Oil-in-Water Nanosized Emulsions for Drug Delivery and Targeting. Tamilvanan Shunmugaperumal

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СКАЧАТЬ the presence of adequate amount of active pharmaceutical ingredient (API) in a dosage form becomes the prime importance to elicit the desired and often required pharmacological activity following administration of the same into human body. But achieving the adequate amount of API in the particular dosage form requires a lot of formulation knowledge input. How to manufacture the dosage form with adequate amount of API? The answer to this query primarily depends on solubility of API followed by its permeability, molecular size, therapeutic index, etc. If the water solubility of API is low, then, the enhancement of API’s solubility becomes a major concern in pharmaceutical industries for converting the inadequate API aqueous solubility amount into adequate category. This type of converting the API amount from inadequate to adequate category needs the tremendous supports from formulation scientist who has the experience to solve this concern. The lucrative way adapted routinely in the pharmaceutical industry for deleting the word inadequate from the API aqueous solubility is just to combine the API with a suitable nanosized API delivery system or just to pulverize or micronize the API into nano‐level size ranges. This book accentuates the use of one of the nanosized API delivery system to erase the inadequate aqueous solubility from API. Before proceeding with the nanosized API delivery system, a brief history of nanotechnology is being described below.

1.1.1. Nanotechnology: Definition

      Pulverized API having nanometer size ranged particles and intact API‐loaded nanoparticles (either preformed or forming in situ) are considered one of the most‐prevalent improvement methods which have been used to overcome the problem of API's poor solubility and, thus, bioavailability, as well as to achieve targeted API delivery. Having said the importance of pulverized API as nanoparticles (NPs) or API‐entrapped nanoparticulate system, there is no single definition of what a NP is. This might be because of the highly multidisciplinary nature of nanotechnology. The term “nanotechnology” was first used by Norio Taniguchi in 1974, at the University of Tokyo, Japan, for any material in the nanometer size range (Taniguchi 1974) and the materials somehow handled by human beings in their everyday life. According to the United States Food and Drug Administration (USFDA), materials are classified as being in the nanoscale range if they have at least one dimension at the size range of approximately 1–100 nm. However, the characteristic properties of nanoscale such as solubility, light scattering and surface effects are predictable and even these properties are indeed continuous characteristics of the bulk materials (Donaldson and Poland 2013), the definitions of “nanomaterial” based on size are often inconsistent and the upper end of the nanoscale at 100 nm is an arbitrary cut‐off (Boverhof et al. 2015). Thus, the 100‐nm limit is often considered constraining and, according to a more‐inclusive definition, particles <1,000 nm in each dimension (submicron particles) is designated as NPs (Keck and Müller 2006). The latter more‐inclusive definition is particularly applicable in the pharmaceutical field since the particle size in the nanometer range can lead to increased dissolution rates because of the increase in surface area and increased saturation solubility (Junghanns and Müller 2008). In this respect, the generation of nanometer range particles from the API molecule itself is coming under NPs with a nomenclature of API nanocrystals or API nanosuspensions. On the other hand, encapsulating the API into a preformed or in situ forming nanosized API delivery carrier is also grouped under NPs. Now the question will arise, at an industrial environment, which type of API is going for API nanocrystals/nanosuspensions formation and which type of API needs to go as cargo in a nanosized carrier? To clarify this confusion, the following discussion is devoted wherein the poorly soluble API is grouped into two categories.

       1.1.1.1. Poorly Water‐Soluble Grease Ball and Brick Dust Molecules

It is now well known that the poor API solubility is an issue for approximately 70–90% of new APIs (Merisko‐Liversidge and Liversidge 2011; Müller and Keck 2012). According to Lipinski (2005) there are two different classes are available within the poorly soluble APIs viz. (i) grease ball and (ii) brick dust molecules.

      Hydrophobic APIs have a limited capacity to interact with the water phase, in accordance with “similia similibus solvuntur” (like dissolves like), and these APIs are solubility‐limited by poor hydration. The poorly soluble APIs restricted in solubility by poor hydration are described in the popular scientific jargon as “grease ball” molecules, due to their high hydrophobicity and lack of interaction with water. Although they possess poor water solubility (insolubility is probably due to the salvation extreme), the grease ball molecules are easily soluble to lipids or oils and therefore these molecules can plausibly be formulated into lipid‐or oil‐based formulations. In contrast, the brick dust molecules are poorly soluble due to crystal packing interactions being insoluble to both aqueous solvents and lipids or oils. So, the aqueous solubility of brick dust molecules could be enhanced by the formation of amorphous materials or particle size decrease, e.g., nanocrystallization. Thus, formulating APIs as nanocrystals should be mainly used as a solubility enhancement formulation approach to brick dust molecules rather than to grease balls.

      In other words, Yalkowsky and coworkers established the General Solubility Equation (GSE), in which the solubility of a compound is expressed as a function of the melting point (T_m) and its lipophilicity (in the form of the octanol‐water partition coefficient, log K_o/w or simply the log P value) (Jain and Yalkowsky 2001). The GSE states the following relationship:

(1.1)

      where S₀ is the intrinsic solubility, i.e., the solubility of the non‐ionised (neutral species).

Specifically, “grease balls” represent highly lipophilic compounds (log K_o/w > 3), which are poorly hydrated and their solubility is solvation limited, whereas “brick dust” compounds display lower lipophilicity and higher melting points (T_m > 200°C) and their solubility is limited by the strong intermolecular bonds within the crystal (Bergström et al. 2007), therefore, they said to have solid‐state‐limited solubility. Collectively, the APIs with solvation‐limited solubility are lipophilic, relatively large molecules and lack conjugated systems. Most of these grease ball molecules have been developed as oral dosage forms, however, the developed dosage forms typically include several different excipients that may improve dissolution (disintegration and dispersion) and solubilization. This indicates that an extensive API development process would be required to bring these grease ball molecules to the market. In contrast, the APIs with solid‐state‐limited solubility (brick dust molecules) are often flat, typically with an extended ring structure and display high aromaticity. These molecular features are important for forming a more stable crystal lattice. Hence, brick dust molecules have been found to benefit from formulation approaches such as particle size reduction and amorphization, whereas grease balls can be formulated as lipid or oil‐based formulations (Tuomela et al. 2016). Table 1.1 shows the various properties of brick dust and grease ball APIs.

It should be noted, however, that while compounds described as solvation‐limited (grease ball) often display intrinsic solubility values in the lower nanomolar scale, none of the compounds included in the solid‐state‐limited (brick dust) category had intrinsic solubility values even in this lower nanomolar scale (Wassvik et al. 2008). Interestingly, griseofulvin which has a solubility of approximately 15 μM was the least soluble compound found in the dataset published by Wassvik et al. (2008). Two fundamental explanations may be given for why this is the case. First of all, after using the GSE relationship [Eq. (1.1)] along with the knowledge that compounds with a log P value of 2 or less will tend to have solid‐state‐dependent solubility, the estimated or expected intrinsic solubility value of compounds having extraordinarily high melting points (of about 325°C) would be about 30 μM. Secondly, most of the solely solubility‐limited compounds СКАЧАТЬ