Recent Advanced of Multiple Unite Pellet System (MUPS) Technology in Formulation of Pharmaceutical Products: A Review

The oral route of drug administration is the most important and most user-friendly route of administration. In recent years, Multiple Unit Pellet Systems (MUPS) tablets are widely used in solid dosage form design. MUPS is considered to provide pharmacokinetic advantages compared to monolithic dosage forms. Combination of drug substances and release profiles can be provided by formulating the MUPS tablets with different pellet qualities or combining pellets with drugs in powder or granulated form. MUPS tablet contains several hundred of coated pellets of active pharmaceutical ingredients which delivered the drug at predetermined rate and absorption to provide constant blood profile. MUPS are easily administered as disintegratable tablet which disperse into their subunits across the stomach and the small intestine, leading to predictable oral transition and constant bioavailability.


Introduction:
The oral route of drug administration is the most important and most user-friendly route of administration [1][2][3][4][5]. In recent years, Multiple Unit Pellet Systems (MUPS) tablets are widely used in solid dosage form design. MUPS is considered to provide pharmacokinetic advantages compared to monolithic dosage forms [6][7][8]. Typically, modified release pellets are contained in MUPS tablets [9][10][11][12]. Modified release drug delivery systems have acquired very important role in pharmaceutical research and development [13].
Tablets are indeed the most popular solid dosage form for oral administration. One category of tablet formulations that has gained remarkable importance in drug therapeutics owing to various benefits it offers is controlled or modified release formulations. Controlled release capsules often containing plurality of coated pellets is yet another category of solid oral formulation that offers analogous therapeutic benefits. A relatively more recent approach that has come into existence is the one that combines the features of both controlled release tablets and modified release capsules in one dosage form. Such a system is known as MUPS tablets. MUPS is abbreviation for Multiple-Unit Pellet System. However, from pharmaceutical industry and research perspective, the term in general refers to MUPS compacted into tablets. Thus, the resulting tablets prepared by compaction 5. Surface of compacted MUPS should be smooth and elegant and devoid of pinholes and other imperfections and should facilitate ease of film coating if needed. 6. Pellets should not show any interaction like developing electrostatic charges; during compression. 7. The pellets should not show any deviation in its release even after compression. 8. The coated pellets during the process of compression should not fuse into a nondisintegrating matrix and should not lose its coating integrity either by breaking or cracking or rupturing the coating layer(s) or pinholes and other imperfections Tablets (11 Article) 1. The compression of multiparticulates into tablets, unlike the hard gelatin capsule, is a tamperproof dosage form and has greater physicochemical and microbiological stability of pellets as they are embedment in the inert matrix.

Advantages of Compaction of MUPS over Conventional Modified-Release Tablets and/or Pellet-Filled Capsules and
2. Tablets have less difficulty in esophageal transport than capsules.
3. Tablets containing coated subunits can be prepared at a lower cost than these subunits filled into hard gelatin capsules because of higher production rate of the tablet press. 4. The expensive control of capsule integrity after filling is also eliminated.
5. In addition, tablets containing multiparticulates without losing the controlled-release properties could be scored, which allow a more flexible dosage regimen.
6. Composing the tablet with equal or different kinds of particles can be combined and so that very specific release profiles can be generated. 7. Once the coated subunits have been developed different dose strengths can be prepared just by varying the tablet size keeping the same compositionno additional development efforts need to be taken. 8. Another option for dose strength variation is the development of dividable multi-unit tablets. Since the release characteristics are related to the single subunits, dividing the tablet does not affect the release characteristics as it is true for monolithic tablets.
9. Rapid and uniform transit of subunits contained in tablets from the stomach into small intestine owing to their small size, drug release is more uniform and possibility of dose dumping is avoided with minimized tendency for inter-subject variations.  11. Uniform emptying of micro pellets from stomach into small intestine facilitates rapid dissolution of enteric coating and drug release resulting in early tmax and Cmax (peak time and peak plasma concentration) in case of delayedrelease formulations. In case of controlled-release preparations, drug release is more uniform and possibility of dose dumping is avoided with minimized tendency for inter-subject variations. [10] Pharmacodynamic advantages: [11] Owing to rapid and uniform gastric emptying and subsequently uniform drug dissolution of pellets in the gastrointestinal tract due to their small size and larger surface, uniform drug absorption is facilitated which results in consistent and controlled pharmacological action.
A further reduction in inter-and intra-subject variability in drug absorption and clinical response is facilitated since the number of pellets per MUPS dosage form is much more than a conventional pellet-filled capsule and possibility of dose dumping(in stomach) and incomplete drug release is further minimized

