Implants- B.Pharm SEM 7- Novel Drug Delivery System

Implantable drug delivery device classification is not a straightforward task as there are a number of complex implants that will fall into hybrid categories. Nevertheless, implantable drug delivery devices can be broadly classified in two main groups: passive implants and active implants. The first group includes two main types of implants: biodegradable and non-biodegradable implants. On the other hand, active systems rely on energy dependent methods that provide the driving force to control drug release. The second group includes devices such as osmotic pressure gradients and electromechanical drives.

1. Implantable Drug Delivery Systems By- Prof. Vedanshu Malviya (M.Pharm- Pharmaceutics) Dr. Rajendra Gode Institute of Pharmacy, Amravati

2. Introduction From the early beginnings, the potential of this mode of delivery in overcoming problems associated with oral administration, such as drug bioavailability, stability, toxicity, and duration of release, was recognized. Implant delivery systems have been subsequently designed to reduce the frequency of dosing, prolong duration of action, increase the patient compliance, and reduce the systemic side effects. IDDSs are very attractive for a number of classes of drugs, particularly those that cannot be delivered via the oral route, are irregularly absorbed via the gastrointestinal tract, or that benefit from site-specific dosing. Examples include steroids, chemotherapeutics, antibiotics, analgesics and contraceptives, and biologics

3. Advantages T argeted local delivery of the drug. Minimizing dose required. Reduces potential side effects. Improving therapeutic efficacy. Drug release at a constant and predetermined rate . Removal of dosage form anytime if not suitable to patient. No need of frequent medication. Drug delivery can be terminated at any time.

4. Disadvantages N eed surgery for the removal. Drug accumulation. The surgical removal of  implants is often more traumatic than their insertion. Heavy Cost. If drug is not suitable then removal of dosage form can requires longer time due to surgery. Care is needed after the insertion.

5. Concept of Implants Implants can be used as delivery systems for either systemic or local therapeutic effects. For systemic therapeutic effects, implants are typically administered SC, intramuscularly, or intravenously, whereby the incorporated drug is delivered from the implant and absorbed into the blood circulation. Implants for local effects are placed into specific body sites, where the drug acts locally, with relatively negligible absorption into the systemic circulation. Implants are typically designed to release the incorporated drug in a controlled manner, allowing the adjustment of release rates over extended periods of time, ranging from several days to years . Examples of Implants includes dental, orthopedic, cardiovascular, and gastric implants.

6. Ideal Characteristics An ideal IDDS should be designed to substantially reduce the need for frequent drug administration over the prescribed treatment duration . As such, it should be environmentally stable, biocompatible, sterile. It should be readily implantable and retrievable by medical personnel to initiate or terminate therapy. Additionally , it must enable rate-controlled drug release at an optimal dose. It should be easy to manufacture and provide cost-effective therapy over the treatment duration

7. Classification of Implants Classification of IDDSs is difficult, given that there are numerous exceptions and hybrids that may be listed under multiple categories. However, drug implants can be broadly subdivided into passive and active systems. Passive systems can be further classified into non-degradable and degradable implants, that typically have no moving parts or mechanisms. Active systems employ some energy-dependent method for providing a positive driving force to modulate drug release. These energy sources may be as diverse as osmotic pressure gradients or electromechanical drives.

8. Passive Implants Passive implants tend to be relatively simple, homogenous and singular devices, typically comprising the simple packaging of drugs in a biocompatible material or matrix. By definition, they do not contain any moving parts, and depend on a passive, diffusion-mediated phenomenon to modulate drug release . Delivery kinetics are partially variable by the choice of drug, its concentration, overall implant morphology, matrix material and surface properties . Further classification is as follows:

9. Non-degradable implantable drug delivery systems While membrane-enclosed reservoirs and matrix-controlled systems are by far the most common, several other variants of non-degradable implants are commercially available. The matrix materials used in all these systems are typically polymers, with a documented history of both pre-clinical and clinical evaluation. Commonly used polymers include elastomers such as silicones and urethanes, acrylates and their copolymers, and copolymers vinylidenefluoride and polyethylene vinyl acetate ( PEVA). Within the polymeric matrices forming most passive monolithic implants, the drug is typically dispersed homogeneously throughout the matrix material . Alternatively , reservoir-type systems are characterized by a compact drug core, surrounded by a permeable non-degradable membrane, the permeability and thickness of which controls the diffusion of the drug into the body

