Biological and physicochemical factors affecting bioavailability

Biological Factors as well as physical-chemical properties of active ingredients and dosage forms design contributing to bioavailability of drugs

1. BIOPHARMACEUTICS (1130-421) Semester 2 ( 2017-2018) Prof. Aly Nada Chairman Department of Pharmaceutics

2. DEFINITIONS Biopharmaceutics: Study of the impact of the physicochemical properties of drugs & drug products (DF), and route of adm. on drug delivery to the body. The goal of biopharmaceutics is to adjust the delivery of drugs for optimal therapeutic activity and safety. Pharmacokinetics: Changes of drug conc. in the DF as well as drug and/or metabolite(s) conc. in the different body fluids and tissues after administration.

3. LADMER System: changes happen to the drug after administration of DF ; liberation, absorption, distribution, metabolism, elimination, and response Liberation is the first step after DF administration by all routes, except IV and P.O. solutions Absorption : Uptake of the drug from the site of administration into the systemic circulation. The drug must be in the molecular state, i.e. solution, except in pinocytosis.

4. Distribution : reversible transfer of drug from one location to another within the body. Metabolism (biotransformation) is a way of deactivating drugs in the body by converting drug molecules into more polar compounds to decrease tubular re-absorption in the kidney and thus increase drug elimination. Elimination : irreversible removal of drug from the body by all routes; Excretion (intact) and biotransformation. Response : pharmacological effectiveness or toxicity of the drug after drug-receptor interaction. Pharmacodynamics : relationship between drug conc. at the receptor site and the response.

5. Bioavailability : The rate and relative amount of a drug from administered DF appearing in the blood. The conc is determined by chemical or microbiological analysis after taking blood samples at different time intervals. Blood, plasma, or serum levels demonstrate the concentration upon the administration of DFs. Disposition : loss of drug due to transfer (Distribution) into other organs/tissues and/or Elimination and Metabolism. Excretion : final elimination from the body via kidney, bile, saliva, intestine, sweat, and milk. Biophase : actual site of drug action (the surface of a cell or one of its organelles).

6. Overall scheme of drug absorption, distribution, and elimination No matter how the drug is given (other than I.V.) it must pass through a number of biological membranes before it reaches the site of action.

7. Physiological Factors Affecting Absorption 1. Membrane physiology Membranes are boundaries which divide and connect morphological and functional units. In pharmacokinetics membrane refers not only to the structure separating the media outside and inside cells, but include the entire barrier separating two functional or anatomic units (cells comprising the vascular endothelium of the brain parenchyma represent the blood brain barrier ).

8. Biologic membrane is mainly lipid in nature but contains small aqueous channels or pores . Surface tension measurements have suggested presence of protein on the membrane. Membranes in different parts of the body have somewhat different characteristics which influence drug action and distribution. In particular, pore size and pore distribution .

9. 1. Blood-brain barrier has effectively no pores . This will prevent many polar materials (often toxic materials) from entering the brain. Smaller lipid materials or lipid soluble materials, such as diethyl ether , halothane , can easily enter the brain. 2. Renal tubules Membranes are relatively non-porous and drugs may be reabsorbed. Only lipid soluble compounds or non-ionized species (dependent of pH and pKa ) are reabsorbed. 3. Blood capillaries and renal glomerular membranes These membranes are quite porous allowing non-polar and polar molecules (up to a fairly large size, just below that of albumin , M.W. 69,000) to pass through. It allows excretion of polar substances (drugs, metabolites, and waste compounds).

10. 2. Transport across the membranes A) Carrier mediated absorption (1) Active (Carrier + Energy) Glucose and amino acids, 5-fluorouracil. saturable, against a concentration gradient, competitive inhibition

11. (2) Facilitated transport (carrier only) A carrier is required but no energy is necessary. e.g. vitamin B12 . Saturable if no enough carrier. No transport against a concentration gradient. B) Passive Transport Most drugs cross biologic membranes by passive diffusion. Diffusion occurs when the drug concentration on one side is higher than that on the other side. Drug diffuses across the membrane in an attempt to equalize the drug concentration on both sides of the membrane. If the drug partitions into the lipid membrane a concentration gradient can be established.

12. The rate of transport across the membrane is governed by Fick's first law of diffusion:- D: diffusion coefficient . This parameter is related to the size and lipid solubility of the drug and the viscosity of the diffusion medium (the membrane). As lipid solubility increases or molecular size decreases then D increases and thus dM / dt also increases. A: surface area . The surface of the intestinal lining (with villae and microvillae ) is much larger than the stomach. This is why absorption is generally faster from the intestine than from the stomach.

