Ndds 4 MICROENCAPSULATION DRUG DELIVERY SYSTEM

NDDS TOPICS BY PROF. SHASHANK CHAURASIYA

1. PREPARED BY: PROF. SHASHANK CHAURASIYA BANSAL COLLEGE OF PHARMAY, BHOPAL MICROENCAPSULATION

2. MICROENCAPSULATION : METHODS & THEIR APPLICATIONS

3. Defination Microencapsulation is a process by which very tiny droplets or particles of liquid or solid material are surrounded or coated with a continuous film of polymeric material. Microencapsulation may be defined as the process of surrounding or enveloping one substance within another substance on a very small scale, yielding capsules ranging from less than one micron to several hundred microns in size.” It is mean of applying thin coating to small particle of solid or droplet of liquid & dispersion. Microencapsulation is a process by which solids, Liquids or even gases may be enclosed in microscopic particles by formation of thin coatings of wall material around the substances INTRODUCTION

4. Particle size: 50-5000 micron. 2 phases: a) Core material b) Coating material The prod u ct ob t ai n ed b y t h is pr o c e ss is ca lled as m i c ro p art ic les, microcapsules, microsphere, coated granules, pellets.. Particles having diameter between 3 - 800µm are known as micro particles or microcapsules or microspheres. Particles larger than 1000µm are known as Macroparticles .

5. A well designed controlled drug delivery system - can overcome some of the problems of conventional therapy. - enhance the therapeutic efficacy of a given drug.

6. To obtain maximum therapeutic efficacy, drug is to be delivered : -to the target tissue -in the optimal amount -in the right period of time there by causing little toxicity and minimal side effects . One such approach is using microspheres as carriers for drugs. Microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers biodegradable in nature particle size less than 200 μm.

7. Microspheres Formulated Microsphere Red one’s are R.B.C Purple one’s are microspheres

8. REASONS FOR MICROENCAPSULATION To protect reactive substances from the environment, To convert liquid active components into a dry solid system, To separate incompatible components for functional reasons, To protect the immediate environment of the microcapsules from the active components. as in isolating vitamins from the Isolation of core from its surroundings, deteriorating effects of oxygen. retarding evaporation of a volatile core. improving the handling properties of a sticky material. isolating a reactive core from chemical attack. for safe handling of the toxic materials. to get targeted release of the drug To control release of the active components for delayed (timed) release or long-acting (sustained) release, The problem may be as simple as masking the taste or odor of the core, To Increase of bioavailability, To produce a targeted drug delivery, Protects the GIT from irritant effects of the drug, Extension of duration of activity for an equal level of active agent.

9. Generally Micro particles consist of two components a) Core material. The solid core can be mixture of active constituents, stabilizers, diluents, excipients and release-rate retardants or accelerators. b) Coat or wall or shell material Compatible, non reactive with core material Provide desired coating properties li k e s tren g th, flexibili t y , impermeability, optical properties, non hygroscopicity, tasteless and stable Fundamental Consideration / Formulation considerations

10. Core Material The material to be coated. It may be liquid or solid or gas. Liquid core may be dissolved or dispersed material. Composition of core material: Drug or active constituent Additive like diluents Stabilizers

11. Coating Material Inert substance which coats on core with desired thickness. Composition of coating: Inert polymer Plasticizer Coloring agent Resins, waxes and lipids Release rate enhancers or retardants ROLE OF POLYMERS : Polymers are substances of high molecular weight made up by repeating monomer units. Polymer molecules may be linear or branched, and separate linear or branched chains may be joined by crosslinks. Polymers are used widely in pharmaceutical systems as adjuvants, coating materials and, a components of controlled and site- specific drug delivery systems

12. Stabilization of core material. Inert toward active ingredients. Controlled release under specific conditions. Film-forming, pliable, tasteless, stable. Non-hygroscopic, no high viscosity, economical. Soluble in an aqueous media or solvent, or melting. The coating can be flexible, brittle, hard, thin etc. Coating Material Properties

13. List of coating material Water soluble resin Water insoluble resin Wax & lipid Enteric resin Gelatin, Ethyl cellulose, Paraffin, Shellac, Gum arabic, Polyethylene, Carnauba wax, Zein, PVP, CMC, Polymethacrylate, Cellulose nitrate, Bees wax, Stearic acid, Cellulose acetate phthalate. Methyl cellulose, Silicones. Stearyl alcohol. Arabinogalactan, Pol y vin y l acrylate, Polyacrylic acid.

