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”(Controlled) Drug Release” - what’s the (big) deal???

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Presentation on theme: "”(Controlled) Drug Release” - what’s the (big) deal???"— Presentation transcript:

1 ”(Controlled) Drug Release” - what’s the (big) deal???

2 Controlled Drug Release The way in which chemicals or drugs are administered have gained increasing attention in the past two decades Normally, a chemical is administered in a high dose at a given time only to have to repeat that dose several hours or days later  Not economical, can result in damaging side effects, why increasing attention has been focused on methods of giving drugs continually for prolonged time periods in a controlled fashion improved efficiency reduced toxicity maintenance of drug levels within desired range fewer administrations increased patient compliance and convenience

3 CDR: More constant agent levels & less frequent administration An implantable drug delivery system should release a therapeutic agent in a controlled manner during a predetermined period Concentrations above which the drug produces undesirable side effects = (Minimum Toxic Concentration) Below which it is not therapeutically effective = (Minimum Effective Concentration) In medicine, the ratio between the effective and toxic levels is known as the therapeutic index:

4  Targeted Sites: – Brain – Lung – Liver – Kidney – Pancreas – Limb – Bladder – GI Tract – Head & Neck – Breast – Prostate CDR: More efficient utilization of agent & Site of action delivery local  High local drug concentrations systemic  Low systemic exposure

5 Pharmacodynamics Biopharmaceutics Elimination Concentration ↔ Receptor ↔ ”Effect” in the tissue Distribution Absorption Dissolution or release from the formulation (preparation) The chemical form of the drug, formulation, the components of the formulation - Rate of absorption - First-pass metabolism  Bioavailability Pharmacokinetics

6  Pharmacokinetics  Pharmacokinetics deals with “the fate of the drug in the body”. WHO’s definition: the study of how drugs are adsorbed into, distributed and broken down in, and excreted from, the body (=LADME-system). So, in basic terms, while …  pharmacodynamics  pharmacodynamics explores what a drug does to the body, pharmacokinetics explores what the body does to the drug.  Biopharmaceutics  Biopharmaceutics explores how the physico-chemical properties and the technological ”design” (formulation) and the additives that are utilized during the manufacturing affects the therapeutical effect

7 The LADME-system

8 Modified Release Drug Products Oral Dosage Forms-extended release -delayed release Intramuscular-depot injections Water immiscible oily injections (dispersions) Subcutaneous-implants Transdermal-patches -iontophoresis Targeted-liposomes

9 USP-NF Recognized Release Forms Extended ReleaseExtended Release -A dosage form that allows at least a 2-fold reduction in dosage frequency of a conventional or immidiate release dosage form. Includes both controlled and sustained release. Delayed ReleaseDelayed Release - A dosage form that releases a discrete portion (or portions) of drug at a time (or times) other than promptly after administration - Example enteric coated Targeted ReleaseTargeted Release - A dosage form that releases drug at a near intended site of action. These may include immediate or extended release types

10 IMPORTANT TO REMEMBER: Controlled and sustained release are NOT synonyms Sustained release describes release of drug from a dosage form over a period of time - oral formulations; enteric coating of tablets with pH-sensitive materials, encapsulated pellets and beads  the release of the agent is substantially affected by the external environment into which it is released Controlled release describes a system in which the rate of drug release is more precisely controlled that that in the sustained release form –porous insoluble tablets containing dispersed drug design of the system itself  Controlled release systems provide a release profile predominantly controlled by the design of the system itself USP-NF Recognized Release Forms

11 Drug Release Matrix Inert solid vehicle in which a drug is suspended. –porous insoluble tablets containing dispersed drug Usually matrix is water insoluble although some swell in water Often formulated as a tablet or small beads The primary method of accomplishing this controlled release has been through incorporating the chemicals within polymers

12 Type of system Diffusion controlled Reservoir devices Monolithic devises Water penetration controlled Osmotic systems Swelling systems Chemically controlled Monolithic systems Pendant chain systems Regulated systems Magnetic or ultrasound Chemical Rate-control mechanism Diffusion thorugh membrane Diffusion through bulk polymer Osmotic transport of water through semipermeable membrane Water penetration into glassy polymer Either pure polymer erosion (surface erosion) or a combination of erosion + diffusion (bulk erosion) External application of magnetic field or ultrasound to device Use of competitive desorption or enzyme-substrate reactions. Rate control is built into device.

13 Most release profiles can be categorized inte three types Zero-order release: First-order release: Square-root-of-time (Higuchi) release: k = release rate constant M t = mass of active agent M 0 = mass of agent in device at t=0 Delivery rates

14 Zero Order Release - Usual gold standard in controlled release Zero order delivery ineffective (e.g.) when... - minimum effective concentraton (MEC) changes with time e.g. Insulin, addictive drugs (heroine, cocaine, etc.), down regulation of hormone receptors, other drugs (nitroglycerin) Drug release from a simple matrix is not zero order Higuchi equation describes release Delivery rates

15 The Higuchi equation relates the release (Q t ) from porous carrier to the physical constants based on simple laws of diffusion: The relative arrangement of these parameters depend on desired way of definition; y-axis, geometry of monolith  the equation is frequently expressed as a general relationship in which the amount released is proportional to the square root of time, indicating a diffusion-driven process: Q t =k H  t and hence: k H =f ( , , C s, A, D) Delivery rates

16 Drug Release Matrix  CR-systems provide a release profile predominantly controlled by the design of the system itself Critical parameters in eq:  = porosity  =tortiosity (pore geometry) C s = solubility of drug D=diffusion coefficient A= loading degree Additional parameters: pore size matrix solubility surface properties -ALL ADJUSTABLE ? 100 nm

17 Adsorption studies !!! Pore size (1.5 nm – 30 nm) Pore wall stability (rate of bioerosion) Surface functionalization with reactive surface groups, eg. hydrophobic (phenyl, vinyl), NH 2, SH, COOH... Critical parameters in eq:  = porosity  =tortiosity (pore geometry) C s = solubility of drug D=diffusion coefficient A= loading degree Additional parameters: pore size matrix solubility surface properties const. Drug Release Matrix Controllable: Pore structure (1D – 3D channel connectivity)

18 Delivery rates: example For Fm3m materials release of ibuprofen was detected to up to 300h The size of the pore windows in the cubic structure Fm3m are descisive As for the mesoporous hexagonally ordered materials studied previously, also the Fm3m materials release exhibit a linear relationship against the square-root of time  diffusion controlled process, as explained by the Higuchi equation Release of ibuprofen from Fm3m materials. Square-root of time (”Higuchi”-) plots of the Fm3m materials shown in the previous figure.

19 Controlled Release Technology PharmaceuticalPharmaceutical - recent advances in genetic engineering  gene (& polypeptide) delivery & stabilization Food and agricultural applicationsFood and agricultural applications PesticidesPesticides CosmeticsCosmetics Household productsHousehold products

20 Thank You !!! Entertainment of the Day !Entertainment of the Day !


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