Modeling the Analysis Process of a Lipid-Based, Multi-Compartment Drug Delivery System
Abstract
Solid lipid microparticles (SLMs) are multi-compartment lipid drug carriers that can be used in various forms via many routes of administration, primarily to obtain prolonged release, protect the drug substance or mask its taste. It is practically impossible to theoretically predict the effectiveness of the incorporation and distribution of active pharmaceutical ingredients (APIs) in SLMs, and these are fundamental features that determine the key properties of the dosage form. The possibility of an effective assessment of these features by selecting or developing sensitive, universal methods, therefore, conditions further development and practical use of this carrier. Therefore, unlike the already available review papers on SLMs, the aim of this mini-review is to focus solely on the issues of API distribution in SLMs and their release. For this purpose, the most important observations and results of our own research were collected and summarized, and then an attempt was made to confront them with the available literature data. Among the methods describing the critical attributes of SLMs, instrumental methods (DSC, AFM, Raman spectroscopy and NMR), quantitative studies for assessing API distribution in SLMs (including entrapment efficiency and drug-loading parameters) as well as different release techniques (without a membrane, in a dialysis bag and in horizontal chambers, taking into account physiological factors) were characterized and compared. The aim of this review is to facilitate the understanding of the SLM properties and to assess their ability to achieve the intended effect in vivo, as well as to standardize studies of such carriers, facilitating a comparison of the results between centers.
1 Introduction
An appropriate composition of excipients forming a drug delivery system (DDS) is essential for the administration of an active pharmaceutical ingredient (API). It is the composition and properties of the drug carrier and its behavior at the site of application that enable the proper administration and action of the drug substance, i.e., the intended therapeutic effect. The drug carrier is the one that provides prolonged release and protects the sensitive drug substance. It is, therefore, not surprising that ongoing efforts in the search for modern active substances are accompanied by continuous work on the selection and improvement of drug carriers most suitable for their administration.
The recent DDSs are often multi-compartment carriers of various natures, which offer greater advantages over conventional drug delivery systems due to increased efficiency, precision of administration and therapeutic efficacy [1,2]. Among multi-compartment structures, lipid systems are becoming increasingly popular because they facilitate the use of poorly water-soluble APIs and are biocompatible [3,4]. The use of a multi-compartment DDS allows for flexibility and the introduction of various modifications to the final composition of the formulation. As a consequence, the efficiency of drug delivery might be significantly improved. Excellent examples of such carriers are solid lipid microparticles (SLMs), combining the advantages of different dosage forms. SLMs, as a multi-compartment and biocompatible system, are suitable for application in various routes in liquid or solid form. As a lipid carrier, it is dedicated primarily to the administration of APIs that are difficult to dissolve in water. Solid particles that do not dissolve or melt at the temperature of the human body are an excellent guarantor of prolonged release, taste masking or protection of the drug substance, of course, provided that the active molecules are effectively enclosed in the lipid matrix.
Designing such a carrier for the administration of a specific API requires extensive research and development work that is aimed at optimizing the DDS in terms of the selection of the concentration/dose, the method of combining the API with the drug carrier and finally the release rate of the drug substance. The main difficulty of this stage is the in vitro testing of the dosage form, assessing its properties and attempting to correlate them with the expected in vivo effect. Not only the selection of instrumental, analytical methods, etc., as well as their sensitivity and suitability for testing the assumed feature of the medicinal product are important, but also the selection of test parameters, taking into account the in vivo conditions at the site of administration/action. These are key studies because it is at this stage that the following are assessed and considered: compatibility of ingredients, carrier effectiveness and finally future patient safety. Pharmaceutical progress in this field and the development of subsequent drug forms with new APIs are supported by useful and universally recognized pharmacopoeial tests of dosage forms or various types of guidelines and recommendations of registration agencies (EMA, FDA). Unfortunately, in the case of modern carriers not yet described in scientific compendia, the search for the most appropriate methods and the use of subsequent modifications of studies adapted from other DDSs slows down technological progress, as it makes it difficult to compare the results between research centers. However, some difficulties cannot be solved without the use of an unusual procedure or procedure developed specifically for the needs of a new carrier.
The presented work is a mini-review based primarily on the results of our own research and over 10 years of experience in working with SLMs, compared and confronted with the available literature data. The focus was exclusively on studies that allowed for the qualitative and quantitative assessment of the distribution of APIs in SLMs and the rate of its release because these are key features determining the use of lipid microparticles as a drug carrier. The effective binding to lipids and the distribution of the drug substance in the lipid matrix is the basis for the use of SLMs as a carrier, providing prolonged release or guaranteeing drug protection or masking its taste. Indirectly, it is possible to assess this, both qualitatively and quantitatively, in studies of the location of the active substance using instrumental and analytical methods (distribution in individual phases). Directly, however, this state is best reflected by the study of the release of the drug substance, which is crucial from the point of view of bioavailability and therapeutic efficacy [5] because, if properly designed, it enables the assessment of the quality and stability of the formulation, as well as providing a chance to predict the properties of the DDS in vivo.
