INTRODUCTION:

Pharmaceutical excipients are FDA approved, inactive and generally recognized as safe (GRAS) ingredients other than the active pharmaceutical ingredient that are added in a pharmaceutical dosage form not for their direct therapeutic actions, but to aid the manufacturing process, to protect, support or enhance stability, or bioavailability and to improve patient acceptability.^1,2 The presence of different excipients in varying concentrations decides the functions and efficacy of the dosage form.³ Excipients make up the bulk, ensure accuracy and precision of drug distribution throughout the dosage, facilitate homogenous blending, mask bitter taste, improve flowability, add bulk density, and modulate the release of API according to requirement.⁴

The term bioavailability, is one of the principal pharmacokinetic properties of drugs, that describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation.⁵

The improvement of oral bioavailability of poorly water-soluble drug can be considered as one of the greatest challenges in drug formulation, up to 90% of all new chemical entities entering drug development programs possess insufficient aqueous solubility.⁶Newly discovered drug molecules have been found to possess poor aqueous solubility with ˂100µg/ml (0.1mg/ml).⁷ Because of their poor aqueous solubility these drugs are usually poorly absorbed. Such drugs can be classified into Class 2 and Class 4 of Biopharmaceutical Classification System (BCS), which is the guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration.^8,9Various problems associated with these drugs include low bioavailability, high intra- and inter-subject variability in pharmacological responses and improper dose-response linearity. The solubility of drugs is a key factor that highly influences the dissolution rate and bioavailability of the following on oral administration.¹⁰ Strategies that have been adopted to overcome these problems include use of surfactants, lipid-based vehicles and excipients, permeation enhancer, and techniques like micronization, salt formation and solid dispersion.¹¹Physiological lipids in formulations reduces the risk of acute and chronic toxicity.¹²The low intrinsic toxicity and biodegradability of lipids used in solid lipid nanoparticles may prove to be valuable in terms of brain tumour management.¹³

Lipid-based excipients are gaining importance in development of formulations with modified release profiles or for the purpose of taste masking. Furthermore, the use of more lipid excipients in formulations is more sensible for higher drug loading.¹⁴ The factors that determine the selection of lipid excipients for a particular formulation include miscibility, solvent capacity, ability to promote self-dispersion of the formulation, purity, chemical stability, melting point, affordability, irritancy, toxicity, digestibility and fate of digested products, and most importantly, regulatory issues.^15-17 It is necessary to have a complete understanding of the functionality of the lipid excipients. This review discusses novel lipids like Compritol 888 ATO, Dynasan 114, glyceryl monooleate (GMO), Maisine CC and Precirol ATO 5 and how they have been employed for designing efficient drug delivery systems for oral, topical, transdermal or parenteral routes of administration.

Lipid excipients:

Lipid excipients offer distinct formulative and physiological advantages, as their degradation products resemble that of the natural end products of intestinal digestion.¹¹ In terms of the lipid-based oral formulations, the preferred oil phases are the digestible food-grade oils. However, the food-grade oils, being of natural origin may show erratic solvent capacity and they also demonstrate poor emulsification properties.

Classification of lipid excipients:

Triglycerides:

Triglycerides are the most commonly used excipients used in lipid-based drug delivery system. They are the only lipid excipients that do not present any safety concerns, since they are fully digested and absorbed.¹¹ Triglycerides are further classified as long chain triglycerides (LCT), medium chain triglycerides (MCT) and short chain triglycerides (SCT). Based on the effective concentration of ester groups they are used as a solvent for drug.¹⁸ MCT have higher solvent capacity than LCT. Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) is used as an absorption enhancer for poorly water-soluble drugs.However, most of the refined vegetable oils contain pure triglycerides.¹⁹

Mixed glycerides:

Mixed glycerides are obtained by partial hydrolysis of vegetable oils. Triglycerides, the starting material and extent of hydrolysis determine the composition of the mixed glycerides.²⁰

Studies on applications of selected lipid excipients in pharmaceutical dosage forms:

Glyceryl behenate or Compritol 888 ATO:

Hu et al. prepared solid lipid nanoparticles (SLNs) by ultrasonic and high-pressure homogenization method using glyceryl monostearate and Compritol 888 ATO, to improve the oral bioavailability of poorly water-soluble drug Cryptotanshinone (CTS). CTS-SLNs obtained using Compritol 888 ATO and glyceryl monostearate as lipid matrix were abbreviated as CP-SLNs and GMS-SLNs respectively. The percentage of CTS released from CP-SLNs was 25.87% and from GMS-SLNs was found to be 37.56% in 72 hrs. It was clear that CP had more effect on sustaining release than the GMS. The in vivo study indicated that SLN changed the metabolism behaviour of CTS to tanshinone IIA and bioavailability of CTS was significantly enhanced by incorporation into SLNs as compared with that in suspension. Thus, CP-SLNs proved to be beneficial in enhancing the oral bioavailability of poorly soluble drugs.²¹

Compritol 888 ATO was used as a release modifier by Patere et al. to retard the release of highly water-soluble drugs, metoprolol succinate (MPL). Different ratios of Compritol 888 ATO were used and the effect of various formulations were evaluated in sustaining release of MPL. Stability studies showed no significant difference in MPL release profile after three months of storage period. The bioavailability of sustained release tablets was compared to the commercially available tablets, MetXL 50 in 12 healthy human volunteers in a crossover design. IVIVC correlation was obtained by deconvoluting the plasma concentration-time curve using a model independent Wagner-Nelson method. Correlations of fraction of drug dissolved in vitro and fraction of drug absorbed in vivo showed a significant linear relationship for sustained release tablets of MPL.²²

Compritol 888 ATO was combined with pH-sensitive polymer Eudragit S 100 to prepare novel lipid-polymer composite microspheres, which were capable of delivering and maintaining high level of 10-hydroxycampothecin in the colon. Results of in vivo bioavailability study of lipid-polymer microspheres in comparison with conventional enteric microspheres revealed that the systemic absorption of 10-hydroxycampothecin from lipid-polymer microsphere was significantly less than that of enteric microspheres. From this study it can be concluded that more drugs can be delivered to the colon from the Compritol 888 ATO- polymer microspheres which may improve the efficiency of treatment by diminishing the side effects of drugs.²³

Solid lipid microparticles (SLMs) loaded with sunscreen agent octyldimethylaminobenzoate were prepared using Compritol 888 ATO as a lipid and Poloxamer 188 as an emulsifier employing melt dispersion technique. The microspheres exhibited satisfactory loading efficiency. Compritol 888 ATO lipid microparticles showed a marked decrease in the photo-induced decomposition of the active agent. This finding can be attributed to the ability of the lipid matrix of the particles to reflect and scatter UV radiations.²³

Cavallari et al. investigated the potential of using microspheres of Compritol 888 ATO with lidocaine embedded inside the mucoadhesive buccal patches to prolong and improve the buccal release of lidocaine. Lidocaine- Compritol 888 ATO microspheres were prepared by spray-congealing process, using a wide pneumatic nozzle and the patch was prepared by solvent-casting method, using various bio adhesives and film forming polymers. Result showed that incorporation of the drug within a lipophilic carrier (Compritol 888 ATO), prolonged the release of drug as it represented a second barrier to drug release.²⁴

Dynasan 114:

Wei et al. observed that use of Dynasan 114-based solid lipid nanoparticles (SLNs) nanoparticles can be a promising way to improve the bioavailability of water-insoluble drugs. Dynasan 114 nanoparticles of loperamide (LPM) and sodium cholate as a stabilizer were prepared using modified solvent evaporation techniques. Two batches of LPM loaded SLNs LPM-SLN-1 and LPM-SLN-2 were prepared with different lipid contents. In vitro release profile of LPM-SLN at pH 1.2 and 6.8 showed continuous release of LPM without any burst effect. The release profiles of LPM- SLN-1 and 2 were similar at pH 1.2 but different in pH 6.8. The release of the drug from LPM-SLN-1 was slower than that from LPM-SLN-2. The oral bioavailability was analysed using Wistar rats. The relative bioavailability was 227% and 153% respectively, as compared to that of the LPM tablets.²⁵

