MULTIPARTICULATE DRUG DELIVERY SYSTEM

BY Miss. JASMIN M. JAIN (T. Y. B. Pharm)

GUIDE Mr. HEMANT H. GANGURDE (M. Pharm)

DEPARTMENT OF PHARMACEUTICS S. N. J. B.S S.S.D.J COLLEGE OF PHARMACY, CHANDWAD.

DRUG DELIVERY SYSTEM Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. Most common routes of administration include the preferred non-invasive peroral (through the mouth), topical (skin), transmucosal (nasal, buccal/sublingual, vaginal, ocular and rectal) and inhalation routes. The choice of the route, however, depends on a) Physical & chemical characters of the drugs b) Effect desired c) Urgency and seriousness of the condition. Local delivery If the target receptor is external or easily accessed then local delivery of the medication can be a feasible and effective approach. Systemic delivery When the target receptor cannot be easily accessed systemic

MULTIPARTICULATE DRUG DELIVERY SYSTEM (MPDDS) Multiparticulate dosage forms are pharmaceutical formulations in which the active substance is present as a number of small independent subunits with diameter of 0.05-2.00 mm. They provide many advantages over single unit systems because of their small size. Multiparticulate drug delivery is less dependent on gastric emptying, resulting in less inter and intra subject variability in GI transit time. MPDDS applies specially to multiple particles such as pellets, beads, microspheres, microcapsules. OBJECTIVE OF MPDDS Sustain release or prolong release medication  Taste masking  Improve stability  Increase solubility or dispersability  Increase therapeutic efficiency

ADVANTAGES OF MPDDS  It minimizes the risk of local irritation.  It results in shorter lag time for Floating Drug Delivery Sysyem  It avoids fortuitous (all or none) emptying process.  It reduces patient-to patient variability i.e. inter-subject variability.  It provides greater flexibility to the formulators.  It spreads more evenly in the GIT, thus improving the therapeutic efficacy of the medicinal agents.  Lower Tendency of Dose Dumping  Greater stability of Chemically incompatible drugs  Ease of Design of Controlled Released Formulation containing more than one drug  Improved Elegance, Product identification, & Patient compliance

DISADVANTAGE OF MPDDS  Low drug loading  Proportionally higher need for excipients  Lack of manufacturing reproducibility and efficacy  Large number of process variables  Multiple formulation steps  Higher cost of production  Need of advanced technology  Trained/skilled personal needed for manufacturing

Mechanism of Drug Release from MPDDS Three delivery systems dominate todays market of oral CR products: matrix, reservoir, and osmotic systems. Release mechanisms from these dosage forms have been the subjects of extensive studies. The mechanism of drug release from MPDDS can be occurring in the following ways: 1. Diffusion a. b. Matrix system Reservoir system

2. Erosion 3. Osmosis

1. Diffusion : In these types of systems, the rate-controlling step is not the dissolution rate but the diffusion of dissolved drug through a polymeric barrier. The process of dissolution of solid particles in a liquid, in the absence of reactive or chemical forces, consists of two consecutive steps: a. Solution of the solid to form a thin film or layer at the solid liquid interface called as the Stagnant film or diffusion layer which is saturated with the drug; this step is usually rapid b. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this step is slower & is therefore the rate determining step in drug dissolution The 2 types of diffusion controlled systems are: a. Matrix System b. Reservoir System a. Matrix System A matrix system consists of active and inactive ingredients that are homogeneously mixed in the dosage form. We divide matrix systems into two categories, based on rate-controlling materials like Hydrophobic and Hydrophilic

 Hydrophobic matrix systems As the term suggests, the primary rate controlling components of a hydrophobic matrix are water insoluble in nature. Eg: waxes, glycerides, fatty acids, ethylcellulose & methacrylate copolymers.

Hydrophilic matrix systems The primary rate-controlling ingredients of a hydrophilic matrix are polymers that would swell on contact with the aqueous solution and form a gel layer on the surface of the system. Eg: HPMC ,polyethylene oxide , HPC, xantham gum. Marketed products of Matrix System Products OPANA ER tab Seroquel XR tab Active ingredient(s) Oxymorphone HCL Quetiapine fumarate Manufacturer Endo Astrazeneca

b. Reservoir System A typical reservoir system consists of a core (the reservoir) and a coating membrane (the diffusion barrier). The core contains the active ingredients and excipients, whereas the membrane is made primarily of rate-controlling polymer(s). Marketed Products: Metadate CD and Ritaline LA

2. Erosion In this system, drug is dispersed throughout the polymer, and the rate of drug release depends on the erosion rate of the polymer. However, some diffusion of the drug from the polymer may also occur. In a surface eroding system, the drug release rate is proportional to the polymer erosion rate and can be controlled by changing the system thickness and total drug content. Surface erosion eliminates the possibility of dose dumping, thus improving device safety.

3. Osmosis The system is composed of a core tablet surrounded by a semipermeable membrane coating having a 0.4mm diameter hole. The core tablet has 2 layers, one containing the drug (the active layer) & the other containing a polymeric osmotic. agent (a push layer). The rate of inflow of water & function of the tablet depends on an osmotic gradient between the contents of the two-layer core & the fluid in the GIT.

CLASSIFICATION OF MPDDS
Depending upon its size and structure MPDDS are classified as follows: 1. Drug crystals 2. Minitablets 3. Microcapsules 4. Nanoparticles 5. Microsphere a. Spheronised granules (pellets) i. ii. iii. Extrusion Spheronization Melt extrusion

b. Drug-loaded Non-pariels (pellets)/Drug layering

1. DRUG CRYSTALS Drug Crystals, of appropriate size and shape can be coated directly with a modified release film coating. 2. MINI TABLETS Minitabs are small tablets with a diameter typically equal to or less than 3mm that are typically filled into a capsule, or occasionally, further compressed into larger tablets. The minitablets may have any shape convenient to the skilled person for designing tablets i.e.Spherical, Cylindrical, Biconvex round, Flat-faced round. The minitablets may be uncoated, or coated with one or more layers of coating.

