Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies.

Solid lipid nanoparticles are at the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery, clinical medicine and research, as well as in other varied sciences. Due to their unique size-dependent properties, lipid nanoparticles offer the possibility to develop new therapeutics. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could be used for secondary and tertiary levels of drug targeting. Hence, solid lipid nanoparticles hold great promise for reaching the goal of controlled and site specific drug delivery and hence have attracted wide attention of researchers. This review presents a broad treatment of solid lipid nanoparticles discussing their advantages, limitations and their possible remedies. The different types of nanocarriers which were based on solid lipid like solid lipid nanoparticles, nanostructured lipid carriers, lipid drug conjugates are discussed with their structural differences. Different production methods which are suitable for large scale production and applications of solid lipid nanoparticles are described. Appropriate analytical techniques for characterization of solid lipid nanoparticles like photon correlation spectroscopy, scanning electron microscopy, differential scanning calorimetry are highlighted. Aspects of solid lipid nanoparticles route of administration and their biodistribution are also incorporated. If appropriately investigated, solid lipid nanoparticles may open new vistas in therapy of complex diseases.

https://www.ijpsonline.com/articles/solid-lipid-nanoparticles-a-modern-formulation-approach-in-drug-delivery-system.pdf

Solid lipid nanoparticles: a modern formulation approach in drug delivery system.

Oral lipid-based drug delivery systems – an overview

http://pharmaquest.weebly.com/uploads/9/9/4/2/9942916/development_of_solid_self-emulsifying_dds.pdf

Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms.

Approaches for the development of solid and semi-solid lipid-based formulations☆

A heightened interest in (trans)dermal delivery is in part driven by the need to improve the existing skin therapies and also the demand for alternative routes of administration, notably for pharmaceutical actives with undesirable oral absorption characteristics. The premise of delivering difficult actives to the skin or via the skin however is weighed down by the barrier function properties of the stratum corneum. Short of disrupting the skin by physical means, scientists have resorted to formulation with excipients known to enhance the skin penetration and permeation of drugs. A vehicle that has emerged over the years as a safe solubilizer and enhancer for a broad range of drug actives is the highly purified NF/EP grade of diethylene glycol monoethyl ether (DEGEE) commercially known as Transcutol®. Whereas numerous studies affirm its enhancing effect on drug solubilization, percutaneous absorption rate, and/or drug retention in the skin, there are few publications that unite the body of the published literature in describing the precise role and mechanisms of action for Transcutol®. In view of the current mechanistic understanding of skin barrier properties, this paper takes on a retrospective review of the published works and critically evaluates the data for potential misses due to experimental variables such as formulation design, skin model, skin hydration levels, and drug properties. The goal of this review is to mitigate the incongruence of the published works and to construct a unified, comprehensive understanding of how Transcutol® influences skin penetration and permeation.

/pdf/skin-penetration-and-permeation-properties-of-transcutol-3v36r9egn3.pdf

Skin Penetration and Permeation Properties of Transcutol®—Neat or Diluted Mixtures

Polyoxylglycerides and glycerides: Effects of manufacturing parameters on API stability, excipient functionality and processing

The importance of lipid-based formulations in addressing solubility and ultimately the bioavailability issues of the emerging drug entities is undeniable. Yet, there is scarcity of literature on lipid excipient chemistry and performance, notably in relation to oxidative stability. While not all lipid excipients are prone to oxidation, those with sensitive moieties offer drug delivery solutions that outweigh the manageable oxidative challenges they may present. For example, caprylocaproyl polyoxylglycerides help solubilize and deliver cancer drug to patients, lauroyl polyoxylglycerides enhance the delivery of cholesterol lowering drug, and sesame/soybean oils are critical part of parenteral nutrition. Ironically, excipients with far greater oxidative propensity are omnipresent in pharmaceutical products, a testament to the manageability of oxidative challenges in drug development. Successful formulation development requires awareness of what, where, and how formulation stability may be impacted, and accordingly taking appropriate steps to circumvent or meet the challenges ahead. Aiming to fill the information gap from a drug delivery scientist perspective, this review discusses oxidation pathways, prooxidants, antioxidants, and their complex interplay, which can paradoxically take opposite directions depending on the drug delivery system.

/pdf/oxidative-stability-in-lipid-formulations-a-review-of-the-caxuxou1.pdf

Jasmine Musakhanian

Papers

Approaches for the development of solid and semi-solid lipid-based formulations☆

Skin Penetration and Permeation Properties of Transcutol®—Neat or Diluted Mixtures

Polyoxylglycerides and glycerides: Effects of manufacturing parameters on API stability, excipient functionality and processing

Oxidative Stability in Lipid Formulations: a Review of the Mechanisms, Drivers, and Inhibitors of Oxidation

Fractionation by gel exclusion HPLC of proteins from acidic and alkaline extractions of Phaseolus beans