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Tropical Journal of Pharmaceutical Research, September 2008; 7 (3): 1067-1075 © Pharmacotherapy Group, Faculty of , University of Benin, Benin City, 300001 Nigeria. All rights reserved .

Available online at http://www.tjpr.org Review Article

Multiparticulate Delivery Systems for Controlled Release

NS Dey*, S Majumdar and MEB Rao Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Khodasinghi, Berhampur, Orissa760010, India

Abstract

Pharmaceutical invention and research are increasingly focusing on delivery systems which enhance desirable therapeutic objectives while minimising side effects. Recent trends indicate that multiparticulate systems are especially suitable for achieving controlled or delayed release oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns as well as reproducible and short gastric residence time. The release of drug from microparticles depends on a variety of factors including the carrier used to form the multiparticles and the amount of drug contained in them. Consequently, multiparticulate drug delivery systems provide tremendous opportunities for designing new controlled and delayed release oral formulations, thus extending the frontier of future pharmaceutical development.

Keywords: Dose dumping, Microparticles, Multiparticulate delivery system, Delayed release

*Corresponding author: Email: [email protected] Phone no: +91-09861352986

1067 Trop J Pharm Res, September 2008; 7 (3) Dey et al

INTRODUCTION Drug safety may also be increased by using Multi-particulate drug delivery systems are multiparticulate dosage forms, particularly for mainly oral dosage forms consisting of a modified release systems. For example, if the multiplicity of small discrete units, each film coat of a single-unit (monolithic) enteric exhibiting some desired characteristics. In coated tablet is damaged, the complete dose these systems, the dosage of the drug will be released into the where it may substances is divided on a plurality of subunit, cause pain or ulceration or reduced efficacy, typically consisting of thousands of spherical depending on the reason for choosing the particles with diameter of 0.05-2.00mm 1. Thus protection of the enteric coating. Equally, if multiparticulate dosage forms are there is damage to the film coating of a pharmaceutical formulations in which the monolithic tablet with a sustained release active substance is present as a number of formulation, this can lead to “dose dumping” small independent subunits. To deliver the and result in dramatic side effects. By recommended total dose, these subunits are contrast, in multiparticulate formulation, the filled into a sachet and encapsulated or release characteristics are incorporated into compressed into a tablet 4. Multiparticulates every single subunit and any damage only are discrete particles that make up a multiple- affects the release behavior of the subunit unit system. They provide many advantages involved, which represents a small part of the over single-unit systems because of their total dose, reducing the likelihood of safety small size. Multiparticulates are less problems 4. dependent on gastric empty ting, resulting in less inter and intra-subject variability in SOME APPROACHES TO gastrointestinal transit time. They are also MULTIPARTICULATE FORMULATION better distributed and less likely to cause local A multiparticulate floating–pulsatile drug irritation 2. Recently much emphasis is being delivery system was developed using porous laid on the development of multiparticulate calcium silicate [RE(R)] and sodium alginate, dosage forms in preference to single unit for time and site specific drug release of systems because of their potential benefits meloxicam 5. such as increased , reduced risk An oral controlled onset extended release of systemic toxicity, reduced risk of local intended to approximate the irritation and predictable gastric emptying 3. chronobiology of rheumatoid arthritis was There are many reasons for formulating a proposed for site specific release to the colon. drug as a multiparticulate system for example, The multiparticulate system consisting of drug to facilitate disintegration in the stomach, or to loaded acetate cores encapsulated provide a convenient, fast disintegrating tablet within Eudragit S-100 microcapsules was that dissolves in water before swallowing designed for chronotherapeutic delivery of which can aid compliance in older patients ketoprofen 6. The site-specific delivery of and children. Multiparticulate systems show to the colon has implications in a number of better reproducible pharmacokinetic behavior therapeutic areas, which include topical than conventional (monolithic) formulations. treatment of colonic disorders such as Crohn’s After disintegration which occurs within a few disease, ulcerative colitis, constipation, minutes often even within seconds, the colorectal cancer, spastic colon and irritable individual subunit particles pass rapidly bowel syndrome 7. through the GI tract. If these subunits have Multiparticulates approaches tried for colonic diameters of less than 2mm, they are able to delivery includes formulations in the form of leave the stomach continuously, even if the pellets, granules, microparticles and pylorus is closed. These results in lower intra nanoparticles. Because of their smaller and inter individual variability in plasma levels particle size compared to single unit dosage and bioavailability. forms these systems are capable of passing through the GI tract easily, leading to low inter