Disadvantages of MUPS:
1. Dosing by volume rather than number and splitting into single dose units as required. 2. Involves capsule filling which can increase the costs or tabletting which destroy film coatings on the pellets. 3. The size of pellets varies from formulation to formulation but usually lies between 1 to 2 mm. [13,[16][17][18] Compaction and drug layering are the most widely used pelletization techniques. Other methods such as globulation, balling are also used in development of pellets in a limited scale. Some of the desirable properties of the pellets include pellets shape should be near spherical and have a smooth surface; both considered important characteristics for subsequent film coating. Additionally, the particle size of pellets should be as narrow as possible. The optimum size of pellets for pharmaceutical use is considered to be between 0.5 and 1mm.

Powder layering:
Powder layering involves the deposition of dry powders of drugs and excipients on neutral spheres with the help of binding liquids. Powder layering involves simultaneous addition of binding agents and dry powders; hence it requires specialized equipments like spheronizer. If the process is setup properly, hourly weight gains up to 300% are possible, which indicates the processing option is very fast and efficient.

Solution / suspension layering:
Solution/suspension layering involves the deposition of solution or suspensions of drug substances and binder over the neutral spheres. Consequently conventional coating pans, fluid bed processor, centrifugal granulators, wurster coaters have been used successfully to manufacture pellets by this method. To achieve uniform layers the bottom spray method should be the processing option of choice. Average weight gain per processing hour is about 15-20 %, because 80 -85 % liquid vehicle have to be evaporated.

Extrusion and Spheronization:
This processing option is the oldest known industrial pelletizing technique. First all ingredients are blended, then by adding liquid a wet dough is formed, which is passed through an extruder with defined dye sizes.
Other pelletization methods such as globulation, cryopelletization, spray drying, spray congealing, balling, and compression are used, although on a limited scale in the preparation of pharmaceutical pellets.   Page | 20206 pellets in compression is fusion of polymer coating of pellets with other pellets and also polymer coating with extra-granular material. This can be counteracted by coating with any non interfering coating agent. For example hydrophobic coating agent prevent fusion of pellets-pellet and pellettabletting excipients.
MUPS with pellets coated using different pelletization techniques with all the desired characteristics for compression of pellets.
Modulation of Pellet Coating: [28] After compaction into MUPS, maintenance of integrity of functional coating present on the surface of drug pellet is vital for preservation of desired product characteristics, which could be taste masking, sustained-release, delayed release or drug stability. Approaches adopted to retain the characteristics of applied membrane coating include:-

a. Use of more elastic coating composition: -
Coating films have been made more elastic to withstand pressures of compaction by use of more elastic materials such as acrylic polymers instead of cellulosic polymers, use of more quantity of plasticizers or a more efficient plasticizer, etc.9 However, there should not be tendency of coated pellets to fuse with each other. Fusion tendency of pellets during compaction can be reduced by incorporation of lubricants and pigments such as talc in the coating composition but such materials are known to reduce elasticity of coating.
b. Increased thickness of coating:-Thicker but elastic polymeric coat can better withstand the deformation and rupturing forces of compression in comparison to thinner coatings.19

c. Elastic/thermoplastic layer on the outer surface of drug pellets:-Presence of an outer coating
comprising of thermoplastic material such as carbowaxes on the surface of drug pellets, on which is applied the functional polymer coating, is known to absorb the stresses that may otherwise tear or fissure the outermost surface coating. [20] d. Powder layer over the surface of polymer coated pellets:-Application of an integral but porous powder layer on the outside of polymer coated pellets results in preferential damage to the powder shell resulting in its breakage thus preventing/reducing transmission of compaction force to polymer coated core drug pellet present beneath.