13. x: Membrane thickness . The membrane in the lung is quite thin thus inhalation allows rapid absorption. (Ch - Cl ): concentration difference. Since V, the apparent volume of distribution , is at least four liters and often much higher, the drug concentration in blood or plasma will be quite low compared with the concentration in the GI tract. It is this concentration gradient which allows the rapid complete absorption of many drug substances. Normally Cl << Ch then:- Absorption of many drugs from G-I tract follows 1st-order kinetics.

14. C) Vesicular transport (Pinocytosis and phagocytosis) Vesicular transport is the process of engulfing particles ( pahagocyosis ) / small solutes or fluid ( pinocytosis ). The cell membrane invaginates to surround the material and then engulfs it and finally incorporating into the cell . Oleao Vitamins ( A, D, E, and K ) and polio vaccine .

15. D) Ion-pair transport Strong electrolyte with extreme pKa values, e.g. QAC , are ionized at all physiologic pH values and therefore penetrate poorly. When these cations are linked with anions , an ion-pair with an overall zero charge will be formed. This neutral complex will diffuse more easily (more lipid soluble). Propranolol + oleic acid & quinine + hexylsalicylic acid

16. Propranolol pK a = 9.5 Quinine pK a = 8.5

17. What happens if: Q:A patient taking ampicillin with a lot of orange juice? Q: A patient taking propranolol with a lot of orange juice? Propranolol Ampicillin

18. Biopharmaceutic Considerations of DFs I) Physicochemical Nature of the Drug pKa and pH : Optimum stability and solubility of drugs and DFs. Erythromycin is formulated as enteric coated tablets to avoid decomposition in acid media. Weak acids precipitate from their salt solutions in acid media, week bases show precipitation in alkaline media. Particle size and distribution : Affects solubility and dissolution of poorly soluble drugs. Polymorphism and solvates : Affect the solubility and dissolution rate. Amorphous particles generally dissolves more rapidly than crystals with more rigid structural forms.

19. Salt formation : May provide slower dissolution, slower bioavailability, and longer duration. Na and K salts of week acids are more soluble than corresponding divalent/trivalent salts. Some soluble salts are less stable than the non-ionized form, e.g. Aspirin Na salt. Chirality : Optically active stereoisomers may have different pharmacokinetic and pharmacodynamic activity; e.g. only S- enantiomer of ibuprofen is active and R-form undergoes pre-systemic conversion to the active form. The conversion is site-specific and formulation dependent ; resulting in variable action.

20. Hygroscopicity : Affect the physical properties, particle size, polymorphs.., as well as chemical and microbiological stability. Partition coefficient: Reflects the relative affinity of the drug for particular phase in emulsions. This will affect release of drugs. Excipient interactions: The excipient itself or the impurities may cause incompatibilities with the active ingredients. The physical properties of the excipients may also modify the release characteristic of the drug.

21. II Formulation factors It is possible to alter drugs’ bioavailability considerably by formulation changes. What are the critical criteria in tablets, capsules, suspensions, suppositories?? Since a drug must be in solution to be absorbed from the G-I tract, you may expect the bioavailability of a drug to decrease in the order solution > suspension > capsule > tablet > coated tablet.

22. II Formulation factors Tablets are carefully formulated, designed, to stay together in the bottle during transport but break up quickly once they are in an aqueous environment.

23. Solutions Drugs are commonly given in solution in cough/cold remedies and in medication for the young and elderly. In most cases absorption from an oral solution is rapid and complete, compared with administration in any other oral dosage form. The rate limiting step is often the rate of gastric emptying. When an acidic drug is given in the form of a salt , it may precipitate in the stomach . However, this precipitate is usually finely divided and is readily redissolved and thus causes no absorption problems.

24. Some drugs which are poorly soluble in water may be dissolved by co-solvents . This is particularly useful for compounds with tight crystal structure, higher melting points that are not ionic. An oily emulsion or soft gelatin capsules (SEDDS) have been used for some compounds to produce improved bioavailability. Suspensions A well formulated suspension is second only to a solution in terms of superior bioavailability. Absorption may well be dissolution limited, however a suspension of a finely divided powder will maximize the potential for rapid dissolution.

25. The addition of a surface active agent will improve dispersion of a suspension and may improve the absorption of very fine particle size suspensions ( deflocculated ), otherwise caking may be a problem. How ? The intestinal fluids usually contain some materials ( name? ) which can act as wetting agents, however drug dissolution testing in vitro may neglect this effect .

26. Capsules In theory a capsule dosage form should be quite efficient. The hard gelatin shell should disrupt rapidly and allow the contents to be mixed with the G-I tract contents. If a drug is hydrophobic a dispersing agent should be added to the capsule formulation. These diluents will work to disperse the powder, minimize aggregation and maximize the surface area of the powder. The rate at which a drug dissolves is dependent on the solubility of the drug.

27. Tablets The biggest problem is overcoming the reduction in effective surface area produced during compression . Rapid dissolution and absorption is not always the objective. Sometimes a slower release is required. In the case of tolbutamide, used to lower blood sugar concentrations, a more sustained release is the target.