Figure 1: Minitablet delivered as a tablet (a) or a capsule (b).

3. MICROCAPSULES In this the drug is centrally located within the polymeric shell of finite thickness and release may be controlled by dissolution, diffusion or both. Steroids, peptides and anti-neoplastics have been successfully administered parenterally by use of controlled release microcapcules.

4. NANOPARTICLES The National Cancer Institute, under the National Nanotechnology Initiative Program, recently defined nano-sized drug carriers as those which are typically 300 nm or smaller in size. The nanoparticles are also called as Nanospheres or Nanocapcules depending upon whether the drug is in a polymer matrix or encapsulated in a shell. The main objective of developing nanosized drug carriers is to enhance the therapeutic potential of drugs so that they are less toxic and more effective.

5. MICROSPHERES Microspheres are small discrete spherical particles, with diameters in the micrometer range(typically 1 m to1000 m (1mm).Microsphere are sometimes referred to as microparticles. Polyethylene and polystyrene microspheres are two most common types of polymer microspheres.

i. Spheronized Granules(Pellets) Pellets are agglomerates of fine powders or granules of bulk drugs and excipients. They consist of small, free-flowing, spherical or semi spherical solid units, typically from about 0.5mm to 1.5 mm, and are intended usually for oral administration. Implants of small, sterile cylinders formed by compression from medicated masses are also defined as pellets in pharmacy.

Mechanism of granule formation Different theories have been postulated related to the mechanism of formation and growth of pellets. The mechanism of pellet formation and growth, the following steps were proposed: nucleation, coalescence, and layering and abrasion transfer.

Figure 2: Pellet growth mechanisms (1) Nucleation, (2) coalescence, (3) layering and abrasion transfer

Methods for preparing pellets Compaction and drug layering are the most widely used pelletisation techniques in pharmaceutical industry, extrusion and spheronization is the most of the compaction techniques popular method. Some of the methods used are: i. Extrusion- technique ii. Spheronization-technique iii. Hot-melt extrusion i. Extrusion Technique Extrusion is a multiple step compaction process comprising dry mixing of the ingredients with excipients, wet granulation of the mass, extrusion of the wetted mass, charging the extrudates into the spheroniser to produce a spherical shape, drying the wet pellets in a dryer and, finally, screening to achieve the required size distribution.

Equipments used in Extrusion technique (Extruders): A variety of extruders are currently in the market, differing in design features and Operational principles. These can be classified as 1. Screw-fed extruders 2. Gravity-fed extruder 3. Rotary-cylinder extruders 4. RAM extruders ii. Spheronizer Technique A spheronizer, known as Marumizer, consists of a static cylinder or stator and a rotating friction plate at the base. The stator can be jacketed for temperature control. iii. Hot Melt Extrusion (HME): Melt extrusion is the process which can be clubbed under extrusion spheronization whereby a drug substance and excipients are converted into a molten or semi molten state and subsequently shaped using appropriate equipment to provide solid spheres or pellets.

The HME offers some advantage over a wet mass extrusion and spheronization method: 1. It is a simple, efficient and continuous process requires. 2. It does not require a lengthy drying stage 3. The absence of water may prevent drug degradation 4. It produces a spherical shape pellets with narrow range particle size distribution. a) Reduce the loss of coating material ii. Drug-loaded Non-pareils (pellets) DrugNonSpherical particles about 1mm in diameter consisting primarily of sucrose and starch called non-pareils which are available in the market. Following techniques can be used to get drug loaded non pareils. The different methods used for preparation of Drug loaded Non-pareils (pellets) are: 1. Drug layering 2. Miscellaneous methods a.Balling b.Compression c.Cryopellitization d.Globulation.

Evaluation & characterization of Multiparticulates

MPDDS TECHNOLOGIES WITH EXAMPLES

MARKETED FORMULATIONS
DRUG Morphine sulfate Carbamazepie BRAND Avinza Carbatrol Equetro ER Carvedilol Dexmethylphenidate Coreg CR Focalin XR COMPANIES King Shire,US Validus GSK Novartis

REFERENCES
a) Sahoo SK, Jain TK, Reddy MK, and Labhasetwar V. Nano-Sized Carriers for Drug Delivery, NanoBioTechonology: Bio-Inspired Devices and Materials of the Future: 329 Jain KK. Drug Delivery System. 1st Edition, Basel: Jain Pharma Biotech Publications. Switzerland: 30-31 Aulton ME. Pharmaceutics, The science of dosage form design. 2nd edition. Edinburgh: Churchill Livingstone.2002: 374-379 Florence AT and Attwood D. Physicochemical principles of pharmacy. 4th edition. London: Pharmaceutical Press. 2006 Patrick GL. An Introduction to Medicinal Chemistry. 3rd edition, Oxford: Oxford University Press. 2005 Laila FA, Chandran S. Multiparticulate Formulation Approach to colon specific drug delivery: current perspectives. J. Pharm Sci, 2006, 9(3): 327-38 Shah NH. Multi-Particulate Dosage Form for Oral Controlled Release: Development Considerations. Hoffmann La-Roche. In Shaji J, Chadawar V, Talwalkar P. Multiparticulate Drug Delivery System. The Indian Pharmacist. June 2007, 6(60): 21-28.

b) c) d) e) f) g) h)