14. Core Material Characteristic Property Purpose of Encapsulation Final Product Form Aspirin Slightly water- soluble solid Taste-masking; sustained release; reduced gastric irritation; separation of incompatibles Tablet or capsule Vitamin A Palmitate Nonvolatile liquid Stabilization to oxidation Dry powder Isosorbide dinitrate Water soluble solid sustained release Capsule Table: Properties of Some Microencapsulated Core Materials.

15. ADVANTAGES: To Increase of bioavailability To alter the drug release To improve the patient’s compliance To produce a targeted drug delivery the outside T o red u ce t he rea c ti v ity o f the co r e in relati o n to environment To decrease evaporation rate of the core material. To convert liquid to solid form & To mask the core taste. Disadvantages It is an expensive process Requires skill Difficult to obtain continuous and uniform film

16. Morphology of Microcapsules The morphology of microcapsules depends mainly on the core material and the deposition process of the shell. Mononuclear (core-shell) microcapsules contain the shell around the core. Polynuclear capsules have many cores enclosed within the shell. Matrix encapsulation in which the core material is distributed homogeneously into the shell material. - In addition to these three basic morphologies, microcapsules can also be mononuclear with multiple shells, or they may form clusters of microcapsules.

17. RELEASE MECHANISMS Even when the aim of a microencapsulation application is the isolation of the core from its surrounding, the wall must be ruptured at the time of use. A variety of release mechanisms have been proposed for microcapsules : by pressure or shear stress. by melting the wall. by dissolving it under particular conditions, as in the case of an enteric drug coating. by solvent action by enzyme attack by chemical reaction by hydrolysis or slow disintegration.

18. MICROENCAPSULATION TECHNIQUES: Air suspension techniques( Wurster) Coacervation process Spray drying & congealing Pan coating Solvent evaporation Polymerization Multiorific-centrifugal Extrusion Single & double emulsion techniques Supercritical fluid anti solvent method (SAS) Nozzle vibration technology

19. I] Physical or Physico-mechanical methods 16 1. Air-suspension coating Inventions of Professor Dale E. Wurster Basically the wurster process consists of the dispersing of solid, particulate core materials in a supporting air stream and the spray-coating of the air suspended particles. Equipment ranging in capacities from one pound to 990 pounds. Micron or submicron particles can be effectively encapsulated by air suspension techniques . Disadvant a g e - Agglomer a tion of the par t icles t o so m e l a r g e r size is normally achieved

20. 18 Processing variables for efficient, effective encapsulation by air suspension techniques: Densi t y , sur face ar e a, m e l ting poin t , solubi l it y , fr i abi l it y , volatility, Crystallinity, and flow-ability of core the core material. C o ating m ateri a l c o nce n tra t ion (or m elt i ng poi n t i f no t a solution). Coating material application rate. Volume of air required to support and fluidizes the core material. Amount of coating material required. 6.Inlet and outlet operating temperatures.

21. 19 Fig. 4: Air Suspension Apparatus .

22. 20 2. Centrifugal extrusion Liq u ids a re encapsu l ated using a rot a ting extrus i on he a d containing concentric nozzles. This process is excellent for forming particles 400–2,000 μm in diameter. Since t h e d rops are fo r m ed by the breakup of a l i q u id je t , the process is only suitable for liquid or slurry. A high pr o duc t ion rate can b e ac h ie v ed, i . e . , u p to 22. 5 k g of microcapsules can be produced per nozzle per hour per head. Heads containing 16 nozzles are available.

23. 21 3. Pan coating Oldest industrial procedures for forming small, coated particles or tablets. The particles are tumbled in a pan or other device while the coating material is applied slowly. Solid particles greater than 600 microns in size are generally considered essential for effective coating. Medicaments are usually coated onto various spherical substrates such as nonpareil sugar seeds, and then coated with protective layers of various polymers.

