**2. Lipid nanoformulations: design approach**

**1. Introduction**

32 Advanced Technology for Delivering Therapeutics

Due to the continuous rise in the number of low solubility drug molecules and lack of more targeted drug therapies, the drug development has become more complex and challenging job within the industry. In fact, up to 90% of today's drug candidates are suffering from low aqueous solubility, which is commonly associated with low bioavailability, high intra‐ and inter‐subject variability and lack of dose suitability [1, 2]. In keeping these challenges in mind, drug formulators must seek new techniques and innovative formulation approaches to

It is more than a decade, when lipid‐based formulations have been considered as a well‐ established strategy for improving oral bioavailability and minimizing variable food effect of poorly soluble compounds. Lipids have been used as carriers in various delivery systems for drug administration, including solutions, suspensions, emulsions, and more attractively self‐ emulsifying/microemulsifying/nanoemulsifying drug delivery systems (SEDDS/SMEDDS/ SNEDDS) that are designed to increase solubility and bioavailability of drugs belonging to the BCS Class II–IV [3]. Among several approaches, which are currently available to incorporate active pharmaceutical drugs into lipid vehicles in a variety of dosage forms, SEDDS, SMEDDS and or SNEDDS have proved to be the most successful approaches in improving the bioavail‐ ability [4]. The initial key achievement of these formulation systems (SEDDS/SMEDDS/ SNEDDS) is to increase the solubilization of the poorly water soluble drugs (PWSDs) by the

These systems advantageously present the drug in solubilized form, and their relatively smaller droplet sizes provide a large interfacial area enhancing the activity of pancreatic lipase to hydrolyze triglycerides and thereby promoting faster drug release containing mixed micelles of bile salts. The development of Neoral® (cyclosporin A) as a commercial product

Nanotechnology has become a buzzword for scientific experts, and efforts are ongoing to extend its applications in various medical and pharmaceutical aspects. The nanoscale tech‐ nologies can be generally categorized into: lipid‐based nanocarriers, polymeric nanocarriers, inorganic nanocarriers, and drug nanoparticles or nanosuspensions [6]. Within the lipid‐based nanocarriers category, there has been a resurgence of interest in nanoemulsions since low energy emulsification methods, such as spontaneous or self‐nanoemulsification, have been developed. SNEDDS are anhydrous homogenous liquid mixtures, composing oil, surfactant, drug and/or cosolvents, which spontaneously form transparent nanoemulsion (20–250 nm

Being nanosized, SNEDDS offer a strong alternative to the more conventional oral formula‐ tions of lipophilic compounds. SNEDDS introduce the drug in solution within nanosized oil droplets. These fine droplets are emptied rapidly from the stomach resulting in faster drug release all over the gastrointestinal (GI) tract. An additional advantage of SNEDDS over simple oily solutions is granting much larger interfacial area for partitioning of the drug between oil and water leading to ease of dispersibility [8]. In contrast to oily solutions, SNEDDS does not

overcome such hurdles and ensure effective treatments for the patients in need.

formation of emulsions and or micellar systems (colloidal solutions).

exhibits an excellent example of the utilization of these systems [5].

droplet size) upon aqueous dilution with mild agitation [6, 7].

Lipid excipients are comprised of a large group of physically and chemically diverse glycer‐ ides, which may be used in simple (single oil solutions of the drug substance) or in more complex nanocarriers (SMEDDS/SNEDDS, drug dissolved in the mixture of glyceride, surfactant and or cosolvent), with considerable flexibility in formulation design [12].

Simple oil formulations are generally composed of mono‐, di‐, or triglycerides or their derivatives and differ on the content of medium‐ (C6‐C10 in chain length) or long‐chain (C12‐ C24 in chain length) fatty acids. Glyceride esters are water immiscible, and their solvent capacities for drug substances vary according to the fatty acid chain length. Many lipid excipients (oils, surfactants), which are regarded as acceptable food grade materials, expected to be well tolerated by the body [13], even as parenteral emulsion dosage form [14]. These excipients have a history of use in a wide variety of pharmaceuticals.

In simple terms, lipid nanoformulations can be distinguished according to their dispersion and digestion in the aqueous content of the gut [15, 16]. Emulsion droplet size has been considered to be an important part in the performance of self‐nanoemulsifying systems since particle size can determine the rate and extent of drug release *in vitro* [17]. However, the relative digestion rate would be expected to vary if the formulation is modified, and the critical factor is the fate of the drug after digestion of the formulation, in particular whether or not the drug remains in a solubilized state.


