P. R. Pote Patil Collage of Pharmacy, Amravati. Kathora Road, Amravati, Maharashtra, India 444602
Pellets are agglomerates of fine powders or granules of bulk drugs and excipients typically ranging from about 0.5 to 1.5 mm. Multi-unit Particulates System technology refers to a pharmaceutical formulation approach in which a single dosage form, such as a tablet or capsule, contains multiple small, discrete pellets or granules. Each pellet acts as an individual drug delivery unit, often coated with one or more layers that control the release rate of the active pharmaceutical ingredient. Multi-Unit Particulate System consists of embedding many small pellet within one formulation. Types of Multi-Unit Particulate System one comprising of coated pellets (reservoir systems), and the other prepared by compaction of matrix and/or uncoated drug pellets.
Tablets and capsules are examples of traditional controlled-release dose forms that can have several drawbacks. Variability in drug release, which can be brought on by things like unequal coating dispersion, inconsistent tablet compression, or insufficient disintegration, is one of the main disadvantages. This may result in less reliable dosing and uneven therapeutic results. Furthermore, the medication is usually released in a single burst by traditional dosage forms, which could lead to fast initial drug concentrations followed by a sustained release, which could cause variations in therapeutic levels. Researchers create multi-unit particle systems to get around these problems. Where the stability, efficacy, and release characteristics of pharmaceutical medicines are strongly influenced by the behaviour of solid particles. These systems, which entail the interaction or aggregation of many particles inside a formulation, are frequently employed in the creation of inhalation powders, controlled-release dosage forms, and nanoparticles for precise drug administration.
Pellets
Controlled-release preparations can be administered orally in single or multiple-unit dosage forms. Among multi-component dosage forms, the most commonly used dosage form is the pellet. It is an ideal dosage form, which on oral administration, disperses or disintegrates rapidly in the stomach to release drug particles, granules and spheroids. 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 0.5 to 1.5 mm, and are intended usually for oral administration. Being small (2mm), pellets or multi-particulates can distribute evenly in the gastrointestinal tract, resulting in fewer adverse effects. Pellets also reduce the risk of dose dumping compared to single-unit dosage forms and result in reproducible bioavailability. Pellets can be either filled into capsules or compressed into tablets as a dosage form to be administered. Pellets offer great flexibility in pharmaceutical solid dosage form design and development. Processing conditions play a significant role in the development of good-quality pellets.1
The various pelletization techniques are extrusion-spheronization, Hot-melt extrusion, Layering techniques, Balling (Spherical agglomeration), Compression, Globulation, Spray drying, Spray congealing and cryopelletization are used. Each technique listed above is superior based on the application for which pelletized drug delivery is being manufactured. Therefore, determining critical process parameters that influence the quality of the product is important during the development process.2
Pellets are formed by converting the active substance into spherical solids with a size ranging from 500 to 1500 µm, using suitable excipients. In some literature, the upper limit of pellet size is 2000 µm. Micropellet size is considered to be the size of the pellets produced by pelletization below 500 µm. Due to various advantages of pellets as drug delivery system as shown in fig:1 it is used for formulation in pharmaceutical field. There are several technological results for the production of pellets and micropellets. Pelletization techniques result in dry, nearly spherical particles with good flow properties.
