SOME MULTIFUNCTIONAL LIPID EXCIPIENTS AND THEIR PHARMACEUTICAL APPLICATIONS

This review is generally focussed on lipid-based excipients in solid oral formulations which increase its bioavailability. Several approaches have been used to deliver the drug efficiently in the body, and lipid excipients are one of the promising drug delivery systems which address challenges like solubility and bioavailability of water-soluble drugs. Lipids excipients can be tailored to meet a wide range of product requirements like disease indication, route of administration, stability, toxicity, and efficacy. This review discusses novel lipids like Compritol 888 ATO, Dynasan 114, and Precirol ATO 5 and how these can be employed for devicing efficient drug delivery models and thereby have used in cosmetic and pharmaceutical industries.


INTRODUCTION
Lipids are essential for life, and the existence of cells specialized in fat storage has been conserved from flies and worms to humans. However, almost all cells maintain the capability to retain and accumulate lipids. Cellular mechanisms of lipid storage are relatively conserved from unicellular organisms, such as yeast, to complex organisms such as plants and mammals [1,2]. An excipient (derived from words excipere to take out, receive) may be defined as any substances mixed with the active pharmaceutical ingredient to give it consistency or used as a vehicle for its administration. It is impossible for any active pharmaceutical ingredient to have properties that allow incorporation in a therapeutic product that meets all the mentioned requirements. Therefore, every therapeutic product is a combination of drug and excipients [3][4][5].
The importance of lipid-based excipients in solid oral formulations has increased during the last decades, due to their outstanding benefits, such as providing modified release profiles or taste masking using solvent-free processing techniques [6]. Lipid-based excipients were first used in the 1960s for embedding drugs in a wax matrix in order to sustain drug release. In the more recent years, these excipients were successfully used in oral drug delivery systems to enhance the bioavailability of poorly aqueous soluble drugs and the novel lipids to control the release of easily soluble drug in the systemic circulation [7,8]. Furthermore, taste masking and the improvement of swallow ability have been achieved with these excipients. Further reasons for the application of lipids in a formulation may be shelf life extension by protecting the drug from other ingredients or from environmental influences, the reduction of gastric irritation and the improvement of general attributes like flowability, lubrication performance, compressibility or mechanical resistance [9,10].

Lipids
Lipids are biological molecules characterized by limited solubility in water and solubility in non-polar organic solvents. Their intermolecular interactions are dominated by the hydrophobic effect and van der Waals interactions. Many lipids are, however, amphipathic molecules, which interact with other molecules and with aqueous solvents via hydrogen bonding and electrostatic interactions [11,12]. Lipids are a diverse group of organic compounds found in plants, animal and micro-organisms. Lipids are non-polar compound and in-soluble in water but sometimes soluble in organic solvents. They comprise one of the three large classes of foods and, with proteins and carbohydrates, are components of all living cells [13][14][15].
One of the most important functions of lipids is the role they play in cell membrane structure and metabolic processes, especially as cell membrane transport agents and precursors of signaling eicosanoids. These roles are becoming increasingly better understood and have allowed for the developments of a diverse number of applications of bioactive lipids both in the pharmaceutical and cosmetic fields.
The major types of lipids that are present in the human body which plays major roles in metabolic processes are: triacylglycerols, free fatty acids, phospholipids, sphingolipids, bile salts, steroids and sterols, cholesterol, eicosanoids, and fat-soluble vitamins. Lipid modification strategies for the production of functional fats and oils include chemically or lipase-catalyzed interesterification or acidolysis reactions and genetic engineering of oilseed crops [16][17][18][19].

Novel Lipids
Novel lipids are the new chemical entities, are designed using increasingly available receptor structural information. Such chemical entities formed are polycyclic and very hydrophobic. Novel lipids are poorly soluble and hence poor bioavailability; in this review, we will be discussing three novel lipids Compritol 888 ATO, Dynasan 114 and Precirol ATO 5 [26].

Description
Glyceryl behenate occurs as a fine white to off-white, free-flowing powder or hard waxy mass with a faint odor it is tasteless, nonreactive with other formulation ingredients. The United States pharmacopeia national formulary (USP NF) describes glyceryl behenate as a mixture of glycerides of fatty acid, mainly behenic acid. Glyceryl behenate is a hydrophobic, non-swelling, wax material commonly used as a lubricant [28,29]. Over the past decade, glyceryl behenate has been used for controlled release applications by direct compression and more recently by hot melt coating, melt granulation or pelletization or the formation of solid lipid nanoparticles. Due to its low density and controlled release nature, it is used for the development of gastric floating matrix tablets [30,31]. Compritol 888 ATO is a lipid excipient that is generally used in the cosmetic and pharmaceutical industry as a surfactant, emulsifying agent and viscosity-inducing agent in emulsions, creams and pharmaceutical product. Based on its chemical composition, Compritol 888 ATO is a blend of different esters of behenic acid with glycerol [32][33][34].

