Controlled and sustained drug delivery system

Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or systemically, for a specified period of time. Continuous oral delivery of drugs at predictable and reproducible kinetics for predetermined period throughout the course of GIT.

1. Physiochemical & Biological Factors Influencing Sustained Release and Control Release Formulation Submitted by: Anshika Chaudhary A10647024002 M. Pharm- Pharmaceutics Amity Institute of Pharmacy Submitted to: Dr. Nitin Sharma Amity Institute of Pharmacy

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3. Definition The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical (physicochemical) properties of the chemical substance on the bio molecule that it interacts with. Physical Properties : responsible for its action Chemical Properties : The drug react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc.

4. Physicochemical Properties 4

5. 1.Molecular Size and Diffusivity A drug's ability to diffuse in polymers, known as diffusivity ( diffusion coefficient D ). The diffusion coefficient (D) of a drug is related to its molecular size or weight, with larger molecules generally having lower diffusivity For drugs with intermediate molecular weight (150-400 Da), the diffusion coefficient typically ranges from 10^-6 to 10^-9 cm^2/sec in flexible polymers, with 10^-8 cm^2/sec being common. Drugs with a molecular weight over 500 Da often have diffusion coefficients so small (less than 10^-12 cm^2/sec) that they exhibit very slow release kinetics in polymer-based extended-release devices .

6. 2. Aqueous Solubility Aqueous solubility is the maximum amount of a substance that dissolves in water at a given pH. The solubility of a drug directly influences its dissolution rate, which affects absorption and bioavailability. Dissolution Rate related to Aqueous Solubility is shown by Noyes-Whitney Equation: dC /dt = KdA.Cs where, dc/dt = Dissolution rate Kd = Dissolution rate constant A = Total surface area of a drug Cs = aqueous saturation solubility Relation : Higher aqueous solubility typically results in a higher dissolution rate

7. Impact on Sustained Release (SR) and Controlled Release (CR) Formulations: Low Solubility : Drugs with low aqueous solubility dissolve slowly , leading to dissolution-limited absorption. These drugs often provide a natural sustained release, making SR/CR formulations less beneficial. Diffusion-based systems are unsuitable due to the low drug concentration driving diffusion. High Solubility : Drugs with high solubility dissolve quickly , leading to rapid absorption and a sharp rise in blood concentration. Formulating these drugs into SR/CR systems is challenging because they tend to release rapidly , causing a " burst release ." Creating slightly less soluble forms of the drug can help achieve sustained release. pH Dependency : Drugs with pH-dependent solubility, such as phenytoin, face challenges in SR/CR formulation due to varying pH levels in the gastrointestinal tract, which affect dissolution and absorption.

8. Biopharmaceutical Classification System (BCS) . Class III and IV drugs are generally poor candidates for SR/CR formulations due to challenges in maintaining consistent drug release and absorption

9. Examples of Poor SR/CR Candidates : 9

10. Partition Coefficient The partition coefficient (P) represents the ratio of a drug's concentration in an oil phase to its concentration in an adjacent aqueous phase. K=Co/ Cw where; Co= equilibrium concentration of all forms of drug in an organic phase at equilibrium Cw = equilibrium concentration of all forms of drug in aqueous phase It influences a drug's bioavailability because biological membranes are lipophilic . 10

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12. pKa -Ionization Constant Drugs mostly in ionized form are poor candidates for oral sustained-release drug delivery systems. Unionized drugs have better absorption; ionized drugs have 3-4 times lower absorption rates. Acidic drugs with a pKa range of 3.0-7.5 are ideal for pH-sensitive ionization. Basic drugs with a pKa range of 7.0-11.0 are ideal for pH-sensitive ionization. For optimal absorption, a drug should be unionized at the site of absorption to an extent of 0.1-5.0%.