Fig.1: Important aspects during Pelletized drug delivery development2
Multiple-Unit Particulate Systems
Modified-release formulations can be administered orally in either single-unit or multiple-unit dosage forms. Single-unit formulations encapsulate the active ingredient within a single tablet or capsule, while multiple-unit dosage forms consist of several distinct particles that are aggregated into one dosage unit. These may take the form of pellets, granules, sugar seeds (non-pareil), minitablets, ion-exchange resin particles, powders, and crystals, with the drugs either encapsulated within or layered around the cores. Although both dosage forms can achieve comparable drug release profiles, multiple-unit dosage forms present several advantages over single-unit systems, such as non-disintegrating tablets or capsules.3
Multi-unit Particulates System technology pertains to a pharmaceutical formulation strategy wherein a single dosage form, such as a tablet or capsule, comprises numerous small, distinct pellets or granules. Each pellet functions as an independent drug delivery unit, frequently coated with one or more layers that regulate the release rate of the active pharmaceutical ingredient (API). Multi-particulates are preferred for modified release systems, characterized by small discrete particles that exhibit uniform release profiles, collectively forming a therapeutic dose through these identical particles known as multi-particle systems. The most commonly utilized multi-particulates are pellets encapsulated in capsules. Other orally administered multi-particulates include granules, mini-tablets, powder crystals, and ion-exchange resin particles shown in fig:2. For parenteral administration, multi-particulates encompass nanoparticles, nanospheres, nanocapsules, microparticles, microspheres, liposomes, and various other vesicular formulations.3,4,5 A more recent development in pharmaceutical formulations is the integration of characteristics from both controlled-release tablets and modified-release capsules into a single dosage form, referred to as MUPS, which stands for Multiple-Unit Pellet System.3
Fig2: Pellets and Micropellets Products4
Multi-Unit Pellet System
Multiple unit pellet systems have been shown to be better than oral modified release products when it comes to intra- and inter-individual variability of in vivo drug absorption. The primary goal of the prior art is to preserve the altered release characteristics of the individual units, whether those are managed by embedding the active ingredient in a polymeric matrix or by applying a film coat. The pharmaceutical sector has experienced considerable progress in drug delivery mechanisms, with the Multiple Unit Pellet System (MUPS) becoming a leading technology for facilitating controlled and prolonged drug release.3,6 MUPS consist of multiple small pellets contained within a single system, allowing for improved drug release profiles, enhanced bioavailability, and reduced side effects compared to conventional single-unit dosage forms. MUPS are composed of numerous small pellets housed within a unified system, which facilitates better drug release characteristics, increased bioavailability, and minimized side effects in comparison to traditional single-unit dosage forms. These pellets can be filled into hard capsules or be compressed together with suitable fillers and binders into disintegrating pellet containing tablets. Multiple-unit pellet systems (MUPSs) offer several advantages when compared to single-unit dose forms. The enhanced performance regarding both the quantity and rate of absorption of the active ingredient results from decreased variability in stomach residence time, which is effectively reflected in the improved consistency of transit time throughout the entire gastrointestinal tract.3,4,5 The first category of MUPS is prevalent, whereas the second category is encountered less often, despite its clear advantages over the compaction of polymer-coated pellets. Ideally, MUPS should exhibit all the characteristics of a conventional tablet produced through compression.3
Fig.3: Multi-Unit Pellet System
As shown in Fig:3 Two distinct categories of Multi-Unit Pellet Systems (MUPS) can be identified based on the characteristics of the pellets intended for compression, specifically those designed for modified release or possessing a particular dissolution profile. The first type consists of coated pellets, which function as reservoir systems, while the second type is created through the compaction of matrix and/or uncoated drug pellets.5
1. MUPS comprising of coated pellets.
2. MUPS comprising of matrix pellets
Fig.4: Schematic representation of types of MUPS-(a) MUPS comprising of coated pellets, and (b) MUPS prepared from uncoated/matrix pellets.5,7
Multiple-Unit Particulate Systems, also known as Multi-Unit Pellet Systems, represent sophisticated drug delivery formulations composed of small, spherical pellets that are enveloped in a polymeric coating. This coating serves to regulate the release profile of the active pharmaceutical ingredient (API), facilitating either modified or sustained release mechanisms shown in Fig:4(a). MUPS are engineered to enhance the bioavailability of drugs with low solubility, improve patient adherence by decreasing the frequency of dosing, and reduce side effects by employing targeted release mechanisms.4
Because the coated pellets in MUPS are usually made up of several small units, the drug distribution can be more uniform and the chance of dose dumping—a major problem with conventional tablet formulations—can be decreased. Depending on the therapeutic requirements, the coating on these pellets can be designed to offer particular release patterns, such as rapid, delayed, or extended-release.