Bertoni et al. demonstrated potential use of Dynasan 114 based solid lipid microparticles (SLMs) for local intestinal treatment. SLMs with Dynasan 114 produced by spray congealing technology using glutathione (GSH) at 5% w/w and 20% w/w, showed 50% of GSH release in first 30mins followed by a plateau phase and slow decrease. Dynasan 114 based SLMs exhibited an excellent biocompatibility for intestinal HT-29 cells at concentrations up to 200 µg/ml. Thus, Dynasan 114 can be used for the encapsulation of biological antioxidant agents in solid lipid microparticles.²⁶

Glyceryl monooleate (GMO):

Lal et al. investigated glyceryl monooleate (GMO)/ Poloxamer 407 nanoparticles as a potential oral drug delivery system to enhance the bioavailability of the poorly water-soluble drug simvastatin. Simvastatin loaded nanoparticles were prepared through fragmentation of the GMO/Poloxamer 407 bulk cubic-phase gel using high pressure homogenization. When tested in beagle dogs, pharmacokinetic profile showed sustained plasma level of simvastatin for over 12 hours. In vitro release of simvastatin crystal showed over 90% release in 1 hour both in simulated gastric fluids and fasted-state simulated intestinal fluids, while in cubic nanoparticles showed <3% simvastatin release in the same media in 10 hrs. The relative oral bioavailability of simvastatin cubic nanoparticles calculated on basis of area under the curve was 241% compared to simvastatin crystal powder. The above results indicated that the cubic nanoparticles have the potential to be used to increase the oral bioavailability of highly lipophilic drugs.²⁷

Lim et al. investigated that the glyceryl monooleate lyotropic mixtures could enhance skin permeation from topical and transdermal formulations. Various phases of GMO/solvent systems containing sodium fluorescein were prepared. Propylene glycol and hexanediol were homogeneously dissolved in the melted GMO. Sodium fluorescein in aqueous solution was diluted to various ratios. Each GMO/solvent system with fluorescein was applied on to the epidermal side of excised pig skin and incubated overnight. The flux of sodium fluorescein was found to be 15.11µg/cm²h in cubic phase, 12.45µg/cm²h in lamellar phase and 8.23µg/cm²h in solution phase. Confocal laser scanning microscopy (CLSM) was performed to observe the distribution of fluorescein in the skin layers. It was observed that the cubic and lamellar phase formulations showed much stronger fluorescein in dermal layer and solution phase formulation was localized in stratum corneum layer.²⁸

Steluti et al. demonstrated that GMO at 10% w/w in propylene glycol significantly improved 5- aminolevulinic acid (ALA) skin delivery for photodynamic therapy (PDT) and can be effective in regression of skin tumours. Photosensitiser (protophorphyrin IX) based GMO/water cubic phase gels loaded with 5- ALA were prepared. In vitro permeation of 5-ALA through hairless mouse skin was found to be increased in presence of GMO in a concentration-dependent manner. The significant difference in flux values (P<0.05) was observed when comparing formulations containing GMO (10, 20, 30% w/w) with a control formulation (without GMO). The formulations when applied in vivo led to an accumulation of protophorphyrin IX in adequate amount.²⁹

Maisine CC:

Maisine CC could act as an absorption enhancer for in-situ forming vesicles for improving drug’s bioavailability. Novel spray dried lactose-based enhanced in situ forming vesicles (EIFV) of fexofenadine HCl were prepared using different absorption enhancer by slurry method. The cumulative percentage of the released drug after 3 hrs ranged from 55.68% to 88.19%. The pharmacokinetics and pharmacological effect of the fexofenadine-loaded optimized formulation showed a significant increase in blood concentration. The absorption half-life time of the optimized EIFV formulation was 1.75±0.41 h and for the marketed product was 2.39±0.36 h, which showed an increase in the AUC in the optimized formulation compared to the marketed product indicating higher oral bioavailability.³⁰

Precirol ATO 5:

Lipid based nanostructured carriers (NLCs) of idebenone (IDE) for delivery to brain were prepared by nanoprecipitation techniques. Precirol ATO 5 NLCs were prepared using Miglyol 840, Tween 80 and Labrasol. IDE NLCs showed an initial burst release of drug, approximately 4-21% of drug release in 0.1 N HCl during the first 2 hrs. Prolonged release in later phase was observed up to 24hrs. At the end of 24 hrs, drug release was 93.56±0.39%. Enhancement in bioavailability of drug was found to be 4.63-fold in plasma and 2.8-fold in brain over plain drug loaded aqueous dispersions.³¹