1068 Trop J Pharm Res September 2008; 7 (3) Dey et al and -intra subject variability. Moreover, release system based on coated pellets multiparticulate systems are to be more containing an osmotic active ingredient has uniformly dispersed in the GI tract and also been prepared. The coating consisted of a ensure more uniform drug absorption 3. A semi permeable membrane of cellulose multiparticulate system of chitosan hydrogel acetate. Following ingestion water penetrates beads has been investigated for colon-specific into the core and forms a saturated of delivery of macromolecules using fluorescein the soluble components. The osmotic is othiocyanate-labeled bovine serum albumin pressure gradient induces a water influx as a model 8. resulting in a rapid expansion of the Multiparticulates may be prepared by several membrane leading to the formation of pores. methods. Different methods require different The osmotic ingredient and the drug are processing conditions and produce released through these pores according to multiparticulates of distinct qualities. Some of zero order kinetics. In comparison with the these methods may be broadly classified as sodium chloride free formulation the inclusion pelletization, granulation, spray drying, and of the osmotically active ingredient results in a spray congealing. Drug particles may be completely different dissolution behavior. Lag entrapped within the multiparticulates or time and dissolution rate were dependent on layered around them. Subsequently, these the coating level and the osmotic properties of multiparticulates may be modified in many the dissolution medium 10 . ways to achieve the desired drug release profile. MECHANISM OF DRUG RELEASE FROM One approach to the modification of drug MULTI-PARTICULATES release profile in multiparticulates is to coat The mechanism of drug release from them. Reasons for the application of coating multiparticulates can be occur in the following onto maltiparticulates are to obtain functional ways: coats, provide chemical stability, improve Diffusion physical characteristics and enhance patient acceptance. Coats are formed from various On contact with aqueous fluids in the polymeric coating materials broadly classified (GIT), water diffuses into as aqueous dispersions, polymer the interior of the particle. Drug dissolution , molten and dry . occurs and the drug solutions diffuse across Depending on the type of coating material the release coat to the exterior. used, functions such as sustained release Erosion (SR), targeted release, delayed release, and pulsatile release can be achieved. Some coatings can be designed to erode The most common method used for the gradually with time, thereby releasing the drug application of coating onto multiparticulates is contained within the particle. air coating. Other methods include compression coating, solvent evaporation, Osmosis coacervation, and interfacial complexation. It In allowing water to enter under the right is also possible to form coated circumstances, an osmotic pressure can be multiparticulates by spray drying and spray built up within the interior of the particle. The 2 congealing . A multiparticulate composition drug is forced out of the particle into the may allow controlled release of the drug over exterior through the coating 1. a wide range of release rates, and permit the release rate to be set at a predetermined rate, DESIGN OF MULTIPARTICULATE DRUG such a formulation may be formed using a DELIVERY SYSTEMS melt-congeal process which maintains the The purpose of designing multiparticulate crystallinity of the drug during the melt- dosage form is to develop a reliable 9 congeal process . A multiparticulate delayed formulation that has all the advantages of a

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Fig 1: Intestinal Protective Drug Absorption System Fig 2: Spheroidal Oral Drug Absorption System

Fig 3: Programmable Oral Drug Absorption System Fig 4: Diffucaps

Fig 5: Minitab single unit formulations and yet devoid of the out through the length of the intestine cause danger of alteration in drug release profile and less irritation, enjoy a slower transit through formulation behavior due to unit to unit the colon and give a more reproducible drug variation, change in gastro –luminal pH and release. As in the case of single unit dosage enzyme population. A generally accepted view forms, for the purpose of the designing is that multiparticulate systems perform better multiparticulate colon specific drug delivery in vivo than single unit system, as they spread system, the presence of specific bacterial

