Non-Traditional Natural Stabilizers in Drug Nanosuspensions

Abstract

Poor solubility of many drugs, with ensuing low bioavailability, is a big challenge in pharmaceutical development. Nanosuspensions have emerged as a platform approach for long-acting injectables and solid dosages that enhance drug bioavailability. Despite improvements in nanosuspension preparation methods, ensuring nanosuspension stability remains a critical issue. Conventionally, synthetic and semi-synthetic polymers and surfactants are used in nanosuspension formulations. However, no polymer or surfactant group is universally applicable to all drugs. This fact, as well as their toxicity and side effects, especially if used in excess, have sparked the interest of researchers in the search for novel, natural stabilizers. The objective of this paper is to provide a comprehensive analysis of non-traditional natural stabilizers reported in the literature published over the last decade. First, physical stability and stabilization mechanisms are briefly reviewed. Then, various classes of non-traditional natural stabilizers are introduced, with particular emphasis on their stabilization potential, safety, and pharmaceutical acceptability. Wherever data were available, their performance was compared with the traditional stabilizers. Furthermore, the benefits and limitations of using these stabilizers are examined, concluding with future prospects. This review is expected to serve as a valuable guide for researchers and formulators, offering insights into non-traditional natural stabilizers in drug nanosuspension formulations.

Introduction

One of the major challenges for a wide range of drugs and drug candidates is their poorly water-soluble nature, which limits both their development and clinical applications [1]. According to the biopharmaceutical classification system (BCS), around 40% of drugs available on the market and 90% of drugs under development are classified as poorly water-soluble [2]. Conventional formulation strategies to enhance the solubility of poorly water-soluble drugs are currently limited [3]. Most widely known strategies involve salt formation and pH adjustment [4], the use of solubilizing excipients (cyclodextrins, water-soluble organic solvents, water-insoluble lipids, etc.) [5,6], emulsion-based systems [7], microemulsion-based systems [2], and solid dispersions [8]. In addition to these techniques, nanonization or nanomilling (i.e., reduction in the drug particle size to the sub-micron range) has emerged as an alternative and reliable approach, offering notable benefits [9]. Fundamentally, reducing the particle size to the nanoscale expands the drug’s surface area, which subsequently leads to increased saturation solubility, dissolution rate, and enhanced bioavailability [10]. Other significant benefits of nanonization include its wide applicability across various drugs and its ease of application [11].

Nanosuspension formulation technology has emerged as a promising drug delivery approach, owing to its desirable characteristics [12]. Unlike lipid-based systems, nanosuspensions are highly efficient in formulating compounds that are not readily soluble in both water and oil [13]. Moreover, the presence of a solid-state allows for increased mass per volume loading, which is vital for high-dose applications. This promotes effective drug delivery with higher therapeutic concentrations, resulting in maximized pharmacological effects [14]. The use of solubilizing excipients such as cyclodextrins often fails to meet these requirements [13]. Major clinical advantages include minimized toxicity due to a lack of solubilizing agents and the possibility of modifications of the drug’s pharmacokinetics through controlled drug release formulations [4].

Drug nanosuspensions can be prepared by several methods broadly categorized as top-down processes (e.g., wet media milling, high-pressure homogenization, etc.) and bottom-up processes (e.g., liquid antisolvent precipitation, melt emulsification, supercritical fluid precipitation, acid-base precipitation, etc.) [15]. Combinative methods, involving sequential implementation of a bottom-up and a top-down process, can also be employed to effectively reduce the particle size [16]. Several review articles already provided an in-depth analysis of nanosuspension preparation methods: Bhakay et al. [15] systematically classified the usage frequency of several nanosuspension preparation methods over the period 2012–2017. Jadhav et al. [17] and Jacob et al. [18] explained top-down and bottom-up technologies in detail, alongside considering additional processes, such as ultrasound-assisted sonocrystallization. Pinar et al. [19] provided a well-documented analysis of drug nanosuspension preparation methods, highlighting both the benefits and drawbacks. Chin et al. [20] conducted an exceptional literature review by providing relevant patents for the associated drug nanosuspension preparation methods. For the sake of brevity, further details regarding nanosuspension preparation methods are not discussed here; readers are encouraged to see these review articles for detailed information about the processes.

