PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM

1. PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM Dr. Basavaraj K. Nanjwade M.Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: nanjwadebk@gmail.com Cell No: 00919742431000 KLE College of Pharmacy, Nipani

2. CONTENTS • Introduction • Objective • Additives used in formulation • Routes of administration • Approaches for formulation • Type of formulation • Classification • Approaches for formulations of Implants • Infusion Devices • References KLE College of Pharmacy, Nipani

3. Objectives • Site-specific delivery • Reduced side effects • Increased bio-availability • Increased therapeutic effectiveness KLE College of Pharmacy, Nipani

4. KLE College of Pharmacy, Nipani

5. Advantages over conventional drug delivery system • Improved patient convenience and compliance. • Reduction in fluctuation in steady-state levels. • Increased safety margin of high potency drugs. • Maximum utilization of drug. • Reduction in health care costs through improved therapy, shorter treatment period, less frequency of dosing KLE College of Pharmacy, Nipani

6. Disadvantages of controlled release dosage forms • Decreased systemic availability • Poor in vitro-in vivo correlation • Possibility of dose dumping. • Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions. • Reduced potential for dosage adjustments. • Higher cost of formulations. KLE College of Pharmacy, Nipani

7. Routes of administration • Intravascular • Intramuscular • Subcutaneous • Intradermal • Intraarticular • Intraspinal • Intrathecal • Intracardiac • Intrasynovial • Intravaginal • Intraarterial KLE College of Pharmacy, Nipani

8. CHARACTERISTICS • Free from living microbes • Free from microbial products such as pyrogens • Should match the osmotic nature of the blood • Free from chemical contaminants • Matching specefic gravity KLE College of Pharmacy, Nipani

9. ADDITIVES USED DURING FORMULATION OF PARENTRALS • Vehicles • Stabilizers • Buffering agents • Tonicity factors • Solubilizers • Wetting, suspending, emulsifying agents • Antimicrobial compounds KLE College of Pharmacy, Nipani

10. APPROACHES FOR FORMUALATION KLE College of Pharmacy, Nipani

11. PARAMETERS MANIPULATED IN THE DESIGN OF PARENTRAL CONTROLLED FORMS Route of administration Vehicles Vaso-constriction Particle size Chemical modification of drug 11 KLE College of Pharmacy, Nipani

12. Approaches • Use of viscous, water-miscible vehicles, such as an aqueous solution of gelatin or polyvinylpyrrolidone. • Utilization of water-immiscible vehicles, such as vegetable oils, plus water-repelling agent, such as aluminum monostearate. • Formation of thixotropic suspensions. KLE College of Pharmacy, Nipani

13. Approaches • Preparation of water-insoluble drug derivatives, such as salts, complexes, and esters. • Dispersion in polymeric microspheres or microcapsules, such as lactide-glycolide homopolymers or copolymers • Co-administration of vasoconstrictors. KLE College of Pharmacy, Nipani

14. TYPE OF FORMULATION • Dissolution-controlled Depot formulations • Adsorption-type Depot preparations • Encapsulation-type Depot preparations • Esterification-type Depot preparations KLE College of Pharmacy, Nipani

15. SaDsCs hd ( )d = Q t Dissolution type depot formulations • Drug absorption is controlled by slow dissolution of drug particles. • Rate of dissolution is given by ; where, Sa – Surface area of drug particles Ds – Diffusion coefficient of drug Cs – Saturation solubility of drug hd – Thickness of hydrodynamic diffusion KLE College of Pharmacy, Nipani

16. Drawbacks • Release of drug molecules is not of zero order kinetics as expected from the theoretical model. • Surface area Sa of drug particles diminishes with time. • The saturation solubility Cs of the drug at the injection site cannot be easily maintained. KLE College of Pharmacy, Nipani

17. Approaches • Formation of salts or Complexes with Low solubility. • E.g., Aqueous suspensions of benzathine penicillin G. • Suspension of macro crystals. • E.g., aqueous suspension of testosterone isobutyrate for I.M. administration. • Exception • Penicillin G procaine suspension in gelled peanut oil for I.M. injection. KLE College of Pharmacy, Nipani

18. (C)f (C)b,m (C)f (C)b 1 a(C)b.m = + Adsorption-type Depot Preparation • Formed by binding of drug molecules to adsorbents. • Only unbound, free species of drug is available for absorption. • Equilibrium conc. of free, unbound drug species (C)f is determined by the Langmuir relationship. • E.g., - Vaccine preparations KLE College of Pharmacy, Nipani

