Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics

The low water solubility of pharmacoactive molecules limits their pharmacological potential, but the solubility parameter cannot compromise, and so different approaches are employed to enhance their bioavailability. Pharmaceutically active molecules with low solubility convey a higher risk of failure for drug innovation and development. Pharmacokinetics, pharmacodynamics, and several other parameters, such as drug distribution, protein binding and absorption, are majorly affected by their solubility. Among all pharmaceutical dosage forms, oral dosage forms cover more than 50%, and the drug molecule should be water-soluble. For good therapeutic activity by the drug molecule on the target site, solubility and bioavailability are crucial factors. The pharmaceutical industry’s screening programs identified that around 40% of new chemical entities (NCEs) face various difficulties at the formulation and development stages. These pharmaceuticals demonstrate less solubility and bioavailability. Enhancement of the bioavailability and solubility of drugs is a significant challenge in the area of pharmaceutical formulations. According to the Classification of Biopharmaceutics, Class II and IV drugs (APIs) exhibit poor solubility, lower bioavailability, and less dissolution. Various technologies are discussed in this article to improve the solubility of poorly water-soluble drugs, for example, the complexation of active molecules, the utilization of emulsion formation, micelles, microemulsions, cosolvents, polymeric micelle preparation, particle size reduction technologies, pharmaceutical salts, prodrugs, the solid-state alternation technique, soft gel technology, drug nanocrystals, solid dispersion methods, crystal engineering techniques and nanomorph technology. This review mainly describes several other advanced methodologies for solubility and bioavailability enhancement, such as crystal engineering, micronization, solid dispersions, nano sizing, the use of cyclodextrins, solid lipid nanoparticles, colloidal drug delivery systems and drug conjugates, referring to a number of appropriate research reports.

Solid-Lipid Nanoparticles

Solid-lipid nanoparticles are used for organized and specific targeting in drug delivery. They are biocompatible and biodegradable and have an average particle size ranging from 50 nm and 1000 nm. They comprise a solid hydrophobic phospholipid coating. This coating consists of a lipid matrix that must be at room temperature in solid form, which is dispersed in H2 O or an aqueous surfactant solution. Solid cores containing the drug are dispersed in the lipid matrix. They are likely to transport both hydrophobic and hydrophilic drugs. Table 8 represents various examples of drugs developed by using SLN technology. Table 9 lists some examples of the frequently used lipid excipients in lipid-based nanocarriers.

Examples of various drugs developed by SLN technology

Drug	Lipid Utilized	Biopharmaceutical Application
5-Fluoro uracil	Dynasan 114 and Dynasan 118	Prolonged release in simulated colonic media
Ibuprofen	Stearic acid, triluarin and tripalmitin	Stable formulation with low toxicity
Apomorphine	Glycerylmonostearate, polyethylene glycol monostearate	Enhanced bioavailability in rats
Idarubicin	Emulsifying wax	Delivery of oral proteins
Calcitonin	Trimyristin	Improvement of the efficacy of proteins
Lopinavir	Compritol 888 ATO	Bioavailability enhanced
Clozapine	Trimyristin, tristearin and tripalmitin	Improvement of bioavailability
Nimesulide	Glycerylbehanate, glyceryltristearate, palmitostearate	Sustained release of the drug
Cyclosporin A	Glycerylmonostearate and glycerylpalmitostearate	Controlled release
Progesterone	Monostearin, oleic acid and stearic acid	Potential for oral drug delivery
Gonadotropin release hormone	Monostearin	Prolonged release
Repaglinide	Glycerylmonostearate and tri stearin	Reduced toxicity

Lipid excipients are frequently used in lipid-based nanocarriers

Excipient	Chemical	Type of Carrier	Comments	References
Soybean oil	Triglycerides (longchain)	Nanoemulsions	Liquid, good biocompatibility, minimal physiological impact, weak solubilizing capacity	[125–127]
Olive oil	Triglycerides (long-chain)	Nanoemulsions	Liquid, healthy, high monounsaturated fatty acids, and simple to emulsify	[126,128–131]
Hemp oil	Medium/long-chain triglycerides blended with low-molecular weight lipids	Nanoemulsions	The liquid contains tocopherols, tocotrienols, phyrosterols, phospholipids, and other important fatty acids, good hydrophilicity, and self-emulsifiability.	[132,133]
Caprylic/capric triglycerides	Triglycerides (medium-chain)	Nanoemulsions	Liquid, solubilizing capacity, compatible with other lipids, easy to emulsify.	[134–139]
Captex® Series	Triglycerides (medium-chain)	Nanoemulsions	Liquid, fine solubilizing and emulsifying capacities, miscible with other lipids	[140–142]
Capmul MCM	Mono/diglycerides (medium-chain)	Nanoemulsions	Liquid, an excellent solvent powder for many organic compounds, can use as an emulsifier.	[143–146]
Capmul MCM C8	Glycerol monocaprylate Nanoemulsions	Nanoemulsions	Liquids, property similar to that of Capmul MCM.	[147–149]
MaisineTM 35-1	Glycerol monolinoleate	SEDDS	Liquid, solubilizer, bioavailability enhancer, oil phase in SEDDS	[150–153]
PeceolTM	Glyceryl monolete	SEDDS; NLCs; Cubosomes	Liquid, lipid dispersion agent, oil-soluble surfactant, moisturizer	[154–156]
Lauroglycol® 90	Propylene glycol monolaurate	Nanoemulsions; SEDDS; NLCs	Liquid, water-insoluble surfactant of SEDDS, solubilizer, bioavailability enhancer, skin penetration solubilizer enhancer.	[157–159]

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Bhalani, D.V.; Nutan, B.; Kumar, A.; Singh Chandel, A.K. Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics. Biomedicines 2022, 10, 2055. https://doi.org/10.3390/biomedicines10092055

excipients formulation