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

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СКАЧАТЬ (ethylene oxide)OFATone‐factor‐at‐a‐timeO/Woil‐in‐waterPBCApoly(n‐butylcyanoacrylate)PCphosphatidyl choline6‐PCn‐hexanoyl lysolecithinPDIpolydispersity indexPEOpolyoxyethylenePFOBperfluorooctyl bromidePPprocessing parameterPPOpolyoxypropyleneTPGStocopheryl polyethylene glycol 1000 succinateQACquaternary ammonium compoundQbDQuality by DesignQbTQuality by TestingQRMquality risk managementQTPPquality target product profileREMrisk estimation matrixRPNrisk priority numberSDSsodium dodecyl sulfateZPzeta potential

2.1. INTRODUCTION

      Therapeutically, the oil‐in‐water (o/w) nanosized emulsions are used mainly as delivery carriers for lipophilic active pharmaceutical ingredient (API) molecules that show pharmacological activities after administration via parenteral, ocular, and transdermal routes. Furthermore, the o/w nanosized emulsions having anionic, cationic, or neutral charged dispersed oil droplets can be made especially by changing the emulsifiers so that the first step of engineered droplet surfaces could be obtained to extract multifunctional activities. The second step of engineered droplet surfaces in emulsions usually attains by decorating the droplet surface with anchoring or homing moiety either by conjugation or simple adsorption reaction. By combining both the surface charge optimization and engineered droplet surfaces, the o/w nanosized emulsions are indeed in recent years useful for API delivery and/or targeting to otherwise inaccessible internal organs of the human body (Tamilvanan 2009).

In contrast to microemulsions, the o/w nanosized emulsions are thermodynamically instable, which can significantly reduce their applicability. As discussed in Chapter 1, the thermodynamic instability behavior of emulsions includes phenomena such as flocculation, coalescence, creaming, and Ostwald ripening. The physical instability of emulsions is due to the spontaneous tendency toward a minimal interfacial area and hence a minimal surface free energy between the dispersed oil phase and the aqueous continuous/dispersion medium. Minimizing the interfacial area is mainly achieved by two mechanisms: first, coagulation possibly followed by coalescence and second, by Ostwald ripening. Coalescence is often considered as the most important destabilization mechanism leading to coursing of dispersions and can be prevented by a careful choice of stabilizers or emulsifiers. The molecular diffusion of solubilizate (Ostwald ripening), however, will occur as soon as curved interfaces are present. During Ostwald ripening, the molecular diffusion of the lipophilic components occurs from small particles to larger particles due to the difference in escaping tendency (vapor pressure) between the two. Ostwald ripening is thus directly proportional to the solubility of the lipophilic component in the dispersion medium as well as to the particle size distribution. Various physical factors such as density difference between the dispersion medium and dispersed oil droplets, strong hydrodynamic agitation, interdroplet interaction, and the droplet interfacial viscoelasticity can affect or perturb the colloidal stability of emulsion droplets and thus their shelf life and therapeutic utility. Therefore, the stabilization of emulsion droplets is in many cases very important and desirable. There are different ways of stabilization of the o/w nanosized emulsions, all of which are related to the modification of the interface between the dispersion medium and emulsified oil droplets. Depending on the intended medical/therapeutic application of nanosized emulsions, various kinds of emulsifier molecules ranging from small surfactants or surface‐active polymers to poly‐layered interfacial coatings produced by multicomponent emulsifier films are considered.

      This chapter initially starts with the different excipients or ingredients used in the emulsion preparation followed by a short overview on the lipophilic APIs’ incorporation pattern into the o/w nanosized emulsions. One more important section included in this chapter is how to optimize a formula for ensuring a quality emulsion formulation. This section introduces a case study that shows the Quality by Design (QbD) approach applied onto the emulsions to optimize a formula during preformulation studies. The effect of the amount of new chemical entity (NCE) or lipophilic API on the physical stability of emulsions, quantity of excipients (oils, emulsifiers, and other excipients) onto the API incorporation patterns, final particle size distribution of dispersed oil droplets of the emulsion on different storage temperature conditions, etc., will be the subject of interest to be discussed in this chapter. It is to be informed to readers that the discussion of majority of the traditional excipients (oils, emulsifiers, and other excipients) can also be found from Chapter 4 wherein the classification of emulsions based on their generation appears.

2.2. FDA‐APPROVED OILS, EMULSIFIERS, AND AUXILIARY OR MISCELLANEOUS EXCIPIENTS

A comprehensive and non‐exhaustive list of different excipients used to make the o/w nanosized emulsions are shown in Table 2.1. Interestingly, the conventional or traditional excipients such as oils and emulsifiers are divided into two categories. The oils are classified according to their origin or source, i.e., animal, mineral, and plant. Based on the charges, the emulsifiers are majorly grouped as amphoteric, anionic, cationic, neutral, and nonionic. The emulsifiers are again separated into two groups depending on the specific activity they produce due to their charge presence. In one group, the amphoteric, anionic, neutral, and nonionic emulsifiers are gathered while the cationic emulsifier is kept alone in other group. All the emulsifiers without the cationic emulsifier is again sub‐grouped based on their solubility, whether lipid/oil or water, and hence the emulsifiers are grouped into two categories, i.e., oil soluble and water soluble. The cationic emulsifier is classified into two based on its chemical nature, i.e., carbohydrates or lipids, and hence the cationic polysaccharides and cationic lipids.

TABLE 2.1. Comprehensive and Non‐exhaustive List of Different Conventional or Traditional Excipients Used to Make the O/W Nanosized Emulsions

СКАЧАТЬ

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Excipients	Selected Examples
Oils	Animal origin: Lanolin, squalene (shark liver oil)
	Mineral origin: Paraffin light, paraffin oil, silicone oil, vaseline
	Plant origin: Arachis oil, castor oil, corn oil, glycerol monostearate, medium‐chain monoglycerides, medium‐chain triglycerides, olive oil, sesame oil, soyabean oil, etc.
Emulsifiers: Amphoteric, anionic, neutral and nonionic	Oil soluble: Cholesterol, cremophor RH, phospholipids (lipoid E 80) including phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, etc.
	Water soluble: Miranol C 2 M (disodium cocoamphodiacetate) Miranol MHT [(1H‐imidazolium, 4,5‐dihydro‐1‐(carboxymethyl)‐1‐(2‐hydroxyethyl)‐2‐undecyl‐, hydrogen sulfate (salt), monosodium salt)] Poloxamer [(poly(ethylene glycol)‐block‐poly(propylene glycol)‐block‐poly(ethylene glycol)] 188 and 407 Polysorbate/Tween 20 {2‐[2‐[3,4‐bis(2‐hydroxyethoxy)oxolan‐2‐yl]‐2‐(2‐hydroxyethoxy)ethoxy]ethyl dodecanoate} Polysorbate/Tween 80 {2‐[2‐[3,5‐bis(2‐hydroxyethoxy)oxolan‐2‐yl]‐2‐(2‐hydroxyethoxy)ethoxy]ethyl (E)‐octadec‐9‐enoate} Transcutol P (diethylene glycol monoethyl ether) Tyloxapol [4‐(1,1,3,3‐tetramethylbutyl)phenol polymer with formaldehyde and oxirane] TPGS (tocopheryl polyethylene glycol succinate)
Emulsifiers: Cationic	Lipid: DMPE, DOTAP, oleylamine, stearylamine
	Polysaccharide: Chitosan
Miscellaneous	α‐Tocopherol, EDTA, glycerin, methylparaben, propylparaben, sorbitol, thiomersal, xylitol