Biopharmaceutical Considerations in the design and development of CRDDS.pptx

considerations

1. Biopharmaceutical Considerations in the Design of Controlled Release Drug Products By: Fariah Qaiser M.Phil Pharmaceutics 1

2. Controlled Release Drug Delivery System Controlled release means controlling the rate at which a drug is released into the system unlike conventional delivery systems that is it delivers the drug at a pre-determined rate for a specified period of time & maintains constant drug levels in blood or tissue. The goals of controlled drug delivery  are to control the duration of release and the amount of drug released, to deliver the drug to a specific part of the body, to get through tissue barriers, and to get through cellular barriers.  2

3. In conventional dosage form, the rate-limiting step in drug’s bioavailability is usually absorption through the bio-membrane; whereas in controlled drug delivery system the rate-limiting step is the release of drug from the dosage form. 3

4. Rationale of Controlled Drug Delivery System . The basic  rationale  of a controlled release drug delivery system is to optimize the biopharmaceutic, pharmacokinetic and pharmacodynamic properties of a drug in such a way that its utility is maximized through reduction in side effects and cure or control of condition in the shortest possible time by using smallest quantity of drug, administered by the most suitable route.   4

5. Dissolution Control Diffusion Control Osmotic Pressure Control Ion Exchange Control Mechanisms of Controlling Drug Release Controlled Release Drug Delivery System Osmotic Pressure Control Dissolution Control Diffusion Control Ion Exchange Control 5

6. 1. Dissolution Control The drug is associated with a polymeric carrier , which slowly dissolves, thereby liberating the drug. The polymeric carrier can be as follows: 1 .  A reservoir system ( encapsulated dissolution system ), whereby a drug core is surrounded by a polymeric membrane. The rate of drug release is determined by the thickness and dissolution rate of the membrane. 2 .   A matrix system , whereby the drug is distributed through a polymeric matrix. Dissolution of the matrix facilitates drug release. 6

7. 2. Diffusion Control The drug must diffuse through a polymeric carrier. Again, two main types of design system are used: 1 .   A reservoir system , whereby the drug is surrounded by a polymeric membrane, known as a rate-controlling membrane (RCM ). The rate of drug release is dependent on the rate of diffusion through the RCM. 2.  A matrix system ( also known as a monolithic device ), whereby the drug diffuses through a polymeric matrix. Matrix System Reservoir System 7

8. 3. Osmotic Pressure Control Osmotic pressure induces the diffusion of water across a semipermeable membrane, which then drives drug release through an orifice of the DDS. 4. Ion-Exchange Control Ion-exchange resins are water-insoluble polymeric materials that contain ionic groups. Charged drug molecules can associate with an ion-exchange resin via electrostatic interaction between oppositely charged groups. Drug release results from the exchange of bound drug ions with ions commonly available in body fluids (such as Na + , K + , or Cl – ). 8

9. Factors Influencing the Design and Performance of Controlled Drug Delivery System BIOPHARMACEUTIC CHARACTERISTICS OF THE DRUG Molecular weight of the drug Aqueous Solubility of the drug Apparent Partition Coefficient Drug Pka and Ionization at Physiological pH Drug Stability Diffusion Coefficient 9

10. Biopharmaceutical Consideration in the Design of Controlled Release Drug Product 10

11. Biopharmaceutics Biopharmaceutics  can be defined as the study of the physical and chemical properties of drugs and their proper dosage as related to the onset, duration, and intensity of drug action, or it can be defined as the study of the effects of physicochemical properties of the drug and the drug product,   in vitro ,  on the bioavailability of the drug,  in vivo ,  to produce a desired therapeutic effect. Biopharmaceutic Characteristics of a Drug in the Design of CRDDS The former depends upon the fabrication of the formulation and the physicochemical properties of the drug while the latter element is dependent upon pharmacokinetics of drug . The performance of a drug presented as a controlled-release system depends upon its: 1. Release from the formulation. 2. Movement within the body during its passage to the site of action . 11

12. Biopharmaceutical Considerations For designing a controlled drug delivery system, the following physicochemical properties of drugs must be considered: 1. The molecular weight of the drug and its Particle Size Drugs of lower the molecular weight , more  accurately, of lower molecular size, are absorbed faster and more completely. Through passive diffusion, about 95% of the drugs are absorbed. Diffusivity is well-defined as the ability of a substance (drug) to diffuse through the membrane . It is inversely related to the molecular size. Thus, drugs with large molecular weight rather large molecular size are not ideally suitable for controlled release systems e.g. peptides and proteins. 12

13. Smaller the particle size of the drug, greater will be the effective surface area, more will be the intimate contact between the solid surface and aqueous solvent that will lead to higher dissolution rate and will enhance the absorption efficiency. Particle size reduction has been used to enhance the solubility and absorption of poorly soluble drugs such as tolbutamide . 13

14. 2 . The diffusion coefficient and molecular size rate-controlling polymeric membranes or matrix different biological membranes. The capacity of a drug to diffuse through these membranes is called diffusibility , diffusivity or diffusion coefficient (D). Diffusibility of the  drug depends on its molecular size or molecular weight. Usually, drugs having a molecular weight within 150 to 400 Da (Dalton) possess diffusivity of 10 –6 –10 –9 cm 2 /sec through flexible polymers. The drugs having  molecular weight more than 500 Da have very small diffusivity such as 10 – 12 cm 2 /sec . 14

