Implantable Drug Delivery System, Unit-II, BP704T: NDDS, Sem-VII, Final year B. Pharm (SPPU 2019P).pptx

unit II
Implantable Drug Delivery Systems: Introduction, advantages and disadvantages,
concept of implants and osmotic pump.

1. IMPLANTABLE DRUG DELIVERY SYSTEM (IDDS) Ms. Kartiki M. Bhandari Asst. Prof. (P’ceutics)

2. “Implants are small, sterile, solid masses consisting of highly purified drug made by compression / molding / extrusion.” Allow targeted / localized delivery & more therapeutic effect at low drug conc. Hence, minimize potential side-effects & offer increased patient compliance . Also delivers drugs which are unsuitable orally, since it avoids 1 st pass metabolism & chemical degradation in GIT, thus, increasing bioavailability . INTRODUCTION

3. More effective at significantly small dose. Targeted & controlled drug delivery for prolonged period. Better control over drug release. Improved patient compliance than other invasive routes. Bypass 1 st pass metabolism & reduce side effects. Improved stability & bioavailability of drugs. ADVANTAGES OF IDDS

4. Invasive therapy (large implants require surgery). Chances of device failure. Chances of localized reactions at site of insertion. Biocompatibility issues due to immune reactions between host & implant. Limited to potent drugs. Inadequate drug release. Therapy cannot be discontinued easily & care is needed after implantation. DISADVANTAGES OF IDDS

5. Substantially reduce the need of frequent drug administration . Environmentally stable, biocompatible, sterile . Readily implantable & retrievable by medical personnel to initiate or terminate the therapy. Enable rate-controlled drug release at optimal dose. Easy to manufacture. Cost-effective . IDEAL CHARACTERISTICS OF IDDS

6. Environmentally stable: should NOT breakdown under influence of light, air, moisture, heat, etc. Biostable: should NOT undergo physico-chemical degradation in contact with biofluids. Biocompatible: should NOT stimulate immune response or thrombosis or fibrosis (otherwise implant will be rejected). Removal: should have removability when required. IDEAL CHARACTERISTICS OF IDDS

7. Non-toxic or non-carcinogenic: degradation products or leached additives should be completely safe. Structural characters: should have minimum surface area, smooth texture & structural characters similar to tissue in which it is implanted; to avoid irritation. Drug release: should release drugs at a constant pre-determined rate for pre-determined period. IDEAL CHARACTERISTICS OF IDDS

8. Implants can be used for either systemic or local therapeutic effects. Systemic implant is administered by SC/IM/IV route; for direct blood absorption. Local implant is placed in specific body sites , where it acts locally, with relatively negligible blood absorption. Implants are designed to release the drug in controlled manner, allowing adjustment of release rates over extended period (several days to years). Ex. of Implants - dental, orthopedic, cardiovascular, gastric, etc. CONCEPT OF IMPLANTS

9. Classification of IDDS is difficult, since numerous exceptions & hybrids can be listed in multiple categories. However, drug-implants are broadly subdivided into: Passive systems: with no moving parts or mechanisms. a) Non-degradable b) Bio-degradable . Active systems: employ energy-dependent method for providing + ve driving force to modulate drug release. a) Osmotic pumps b) Propellent infusion pumps c) Electromechanical drives . CLASSIFICATION OF IMPLANTS

10. Passive implants tend to be relatively simple, homogenous & singular devices , typically simple packaging of drugs in biocompatible material or matrix. By definition, they do not contain any moving parts , & depend on passive, diffusion-mediated phenomenon to modulate drug release. Delivery kinetics are partially variable by choice of drug, conc., implant morphology, matrix material & surface properties. Further classified as: a) Non-degradable & b) Bio-degradable . PASSIVE IMPLANTS

11. Although reservoirs & matrix systems are most common, several other variants of non-degradable implants are available. Matrix materials used in these systems are polymers , with documented history of both pre-clinical & clinical evaluation. Commonly used polymers - elastomers like silicones & urethanes, acrylates & their co-polymers, vinylidene fluoride & polyethylene vinyl acetate. NON-DEGRADABLE PASSIVE IMPLANTS

12. The drug is dispersed homogeneously within polymeric matrices forming most passive monolithic implants. Alternatively, reservoir systems are characterized by compact drug core, surrounded by permeable non-degradable membrane. The permeability & thickness of membrane controls the drug diffusion rate. NON-DEGRADABLE PASSIVE IMPLANTS

13. To overcome drawbacks of non-bio-degradable implants , bio-degradable systems with polymers - poly(lactic acid), poly(lactic-co-glycolic acid), poly(caprolactone) or their block co-polymers are developed. Major advantage of these systems  biocompatible polymers used are broken down into safer metabolites & absorbed / excreted. Labile polymers ; prone to degradation by hydrolysis / enzymes (ester, amide, & anhydride bonds) are characteristic backbone of bio-degradable polymers. Complete degradation of implant avoids surgical removal after therapy. BIO-DEGRADABLE PASSIVE IMPLANTS