Modulation of Core Pellet:
Besides the role of polymer coating on the pellets, the nature of core drug pellet can dramatically influence the damage to its own structure and the coating on its surface. Following pellet-related factors influence compaction characteristics:a. Composition:-Besides the inherent nature of drug, the other excipients that comprise core pellets can influence compaction characteristics. Presence of hard and brittle materials produce rigid pellet core that resists bulk deformation while elastic/plastic materials such as microcrystalline cellulose get easily deformed.
b. Pellet porosity:-If the pellets being compacted are coated, during compaction, pellet deformation (change in shape of pellets) and densification (reduction in pellet porosity) occurs to a larger extent while fragmentation is seen to a lesser extent. Porous pellets get more deformed during compaction, due to the higher freedom degree of rearrangement of the powder particles within them. On the other hand, more compact pellets are more intensively buffered during compaction by powder particles, because they cannot widely rearrange. [11] c. Pellet size: -Larger pellets deform more easily than smaller pellets.12 d. Pellet elasticity: -Findings of various researchers on elasticity of core pellets are discordant. Bodmeier et al. claimed that the bead core should possess some degree of elasticity, in order to accommodate changes in shape and deformation during tabletting18. To sum up, pellets that are smaller in size, stronger mechanically, less porous and more uniform in size distribution are more suited for compaction without deformation than pellets with wide size distribution, greater porosity, larger size and mechanically soft. Further, the polymer coating on such core drug pellets should be thick and elastic [21][22][23][24][25][26].
Often a combination of above approaches can be employed to result in a MUPS that retains the desired drug release and product characteristics. Page | 20207 a. Faster drug release:-The deformation of the substrate pellet may stretch out the coating, making it thinner or more permeable, which has a negative effect on the control of the drug release. This often explains that the release rate increases with increased irregularity of the compacted reservoir pellets. b. Prolonged drug release:-The densification of the substrate pellet may compress the coating, making it thicker or less permeable, and consequently prolong the drug release Matrix pellets:-Pellets which inherently contain excipients that retard drug release by being contained within the matrix of pellet structure, for example matrix pellets of swellable polymers or waxes, retain their controlled release characteristics to a larger extent even on compression since the release of drug from such pellets depend upon swelling or erosion of matrix rather than by diffusion through the membrane.23,24 However, an important point that needs consideration in the design of MUPS of such matrix pellets is fusion of pellets with each other during compaction which may not be obvious during compression of coated pellets. Fusion of matrix pellets as a result of compaction can be avoided by application of film coating on such pellets or excessive blending with a hydrophobic agent separately prior to mixing them other extra granular materials before compression into tablets. [27][28][29][30]      Design of tabletting machine, powder feeding mechanism, etc.

Mechanisms involved in Compression of MUPS:
Four stages are considered in compression into MUPS includes: 1. Deformation of functional coating layer, 2. Densification of polymeric coating layer, 3. Fragmentation. 4. Attrition of pellets.
Owing to the irregular shape and to the surface roughness of granules, it is rather difficult to determine the degree of incidence of the suggested mechanisms. Recently, the use of nearly spherical units, here defined as pellets, brought new light into the mechanistic knowledge of the compaction process of porous particles and justified the use of these units as an alternative model system. It has been suggested that permanent deformation and densification are the major mechanisms involved in

Marketed Products OF MUPS (13 atricle)
Losec MUPS is the second highest selling pharmaceutical drug product in Sweden in the year 2002 [43]. Another patent is of European Patent Office by Astrazeneca EP 723437 for Nexium and Losec for compression of proton pump inhibitor to tablets for MUPS into the market. Various marketed products are tabulated in Table I.  [48]