Elsevier

Journal of Controlled Release

Volume 188, 28 August 2014, Pages 18-30
Journal of Controlled Release

Review
Solid lipid excipients — Matrix agents for sustained drug delivery

https://doi.org/10.1016/j.jconrel.2014.06.004Get rights and content

Abstract

Lipid excipients are attracting interest from drug developers due to their performance, ease of use, versatility and their potential to generate intellectual property through innovation in drug delivery particularly in the case of modifying drug release systems. Many articles have described the use of lipid excipients to develop matrix modified release dosage forms in a range of processing techniques, therefore a comprehensive review is timely to collect together and analyze key information.

This review article focuses on the utility of lipid excipients in solid sustained drug delivery systems with emphasis on the efficiency and robustness of these systems with respect to: (i) the choice of the manufacturing process and impact on drug release, (ii) the fundamental drug release mechanisms, (iii) resistance of the drug formulation under physiological conditions and (iv) long-term stability. Understanding the functionality of these versatile excipients in formulation is elementary for the development of highly robust lipid-based sustained release medicines.

Introduction

Most pharmaceutical excipients originate from other industries: pharmaceutical grade polymers have evolved from the domestic (household) chemicals and food industry. Lipid excipients are derived predominantly from the food industry where they were used as additives for emulsification, solubilization, stabilization and lubrication. Lipid excipients have been refined and fine-tuned for the pharmaceutical industry to provide solutions to drug delivery challenges including drug solubility, drug dissolution properties and also to resolve manufacturing issues, to name a few.

The term “lipid” describes a family of products with diverse physicochemical properties. Their composition includes oils, fats, waxes and fatty acids. Naturally occurring lipids are typically triglycerides, esters of glycerol and three fatty acids (triacylglycerols). These glycerides exhibit wide variety in acid chain length and saturation. In pharmaceutics short chain and unsaturated long chain fatty acids, being liquid or semi-solid, are approved for use in creams, ointments, emulsions, dispersions, pessaries and suppositories. In oral drug delivery, they are widely adopted to effectively maintain the solubility and increase the bioavailability of poorly soluble drug compounds [1], [2], [3], [4]. In contrast, long chain saturated fatty acids are solid at ambient temperature and water insoluble. They are hydrophobic and chemically inert and were developed primarily as lubricants to aid manufacturing of solid dosage forms [5].

A broad range of pharmaceutical grade lipid excipients has been commercialized over the past 50 years for the development of advanced drug delivery systems, as summarized and classified by Fahy et al. [6]. The physicochemical properties of complex naturally occurring lipid compounds were optimized by modifying their chemical composition (e.g. establishing defined mixtures of esterified fatty acids) and by processing fatty acids with various functional groups such as glycerol, polyethylene glycol, polyglycerol or propylene glycol. By doing so, the melting point (range) and hydrophilic lipophilic balance (HLB) value was adjusted in relation to a given application. Solid lipid excipients with high melting point (long acid chain length) and low HLB value (less polar alcohol) are suitable to retain water soluble drug molecules within the dosage form [7]. The growing interest in using lipid excipients as release modifiers in oral controlled drug release formulations is relatively recent (i.e. Ketas 10 mg capsules; [8]) and is driven by three main factors:

  • 1.

    Pharmaceutical industry life cycle management strategy and the reformulation of existing drugs to extend intellectual property and preserve revenue from existing brands.

  • 2.

    Development of new processing and manufacturing techniques enabling cost effective production of more complex dosage forms.

  • 3.

    Increasing understanding of functional excipients and formulation flexibility.

The most common approach to delay, extend or sustain drug release is by the use of swellable/erodible matrices formed by polymers. Indeed it is estimated that around 70% of the sustained release dosage forms approved by the USA FDA contain swellable cellulosic polymers; irrefutable proof of their efficacy. Alternatively, lipid excipients used as sustained release (SR) agents provide different biopharmaceutical properties compared to polymers, fundamentally the drug release mechanism is different and this provides formulators with broader options for controlling drug release scope to develop innovative dosage forms.

Much work has been published on using lipid excipients in sustained drug delivery systems. This review aims to highlight key lessons from these studies including: evaluation of the efficiency of solid lipid excipients utilized in sustained release formulations and how flexible they are in terms of processing options and robust in terms of storage stability. A short insight into the underlying drug release mechanism is given with special emphasis on developments of in vitro studies in correlation with in vivo conditions. By reviewing the state of the art as regard the use of lipid excipients in sustained release systems the physicochemical and biopharmaceutical features of lipid excipients and impact on formulation and processing will be better understood.

Section snippets

Lipid excipients in oral solid dosage forms

Over the last four decades naturally occurring triglycerides have been physicochemically modified to develop excipients suitable for the development of drug delivery systems. Conversely to polymers, solid lipids are crystalline in nature and do not exhibit a glass transition (Tg) or minimum film forming temperature (MFT). Instead they have reasonable melting ranges and melting points which are determined by their chemical structure (and composition). In general, the melting points of solid

Drug release mechanism from lipid matrices

A thorough understanding of the underlying drug release mechanism facilitates improved formulation development and drug product safety [79]. Many polymer-based sustained drug delivery systems have been evaluated in detail [80], [81], but relatively little is known of drug delivery from lipid-based formulations. The following chapter gives an overview on recently described drug release mechanisms from lipid matrices and how this knowledge can help to simplify product development.

In vitro dissolution testing

Standardized pharmacopoeial test methods are well established and give fundamental data on the drug release behavior of lipid-based sustained release dosage forms in vitro. In order to obtain predictive data for in vivo release characteristics based on in vitro data, more reliable dissolution methods which simulate the in vivo conditions during gastrointestinal passage are required. pH values, fasted and fed state, hydrodynamics, systemic pressures [102], [103], all potentially influence drug

Long-term stability of solid lipid formulations

Lipid excipients are derived from naturally occurring compounds and they are known to have polymorphic behavior due to their crystalline structure, which can impact the drug release properties and stability of the dosage. However, drug formulations must demonstrate physical and chemical stability during storage to prevent any changes in product quality and drug delivery properties over time. This is a prerequisite for sustained drug release systems as their fundamental purpose in vivo is to

Conclusion

The rationale for the use of certain types of lipid excipients in sustained release formulations is first and foremost associated with their hydrophobicity and inertness which enables the production of ffective release retarding matrices. Their performance is comparable to polymer-based matrices with the addition of interesting biopharmaceutical properties.

The solid-state properties of lipid matrices that can affect drug release and stability are increasingly understood due to the gradual

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