10. Non-biodegradable Implants ( A) Norplant and (B) Implanon . A. B. Upto 5 Years Upto 3 Years

11. Biodegradable Implants To overcome the drawbacks of non-biodegradable implants, biodegradable systems, based on polymers such as poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), poly( caprolactone ) (PCL) or their block copolymer variants with other polymers have been developed. A major advantage of biodegradable systems is that the biocompatible polymers used for fabricating these delivery systems are eventually broken down into safe metabolites and absorbed or excreted by the body. Labile polymers that are prone to degradation by hydrolysis or enzymes, such as ester, amide, and anhydride bonds, are characteristic of the backbone of biodegradable polymers. Complete degradation of the implant post drug release makes surgical removal of the implant after the conclusion of therapy unnecessary, thereby reducing potential complications with explantation and increasing patient acceptance and compliance

12. Cont… Although the acidic byproducts of polyester degradation can cause instability of proteins and localized inflammation, some therapeutic proteins, such as recombinant human growth hormone and insulin, have been evaluated for delivery In general, the development of biodegradable systems is a more complicated task than formulating non-degradable systems. When fabricating new biodegradable systems, variables to be taken into consideration include the in vivo degradation kinetics of the polymer, which must ideally remain constant to maintain sustained release of the drug.

13. Examples of Bio-Degradable Implants The Gliadel wafer is one of the earliest examples of a biodegradable IDDS, approved by the FDA in 1996. It consists of biodegradable polyanhydride disks (1.45 cm in diameter and 1.0 mm thick), designed to deliver the chemotherapeutic drug, bis-chloroethylnitrosourea (BCNU) or carmustine , directly into the cavity created after surgical resection of the tumor (high-grade malignant glioma). The biodegradable polyanhydride copolymer in a 20:80 molar ratio of poly[ bis (p- carboxyphenoxy ) propane:sebacic acid], has been used to control local delivery of carmustine . Profact Depot or Suprefact Depot contain buserelin acetate ( gonadotropinreleasing hormone agonist) and PLGA (75:25 molar ratio) is used as a drug carrier. The implant is designed for 2- and 3-month drug release, where the duration of action depends upon the relative ratio of drug and PLGA in the implants.

14. Active Implants Active implant systems harness a positive driving force to enable and control drug release. As a result, these are typically able to modulate drug doses and delivery rates much more precisely than passive systems. However, this comes at a higher cost, both in terms of complexity and actual device price . Active Implants include: Implantable Pump Systems A) Osmotic Pumps B) Propellant Infusion Pumps C) Electromechanical Drives

15. Cont… External control of dosing is a requirement for many drugs, a feature that is difficult to obtain when using biodegradable or non-degradable delivery systems. These type of systems have been used to provide the higher precision and remote control needed in these situations. Additionally, they offer a number of advantages, such as evasion of the GI tract, avoidance of repeated injections, and improved release rates (faster than diffusion-limited systems).

16. Osmotic Pumps The design comprises a drug reservoir surrounded by a semipermeable membrane, which allows a steady inflow of surrounding fluids into the reservoir through osmosis. A steady efflux of the drug then ensues via the drug portal, an opening in the membrane, as a result of the hydrostatic pressure built on the drug reservoir. Nearly constant or zero-order drug release is maintained until complete depletion of the drug packaged in the reservoir. This pump comprises a rigid, rate controlling outer semi permeable membrane surrounding a solid layer of salt coated on the inside by an elastic diaphragm and on the outside by the membrane. In use, water is osmotically drawn by the salt chamber, forcing drug from the drug chamber.

17. Advantages They typically give a zero order release summary after an initial lag. Deliveries may be belated or pulsed if preferred. Drug discharge is free of gastric pH and hydrodynamic state. They are well unspoken and characterized. The release mechanisms are not dependent on drug. A high quantity of in-vitro and in-vivo correlation ( ivivc ) is obtained in osmotic systems. Superior release rates are promising with osmotic systems compared with predictable diffused controlled drug delivery systems. The release from osmotic systems is modestly affected by the presence of food in gastro intestinal tract. The release rate of osmotic systems is highly expected and can be planned by modulating the release control parameters.

18. Disadvantages Special equipment is necessary for making an orifice in the system. It may cause irritation or ulcer due to release of soaked solution of drug. Dose dumping. Retrieval therapy is not possible in the case of unpredicted adverse events. If the coating process is not well controlled there is a danger of film defects, which outcome in dose discarding. Size hole is dangerous. Extraordinary equipment is necessary for creating the orifice in the system. Habitation time of the system in the body varies with the gastric motility and food eating.