Rationale for the use of compritol 888 ATO in novel drug delivery system
Compritol 888 ATO has been extensively employed as a matrixforming agent in the preparation of different sustained-release tablets. It has also been investigated as a hot-melt coating agent for powders or granules for controlled release purposes [35,36]. It has provided several noteworthy advantages over polymers as it is generally required in lesser amounts to achieve the desired effect and it does not crack during tablets compression. Moreover, Compritol 888 ATO has been examined for the preparation of pellets and orally disintegrating tablets. In addition, it has been used as a taste-masking agent to improve drugs palatability by concealing the bitter or unpleasant taste. Different researches have highlighted the applicability of Compritol 888 ATO in the preparation of aqueous colloidal dispersions such as solid lipid microparticles (SLMs), solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for entrapment of lipophilic drugs [37][38][39][40][41]. Compared to homogenous glycerides, Compritol 888 ATO is superior in terms of drug entrapment ability due to its complex nature and less perfect orientation thus leaving more space for the drug to be loaded. Also, the long-chain length of behenic acid in Compritol 888 ATO enhances the intermolecular entrapment of the drug by interchain intercalation. Generally, lipid polymorphism occurs due to the difference in lateral packing possibilities of fatty acid chains in a particular organization of hydrocarbon chains. Lipids exist in different three-dimensional structures: unstable, metastable and the most stable modification [42][43][44][45][46]. Additional intermediate form exists between the most stable and metastable. Studying the polymorphic behavior of Compritol 888 ATO alone and within the SLNs and NLCs, it was found that the lattice arrangement of Compritol 888 ATO crystals generally comprises small amounts of the unstable polymorphic form that disappears after thermal stress [47]. In preparing SLNs, the stresses that might affect lipid stability are the initial melting procedure of the lipid to produce the hot preemulsion and the subsequent high temperature and high pressure during the hot homogenization process. Partial formation of lowerenergy lipid modifications and reduction in crystallinity take place due to the transformation of Compritol 888 ATO into lipid nanoparticles. Also, the added surfactant during lipid nanoparticles preparation contributes to the lowering of the melting enthalpy of Compritol 888 ATO by distributing the melted lipid phase and distorting its crystallization [48][49][50]. It is postulated that the surfactant may immobilize lipid molecules by interfacial contact and, consequently, avoid reorientation of less-ordered configurations into the more organized structural lattice. It is important to understand the thermal behavior of Compritol 888 ATO when used for hot-melt coating process since it undergoes melting and exposure to high temperatures [51,52]. The thermal history, glycerides are exposed to, determines its crystal structure's composition in terms of including hexagonal, orthorhombic and triclinic, each with different polymorphic transition temperatures and melting points. The polymorphic transitions affect drug release as better drug sustained release is related to the metastable polymorph [53,54].

Composition and types of Compritol
Compritol 888 ATO (glyceryl dibehenate or glyceryl behenate is a hydrophobic mixture of mono-(12-18% w/w), di-(45-54% w/w) and tri-(28-32% w/w) behenate of glycerol with melting point in range of 65-77 °C and with hydrophilic-lipophilic balance (HLB) of 2 Compritol 888 ATO is prepared by the esterification of glycerin by behenic acid without the use of catalysts. The raw materials used in preparing are of vegetable origin and the esterified material is atomized by spray cooling [55].

Properties of Compritol ATO 888
Compritol 888 ATO is a novel lipid and it is used for retardant release, the binding agent also etc. Properties of Compritol 888 ATO is shown in table 2. [59,60]. Several studies have been conducted to examine the thermal behavior, crystallinity and possible interactions of the Compritol 888 ATO and the drug that may impact its release. Compritol 888 ATO has been mainly characterized using differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) [61]. Generally, lipid polymorphism occurs due to the difference in lateral packing possibilities of fatty acid chains in a particular organization of hydrocarbon chains. The polymorphic form of Compritol 888 ATO either depends on parameters such as crystallization rate and temperature during production or storage. In slow crystallization rates, each glyceride crystallizes separately, producing a complex matrix containing different lamellar phases. On the contrary, a fast crystallization rate, or more produces a single lamellar phase [62,63].