This adaptability makes MUPS appropriate for chronic illnesses that necessitate long-term medication adherence by enabling the customization of treatment plans for a range of disorders. MUPS with coated pellets from various pelletization processes which possess all the required properties for pellet compression.7
The advantages of pellet-based formulations and the controlled release potential of matrix systems are combined in the Multi-Unit Particulate System, which uses matrix pellets as an enhanced drug delivery method. In this formulation, the active pharmaceutical ingredient (API) is embedded within a matrix composed of excipients that can influence the drug's release characteristics. As shown in fig:4(b) Matrix pellets are engineered to deliver the drug gradually over an extended duration, facilitating prolonged therapeutic effects and reducing the necessity for frequent dosing. The matrix may consist of a range of materials, including polymers or waxes, chosen according to the specific release properties required. This configuration facilitates zero-order kinetics, allowing for a steady release of the drug, which minimizes variations in plasma concentrations and improves overall bioavailability.5,6
Used generally in controlled release formulations. The pellets are coated with swellable or erodible polymers instead of diffusible polymers. A major challenge encountered with matrix pellets during the compression process is the adhesion of the polymer coatings to each other and to extragranular materials. This problem can be alleviated by utilizing a non-interfering coating agent. For example, a hydrophobic coating agent can successfully inhibit fusion.7
Advantages of Multi-Unit Particulate System
Compressed multi-particulate systems are well-suited for scenarios in which drug pellets are combined with various excipients, allowing for rapid disintegration, sustained release, and an unchanged release profile despite the compression process. Pellets that are compressed into multi-unit pellet systems (MUPS) exhibit superior flow characteristics attributed to their nearly spherical form, in contrast to traditional granules utilized in tablet or capsule formulations. In controlled-release formulations, the release of the drug is more consistent, effectively reducing the risk of dose dumping and minimizing inter-subject variability. Additionally, these formulations necessitate smaller quantities of lubricants to enhance flow.7
The Multiple Unit Particulate System (MUPS) offers several regulatory benefits, including the potential for extended patent protection and opportunities for product line expansion. This formulation is both versatile and uniquely identifiable, making it difficult for competing firms to replicate. The multi-unit design facilitates a more even distribution of the active pharmaceutical ingredient (API) across the gastrointestinal tract, thereby minimizing the likelihood of dose dumping and ensuring reliable therapeutic outcomes. The controlled release characteristics of MUPS facilitate customized release profiles, permitting both rapid and prolonged drug release, which can reduce side effects and enhance bioavailability. Furthermore, MUPS tablets are typically smaller and more manageable to swallow than conventional tablets, rendering them more appropriate for patients, including children and the elderly. As MUPS represents a tablet dosage form, it provides all the benefits associated with tablets in comparison to capsule formulations.
