products. The commonly adopted approaches to determine statistical differences are - 1. Analysis of variance (ANOVA) is a statistical procedure used to test the data for differences within and between treatment and control groups. A statistical difference between the pharmacokinetic parameters obtained from two or more drug products is considered statistically significant if there is a probability of less than 1 in 20 or 0.05 (p 0.05). The probability p is used to indicate the level of statistical significance. If p 0.05, the differences between the two drug products are not considered statistically significant. 2. Confidence interval approach – Also called as two one-sided test procedure, it is used to demonstrate if the bioavailability from the test product is too low or high in comparison to the reference product. 9/19/2024 48  Methods for enhancement of bioavailability The three conceptual approaches in overcoming the bioavailability problems of drugs are: 1. The Pharmaceutical Approach which involves modification of formulation, manufacturing process or the physicochemical properties of the drug without changing the chemical structure. 2. The Pharmacokinetic Approach in which the pharmacokinetics of the drug is altered by modifying its chemical structure. This approach is further divided into two categories – Development of new chemical entity (NCE) with desirable features Prodrug design. 3. The Biological Approach whereby the route of drug administration may be changed such as changing from oral to parenteral route. 9/19/2024 49  The second approach of chemical structure modification has a number of drawbacks of being very expensive and time consuming, requires repetition of clinical studies and a long time for regulatory approval. Moreover, the new chemical entity may suffer from another pharmacokinetic disorder or bear the risk of precipitating adverse effects. Only the pharmaceutical approach will be suitable for the enhancement of bioequivalance. 9/19/2024 50 There are several pharmaceutical ways at altering the biopharmaceutical properties – A. Enhancement of drug solubility or dissolution rate, as it is the major rate-limiting step in the absorption of most drugs. This approach applies to class II drugs according to BCS. B. Enhancement of drug permeability. This approach applies to class III drugs according to BCS. C. Enhancement of drug stability. This approach applies to class V drugs according to BCS. D. Enhancement of gastrointestinal retention. This approach can apply to class II, III or V drugs 9/19/2024 51  Enhancement of Drug Solubility or Dissolution Rate 1. Micronization: Reducing the size of the solid drug particles to 1 to 10 microns commonly by spray drying or by use of air attrition methods (fluid energy or jet mill). The process is also called as micro-milling. Examples of drugs whose bioavailability have been increased by micronization include griseofulvin and several steroidal and sulpha drugs. 9/19/2024 52 2. Nanonisation: It‗s a process whereby the drug powder is converted to nanocrystals of sizes 200 - 600 nm, e.g. amphotericin B 3. Supercritical Fluid Recrystallization: Another novel nanosizing and solubilisation technology of particle size reduction via supercritical fluid (SCF) processes. Supercritical fluids (e.g. carbon dioxide) are fluids whose temperature and pressure are greater than its critical temperature (Tc) and critical pressure (Tp), allowing it to assume the properties of both a liquid and a gas. Once the drug particles are solubilised within SCF, they may be recrystallised at greatly reduced particle sizes. 9/19/2024 53 4. Use of Surfactants: Surfactants are very useful as absorption enhancers and enhance both dissolution rate as well as permeability of drug. They enhance dissolution rate primarily by promoting wetting and penetration of dissolution fluid into the solid drug particles. They are generally used in concentration below their critical micelle concentration (CMC) values since above CMC, the drug entrapped in the micelle structure fails to partition in the dissolution fluid. Nonionic surfactants like polysorbates are widely used. Examples of drugs whose bioavailability have been increased by use of surfactants in the formulation include steroids like spironolactone. 9/19/2024 54 5. Use of Salt Forms: Salts have improved solubility and dissolution characteristics in comparison to the original drug. Alkali metal salts of acidic drugs like penicillins and strong acid salts of basic drugs like atropine are more water- soluble than the parent drug. Factors that influence salt selection are physical and chemical properties of the salt, safety of counterion, therapeutic indications and route of administration. Salt formation does have its limitations – It is not feasible to form salts of neutral compounds. It may be difficult to form salts of very weak bases or acids. The salt may be hygroscopic, exhibit polymorphism or has poor processing characteristics. Conversion of salt to free acid or base form of the drug on surface of solid dosage form that prevents or retards drug release. 