1070 Trop J Pharm Res September 2008; 7 (3) Dey et al populations in the colon and increasing pH the drug in the stomach which subsequently gradient have been extensively explored as pass into the duodenum and along the triggering mechanism in order to initiate colon gastrointestinal tract in a controlled and specific drug release. gradual manner, independent of the feeding state. Release of active ingredient from the Multiparticulate crystalline drug multiparticulates occurs through a process of compositions diffusion either through the polymeric A multiparticulate for controlled release of a membrane and /or the micro matrix of the drug comprises a crystalline drug, a glyceride polymer/active ingredient formed in the having at least one alkylate substituent of not extruded/spheronized multiparticulates. The less than 16 carbon atoms, and a poloxamer, intestinal protection of IPDAS is by virtue of wherein at least 70 wt % of the drug in the the multiparticulate nature of the formulation multiparticulate is crystalline. The which ensures wide dispersion of irritant drug multiparticulate comprises crystalline drug throughout the gastrointestinal tract. particles embedded in the glyceride/ Naprelan®, which is marketed in the United poloxamer mixture. The poloxamer 16 is States, employs IPDAS technology. This substantially homogeneously distributed innovative formulation of naproxen sodium is throughout the glyceride 14 and is present as 11 a unique controlled release formulation a separate phase from the glyceride 14 . 1,12 indicated both for acute and chronic pain . Multiparticulates as NDDS Spheroidal oral drug absorption systems Incorporating an existing medicine into a novel Spheroidal Oral Drug Absorption System drug delivery system (NDDS) can significantly (SODAS) (Figure 2) is a multiparticulate improve its performance in terms of efficacy, technology that enables the production of safety and improved patient compliance. In customized dosage forms and responds the form of a NDDS, an existing drug directly to individual drug candidate needs. It molecule can get new life, thereby increasing can provide a number of tailored drugs its market value and competitiveness and release profiles including immediate release of even extending patent life 1. drug followed by sustained release to give rise Intestinal Protective Drug Absorption to a fast onset of action which is mainted for System 24 hours. Alternatively, the opposite scenario Intestinal protective drug absorption system can be achieved where drug release is (IPDAS) (Figure 1) is a multiparticulate tablet delayed for a number of hours 1,13 . technology that has been developed to Programmable Oral Drug Absorption enhance the gastric tolerability of potentially System irritant or ulcerogenic drugs such as the Programmable Oral Drug Absorption System NSAIDs. It consists of high density controlled (PRODAS) (Figure 3) is presented as a release beads that are compressed into a number of mini tablets contained in hard tablet form. The beads may be manufactured . It thus combines the benefits by techniques such as extrusion of tableting technology within a capsule. It is spheronization and controlled release can be possible to incorporate many different achieved with the use of different polymer minitablets, each one formulated individually systems to coat the resultant beads. and programmed to release drug at different Alternatively, the drug can also be coated into sites within the GIT. These combinations may on an inert carrier such as non-pareil seeds to include immediate release, delayed release, produce instant release multiparticulates. and/or controlled release mini tablets. It is also Controlled release can be achieved by the possible to incorporate mini tablets of different formation of a polymeric membrane onto sizes so that high drug loading is possible. these instant release multparticulates. Once Their size ranges usually from 1.5 – 4 mm in an IPDAS tablet is ingested, it rapidly 1, 14 diameter . disintegrates and disperses beads containing