13. Drug Stability

14. Protein Binding 14

15. Biological Factors 15

16. 1.Absorption The rate, extent, and uniformity of drug absorption are crucial for formulating sustained-release and control- release systems. Goal: control the drug delivery system, ensuring that the release rate is significantly slower than the absorption rate. Given that the transit time of dosage forms in the absorptive regions of the gastrointestinal (GI) tract is roughly 8-12 hours, the maximum absorption half-life should ideally be around 3-4 hours. If the absorption rate is too slow, the dosage form may leave the absorptive areas before the drug release is complete, making it unsuitable for extended release . Therefore, drugs with lower absorption rate constants are generally poor candidates for sustained-release formulations

17. Factors contributing to low absorption rates include Poor water solubility Low partition coefficient Acid hydrolysis Metabolism Specific site of absorption in the GI tract Certain drugs are unsuitable for sustained/controlled release systems, such as: Drugs absorbed by active transport: Methotrexate, Enalapril, Riboflavin, etc. Drugs absorbed via amino acid transporters: Cephalosporins, Gabapentin, Levodopa, etc. Drugs absorbed through oligopeptide transporters: Captopril, Lisinopril, Cephalexin, etc. Drugs needing local therapeutic action in the stomach: Misoprostol, 5-fluorouracil, Antacids, etc.

18. 2. Distribution 18

19. 3. Metabolism The metabolism of a drug can either inactivate an active drug or convert an inactive drug to active metabolite. Complex metabolic patterns would make the S.R/C.R design much more difficult particularly when biological activity is wholly or partly due to a metabolite (example; isosorbide 2, 5-dinitrate).

20. 4.Elimination Half life Half life is the time taken for the amount of drug in the body (or the plasma concentration) to fall by half . It is determined by both clearance (Cl) and volume of distribution (VD). T1/2= 0.693.Vd/Cl In Volume of Distribution ( Vd ): If Vd is Increased : More the drug is concentrated in tissues relative to blood. Results in a longer half-life of the drug. If Vd is Decreased: More the drug is concentrated in the blood. Results in a shorter half-life of the drug.

21. In Clearance (Cl): If Clearance is Decreased : Drug stays in the body longer. Results in a longer half-life of the drug . If Clearance is Increased : Drug is removed from the body faster. Results in a shorter half-life of the drug. 22

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23. 5. Duration of Action: The time period during which blood levels of a drug remain above the Minimum Effective Concentration (MEC) and below the Maximum Safe Concentration (MSC), or within the therapeutic window. Drugs with a long duration of action are typically unsuitable for Sustained Release (S.R) or Controlled Release (C.R) formulations. Factors Affecting Long Duration of Action Receptor Occupation Tissue Binding Half-Life Metabolism Partition Coefficient Irreversible Binding to Cells

24. 6. Therapeutic Index It is the ration of median toxic dose and median effective dose. Therapeutic index = TD50/ED50 where ; TD is the toxic dose and ED is the effective dose. Drugs with a low therapeutic index are unsuitable for sustained-release formulations due to the risk of dose dumping and potential toxicity. Drugs with a TI value above 10 are generally considered safe, while those with low TI values are poor candidates for controlled-release products

25. 7. Absorption Window Some drugs exhibit region-specific absorption in the gastrointestinal tract due to differences in drug solubility and stability across various regions, influenced by changes in environmental pH, enzyme degradation, and other factors. These drugs have an absorption window, primarily in the stomach or upper small intestine, where absorption occurs. Once this window is crossed, drugs released from sustained or controlled-release systems may go largely unabsorbed, limiting their bioavailability . Examples include: Acyclovir Captopril Metformin Gabapentin Atenolol Furosemide Ranitidine

26. 8.Plasma Concentration Response Relationship The pharmacological activity of a drug is typically more closely related to its plasma concentration than to the administered dose. Drugs whose pharmacological effects are independent of plasma concentration are not ideal candidates for oral sustained-release (SR) drug delivery systems. 9.Patient Physiology The physiological conditions of the patient, such as gastric emptying rate, residence time, and GI motility, can directly or indirectly affect the drug's release from the dosage form.

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