9/19/2024 55  6. Use of Precipitation Inhibitors A significant increase in free drug concentration above equilibrium solubility results in supersaturation, which can lead to drug precipitation or crystallization. This can be prevented by use of inert polymers such HPMC, PVP, PVA, PEG, etc. which act by one or more of the following mechanisms - Increase the viscosity of crystallization medium thereby reducing the crystallization rate of drugs. Provide a steric barrier to drug molecules and inhibit crystallization through specific intermolecular interactions on growing crystal surfaces. Adsorb onto faces of host crystals, reduce the crystal growth rate of the host and produce smaller crystals. 9/19/2024 56 7. Alteration of pH of the Drug Microenvironment This can be achieved in two ways—in situ salt formation, and addition of buffers to the formulation e.g. buffered aspirin tablets. 8. Use of Amorphs, Anhydrates, Solvates and Metastable Polymorphs: In general, amorphs are more soluble than metastable polymorphs, anhydrates are more soluble than hydrates and solvates are more soluble than non-solvates. 9. Precipitation: In this method, the poorly aqueous soluble drug such as cyclosporine is dissolved in a suitable organic solvent followed by its rapid mixing with a non-solvent to effect precipitation of drug in nanosize particles. The product so prepared is also called as hydrosol. 9/19/2024 57 11. Selective Adsorption on Insoluble Carriers: A highly active adsorbent such as the inorganic clays like bentonite can enhance the dissolution rate of poorly water- soluble drugs such as griseofulvin, indomethacin and prednisone by maintaining the concentration gradient at its maximum. The two reasons suggested for the rapid release of drugs from the surface of clays are—the weak physical bonding between the adsorbate and the adsorbent, and hydration and swelling of the clay in the aqueous media. 12. Solid Solutions: The three means by which the particle size of a drug can be reduced to submicron level are— Use of solid solutions, Use of eutectic mixtures, and Use of solid dispersions. 9/19/2024 58  A solid solution is a binary system comprising of a solid solute molecularly dispersed in a solid solvent. Since the two components crystallize together in a homogeneous one phase system, solid solutions are also called as molecular dispersions or mixed crystals. Because of reduction in particle size to the molecular level, solid solutions show greater aqueous solubility and faster dissolution than eutectics and solid dispersions. They are generally prepared by fusion method whereby a physical mixture of solute and solvent are melted together followed by rapid solidification. Such systems, prepared by fusion, are often called as melts e.g. griseofulvin-succinic acid (Fig. 11.5). 9/19/2024 59 9/19/2024 60  13.Eutectic Mixtures: These systems are also prepared by fusion method. Eutectic melts differ from solid solutions in that the fused melt of solute-solvent show complete miscibility but negligible solid- solid solubility i.e. such systems are basically intimately blended physical mixture of two crystalline components. A phase diagram of two-component system is shown in Fig. 11.8. When the eutectic mixture is exposed to water, the soluble carrier dissolves leaving the drug in a microcrystalline state which solubilises rapidly. Fig. 9/19/2024 61 9/19/2024 62 Examples of eutectics include paracetamol-urea, griseofulvin- urea, griseofulvin-succinic acid, etc. Solid solutions and eutectics, which are basically melts, are easy to prepare and economical with no solvents involved. The method, however, cannot be applied to: Drugs which fail to crystallize from the mixed melt. Drugs which are thermolabile. Carriers such as succinic acid that decompose at their melting point. The eutectic product is often tacky, intractable or irregular crystal. 9/19/2024 63  14. Solid Dispersions These are generally prepared by solvent or co-precipitation method whereby both the guest solute and the solid carrier solvent are dissolved in a common volatile liquid solvent such as alcohol. The liquid solvent is removed by evaporation under reduced pressure or by freeze-drying which results in amorphous precipitation of guest in a crystalline carrier. Thus, the basic difference between solid dispersions and solid solutions/eutectics is that the drug is precipitated out in an amorphous form in the former as opposed to crystalline form in the latter; e.g. amorphous sulphathiazole in crystalline urea. Such dispersions are often called as co- evaporates or co-precipitates. The method is suitable for thermolabile substances but has a number of disadvantages like higher cost of processing, use of large quantities of solvent, difficulty in complete removal of solvent, etc. 9/19/2024 64  15. Molecular Encapsulation with Cyclodextrins The beta- and gamma-cyclodextrins and several of their derivatives are unique in having the ability to form molecular inclusion complexes with hydrophobic drugs having poor aqueous solubility. The molecularly encapsulated drug has greatly improved aqueous solubility and dissolution rate. There are several examples of drugs with improved bioavailability due to such a phenomenon — thiazide diuretics, barbiturates, benzodiazepines and a number of NSAIDs. 