19. Encapsulation-type Depot Preparations • Prepared by encapsulating drug solids within a permeation barrier or dispersing drug particles in a diffusion matrix. • Membrane – biodegradable or bioabsorbable macromolecules • Gelatin, Dextran, polylactate, lactide-glycolide copolymers, phospholipids, and long chain fatty acids and glycerides. KLE College of Pharmacy, Nipani

20. Encapsulation-type Depot Preparations • E.g., Naltrexone pamoate-releasing biodegradable microcapsules. • Release of drug molecules is controlled by • Rate of permeation across the permeation barrier • The rate of biodegradation of the barrier macromolecules. KLE College of Pharmacy, Nipani

21. Esterification-type Depot Preparation • Esterifying a drug to form a bioconvertible prodrug-type ester. • Forms a reservoir at the site of injection. • Rate of absorption is controlled by • Interfacial partitioning of drug esters from reservoir to tissue fluid. • Rate of bioconversion of drug esters to regenerate active drug molecules. • E.g., Fluphenazine enanthate, nandrolone decanoate, and testosterone 17B-cyprionate in oleaginous solution. KLE College of Pharmacy, Nipani

22. CLASSIFICATION INJECTABLES IMPLANTS INFUSION DEVICES Solutions Suspensions and Emulsions Microspheres and Microcapsules Nanoparticles and Niosomes Liposomes . Resealed Erythrocytes Osmotic Pumps Vapor Pressure Powered Pumps Intraspinal Infusion Pumps Intrathecal Infusion Pumps KLE College of Pharmacy, Nipani

23. Solutions • Aqueous solutions • High viscosity solutions • For comp. with mol. wt. more than 750 • For water sol. drugs • Gelling agents or viscosity enhancers are used • Complex formulations • Drug forms dissociable complex with macromolecule • Fixed amount of drug gets complexed • Given by I.M. route KLE College of Pharmacy, Nipani

24. Solutions • Oil solutions • Drug release is controlled by controlling partitioning of drug out of oil into surrounding into aqueous medium • For I.M. administration only • No. of oils are limited KLE College of Pharmacy, Nipani

25. Suspensions • Aqueous suspensions • Given by I.M. or S.C. routes • Conc. of solids should be 0.5 to 5 % • Particle size should be < 10 μm KLE College of Pharmacy, Nipani

26. Suspensions • Drug is continuosly dissolving to replenish the lost. • For oil soluble drugs • Only crystalline and stable polymorphic drugs are given by this form • Viscosity builders can be used. • E.g., Crystalline zinc insulin KLE College of Pharmacy, Nipani

27. Suspensions • Oil suspensions • Given by I.M. route. • Process of drug availability consists of dissolution of drug particles followed by partitioning of drug from oil solution to aqueous medium. • More prolong dug action as compared to oil solution and aqueous suspension. • E.g., Penicillin G procaine in vegetable oil KLE College of Pharmacy, Nipani

28. Emulsions • Can be given by I.M., S.C., or I.V. routes • O/w systems are not used due to large interfacial area and rapid partitioning. • W/o emulsions are used for water soluble drugs. • Multiple emulsions are used generally such as w/o/w and o/w/o since an additional reservoir is presented to the drug for partitioning which can effectively retard its release rate. KLE College of Pharmacy, Nipani

29. Emulsions • Release of water soluble drugs can be retarded by presenting it as oil suspension and vice versa. Water soluble drug e.g., 5-Fluorouracil Oil soluble drug e.g., lipidol Aqueous phase Oil phase KLE College of Pharmacy, Nipani

30. Microsphere • Each microsphere is basically a matrix of drug dispersed in a polymer from which release occurs by first order process. • Polymers used are biocompatible and biodegradable. • Polylactic acid, polylactide coglycolide etc. • Drug release is controlled by dissolution degradation of matrix. • Small matrices release drug at a faster rate. KLE College of Pharmacy, Nipani

31. Microsphere • For controlled release of peptide/protein drugs such as LHRH which have short half-lives. • Magnetic microspheres are developed for promoting drug targeting which are infused into an artery. • Magnet is placed over the area to localize it in that region. KLE College of Pharmacy, Nipani

32. Microcapsules • Drug is centrally located within the polymeric shell. • Release is controlled by dissolution, diffusion or both. • For potent drugs such as steroids, peptides and antineoplastics. KLE College of Pharmacy, Nipani