1071 Trop J Pharm Res September 2008; 7 (3) Dey et al

Diffucaps As a result, combination products can be In this multiparticulate system, drug profiles developed to allow for two or more release are created by layering an active drug onto a profiles within a single capsule. Eurand neutral core such as sugar spheres, crystals minitabs offer high drug loading, the ability to or granules followed by the application of a fine tune release rates for targeted delivery rate-controlling, functional membrane (Figure and content uniformity for more accurate 4). The coating materials can be water dosing. Eurand Minitabs offer high drug soluble, pH dependent or independent or loading, a wide range of release rate designs, water insoluble depending on the individual and fine tuning of these release rates. The needs of compound. The resultant beads are capsules can be opened and the contents small in size approximately 1mm or less in used as a "sprinkle" formulation 1, 16. diameter. By incorporating beads of differing Stabilized Pellet Delivery System drug release profiles into hard gelatin Stabilized pellet delivery system technology capsules, combination release profiles can be uses functional polymers or a combination of achieved. It is possible to customize any functional polymers and specific additives, combination of sustained release, pulsatile such as composite polymeric materials to release and immediate release profiles deliver a drug to a site of optimal absorption depending on the specific needs of the along the intestinal tract. The active drug is product. incorporated in multiparticulate dosage forms The drug layering process can be conducted such as DIFFUCAPS or Eurand MINITABS, either from aqueous or solvent based drug which are then subsequently coated with pH solutions. Eurand has also developed a dependent/independent polymeric formulation technology that combines the membranes that will deliver the drug to the customized drug release offered by Diffucaps desired site. These are then filled into hard with technologies that enhance the solubility gelatin capsules. This technology is designed of insoluble drugs in the gastrointestinal tract. specifically for unstable drugs and Eurand is using this technology to provide a incorporates a pellet core of drug and degree of delivery control that goes beyond protective polymer outer layer(s) 1. that of single technology systems. Diffucaps beads are small in size, Pelletized Delivery System approximately 1mm in diameter, and are filled Pelletized Delivery System (PDS) is a into a capsule to create the final dosage sustained release system using pellets or form. Beads of differing drug release profiles beads manufactured using marumerization/ can be easily combined in a single capsule pheronization/pelletization techniques or by providing high levels of control over release layering powders or solutions on nonpareil profiles. Diffucaps beads of different drugs seeds. Release modulating polymers are can be combined to make convenient single sprayed on the beads using various coating dose units for combination therapies 1, 15 . techniques. The coated beads are filled in to hard gelatin capsules. Drug release occurs by Minitabs diffusion associated with bioerosion or by The Eurand MINITABS technology (Figure 5) osmosis via the surface membrane. The is unique in that it offers the advantages of a release mechanism can be pH-activated or tablet combined with those of a pH-independent. The beads can be multiparticulate drug form. Eurand MINITABS formulated to produce first order or zero order are tiny (2mm x 2mm) tablets containing - release 1. forming that control drug release rate. Additional membranes may be added to Pelletised tablet further control release rate. The small size of Pelletised tablet (Peltab ®) system utilizes Eurand minitabs means that they can be filled polymer-coated drug pellets or drug crystals, into capsules as a final dosage form. which are compressed into tablets. In order to provide a controlled release, a water insoluble

1072 Trop J Pharm Res September 2008; 7 (3) Dey et al polymer is used to coat discrete drug pellets KV/24 or crystals, which then can resist the action of KV/24 is a patented, multiparticulate drug fluids in the GIT. This technology incorporates delivery technology that encapsulates one or a strong polymer coating enabling the coated more drug compounds to achieve release in a pellets to be compressed into tablets without pre-determined fashion over a 24-hour period significant breakage 1. after . KV/24 technology is based upon coating a neutral core (non- Multiparticle Drug Dispersing Shuttle pareiled bead) with a drug substance, then Multiparticle drug dispersing shuttle sequentially coating with one or more (Multipart ®) consists of a tablet carrier for the polymers to achieve a once-a day release delivery of controlled release beads or pellets profile. The drug can either be combined with through the GIT which preserves the integrity the neutral core or incorporated into the and release properties of the beads. The coating process 1 . distribution of the beads is triggered by the disintegration of the tablet carrier in the Flashtab stomach. Drug release from the beads is Flashtab technology is a fast triggered by super disintegration of the tablets. dissolving/disintegrating oral tablet It can be pH-activated or pH-independent and formulation. It is a combination of taste can occur by disintegration or osmosis. The masked multiparticulate active drug beads can be formulated to produce first or substances with specific excipients zero order release 1. compressed into tablets. A disintegrating agent and a swelling agent are used in Macrocap ® combination with coated drug particles in this Macrocap ® consists of immediate release formulation to produce a tablet that beads made by extrusion/ spheronization/ disintegrates in the mouth in less than one pelletization techniques or by layering minute. These oro-dispersible tablets disperse powders or solutions on nonpareil seeds. rapidly before the patient swallow them 1. Release modulating polymers are sprayed on InnoHerb the beads using various coating techniques. This technology is used coating the pellets The coated beads are filled in hard gelatin inside of the capsule, InnoHerb capsules. Drug release occurs by diffusion Phytogranules. The multiparticulate is made associated with bioerosion or by osmosis via up of many micropellets or small beads the surface membrane. The release containing active herbal compounds. The mechanism can be pH-activated or pH- special coating for each plant extract contains independent. The beads can be formulated to 1 top quality standardised dried extracts which produce first or zero order release . assures efficacy and safety of the semi-