9/19/2024 65  BIOAVAILABILITY ENHANCEMENT THROUGH ENHANCEMENT OF DRUG PERMEABILITY ACROSS BIOMEMBRANE The rate-limiting step in drug absorption is transport through the intestinal epithelium owing to poor permeability. Several approaches besides the use of lipophilic prodrugs that increase the drug permeation rate are: 1. Lipid Technologies 2. Ion Pairing 3. Penetration Enhancers 9/19/2024 66  Lipid Technologies With an increase in the number of emerging hydrophobic drugs, several lipid-based formulations have been designed to improve their bioavailability by a combination of various mechanisms briefly summarized as follows: Physicochemical—Enhanced dissolution and solubility. Physiological—potential mechanisms include - Enhancement of effective luminal solubility by stimulation of secretion of bile salts, endogenous biliary lipids including phospholipids and cholesterol which together form mixed micelles and facilitate GI solubilization of drug. Reduction in gastric emptying rate thereby increasing the time available for dissolution and absorption. Increase in intestinal membrane permeability. Decreased intestinal blood flow. Decreased luminal degradation. Increased uptake from the intestinal lumen into the lymphatic system (and a reduction in first-pass hepatic and GI metabolism). 9/19/2024 67  Ion Pairing The ion pairing approach involves co-administration of a hydrophilic or polar drug with a suitable lipophilic counterion, which consequently improves the partitioning of the resultant ion-pair (relatively more lipophilic) into the intestinal membrane. In fact, the approach seems to increase the oral bioavailability of ionizable drugs, such as atenolol, by approximately 2-fold. However, it is important that a counterion possess high lipophilicity, sufficient aqueous solubility, physiological compatibility, and metabolic stability. 9/19/2024 68  Penetration Enhancers Compounds which facilitate the transport of drugs across the biomembrane are called as penetration/permeation enhancers or promoters. Penetration enhancers can be divided into three categories – 1. Substances that act very quickly have a strong effect and cause injury to the membrane (which is reversible), e.g. fatty acids such as oleic, linoleic and arachidonic and their monoglycerides. 2. Substances that act quickly, cause temporary injury but have average activity, e.g. salicylates and certain bile salts. 3. Substances having average to strong activity but cause sustained histological changes, e.g. SLS, EDTA and citric acid. 9/19/2024 69  BIOAVAILABILITY ENHANCEMENT THROUGH ENHANCEMENT OF DRUG STABILITY 1. Enteric Coating: Enteric-coated systems utilize polymeric coatings that are insoluble in the gastric media and therefore, prevent or retard drug release in the stomach. Such systems release the drug in the alkaline milieu of intestine. Bioavailability of drugs that are unstable in the gastric milieu, for e.g. erythromycin, penicillin V, pancreatin and benzimidizoles such as omeprazole can be improved by enteric coating. 9/19/2024 70 2. Complexation: Complexation, in certain instances, can be used to increase the stability of drug in the GI milieu, particularly those of ester drugs and thus enhance their oral availability. Generally speaking, β-cyclodextrins are potential carriers for achieving such objectives but other complexing agents, such as caffeine, sodium salicylate, sodium benzoate, and nicotinamide, may also be used. 9/19/2024 71 3. Use of Metabolism Inhibitors: Co-administration of a drug with low bioavailability and its metabolism inhibitor, which can selectively inhibit any of the contributing processes, would result in increased fractional absorption and hence a higher bioavailability. Current novel approaches in this area include: Bioadhesive delivery systems that can reduce the drug degradation between the delivery system and absorbing membrane by providing intimate contact with GI mucosa. Controlled-release microencapsulated systems that can provide simultaneous delivery of a drug and its specific enzyme inhibitor at the desired site for required period of time. Immobilization of enzyme inhibitors on mucoadhesive delivery systems. 9/19/2024 72  BIOAVAILABILITY ENHANCEMENT THROUGH GASTROINTESTINAL RETENTION Gastro-retentive drug delivery systems (GRDDS) are designed on the basis of delayed gastric emptying and CR principles, and are intended to restrain and localize the drug delivery device in the stomach or within the upper parts of the small intestine until the entire drug is released. Excipients that are bioadhesive or that swell on hydration when incorporated in an oral dosage form, can promote gastro- retention and absorption by – Increased contact with epithelial surfaces Prolonging residence time in the stomach Delaying intestinal transit. 9/19/2024 73  Thank you 9/19/2024 74