Over the last few decades, substantial progress has been made in nanosuspension preparation methods; however, ensuring the physical stability of a nanosuspension continues to pose challenges [21]. As nanosuspensions are thermodynamically unstable systems, they tend to undergo aggregation, Ostwald ripening, and sedimentation, all of which result in physical instability over time during nanosuspension preparation and their storage [22]. Nanosuspension stability is of primary concern in formulation development, and a successful nanosuspension formulation entails selecting stabilizers and their concentrations judiciously [19]. Typically, synthetic (and semi-synthetic) polymers and surfactants are used in nanosuspension formulations due to their consistent quality, customizable properties, and good stability performance [23]. Hydroxypropyl methylcellulose (HPMC) is one of the most commonly employed non-ionic, semi-synthetic polymers [24]. Despite its cellulose-based origin, it is chemically modified by substituting hydroxyl groups with methyl and hydroxypropyl groups [25]. Other well-known examples of conventionally used chemically synthesized polymers and surfactants include polyvinyl alcohol (PVA) [26], polyvinyl pyrrolidone (PVP) [19], Poloxamer 188 (P-188) [17], Poloxamer 407 (P-407) [27], hydroxyl ethyl cellulose (HEC) [18], sodium dodecyl sulfate (SDS) [28], Soluplus [29], and D-α-tocopherol polyethylene glycol succinate (TGPS) [30]. In order to ensure clarity and conciseness throughout the paper, henceforth, these stabilizers will be referred to as traditional stabilizers. All stabilizers excluded from this category (i.e., natural stabilizers, colloidal superdisintegrants, charged nanoparticles) will be designated as non-traditional stabilizers.

Traditional stabilizers are widely used in formulations, and appear frequently in the majority of review papers covering nanosuspension stability. For example, Li et al. [31] compiled a vast range of publications from 2006 to 2015, focusing on the stabilization of drug nanosuspensions produced by wet media milling. They reported the drug concentration, type, and concentration of the stabilizer, as well as the average particle size after milling. Pinar et al. [19] classified stabilizers used in nanosuspension formulations by their type (i.e., polymer, surfactant) with detailed information on their structural properties. Peltonen and Hirvonen [32], presented a table highlighting the process used for preparing the nanosuspension, along with the drug and the stabilizers present in each formulation. Chin et al. [20] summarized several stabilization systems and individual stabilizers used in nanosuspensions. Wu et al. [33] conducted a comprehensive literature analysis detailing the nanosuspension preparation methods, drug delivery routes, and the stabilizers utilized in formulations. In essence, these excellent review papers mostly offer broad information on traditional stabilizers. However, none of these review papers provided any comprehensive insights into non-traditional, natural stabilizers. Even a cursory look at these review papers suggests the need for a comprehensive review of natural stabilizers.

Unfortunately, the literature reviews focusing on non-traditional, natural stabilizers (i.e., saponins, gypenosides, alginates, food proteins, serum proteins, gums, etc.) are notably scarce. In the context of nanosuspension stability, these stabilizers are often either mentioned in a few sentences or not mentioned at all. In certain review articles, protein-based stabilizers [17,18] and food protein-based stabilizers [14,21] are touched upon briefly. Conversely, Beneke et al. [34] carried out in-depth research, primarily focusing on plant-derived polysaccharides. Nevertheless, marine and animal-sourced natural compounds, as well as lipid-based and protein-based substances, were not considered within the scope of the review. One study involving non-traditional natural stabilizers was led by Elsebay et al. [29]. This study holds significance as it covers not only the use of non-traditional natural stabilizers in formulations, but also their role in processes, such as lyophilization (freeze-drying) and spray drying. The primary limitation of their study lies in its limited focus on non-traditional natural stabilizers, which lacks analysis regarding stabilizer efficiency, optimal concentrations, comparison with traditional stabilizers, and long-term stability results.

To date, to the best of our knowledge, no review article has a sole focus on non-traditional natural stabilizers in the formulation of drug nanosuspensions. Hence, the primary objective of this paper is to perform an in-depth review of non-traditional natural stabilizers, which have been documented in the literature mainly over the last decade. Moreover, this paper provides detailed information on stability outcomes, zeta potential, and particle size, alongside formulation and process parameters, including drug type, drug concentration, stabilizer type, stabilizer concentration, and nanosuspension preparation method. The thematic coverage of this review is illustrated in Figure 1.

First, physical instability (aggregation, Ostwald ripening, etc.) and stabilization mechanisms are covered to establish a basis for assessing stabilizer effectiveness. Then, non-traditional, natural stabilizers are examined in detail, with a focus on their stability potential, pharmaceutical safety and acceptability, and health concerns. Finally, the advantages and drawbacks associated with the use of these stabilizers are discussed, concluding with remarks on future outlooks. We anticipate this holistic approach will provide valuable insights to researchers, aiding in the development of drug nanosuspensions with non-traditional natural stabilizers.

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Ozsoysal, S.; Bilgili, E. Non-Traditional Natural Stabilizers in Drug Nanosuspensions. J. Pharm. BioTech Ind. 20241, 38-71. https://doi.org/10.3390/jpbi1010005


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