® permeable membrane, improves stability, Orbexa ® mask taste/smell and affords gastro-protection Orbexa technology is a multiparticulate as well as promote controlled release of system that enables high drug loading and is actives, optimal availability and better suitable for products that require granulation. absorption 17 . This technology produces beads that are of controlled size and density using granulation, Layering process for multiparticulate extrusion and spheronization techniques. This dosage form process is unique in that it allows for higher Layering processes involve loading inert drug loading than other systems, is flexible cores with drugs and/or excipients. Inert and is suitable for use with sensitive materials 1 cores, placed in a suitable vessel such as a such as enzymes . coating pan or a fluid bed, may be layered

according to different methods. Some

methods consist of spraying onto the cores a

1073 Trop J Pharm Res September 2008; 7 (3) Dey et al solution/suspension containing both drug and include an inert core, such as a carbohydrate binding agent. Others are based on layering sphere, a layer of IL-11 and an enteric coat. the drug directly in powdery form where drug The enteric coat can include, e.g., a pH loading occurs by gravity and adhesion is dependent polymer, a plasticizer, and an ensured by a sprayed onto the antisticking agent/glidant. Preferred polymers cores. include e.g., methacrylic acid copolymer, The layering process is particularly suitable for cellulose acetate phthalate, hydroxyl propyl production of small drug loaded units, methylcellulose phthalate, polyvinyl acetate multiples of which are placed into capsules for phthalate, shellac, hydroxylpropyl patient delivery. In the case of spherical inert methylcellulose acetate succinate and cores such as non-pareils, the layering carboxymethylcellulose. Preferably, an inert techniques from solution/suspensions produce seal coat is present in the composition as a homogeneous drug loaded particles, which barrier between the IL-11 layer and enteric retain an approximately spherical shape. They coat. The inert seal coat can be e.g. hydroxyl are therefore particularly suitable for propyl methyl cellulose, povidone, successively film coating to build up the hydroxylpropyl cellulose or another particle with the aim of providing a desired pharmaceutically acceptable binder. drug release profile 18 . Suitable sustained release polymers include, e.g., amino methacrylate copolymers Delayed release oral polypeptides (Eudragit RL, Eudragit RS), ethylcellulose or In one embodiment, the composition further hydroxypropyl methylcellulose. In some includes an inert core. The inert core can be, embodiments, the methacrylic acid copolymer e.g., a pellet, sphere or bead made up of is a pH dependent anionic polymer solubilizing sugar, , microcrystalline cellulose or any above pH 5.5. The methacrylic acid copolymer other pharmaceutically acceptable inert can be provided as a dispersion and be . A preferred inert core is a present in the composition at a concentration carbohydrate, such as a monosaccharide, of 10-20% wt/wt. A preferred methacrylic acid disaccharide, or , i.e., a copolymer Eudragit ® L30D-55 19 . polymer including three or more sugar Multiparticulate mucoadhesive molecules. An example of a suitable formulations carbohydrate is . In some embodi- In a preferred embodiment, illustrated by way ents, the sucrose is present in the composition of example, there is provided a supply of gas- at a concentration of 60-75%. developing components as well as a number When the bioactive polypeptide is IL-11, the of film-like, stacked individual particles which IL-11 layer is preferentially provided with a consist of a mucoadhesive, active substance- stabilizer such as methionine, glycine, containing layer and of a backing layer polysorbate 80 and phosphate buffer, and/or a controlling the direction of active substance pharmaceutically acceptable binder, such as release, these components being located hydroxypropyl methylcellulose, povidone or within a polymer enclosure which is resistant hydroxypropyl ‘cellulose. The composition can to gastric juice but permeable to intestinal additionally include one or more juice. Here, the active substance may be pharmaceutical excipients. Such pharmaceu- present embedded in the film-like component. ical excipients include, e.g., binders, The process for the production of a gastric disintegrants, fillers, plasticizers, lubricants, juice-resistant device, consisting of at least glidants, coatings and suspending/ ispersing one active substance in the form of a agents. In some embodiments, the multiparticulate preparation with muco- composition is provided as a multiparticulate adhesive properties, and of a blowing agent system that includes a plurality of enteric which on contact with liquid produces gas coated, IL-11 layered pellets in a capsule individual particles being enclosed by a gastric dosage form. The enteric coated IL-11 pellets juice-resistant, intestinal juice-soluble polymer

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