Oil-in-Water Nanosized Emulsions for Drug Delivery and Targeting. Tamilvanan ShunmugaperumalЧитать онлайн книгу.
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
| 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 |
2.2.1. Issues Related to Oil Selection to Make the O/W Nanosized Emulsions for Medical Application
In general, the o/w nanosized emulsion should be formulated with compatible vehicles and additives. The components of internal (dispersed oil droplets) and external (aqueous continuous medium) phases of nanosized emulsions should be chosen to confer enhanced solubility and stability to the incorporated therapeutically active lipophilic API. In principle, the function of selected excipients should not only be limited to improve the overall physical stability of the emulsions or enhance the API's solubility but also they should contribute to influence the biofate or therapeutic index of the incorporated API after administration via parenteral, ocular, percutaneous, and nasal routes. The general considerations concerning excipient selection and optimum concentrations mainly in relation to the oils, emulsifiers, and miscellaneous excipients are presented comprehensively below.
At the time of preformulation studies, the solubility data of APIs need to be generated in the different oil selected, that too either alone or in combination of one oil with other oils in a definite ratio. Two more important points should be kept in mind before selecting the oil or oil combination. First point is compatibility of the oil or oil combination not only with other formulation excipients but also with the site of applications, i.e., ocular/skin tissues. Second point is related to auto‐ or self‐oxidation potential of oil or oil combination during and after emulsion manufacturing, because oils are triglycerides and are prone to auto‐ or self‐oxidation over the emulsion's processing and storage time periods. To minimize or to eliminate some extent the auto‐ or self‐oxidation, the additional excipient recommended to include in the emulsion formula is antioxidants, especially α‐tocopherol in the concentration range from 0.001 to 0.002% w/w.
The final oil‐phase concentration in emulsions meant for ocular use is now widely accepted to be at or below 5% w/w taking into account that the emulsion must be kept in a low‐viscosity range of between 2 and 3 centipoises, which also is the optimal viscosity for ocular preparations (Lee and Robinson 1986). This viscosity range may be suitable to take the emulsion into the syringe (i.e., syringeability) for parenteral application into human body. However, for all other medical uses, the amount of oil may be varied but generally is within 5–20% w/w. Sometimes, a mixture of oils may be employed to facilitate API solubilization in the oil phase. Jumaa and Müller (1998, 1999) reported the effect of mixing castor oil with medium‐chain triglycerides (MCT) on the viscosity of castor oil. Mixing of castor oil with MCT at a ratio of 1 : 1 (w/w) led to a decrease in the viscosity of castor oil and simultaneously to a decrease in the interfacial tension of the oil phase. The presence of free fatty acids in the castor oil (may be as an impurity) can act as coemulsifiers to lower the interfacial tension between dispersed oil droplets and continuous aqueous medium and subsequently to produce a more stable emulsion formulation in comparison with the other oil phases. In addition to the digestible oils from the family of triglycerides, including soybean oil, sesame seed oil, cottonseed oil, and safflower oil, which are routinely used for making medical emulsions, alternative biocompatible ingredients such as α‐tocopherol and/or other tocols were also investigated for API delivery purposes via o/w emulsions (Constantinides et al. 2004, 2006). But the emulsions formed from tocols are often considered as microemulsion systems with few exceptions (Constantinides et al. 2004, 2006). Very recently, it was shown that playing with oil combinations could generate the dispersed oil droplets with bi‐compartmental structure possessing different polarity and thus paving the strategy of dual API loading in the o/w macro‐ and nano‐sized emulsions (Puri et al. 2019). The details of this type of emulsions are discussed in Chapter 7.
2.2.2. Issues Related to Emulsifier Selection to Stabilize the O/W Nanosized Emulsions for Medical Application
Not only the chemical nature of emulsifiers but also their concentration used determine the type of emulsion produced. For example, the spontaneously forming thermodynamically