14. Reduce complications with explantation & increase patient compliance . Although acidic byproducts of polyester degradation cause instability of proteins & localized inflammation, some proteins, like recombinant human growth hormone & insulin , have been evaluated for delivery. But, forming bio-degradable system is more complicated than non-degradable. While fabricating bio-degradable system, in-vivo degradation kinetics of polymer (which must ideally remain constant to maintain sustained-release) are taken into consideration. BIO-DEGRADABLE PASSIVE IMPLANTS

15. The “ Gliadel wafer® ” is earliest bio-degradable IDDS, approved by FDA (1996). It consists of bio-degradable polyanhydride discs (1.45 cm diameter & 1 mm thick), designed to deliver chemotherapeutic drug , bis- chloroethylnitrosourea (BCNU) / carmustine, directly into cavity created after surgical resection of tumor (high-grade malignant glioma / hodgkin's lymphoma). Bio-degradable polyanhydride co-polymer in 20:80 ratio of poly[bis(p- carboxyphenoxy )propane]:sebacic acid; controls local delivery of carmustine. EXAMPLE OF BIO-DEGRADABLE PASSIVE IMPLANTS

16. “ Profact Depot® or Suprefact Depot® ” contains buserelin acetate (gonadotropin-releasing hormone agonist) & PLGA (drug-carrier) in 75:25 ratio. Implant is designed for 2- & 3-month drug release, where duration of action depends upon relative ratio of drug & PLGA in implants. EXAMPLE OF BIO-DEGRADABLE PASSIVE IMPLANTS

17. Active implants uses + ve driving force to enable & control drug release. They modulate drug doses & delivery rates more precisely than passive systems. External control of dosing is requirement for many drugs & is difficult to obtain by using bio-degradable or non-degradable systems. Active system provides higher precision & external control needed. They also offer number of advantages  bypassing GlT, avoiding repeated injections, & improved release rates than passive systems. Drawback  higher cost & complex nature . ACTIVE IMPLANTS

18. Active implants include “ Implantable Pump Systems ” classified as: a) Osmotic Pumps b) Propellant Infusion Pumps c) Electromechanical Drives ACTIVE IMPLANTS

19. Osmotic pumps are designed by semi-permeable membrane that surrounds drug reservoir. Membrane should have orifice which allows drug release. Osmotic gradients will allow steady inflow of fluid within implant. This increase hydrostatic pressure within implant which forces efflux of API from an orifice. This design allows constant drug release ( zero-order kinetics ) with favorable release rate; but the drug loading is limited. CONCEPT OF OSMOTIC PUMP

20. CONCEPT OF OSMOTIC PUMP

21. Historical development of osmotic systems includes seminal contributions like - the Rose-Nelson® pump, the Higuchi-Leeper® pumps, the Alzet® & Osmet® systems, the elementary osmotic® pump, the push-pull® or GITSR® system. Recent advances include development of controlled-porosity osmotic pump, asymmetric membrane-based systems , etc. CONCEPT OF OSMOTIC PUMP

22. “ Osmotic agent : used for fabrication of osmotic device that maintains conc. gradient across membrane; by generating driving force for water uptake & assist in maintaining drug uniformity in hydrated formulation.” Usually are ionic compounds consisting of inorganic salts or sugars . Ex . sod. / pot. chloride, Mg / sod. / pot. sulphate, sod. bicarbonate, glucose, sorbitol, sucrose & inorganic salts of carbohydrates. CONCEPT OF OSMOTIC PUMP

23. Gives zero-order release & deliveries can be delayed or pulsed. Drug discharge is free of gastric pH & hydrodynamic state. Release mechanisms are NOT drug-dependent. High in-vitro & in-vivo correlation (IVIVC). Superior & promising release rates compared to passive diffusion systems. Presence of food rarely affect drug release. Highly expected release rate; which can be pre-determined by modifying release-control parameters. ADVANTAGES OF OSMOTIC PUMP

24. Special equipment is necessary for making an orifice in system. May cause irritation or ulcers. More chances of dose dumping. Retrieval therapy is very difficult in case of unpredicted adverse events. If coating is not well-controlled, there is a risk of film defects resulting in dose discarding. Habitation time of system in the body varies with GI motility & food. DISADVANTAGES OF OSMOTIC PUMP

25. Drug solubility. Delivery orifice (laser drill, use of leachable substances in semi-permeable coating, systems with passageway produced in-situ ). Osmotic pressure. Semi-permeable membrane. Membrane thickness. Type & nature of polymer. Type & amount of plasticizer. FACTORS AFFECTING OSMOTIC PUMP

26. ALZET® OSMOTIC PUMP

27. ANY QUESTIONS…???