15. The aqueous solubility of the drug For oral controlled release dosage form, the drug should have excellent aqueous solubility and are independent of pH; such drugs are good candidates . Solubility refers to the concentration of solute in a saturated solution. The amount of drug absorbed into systemic circulation is a function of the amount of the drug present in an unionized form in a solution of G.I fluid . Before absorption, the drug must go into a solution of GI fluid and then partitions into the absorbing membrane . Thus, absorption of a drug is related to its partitioning between the lipid layer and an aqueous phase, and the rate of dissolution is related to its aqueous solubility. 15

16. The Noyes-Whitney equation can express the relation between the rate of dissolution and aqueous solubility as below; Where, dC /dt is the rate of dissolution kD is the dissolution rate constant A is the total surface area of the drug particle CS is the saturation solubility of the drug. Thus, drugs which are soluble in water are generally absorbed adequately when administered orally. On the other hand, poorly soluble drugs have low dissolution rates, and their bioavailability becomes a problem . 16

17. pH of the medium can influence the total solubility of a weakly acidic or weakly basic drug having a given pKa . According to the pH-partition hypothesis, the unionized form of a weakly acidic drug present in the stomach (pH ≈ 1–2) will be absorbed very well. Similarly, weakly basic drugs predominantly remain unionized in the small intestine (pH ≈5–7) and will be excellently absorbed; but these drugs remain in ionized form in the stomach resulting in poor absorption. Therefore, it can be summarized ‘for better absorption in GI tract (oral route) the drug must have an adequate aqueous solubility, must be released from the dosage form at a required rate, and be available as unionized form at the site of its absorption’ 17

18. 4. Apparent partition coefficient The partition coefficient is  the measure of the lipophilicity of a drug and an indication of its ability to cross the cell membrane . It is defined as the ratio between un-ionized drug distributed between the organic and aqueous layers at equilibrium. Larger the apparent partition coefficient of a drug (Ko/w), greater its lipophilicity and hence, greater would be its rate and extent of absorption. These types of drugs even cross the highly selective blood-brain barrier. Both permeation of a drug across the biological membrane and diffusion through the rate controlling membrane or matrix depend on the partition coefficient of the drug. After administration and before elimination from the body the drug is supposed to diffuse through various biological membranes. These membranes perform primarily as a lipid-like barrier . 18

19. The apparent oil/water partition coefficient of a drug is considered as a measure of its membrane permeability . The apparent oil/water partition coefficient, K is defined as; Where Co represents the equilibrium concentration of all forms of the drug in an organic phase , usually in n-octanol, and Cw represents the equilibrium concentration of all forms of the drug in the aqueous phase . There should be an optimum partition coefficient for required permeability. When the value of partition coefficient is more than the optimum value, the aqueous solubility of a drug is reduced, and the lipid solubility is increased; under this circumstance once the drug enters into lipid membrane cannot diffuse out of the lipid membrane. Usually, the optimum value of K is 1000 when measured using the n-octanol/water system. Drugs having partition coefficient value more than or less than the optimum values are not suitable candidates for making controlled release formulations. 19

20. 5. Drug pKa and ionization at Physiological pH pKa is  a number that describes the acidity of a particular molecule . It measures the strength of an acid by how tightly a proton is held by a Bronsted acid. Drug molecules are therapeutically active only in their unionized form and in this form the drug can easily penetrate the lipoidal membrane. The amount of drug that remains in unionized form is a function of its dissociation constant and pH of the fluid at the site of absorption . 20

21. Henderson-Hasselbalch equation. For a weak acid: pH = pKa + log(A - /HA), where A -  is the ionized drug and HA the unionized drug. For a weak base: pH = pKa + log(B/HB + ), where B is the unionized drug and HB +  is the ionized drug. Thus, when the local pH is equal to the pKa of the drug, the drug will be 50% ionized and 50% unionized (log 1 = 0). When the pH of the environment is less than the pKa of the compound, the environment is considered acidic and the compound will exist predominately in its protonated form. When the pH of the environment is greater than the pKa of the compound, the environment is considered basic and the compound will exist predominately in its deprotonated form. Thus, the drug which remains in ionized form at its absorption site is not suitable for SR/CR dosage form. Drugs, such as hexamethonium , exist largely in ionized forms are poor candidates for controlled delivery systems 21

22. 6. Drug Stability Once the drug is administered, biological fluids that are in direct contact with a drug molecule may influence the stability of drug. Drugs may be susceptible to both chemical and enzymatic degradation, which results in the loss of drug activity. Drugs with poor acidic stability, when coated with enteric coating materials will bypass the acidic stomach and release the drug at lower portion of the GI tract. Drugs unstable in gastric pH, e.g. propantheline can be designed for sustained delivery in intestine with limited or no delivery in stomach. On the other hand, a drug unstable in intestine, e.g. probanthine , can be formulated as gastro retentive dosage form. 22

23. Marketed formulations of drugs with the technology used 23

24. Thank You 24