Applications of Compritol 888 ATO
Glyceryl behenate is used in cosmetics, foods and oral pharmaceutical formulations. In cosmetics, it is mainly used as a viscosity-increasing agent lipophilic matrix or coating for sustained released tablets and capsules. Viscosity-increasing agent in silicon gels (cosmetics). Viscosity-increasing agent in w/o or o/w emulsions (cosmetics). Glyceryl behenate is mainly used as a tablet and capsule lubricant and as a lipidic coating excipient. Used in the preparation of sustained-release tablets, as a matrix-forming agent for the controlled release of water-soluble drugs and as a lubricant in oral solid dosage formulations and can also be used as a hot-melt coating agent sprayed onto a powder [64][65][66].
Modified-release dosage forms: Lipid nanoparticles have gained great interest during the past decade as they are more biocompatible and more stable compared to polymeric nanoparticles. Also, they offer high drug entrapment along with the feasibility of delivering both lipophilic and hydrophilic drugs. Compritol 888 ATO is considered one of the most applied and cited excipients in preparing SLNs and NLCs. Compritol 888 ATO-based nano-lipid carriers have been successfully utilized for ocular, oral, pulmonary, topical, transdermal and rectal delivery routes. Authors have selected it because of its favorable characteristics exemplified by its nonpolarity and lower cytotoxicity than other lipids [67].
Microparticles or spheres: Compritol 888 ATO used as core forming agent in preparing lipid-based porous microspheres. It has been shown that drug release from microspheres was dependent on Compritol 888 ATO and the increase in their concentration caused a reduction of drug release from the microspheres [68].
Compritol 888 ATO has been used in pellet lipophilic binders to prolong the release of drug from matrix pellets. Pellets exhibited excellent floating ability combined with sustained-release property due to the lipophilic nature of Compritol 888 ATO [69].
Compritol 888 ATO has been successfully used by different research groups as a sustained-release matrix for tablets, to reduce the frequency of administration of drug [70].
In the hot-melt extrusion (HME) process, Compritol 888 ATO has been utilized for preparing extrudates with the immediate or sustained release [71].

Composition and name of manufactures of Precirol ATO 5
Glycerides are a family of excipients which have generated considerable interest in the preparation of oral dosage forms. Some glycerides such as Precirol ATO 5 (glyceryl palmitostearate) can be used for the preparation of sustained-release dosage forms. The esterification of glycerol by long-chain fatty acid gives them a pronounced hydrophobic character with a low HLB value of 2 [73,74].
Glyceryl palmitostearate (Precirol ATO 5) is a mixture of mono-, di-, and triglycerides of C16 and C18 fatty acids, Glyceryl palmitostearate is used in oral solid-dosage pharmaceutical formulations as a lubricant [75].

Properties of Precirol ATO 5
Precirol ATO 5 is a novel lipid and its property is shown in table 3 [77].

Applications of Precirol ATO 5
Glyceryl palmitostearate is widely used in oral solid-dosage pharmaceutical formulations as a lubricant. Tablet disintegration and time strengths depends on mixing time of glyceryl palmitostearate, as an increase in the blending time, increases disintegration time of tablets and also decreases the strength of tablet. It is used as a lipophilic matrix for the preparation of sustained-release product [78][79][80].
Tablet formulations may be developed by granulation or any hot-melt technique, the former producing tablets that have a faster release profile. Release rate decreases with increased glyceryl palmitostearate content. Glyceryl palmitostearate is used to form microspheres, which may be used in capsules or compressed to form tablets,) pellets, coated beads and biodegradable gels. It is also used for taste-masking. It is used as a lipid in Solid Lipid Nanoparticles and other lipids nano and microparticulate colloidal delivery system [81,82].

Function of Precirol ATO 5
Biodegradable material is well used as a coating agent, gelling agent,

Composition and name of manufactures of Dynasan 114
Trimyristin is an ester with the chemical formula C45H86O6. It is saturated fat, which is the triglyceride of myristic acid (C-14). Trimyristin is a white to yellowish-gray solid that is insoluble in water, but soluble in ethanol, benzene, chloroform, dichloromethane, and ether [84].
Dynasan 114 is manufactured by some of these limited private corporations: IOI Oleo limited, Toronto research chemical, Sasol Germany GmbH, Cremer care [87,88].

Properties of Dynasan 114
Dynasan 114 is novel lipid and it is used for control release, pore form also and its property is shown on  Ethanol and water

Applications of Dynasan 114
Trimyristin is the triglyceride of myristic acid, which is found naturally in many vegetable fats and oils. Dynasan 114 microcrystalline triglycerides are used in the cosmetic and pharmaceutical industries as adjuvants in the preparation of, In tablets as lubricants having a very low influence on disintegration, In suppositories, vaginal ovula and pharmaceutical/cosmetic sticks as crystallisation accelerators and seeding agents to improve the solidification process, In ointments, creams and lotions as bodyimparting and structure-forming components.
Further, they can be used in cream and lotions as body imparting and structure forming. It is used in the pharmaceutical industry as a Biodegradable material, coating agent, gelling agent, release modifying agent, sustained-release agent, diluents in tablet and capsule formulation, Lubricant, taste-masking agent [93,94].

CONCLUSION
By increasing the bioavailability of numerous poorly soluble drugs along with formulations for physiologically well-tolerated class, the lipid excipients provide vast possibilities in this emerging technology. Understanding the physicochemical nature of the compound, alimentary canal and target receptor mechanisms, better and proficient drug delivery systems can be designed. Characterization, proper evaluation, and classification of these drug delivery systems are prerequisites to developing formulations and thereby boosting the pharmaceutical industry.