Since there are already two classic reviews on SLMs [6,7], this paper has been prepared in a different way, focusing only on the practical aspects of SLM analysis, limited to the key features—API distribution and release. The studies described in detail in previous reports are now presented in a cross-sectional way, comparing the advantages and limitations, discussing the essence of the issues and comparing other proposed approaches described in the literature. The experience in SLM analysis that we have tried to share in the prepared document, together with critical commentary, has been gained over the years while conducting all the described research.
The research conducted by our team focused mainly on SLMs with a size limited from a few to a dozen micrometers in a liquid or powder state. Among the numerous possible applications of SLMs, the topical application of a SLM dispersion to the eye in the form of drops was quite often referred to [8]. Due to the size of lipid microparticles, the possibility of thermal sterilization and the form of the dispersion, which can be applied in the form of sterile eye drops, this carrier meets all the requirements for such a route of application. Moreover, earlier in vivo studies conducted on rabbits have already demonstrated the efficacy and good tolerance of this carrier after administration to the conjunctival sac [8]. For experimental purposes, the following aspects were selected as factors differentiating the tested formulations: lipid, drug substance, active substance concentration and carrier form (dispersion or powder).
SLMs with model drug substances such as cyclosporine, indomethacin, hydrocortisone, diclofenac sodium or clotrimazole were analyzed, and for comparative purposes, SLM placebo were tested. In selected experiments, SLM in the form of powder, which was obtained in the spray-drying process, were used for the studies. The lipid matrix of the microspheres was formed from the solid lipid Compritol 888 ATO (glycerol dibehenate), selected as the most beneficial, as well as other lipids, e.g., Precirol ATO 5 (glycerol palmitostearate) or stearic acid.
All analyses presented in this paper can be used in SLM studies, regardless of the proposed route of administration. The only limitation is the type of parameters prevailing in vivo in the conjunctival sac proposed for the release study (enzyme lysozyme, artificial tear fluid), which require appropriate modification, depending on the method of application. Similarly, the model active substances used do not limit in any way the broader usefulness and interpretation of the presented results.
2 Types of Solid Lipid Particles
Solid lipid particles, also called lipospheres, are an example of a versatile carrier with many potential applications [9,10,11]. They can be divided into three categories: the first one, developed in the 1990s, is called SLNs (solid lipid nanoparticles), and the next ones are NLCs (nanostructured lipid carriers) and SLMs (solid lipid microparticles). SLNs were obtained by replacing the oil in an o/w emulsion for parenteral administration with a matrix of lipids solid at human body temperature [12] and were proposed as an alternative drug carrier to emulsions or liposomes [13]. Thus far, SLNs have been the most often studied among solid lipid particles.
SLMs were created based on SLNs, but as larger particles, combining the advantages of lipid carriers (such as SLNs) with microparticle-scale formulations (such as polymer microspheres) while eliminating the risk associated with the “nano” size or the potential toxicity of polymers [14]. The lack of accumulation in the body and toxicity of polymer decomposition products is a necessary condition for exceeding the regulatory requirements and their practical application [15]. Even in the case of the already commonly used PLGA (poly(lactide-co-glycolic acid)) polymers, it was found that their local toxicity may depend on other formulation components (e.g., chitosan, polyvinyl alcohol or poloxamer 188) [16]. The advantage of microcarriers over nanoparticles is also the fact that they do not penetrate the interstitial tissue and are not transported by the lymph [17]. Lipid dosage forms are currently of great interest because they provide good in vivo tolerance and biodegradability, as they are composed mainly of physiological and biocompatible components.
In justifying the purpose of the presented data, enriched with commentary resulting from our own experience and research, it should be noted first of all that SLMs have a much shorter research history and a much smaller amount of available data than their “nano” counterparts, i.e., SLNs [18]. Although SLMs and SLNs are similar in terms of their compositions, the discrepancy in their size of at least one order (200 nm vs. 2 µm) results in undeniable differences, both in terms of the manufacturing methods, methods and routes of administration and finally the properties and morphology of particles. For this reason, a much larger experimental database on SLNs cannot be an exhaustive source of information for the development of SLM formulations. Of course, due to the aforementioned similarities and the much poorer scope of literature data relating to SLMs, the SLN test results often become a starting or reference point, but they cannot replace the analyses of lipid microparticles, which significantly differ in properties and require an appropriate research methodology, adapted primarily to the size of the tested particles.
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Following excipients are mentioned in the study besides other: Compritol 888 ATO, Precirol ATO 5
Wolska, E.; Sznitowska, M. Modeling the Analysis Process of a Lipid-Based, Multi-Compartment Drug Delivery System. Processes 2025, 13, 460. https://doi.org/10.3390/pr13020460
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