Excipient selection for sustained release formulations

Sustained - release (SR) matrices are designed to release a drug slowly over an extended period of time. Formulations must be robust to ensure drug release over time and avoid dose-dumping. Innovator companies consider sustained-release oral dosage forms as a means to maximize drug efficacy, minimize the potential for adverse events, address clinical considerations such as dosing frequency, and respond to patient preference for simplified medication regimens for chronic disease. Key growth drivers in the rapidly expanding sector of sustained-release oral drug delivery include selection of excipients, enabling technologies, trends in patient preference and increasing physician comfort with the ability of prolonged drug release to deliver reliable blood levels. Excipients play a central role in the drug development process, in the formulation of sustained- release oral dosage forms and in their administration. The intended function of an excipient is to guarantee the required physicochemical and biopharmaceutical properties of the pharmaceutical preparation. Excipients that provide sustained-release characteristics to oral solid dosage forms allow not only control of the rate of the API (active pharmaceutical ingredient) release, but also targeting of where that release occurs.

Excipients are key ingredients in sustained-release formulations. They act as matrix formers in matrix delivery systems and as polymeric membranes for drug powders and multi-particulate systems in oral solid dosage (OSD) forms. Plasticizers and pore formers impact drug release in coated products, and, often, two-polymer chemistries are used to provide tailored drug release.

Right excipient choice:

An excipient can be used in many ways. Sustained-release excipients release the drug slowly so that it reaches the target site. Due to this fact it is in great demand. Sustained release excipients reduce the indirect cost associated with conventional excipients. The sustained release excipients are one of the type of excipients that are added to the drug along with active pharmaceutical ingredients of medication. Sustained release excipients are pharmacologically non-active ingredients of the drug formulation.

Excipient selection is often heavily influenced by past experience and knowledge that the excipient has been used in a previously approved product. Though the number and variety of available excipients has significantly expanded over the past decade, formulators often hesitate to be the first to utilize a novel excipient but no need to worry since the excipient selection early in the formulation development process is based on the API characteristics. Designing polymer-based sustained- release dosage formulations pose a number of challenges to formulators that include but are not limited to excipient selection, an understanding of the drug release mechanism, manufacturing process considerations, and an understanding of the API characteristics that may contribute to physical and chemical challenges.

Several factors must be considered when selecting specific excipients for sustained-release formulations. Dosage form type and design need to be considered along with the solubility of the API to ensure that the desired dissolution profile can be achieved with a given excipient, and/or that a good in vitro-in vivo correlation is obtainable.

Sustained-release behaviour can be achieved using polymer coatings on solid dosage forms or by the incorporation of various types of polymer matrix systems, enzyme-activated systems, or systems that respond to changes in physical conditions within the formulation. Mechanisms include dissolution, diffusion, osmotic pressure, maintaining a hydrologic or hydrodynamic balance, and ion exchange. Pharmaceutical companies are involved in developing extended drug delivery systems that would allow easy administration and improve drug efficacy.

Polymers held the largest share in the sustained-release excipients market due to their wide usage in sustained-release formulations. Polymer based product type anticipated to be the most attractive in coming years. Polymers have been used extensively in the formulation of sustained-release tablets. Sustained-release products are advantageous as they provide a reduction in dosing frequency and better control of the therapeutic window. Matrix tablets based on hydrogel forming polymers are commonly used in this regard. Methacrylate polymers are broadly used in sustained-release dosage forms and provides gastro-resistant functionality. Ethyl cellulose remains the polymer of choice in multi-particulate drug delivery systems with or without an additional coating platform, the use of which is dependent on the characteristics and dosage form type of the drug. In monolithic delivery systems, hydroxypropyl methylcellulose (HPMC) continues to be the excipient of choice, although the use of two-polymer matrix systems is growing.

Lipid-based matrices are water-insoluble and do not swell or erode when in contact with aqueous media. When used as sustained-release agents, they form an inert matrix from which the drug diffuses slowly.

Higher contribution of sugars in sustained-release formulations can be attributed to properties such as spherical shape and porous nature, which improves flowability and lowers friability. This makes it the choice of excipient for a wide range of pharmaceuticals.

Minerals are an important class of excipients owing to properties such as reactivity to acids, swelling capacity, specific surface area, and high absorption capacity.

Increasing use of gelatin, alcohol, and chitosan in sustained-release formulations is also anticipated to propel segment growth. Use of gelatin in manufacturing powder, liquid, and oil-based pastes such as solids, semisolid, and liquid forms of formulations is expected to drive the gelatin segment in the future. Sugars used in drug formulations are also applicable as drug delivery agents in pulmonary route-based formulations.

Role of Excipient manufacturers:

Given that excipients are key ingredients in sustained-release formulations, it may seem surprising that excipient choices are somewhat limited. New excipients/ novel excipients that may provide solutions and support to move existing formulations into new areas, most new excipients, therefore, are modifications or combinations of previously approved excipients.

Excipient manufacturers need to work side-by-side with drug product manufacturers as early as possible in the drug product development process in order to not only identify the issues, but to mitigate the impact of the issues proactively. Excipient manufacturers must understand every detail of their processes and polymers in order to achieve the best solutions for their customers. Several excipient manufacturers work closely with our customers to understand their specific needs, and, over time, they have developed new solutions to meet sustained-release formulation challenges as they have arisen. Partnering with our customers not only helps us in suggesting the right solutions for their formulations, but also helps drive our development of new excipients to meet the ever-changing needs of the market. We have found this type of partnership to be the best strategy for addressing the challenges faced by the pharmaceutical market today. 

Conclusion:

As sustained drug release systems are meticulously developed according to their usage, they prove to be beneficial for geriatric and pediatric populations. Identifying the correct formulation method and using the suitable excipient in relation to the API may result in efficient pharmacological treatment by means of administrating a lower dose, which may have a significant cost implication. In summary, the importance of sustained - release drug delivery is increasing day by day. This has been reflected in the increased number of sustained - release drugs that have been commercialized largely due to the availability of effective sustained release excipient and technology. Process improvements, the role of plasticizers and other protective excipients has helped in providing cost and performance benefits. Many of the challenges in sustained release can now be overcome.

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About the Author:

Dr. Ajay Kumar Singh, M.Sc. (Gold Medalist), Ph.D. is the author and founder of “Pharma Solutions by Dr. Ajay”.

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