Effect and fate of lipid excipients in vivo:

Effect of lipid excipients in vivo:

The products of lipid digestion delay gastric emptying, and much pharmaceutical interest has focused on the relationship between gastric emptying, food ingestion, and the transit behaviour of non-disintegrating-controlled release dosage forms. The rate of dissolution for water insoluble drugs frequently turns into a factor limiting process in their fascination progress from GI tract.³² Although there is very little information as to how pharmaceutically relevant volumes of lipid impact on transit profiles, it is likely that any effect would not significantly impact the bioavailability of the co-administered drug.³³

The presence of lipids in the GI tract stimulates an increase in secretion of bile salts (BS) and endogenous biliary lipids including phospholipid (PL) and cholesterol (CH), leading to the formation of BS/PL/CH intestinal mixed micelles which increases the solubilization capacity.³⁴ Constituents of the mixed micellar phase can modify the intestinal permeability of poorly water-soluble compounds via three mechanisms. Firstly, the presence of lipid digestion products and bile salts may alter the intrinsic permeability of the intestinal membrane, leading to increased absorption via transcellular routes. Secondly, solubilisation of lipophilic drugs within bile salt mixed micelles may facilitate diffusion through the aqueous diffusion layer, improving absorption. Thirdly, drug solubilisation may decrease the intermicellar fraction of drug, which could potentially lead to a decrease in absorption.³⁴

Digestion of triglyceride lipids:

Several important steps in triglyceride digestion occur within the stomach. In normal adult humans, lipase activity is readily detected in the gastric fluid, appears to account for 10–30% of triglyceride hydrolysis. Lipase produced in serous glands at the base of the tongue or in acinar cells in pharyngeal tissue, swallowed along with the food bolus. Lingual lipase generating free fatty acids in the mouth and pharynx may play a role in gustatory fatty acid signalling. The lipase found in gastric fluid originate mainly within chief cells of the gastric mucosa. Secretion of gastric lipase can be stimulated by cholinergic agents, gastrin. Gastric lipase has a broad pH optimum (pH 2–6) and is resistant to pepsin and therefore active within the environment of the stomach. Gastric lipase emptied into the duodenum continues to be active within the environment of the small intestine, although pancreatic lipase is the enzyme responsible for most of the triglyceride hydrolysis. Gastric lipase preferentially hydrolyses the ester bond in the 3 position of triacylglycerol, generating mainly fatty acids and diglycerides.³⁵

Within the stomach, there is acid-peptic digestion of the protein component of food lipoproteins and liberation of oil droplets. The churning action of gastric contractions against the closed pylorus results in the formation of an emulsion containing small lipid particles (less than 2nm) that can then be emptied from the stomach into the duodenum. These small oil droplets with a large surface-to-volume ratio are the preferred substrate for the colipase –pancreatic lipase enzyme system that is responsible for the majority of triglyceride digestion in adults.³⁵

Enzymatic breakdown of lipids:

Short chain lipids showed higher degradation compared to the longer chain lipids.²⁶ Bile salts (0.21mM concentrations) have been proven to inhibit absorption and degradation by lipase, but they do not have any inhibitory effect on colipase.³⁷ A combination of longer chain fatty acid and non-ionic emulsifier was found to offer better stability.^36,37

The lipid-based carrier systems are generally found to be least toxic/nontoxic when administered by the oral, transdermal, intramuscular (i.m.), intravenous (i.v.), dermal, and subcutaneous routes. The use of physiological lipids in the compositions that can be easily metabolized by the body can lead to high biocompatibility.

CONCLUSIONS:

Lipid excipients can prove to be highly beneficial for improving bioavailability of poorly water-soluble drugs. They can be digested to safe by-products by body’s metabolic and enzymatic activity. Thus, suitable lipid excipients can open up new dimensions in design and development of oral, topical, transdermal or parenteral formulations. are one of the promising drug delivery systems that exhibits challenges like solubility and bioavailability of water-soluble drugs. Incorporation of lipids excipients in formulations can meet a wide range of product requirements like disease indication, route of administration, stability, toxicity, and efficacy.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 11.02.2021 Modified on 15.04.2021

Research J. Pharm. and Tech. 2022; 15(5):2334-2338.

DOI: 10.52711/0974-360X.2022.00388