November 15, 2016
Traditional immediate release (IR) systems, such as tablets and capsules, are designed to act as reservoirs from which the active ingredient(s) can be released over a predetermined time interval. Alternatively, modified release (MR) systems are fabricated by altering the timing and/or the rate of release of the active substance to achieve continuous release of active(s) over an extended period after ingestion.1 Per FDA’s definition, MR oral solid dosage forms can be described as either extended release (ER) or delayed release (DR).2 DR systems are usually designed to delay the release of active(s) until the dosage form has passed through the lower pH of the stomach and is exposed to the higher intestinal pH. These systems are also referred to as enteric-coated dosage forms. An ER dosage form is designed to initially release an adequate amount of active(s) or the loading dose, and then the remaining amount or maintenance dose, is slowly released.3,4
Sustained release, sustained action, prolonged action, controlled release, extended action and time release are commonly used terms to identify delivery systems that are designed to continuously release actives over an extended period of time after administration of a single dose. Although, oral IR delivery systems have been the most convenient and predominant route of administration in the industry,5 consumer inconvenience due to frequent dosing can result in missed doses and non-compliance.6,7 The objective of MR delivery systems is to achieve improved efficacy, reduced dosing frequency, minimized side effects, uniformed release of actives over a prolonged period of time and improved consumer compliance.8,9
Despite several advantages, MR products have a few shortcomings. For example, the risk of dose dumping—when the entire amount of active is released immediately after ingestion—can possibly cause a health issue. In the case of acute discomfort after ingesting a dose, the prompt termination of intake cannot easily be achieved. Additionally, relatively higher costs of product development and formulation, along with less flexibility in adjusting doses and larger sizes of such products, can also be deterring factors for the formulator when developing MR delivery systems for nutraceuticals.10,11,12
An ideal ER delivery system should be able to release the actives at a predetermined rate, dissolve in the gastrointestinal (GI) fluids, and be absorbed at a rate that is sufficient to replace the equivalent amount that is being metabolized and excreted. Most technologies used to achieve this objective are based on polymeric systems. In general, synthetic and semi-synthetic polymers are preferred over natural polymers due to lesser material variability. Most of the commercially available ER products can be classified into three broad categories: matrix, reservoir and osmotic systems. Matrix systems are the most widely used in nutraceutical applications to achieve extended release. These systems are effective, versatile, economical and easy to scale up for manufacturing using conventional equipment, without additional capital investment.
In a typical matrix system, active(s) and rate-controlling material(s) are homogenously dispersed and mixed in a dosage form. Matrix-type systems can be further classified into hydrophilic and hydrophobic matrices based on the aqueous solubility of rate-controlling material used in the formulation. In hydrophilic systems, the rate-controlling material is relatively water soluble and tends to swell, whereas, hydrophobic systems consist of water-insoluble inert materials, with minimal swelling upon exposure, to a dissolution medium. Hydroxypropylmethyl cellulose (HPMC), methyl cellulose, hydroxypropyl cellulose, xanthan gum, alginates and modified starches are commonly used in hydrophilic matrices.13 Polyethylene, polyvinyl chloride, ethyl cellulose and acrylates are used in hydrophobic matrices.14 Several physicochemical factors may influence the release rate of actives from the matrix. Dose size, ionization, partition coefficient and aqueous solubility of the actives are paramount and should be considered when developing such matrices.15 In vitro assessment of the matrix during product development is equally crucial for a successful ER delivery system. To achieve this objective, a dissolution profile of the formulation is usually studied by using the United States Pharmacopeia (USP) dissolution apparatus to verify the desired in vitro release rate.
A typical reservoir system consists of a core, containing active ingredient(s), surrounded by a hydrophobic rate-controlling film. A reservoir system is mostly used to modify the release rate of highly water-soluble materials. In this delivery system, the materials are either coated or microencapsulated with slowly dissolving materials such as cellulose and polyethylene glycol. Solubility and thickness of the coating are major contributing factors in controlling the dissolution rate of such systems.16,17
The basic principal of an osmotic system is similar to a reservoir system, the main difference being that the core in an osmotic system is surrounded by a semi-permeable membrane with an orifice for the release of bioactive materials. The release of the active from such systems is mainly governed by solubility and osmotic pressure of the core; size of the delivery orifice; and physicochemical characteristics of the rate-limiting, semi-permeable membrane.18
The market for MR delivery systems in the nutraceutical industry has come a long way, and will continue to grow with increasing consumer demand. By far, the matrix system is the most preferred delivery system in the nutraceutical industry for ER products. This technology offers a relatively simpler approach to manufacturing, involving the direct compression of blended actives and inactive materials in a solid dosage form, where the active is embedded in the matrix of rate-limiting materials. In some cases, depending on the nature of the materials, a granulation step may be necessary prior to compression.
Naeem Shaikh, Ph.D., leads the formulation team and drives the research that helps inspire and propel the product momentum at National Enzyme Co. (nationalenzyme.com). As an accomplished and published scientist, Shaikh leverages 28 years of renowned experience, with previous research ranging from micro-encapsulation to release methods for solid and liquid dosage forms.
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2FDA, Guidance for Industry: SUPAC-MR: US Food and Drug Administration, Center for Drug Evaluation and Research. 1997.
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5Shaikh NA. 2016, May/Jun - Orally Disintegrating Tablets – An Overview, INSIDER, Retrieved from http://www.naturalproductsinsider.com/articles/2016/06/an-overview-of-orally-disintegrating-tablets.aspx
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14Sayed I et.al. “Preparation and comparative evaluation of sustained release metoclopramide hydrochloride tablets." Saudi Pharmaceutical Journal. 2009;17:283-288.
15Wani M. Controlled release system – A review. 2008;6(1). Retrieved from www.pharmainfo.net/review.
16Shargel L. “Modified release drug products." Applied Biopharmaceutics and Pharmacokinetics, 4th ed. 1999:169-171.
17Venkatraman S et al. “An overview of controlled release systems." Handbook of Pharmaceutical controlled release technology. 2000;431-465.
18Thakor R et al. “Review: Osmotic drug delivery systems current scenario." Journal of Pharmaceutical Research. 2010;3(4):771-775.+
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