The formulation has the capability to conceal undesirable flavors, thereby improving palatability. Additionally, Multiple Unit Particulate Systems (MUPS) can integrate various active pharmaceutical ingredients (APIs), facilitating combination therapies within a single dosage form and simplifying treatment protocols. In summary, MUPS exemplify a flexible and efficient strategy in contemporary pharmacotherapy, harmonizing effectiveness, safety, and patient compliance.4,5,7
Disadvantages of Multi-Unit Particulate System
MUPS (Multiple Unit Particulate System) presents several benefits; however, it is not without its limitations. The manufacturing process of the Multiple Unit Particulate System entails the encapsulation of numerous small pellets within a unified system, necessitating advanced technology and specialized equipment. Additionally, the dimensions and texture of the Multiple Unit Particulate System may be unappealing to certain patients, potentially resulting in compliance challenges.4
Drug Release Mechanism of Microparticles
The method employed in the production of particles and excipients significantly affects the drug release mechanism. Typically, the release occurs through multiple mechanisms, with one mechanism being predominant. The drug release profile of a multiparticulate formulation can be understood as the cumulative effect of the release profiles of the individual subunits that constitute the system. Microparticles characterized by a matrix structure can facilitate drug release through various mechanisms. The interplay between the matrix structure and the release dynamics is crucial. In these systems, the characteristics of the polymer, alongside the active pharmaceutical ingredient, play a significant role. As shown in fig:5 Drug release from the microparticles primarily occurs via diffusion, which may take place through pores that are saturated with the release medium or through the polymeric network itself. Many polymers exhibit swelling upon water absorption, leading to the creation of additional pores, alterations in osmotic pressure, and an enhancement in the effective diffusion of the drug, thereby increasing the quantity of drug molecules released into the aqueous environment. Furthermore, both surface and bulk erosion of the matrix can also contribute to the release process in fig:5. In instances involving particles characterized by heterogeneous structures, both the polymer coating and the core are significant factors. There exist water-soluble inert pellet cores exhibiting osmotic properties, wherein the release of the active pharmaceutical ingredient (API) is driven by osmotic pressure. The polymeric layers that develop on the core can either be water-soluble or may create a permeable or semi-permeable membrane. The primary mechanism of transport is diffusion through the permeable polymeric membrane, whereas osmosis takes place via the semi-permeable membrane, leading to the development of microcracks that facilitate the release of the active ingredient. Additionally, small, water-soluble compounds, referred to as pore formers, may be employed to adjust the drug release rate. In the context of microparticles, the active substance can be released in response to various stimuli, whether single, dual, or multiple. Drug release can be triggered by internal or external factors and is classified into physical, chemical, or microbiological stimuli.4
Fig.5: Drug Release Mechanism of Microparticles.4
The compaction of pellets presents significant challenges. Currently, there are only a limited number of tablet products that contain multiple units, including Beloc® ZOK and Antra® MUPS. Beloc® ZOK is an extended-release formulation that utilizes multiple-unit tablets to deliver the antihypertensive medication metoprolol succinate, ensuring a consistent release of the drug characterized by zero-order kinetics (ZOK). Antra® MUPS, on the other hand, is a multiple-unit pellet system (MUPS) composed of micropellets containing the proton pump inhibitor omeprazole.
Polymers
Polymers utilized in the film-coating of solid dosage forms can be categorized into two primary groups: cellulosic and acrylic polymers. Acrylic polymers are commonly available under trade names such as Kollicoat® and Eudragit®, while ethyl cellulose is the predominant cellulosic polymer employed for extended-release applications. To address challenges related to the use of organic polymer solutions, many of these polymers have been developed into aqueous colloidal dispersions, including latexes or pseudolatexes. Numerous investigations into the compaction of pellets coated with ethyl cellulose have indicated that the coating sustains damage, resulting in a reduction of the extended-release characteristics. The release of the drug from compressed niacin/microcrystalline cellulose pellets, which are coated with the aqueous colloidal ethyl cellulose dispersion known as Surelease®, occurred at a significantly accelerated rate in comparison to the release from uncompressed pellets. Additionally, when evaluating the properties of ethyl cellulose films, it is noted that films made from acrylic polymers exhibit greater flexibility, making them more appropriate for the compression of coated pellets. Elongations exceeding 75% were achieved with the acrylic polymers, Eudragit® RL/RS, and the compression of pellets was successfully performed without compromising the integrity of the coating. Various aqueous acrylic polymer dispersions were utilized to coat crystals, granules, and pellets, which were then compressed into rapidly disintegrating tablets. Multiparticulates coated with flexible polymers, such as Eudragit® NE 30 D, as well as plasticized Eudragit® RS/RL 30 D, could be compressed without causing significant damage to the coating. In contrast, enteric coatings made from Eudragit® L 30 D-55, a copolymer of methacrylic acid and ethyl acrylate, exhibited brittleness, leading to film damage during pellet compression. This issue could be mitigated by blending the enteric polymer with the flexible Eudragit® NE 30 D.8
BIOEQUIVALENCE BETWEEN OMEPRAZOLE MUPSTABLETS AND OMEPRAZOLE CAPSULES.