24. 22 Fig. 5: Representation of a typical pan coating

25. 23 4. Spray-drying In m odern spr ay drye rs the visc o si ty of the solutions t o be sprayed can be as high as 300mPa.s S p ray drying and s p ray conge a l ing- dis p ersing the c o r e material in a liquefied coating substance and spraying. S pray dry i n g i s e f fected by rapid evapor a t i on of a solv e nt in which the coating material is dissolved.

26. 24 The equipment components of a standard spray dryer include an air heater, atomizer, main spray chamber, blower or fan, cyclone and product collector.

27. 25 Spray congealing c an be a cco m p l ish e d w i th spray d rying equipment when the protective coating is applied as a melt. Core material is dispersed in a coating material melt rather than a coating solution. Coating solidification (and microencapsulation) is accomplished by spraying the hot mixture into a cool air stream.

28. 26 Airflow There are three modes of contact: Co-current Counter-current Mixed-flow

29. 27 5. Vibrational Nozzle The process works very well for generating droplets between 100–5,000 µm Units are deployed in industries and research mostly with capacities of 1–10,000 kg per hour at working temperatures of 20–1500 C. Nozzles heads are available from one up to several hundred thousand are available.

30. 28 Fig. 7: Formation of Droplets Using Vibrational Nozzle Technique.

31. II] Physico-chemical methods 29 1. Ionotropic gelation C h e m ical r ea ct ion b e t ween sodi u m alg i n a t e and c al c i u m chloride or other Counter ion solution such as barium chloride. Verapamil hydrochloride causes gastric irritation on sudden release. It is usually administered as conventional tablets containing 40-120 mg, 3 times a day. Due to its ready solubility in water and shorter half-life. Microparticulate system of verapamil hydrochloride for prolonged release delivery system.

32. 30 2. Coacervation-Phase Separation Patents of B.K. Green et al. Three steps carried out under continuous agitation: Formation of three immiscible chemical phases Deposition of the coating Rigidization of the coating

33. 31 Fig. 8: Schematic representation of the coacervation process. Core material dispersion in solution of shell polymer; separation of coacervate from solution; coating of core material by microdroplets of coacervate; coalescence of coacervate to form continuous shell around core particles.

34. III] Chemical process 32 1. Solvent Evaporation In the case in which the core material is dispersed in the polymer solution, polymer shrinks around the core. In the case in which core material is dissolved in the coating polymer solution, a matrix - type microcapsule is formed. The core materials may be either water - soluble or water - insoluble materials. A variety of film - forming polymers can be used as coatings.

35. 33 Used by companies including the NCR Company, Gavaert Photo - Production NV, and Fuji Photo Film Co., Ltd . eg. Evaluation of Sucrose Esters as Alternative Surfactants in Microencapsulation of Proteins by the Solvent Evaporation Method.

36. 34 2. Polymerization Interfacial polymer In Interfacial polymerization, the two reactants in a polycondensation meet at an interface and react rapidly. In-situ polymerization In a few microencapsulation processes, the direct polymerization of a single monomer is carried out on the particle surface.

37. C o ntinue… 35 e.g. Cellulose fibers are encapsulated in polyethylene while immersed in dry toluene. Usual deposition rates are about 0.5μm/min. Coating thickness ranges 0.2-75μm. 3) Matrix polymer In a n u m ber o f pr o cesse s , a c o re m ater ia l is i m bedded in a polymeric matrix during formation of the particles. Prepa res m i c rocapsu l es co n tai n i n g pr o tein solu t ions by incorporating the protein in the aqueous diamine phase. National Lead Corporation- utilizing polymerization techniques

38. A P P L IC A TION OF MIC R O E N C A P S U L A TION T E C H NI Q U E S :

39. Applications of Microcapsules and Microspheres 1. Agricultural Applications Reduce insect populations by disrupting their mating process. Protects the pheromone from oxidation and light during storage and release. 2. Catalysis Safe handling, easy recovery, reuse and disposal at an acceptable economic cost. Metal species such as palladium (II) acetate and osmium tetroxide have been encapsulated in polyurea microcapsules and used successfully as recoverable and reusable catalysts without significant leaching and loss of activity.