28. Modified-Release Drug Products Modified-release DFs are formulated to deliver the active ingredient(s) at a controlled predetermined rate and/or location to accomplish therapeutic/convenience objectives not offered by conventional DFs. 1. Extended-Release DFs, reducing the frequency of dosing (e.g. sustained-R). 2. Delayed-Release DFS, releasing a discrete part(s) at predetermined time(s) (e.g. enteric coated products). 3. Targeted-Release DFs which release the drug at or near the site of action (e.g. colon-targeted products)

29. Benefits Short half-life drugs: less frequent dosing and thus better compliance. Reduce variations in plasma/blood levels. Reduce side effects. Problems More complicated formulation, may be more erratic in result. A sustained release product may contain a larger dose , i.e. the dose for two or three (or more) 'normal' dosing intervals. A failure of the controlled release mechanism may result in release of a toxic dose. more expensive technology

30. Techniques/Types of MR products Erosion (erodible carriers + AI) Reservoir systems (AI inside insoluble coat) Osmotic pump (insoluble coat with a small hole)

31. 1. Erodible Systems Eroding matrix released drug Time 2. Reservoir system: Drug inside a shell-like system Time

32. Techniques/Types of MR products (cont.) Osmotic pump (insoluble coat with a small hole)

33. In-vitro testing of dosage forms Disintegration Disintegration time is the time to pass through a sieve while agitated in a specified fluid. Indicates the time to break down into small particles. Dissolution The time for the drug to dissolve from the DFs. Factors affecting dissolution; the dissolution medium , agitation , temperature are carefully controlled. The dissolution medium may be water, simulated gastric juice, buffers or 0.1M HCl . Surfactants / solvents may be included to maintain sink conditions.

34. Noyes Whitney Equation

35. Dissolution tests are used as quality control test to measure variability between batches . Thus the in vitro test may be a quick method of ensuring in vivo performance ( in-vitro/in-vivo correlation ). The dissolution testing conditions is different with each formulation ( Refer to the given examples ). A reasonable approach involves selecting dissolution conditions , which can distinguish between acceptable and unacceptable DFs. This is usually achieved by maintaining sink conditions for dissolution ( to prevent saturation ) by appropriate choice of dissolution conditions ( volume, type of stirrer, rate of stirring, pH, solvents, surfactants ..).

36. In Vivo-in Vitro Correlation (FDA/CDER) The issue of in vivo-in vitro correlation (IVIVC) has been of great importance for pharmaceutical industry, academics, and regulatory agencies. The FDA defines the IVIVC as the correlation between an in vitro property of a dosage form and a relevant in vivo response, usually the in vitro property is the rate and extent of drug dissolution and the in vivo response is the amount of drug absorbed or the plasma drug concentration-time profile. Pharmaceutical manufacturers usually attempt to develop and optimize the conditions of in vitro dissolution testing procedures for a particular formulation that can predict the in vivo performance of that formulation.

37. The in vivo performance of the formulation is determined from pharmacokinetic studies performed in normal volunteers. The amount of drug released in vitro from the formulation at different time points under the different dissolution conditions is compared with the rate and extent of drug absorption in vivo. When good correlation exists between a certain in vitro dissolution test performed under specific conditions and the in vivo rate and extent of drug absorption, this indicates that good IVIVC is established between this specific dissolution test and the in vivo performance of the formulation under investigation.

38. When IVIVC is established, the in vitro dissolution testing data only can be used to prove that changes in formulation composition, manufacturing process, suppliers , equipment, and batch size do not affect the in vivo drug absorption. Without the establishment of the IVIVC, minor formulation changes will require in vivo studies in human volunteers to prove that the modified formulation has the same rate and extent of drug absorption as the original formulation, that is, new and old formulations are bioequivalent.

39. Biopharmaceutics Classification System (BCS ) The biopharmaceutics classification system (BCS) classifies drugs according to their solubility and permeability. This enables successful prediction of bioavailability from solid oral dosage forms for drugs. This classification system also provides a guideline for determining the conditions under which IVIVC is expected [ Amidon et al, 1995 ]. For BCS class I drugs that have high solubility and high permeability, the rate determining step for drug absorption is likely to be drug dissolution and gastric emptying rate.

40. The IVIVC for BCS class I drugs is expected if the dissolution rate of the formulation is slower than the gastric emptying rate. On the contrary, for BCS class II drugs that have low solubility and high permeability, the rate determining step for drug absorption is the dissolution rate. The IVIVC for BCS class II drugs is expected when the in vitro drug dissolution rate is similar to the in vivo drug dissolution rate [ Dahan et al, 2009]. Whereas the BCS class III and class IV drugs have poor permeability and the rate determining step for drug absorption is most likely to be the permeability across the GIT membrane. So the IVIVC is not expected for BCS class III &class IV.