Introduction: A novel tablet formulation of the acid pump inhibitor omeprazole has been created, available in dosage strengths of 10, 20, and 40 mg, serving as an alternative to the existing capsule form. This formulation utilizes a multiple-unit pellet system (MUPS®) and consists of numerous small pellets that are individually coated with an enteric layer. The tablets dissolve quickly in the stomach, allowing the pellets to be efficiently released into the duodenum, where omeprazole is absorbed. The tablet is compact and easy to ingest, and it can also be dissolved in water, facilitating straightforward administration and enabling convenient tube feeding. The current studies have examined the bioequivalence between the capsule and the MUPS® tablet.
Method: Research has been conducted to compare the bioavailability of the MUPS® tablet with that of the standard capsule following the administration of a single dose across all three strengths. The 20 mg dosage of omeprazole, being the most commonly utilized, was selected for comparison after daily dosing over a period of six days. These comparisons were carried out with healthy male volunteers. The studies primarily assessed the area under the plasma concentration versus time curve (AUC) and the maximum plasma concentration (Cmax) as key indicators of the extent and rate of bioavailability. Ninety percent confidence intervals (CI) were established for the ratios of the true mean values of AUC and Cmax between the tablet and capsule. Bioequivalence was determined if the 90% CI fell entirely within the predefined limits of 0.80 to 1.25.
Conclusions: Bioequivalence has been established between the omeprazole MUPS® tablets in dosages of 10, 20, and 40 mg and the omeprazole capsules of equivalent strength. Both formulations exhibited good tolerability.9
CONCLUSION
The Multiple Unit Pellet System (MUPS) signifies a notable progression in the realm of pharmaceutical drug delivery, enhancing bioavailability, enabling controlled release, and diminishing side effects in comparison to traditional single-unit dosage forms. By integrating numerous small pellets into a singular dosage unit, MUPS guarantees consistent drug distribution throughout the gastrointestinal tract, thereby reducing both inter- and intra-individual variability. MUPS formulations are classified into two main types: coated and matrix pellets, each tailored for distinct release characteristics. Coated pellets operate as reservoir systems, managing drug release via polymeric coatings, whereas matrix pellets incorporate the active ingredient within excipients to facilitate sustained release. This versatility renders MUPS especially advantageous for chronic conditions that necessitate long-term adherence to medication.
Although MUPS manufacturing offers several benefits, such as improved patient adherence, minimized dose dumping, and favorable regulatory aspects, it also presents challenges stemming from the intricacies of pellet compaction and the requirement for specialized technology. The choice of polymers, including ethyl cellulose and acrylic-based coatings, is vital for maintaining the stability and integrity of the release mechanism. In summary, MUPS technology remains a fundamental element in contemporary drug formulation, facilitating more accurate and tailored drug delivery, which enhances therapeutic results while catering to patient convenience and compliance.
List of Abbreviations:
MUPS – Multi-unit Particulate System
API – Active Pharmaceutical Ingredients
AUC – Area Under Curve
CI - Confidence Intervals
Declarations:
ACKNOWLEDGEMENTS
The authors would like to acknowledge the support of P. R. Pote Patil College of Pharmacy, Amravati, Maharashtra, India, for providing the resources and environment conducive to the completion of this review.
REFERENCES
Anisha Gulhane, Dr. Bhushan Bhoyar, A Review on Multi-Unit Particulate System: Advanced Technology for Novel Drug Delivery System, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 6, 780-789. https://doi.org/10.5281/zenodo.15597547
10.5281/zenodo.15597547