**Table 1.** Common excipients for designing self‐nanoemulsifying formulations and the list of their suppliers.

## **2.1. Excipients used to design lipid‐based nanoformulations**

**Func‐ tion** 

Oil **Medium‐chain triglycerides (C8‐C10)**: Fractio‐

**Long‐chain triglycerides (C14‐C22):** Vegetable oils are glyceride esters of mixed unsaturated long‐chain fatty acids, commonly

**Mixed mono‐, di‐ and triglycerides:** Novel semisynthetic medium‐ and long‐chain derivatives. Esters of propylene glycol and mixture of mono‐ and diglycerides

**Polar oil**: Some excipients which are traditionally thought of as hydrophobic surfactants, such as sorbitan fatty acid

**Water insoluble:** Oleate esters, such as poly‐ oxyethylene (20) sorbitan trioleate, PEG‐6‐sor‐ bitan oleate and polyoxyethylene (25) glyceryl trioleate are commonly used in the pharma‐

**Water soluble:** The popular castor oil derivatives with saturated alkyl chains result‐ ing from hydrogenation of materials derived

derivatives include polysorbate 80 which are predominantly ether ethoxylates and

The most popular water soluble cosolvents are propylene glycol, polyethylene glycol, ethanol and glycerol. Others are diethylene

propylene carbonate, tetrahydrofurfuryl alcohol, polyethylene glycol ether

from a vegetable oil. Other

phospholipids

glycol monoethyl ether,

ides of caprylic/capric acid

34 Advanced Technology for Delivering Therapeutics

known as long‐chain triglycerides

of caprylic/capric acid

esters

ceutical industries

Nonionic surfac‐ tant

Cosol‐ vent

Other exci‐ pient nated coconut oil and palm seed oil, triglycer‐

**Composition and description Commercial name Supplier** 

Miglyol 812, 810, Capmul MCM, Captex 355, etc.

Soybean oil, sesame oil, corn oil, olive oil, peanut oil, cottonseed oil, rapeseed oil, etc.

Imwitor 988, Imwitor 308, Maisene 35‐1, etc.

Polysorbate 85 (Tween 85), TO‐106 V, Tagat TO, etc.

Cremophor RH40, Cremo‐ phor EL, HCO30, Tween 20, 80, poloxamer 407, vari‐ ous Labrasols, Labrafac Labrafils, Gelucires, Soy phosphatidylcholine, etc.

PG, PEG 300, PEG 400, 600, transcutol, glycofurol,

butylated hydroxytoluene (BHT), butylated hydrox‐ yanisole (BHA), propyl gal‐ late, ascorbyl palmitate,

etc.

etc.

**Table 1.** Common excipients for designing self‐nanoemulsifying formulations and the list of their suppliers.

Many oil‐soluble antioxidants α‐Tocopherol, β‐carotene,

Span 80, 85, etc.

Gattefosse corporation, France; Abitec Corp., Janesville, USA; Sasol GmbH, Witten,

Tokyo, Japan;

Germany

Hamburg, Germany; **L**ipoid, Germany; BASF Co.,

Germany; Nikko Chemicals Co.,

**Cremer Oleo GmbH & Co. KG,**

Excipients play a key role in designing successful nanoformulations with a sound control strategy and influence business‐critical and clinically significant drug product performance outcomes such as stability, bioavailability and manufacturability. The design of lipid‐based nanoformulations, particularly SNEDDS, is comparatively simple as the drug need to be incorporated into a suitable oil‐surfactant mixture, which could be filled in a soft or hard gelatin capsules. Various choices of lipid excipients are available in the market. Numerous lipids are amphiphilic in nature, which contain both hydrophilic and lipophilic portions (fatty acid) [18]. The morphology of the lipids should be assessed as melting point increases when the length of fatty acid chain increases, but it decreases when unsaturation of the fatty acid increases [19]. Choice of excipients for successfully designed lipid‐based nanocarriers is determined based on factors, such as miscibility; solvent capacity; self‐dispersibility; digestibility; irritancy; toxicity; purity; chemical stability; compatibility with capsule; melting point; and cost. Since these excipients can affect the drugs bioavailability, it is necessary to identify the characteristics of these excipients. Details of the lipids (oils, nonionic surfactants, cosolvents), their compo‐ sitions and list of suppliers are given in **Table 1**.