19. Examples of Osmotic Agents Water-soluble salts of inorganic acids   Magnesium chloride or sulfate; lithium, sodium, or potassium chloride; sodium or potassium hydrogen phosphate   Water-soluble salts of organic acids   Sodium and potassium acetate, magnesium succinate, sodium benzoate, sodium citrate Carbohydrates   Mannose, sucrose, maltose, lactose   Water-soluble amino acids and organic polymeric Osmogens   Sodium carboxy methyl cellulose, Hydroxy propyl methyl cellulose, Hydroxy ethyl methyl cellulose, Methylcellulose, Polyethylene oxide, Polyvinyl pyrollidone etc.  

20. Example of Osmotic Pump

21. Evaluation of Osmotic Implants

22. Factors Affecting Design of Osmotic Implants Drug Solubility Delivery Orifice ( Laser Drill, Use of Leachable Substances in the Semi Permeable Coating, Systems with Passageway Produced In-Situ) Osmotic Pressure Semi Permeable Membrane Type and Nature of Polymer Membrane Thickness Type and Amount of Plasticizer

23. Drug Solubility For the osmotic system, solubility of drug is one of the most essential parameters affecting drug release kinetics from osmotic pumps. The kinetics of osmotic drug release is directly related to the drug solubility within the drug core. Assuming a tablet core of pure drug, the portion of core released with zero-order kinetics is given by equation. F(z ) = 1 – S/ ρ (1) Where, F (z) = fraction released by zero-order kinetics, S = drug’s solubility (g/cm3) and ρ = density (g/cm3) of the core tablet.

24. Delivery Orifice Greater part of osmotic delivery systems contain at least one delivery orifice formed in the membrane for drug release . Size of delivery orifice must be optimized to manage the drug release from osmotic system. The size of the delivery orifice must be lesser than a maximum size to minimize drug delivery by diffusion through the orifice. Additionally the area must be sufficiently large, above a maximum size to minimize hydrostatic pressure increase in the system. If not the hydrostatic pressure can demolish the membrane and affect the zero-order delivery rate consequently , the cross-sectional area of the oral cavity should be maintained between the minimum and maximum values .

25. Osmotic Pressure The subsequently release-controlling factor that must be optimized is the osmotic pressure gradient between inside the section and the external environment. The release rate of a drug from an osmotic system is straightly proportional to the osmotic pressure of the core relative to the osmotic pressure of the core The simplest and most expected way to achieve a constant osmotic pressure is to maintain a soaked solution of osmotic agent in the compartment. If a soaked solution of the drug does not possess enough osmotic pressure, an additional osmotic agent must be added to the core formulation.

26. Semi Permeable Membrane Some of the membrane variables that are significant in the devise of oral osmotic system are : Cellulose acetate, cellulose dilacerate, cellulose triacetate, cellulose propionate , cellulose acetate butyrate, ethyl cellulose and eudragit.

27. Type and Nature of Polymer Any polymer porous to water but impermeable to solute can be selected . Examples: Hydrophilic and Hydrophobic Polymers Hydrophilic polymers Hydroxyl ethyl cellulose, carboxyl methylcellulose, hydroxyl propyl methylcellulose, high molecular weight poly(vinyl pyrrolidone) Hydrophobic polymers Ethyl cellulose and wax materials

28. Membrane Thickness Thickness of the membrane has a perceptible result on the drug discharge from osmotic system, which is inversely relative to each other . It is helpful in the valuation of Osmotic DDS

29. Type and Amount of Plasticizer In pharmaceutical coatings, low molecular weight diluents are added to change the physical properties and get better film-forming individuality of polymers. Visco elastic performance of polymers significantly. In particular, plasticizers can turn a hard and fragile polymer into a softer , more flexible material and possibly make it more resistant to automatic stress. These changes also affect the permeability of polymer films . Examples: Di alkyl phthalates and other phthalates, tri octyl phosphates and other phosphates, alkyl adipates , tri ethyl citrate and other citrates, acetates, propionates, glycolates , glycerolates , myristates , benzoates , sulphonamides and halogenated phenyls

30. Reference Parmar N S, Vyas S K. Advances in controlled and novel drug delivery . CBS Publishers, New Delhi, 28-29, 2008. Swarbrick J, Boylan C J. Encyclopedia of pharmaceutical technology . Marcel Decker Inc , New York, 4th Edition, 310, 1991. Verma R K, Krishna D M, Garg S. Formulation aspects in the development of osmotically controlled oral drug delivery systems . J Cont Rel , 79:7–27, 2002. Schultz P, Kleinebudde P. A new multi particulate delayed release system. Part I. Dissolution properties and release mechanism . J Cont Rel , 47:181–189, 1997.