33. Nanoparticles and Niosomes • Nanoparticles are called as nanospheres or nanocapsules depending upon the position of drugs • Polymer used are biodegradable ones. • Polyacrylic acid, polyglycolic acid • For selective targeting therapy. • Nanosomes are closed vesicles formed in aqueous media from nonionic surfactants with or without the presence of lipids. KLE College of Pharmacy, Nipani

34. liposomes OLV ULV MLV LUV MUV Liposomes • Spherule/vesicle of lipid bilayers enclosing an aqueous compartment. • Lipid most commonly used are phospholipids, sphingolipids, glycolipids and sterols. GUV KLE College of Pharmacy, Nipani

35. Liposomes • Water soluble drugs are trapped in aqueous compartment. • Lipophilic ones are incorporated in the lipid phase of liposomes. • Can be given by I.M., S.C., for controlled rate release. • Can be given by I.V. for targeted delivery. KLE College of Pharmacy, Nipani

36. Liposomes KLE College of Pharmacy, Nipani

37. Resealed Erythrocytes • Biodegradable, biocompatible, nonimmunogenic. • Can circulate intravascularly for days and allow large amounts of drug to be carried. • Drug loading in erythrocytes is easy. • Damaged erythrocytes are removed by liver and spleen. KLE College of Pharmacy, Nipani

38. Ideal Characteristics • Envionmentally stable • Biostable • Biocompatible • Nontoxic and noncarcinogenic • Nonirritant • Removable • Provide constant release KLE College of Pharmacy, Nipani

39. Advantages and Disadvantages • Advantages • More effective and more prolonged action • Small dose is sufficient • Disadvantages • Microsurgery is required KLE College of Pharmacy, Nipani

40. Approaches to implantable drug delivery CDD by diffusion Activation process Feedback regulated Osmotic pressure Vapour pressure Magnetically activated Phonophoresis Hydration activated Hydrolysis activated Bioerosion Bioresponsive Polymer membrane Matrix diffusion Microreservoir KLE College of Pharmacy, Nipani

41. nonporous Polymeric membrane microporous semipermeable Polymer membrane permeation controlled DDS • Reservoir is solid drug or dispersion of solid drug in liquid or solid medium. • Drug enclosed in reservoir and reservoir is enclosed in rate limiting polymeric membrane. KLE College of Pharmacy, Nipani

42. Polymer membrane permeation controlled DDS • Encapsulation of drug in reservoir can be done by encapsulation, microencapsulation, extrusion, molding or any other technique. • E.g., Norplant Subdermal Implant. KLE College of Pharmacy, Nipani

43. Polymer Matrix diffusion controlled DDS • Drug is homogeneously dispersed throughout polymer matrix. • Polymers used are : • Lipophilic polymers • Hydrophilipic polymers • Porous • Decreasing release with time • E.g., Compudose implant KLE College of Pharmacy, Nipani

44. Membrane-Matrix Hybrid type Drug Delivery Device • Hybrid of first two • Minimizes the risk of dose dumping • Drug reservoir is homogeneous dispersion of drug solids throughout a polymer matrix, and is further encapsulated by polymeric membrane • E.g., Norplant II Subdermal Implant KLE College of Pharmacy, Nipani

45. Microreservoir Partition Drug Delivery Device • Drug reservoir is a suspension of drug crystals in an aqueous solution of polymer. • Device is further coated with layer of biocompatible polymer. • Polymer used for matrix : water soluble polymers • Polymer used for coating : semipermeable polymer KLE College of Pharmacy, Nipani

46. Microreservoir Partition Drug Delivery Device KLE College of Pharmacy, Nipani

47. Controlled drug delivery by activation process • Osmotic pressure activated • Vapor pressure activated • Magnetically activated KLE College of Pharmacy, Nipani

48. Osmotic pressure activated • Osmotic pressure is used as energy source • Drug reservoir is either a solution or semisolid formulation • Cellulosic outer membrane • Polyester internal membrane KLE College of Pharmacy, Nipani

49. Vapor pressure activated • Vapor pressure is used as the power source. • Drug reservoir is a solution formulation. • Fluid which vaporizes at body temperature is used such as fluorocarbon. • E.g., Infusaid Pump for Heparin. KLE College of Pharmacy, Nipani

50. Vapor pressure activated KLE College of Pharmacy, Nipani