40. 3. Food Industry Adding ingredients to food products to improve nutritional value can compromise their taste, colour, texture and aroma. Sometimes they slowly degrade and lose their activity, or become hazardous by oxidation reactions. Ing r e d ients can a l so r e a c t w i th co m ponen t s pre se n t i n t h e food system, which may limit bioavailability. 4. Pharmaceutical Applications Potential applications of this drug delivery system are replacement of therapeutic agents (not taken orally today like insulin), gene therapy and in use of vaccines for treating AIDS, tumors, cancer and diabetes. The delivery of corrective gene sequences in the form of plasmid DNA could provide convenient therapy for a number of genetic diseases such as cystic fibrosis and hemophilia.

41. Lupin has already launched in the market worlds first Cephalexin (Ceff-ER) and Cefadroxil (Odoxil OD) antibiotic tablets for treatment of bacterial infections. Aspirin controlled release version ZORprin CR tablets are used for relieving arthritis symptoms. Quinidine gluconate CR tablets are used for treating and preventing abnormal heart rhythms. Niaspan CR tablet is used for improving cholesterol levels and thus reducing the risk for a heart attack. Some of the applications of microencapsulation can be described in detail as given below: Prolonged release dosage forms. selectively Prepare enteric-coated dosage forms absorbed in the intestine rather than the stomach. It can be used to mask the taste of bitter drugs. To reduce gastric irritation.

42. Used to aid in the addition of oily medicines to tableted dosage forms. To overcome problems inherent in producing tablets from otherwise tacky granulations. This was accomplished through improved flow properties. eg. The non-flowable multicomponent solid mixture of niacin, riboflavin, and thiamine hydrochloride and iron phosphate may be encapsulated and made directly into tablets . To protect drugs from environmental hazards such as humidity, light, oxygen or heat. eg. vitamin A and K have been shown to be protected from moisture and oxygen through microencapsulation . The separations of incompatible substances, eg . pharmaceutical eutectics. The stability enhancement of incompatible aspir i n - acco m p l ished by chlorpheniramine maleate mixture was microencapsulating both of them before mixing.

43. 67 Pharmaceutical Application To improve the flow properties. e.g. Thiamine, Riboflavine To enhance the stability. e.g. Vitamins To reduce the volatility of materials. e.g. Peppermint oil, Methyl salicylate To avoid incompatibilities. e.g. Aspirin and Chloramphenicol T o m ask the unpeasa n t taste and odou r . e.g. A m inophy l l i n e , castor oil To convert liquids into solids. e.g. Castor oil, Eprazinone, To reduce gastric irritation. e.g. Nitrofurantoin, Indomethacin

44. Microencapsulation has been employed to provide protection to the core materials against atmospheric effects, e.g., Vitamin A Palmitate. Separation of incompatible substance has been achieved by encapsulation To mask the bitter taste of drugs like Paracetamol, Nitrofurantoin etc. To reduce gastric and other gastro intestinal (G.I) tract irritations, For eg, sustained release Aspirin preparations have been reported to cause significantly less G.I. bleeding than conventional preparations A liquid can be converted to a pseudo-solid for easy handling and storage. eg.Eprazinone. H y gros c o p ic pro p erties o f core m a t e rials m a y b e re d uced by microencapsulation e.g. Sodium chloride. Carb o n tetra chl o ri d es a nd a n u m b e r o f other s u b stances h a ve been microencapsulated to reduce their odour and volatility To reduce volatality of liquids like peppermint oil Helps to prepare SRDF and enteric c oated pro d u c ts, co n tr o lled rele a s e products Used to improve flow properties before compression into tablets 68

45. Brand name API Manu f actu r er OROS CT (osmotically active tablets) Colon specific drugs Alza corp. ReGel (on c o g el) Paclitaxel Macro Med Inc. Clopigrel clopidogrel+ Aspirin Lupin pinnacle Clobitab clopidogrel+ Aspirin Lupin pinnacle Atoplus Atorvastatin Triton (calyx) 69

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