Skin Penetration and Permeation Properties of Transcutol® in Complex Formulations.

Percutaneous delivery is explored as alternative pathway for addressing the drawbacks associated with the oral administration of otherwise efficacious drugs. Short of breaching the skin by physical means, the preference goes to formulation strategies that augment passive diffusion across the skin. One such strategy lies in the use of skin penetration and permeation enhancers notably of hydroxylated solvents like propylene glycol (PG), ethanol (EtOH), and diethylene glycol monoethyl ether (Transcutol®, TRC). In a previous publication, we focused on the role of Transcutol® as enhancer in neat or diluted systems. Herein, we explore its' role in complex formulation systems, including patches, emulsions, vesicles, solid lipid nanoparticles, and micro or nanoemulsions. This review discusses enhancement mechanisms associated with hydroalcoholic solvents in general and TRC in particular, as manifested in multi-component formulation settings alongside other solvents and enhancers. The principles that govern skin penetration and permeation, notably the importance of drug diffusion due to solubilization and thermodynamic activity in the vehicle (formulation), drug solubilization and partitioning in the stratum corneum (SC), and/or solvent drag across the skin into deeper tissue for systemic absorption are discussed. Emphasized also are the interplay between the drug properties, the skin barrier function and the formulation parameters that are key to successful (trans)dermal delivery.

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

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.

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

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. Graphical Abstract Transcutol has affinity for the hydrophilic head groups of the stratum corneum structures.

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

Lipid-based formulations are a viable option to address modern drug delivery challenges such as increasing the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs), or sustaining the drug release of molecules intended for chronic diseases. Esters of fatty acids and glycerol (glycerides) and polyethylene-glycols (polyoxylglycerides) are two main classes of lipid-based excipients used by oral, dermal, rectal, vaginal or parenteral routes. These lipid-based materials are more and more commonly used in pharmaceutical drug products but there is still a lack of understanding of how the manufacturing processes, processing aids, or additives can impact the chemical stability of APIs within the drug product. In that regard, this review summarizes the key parameters to look at when formulating with lipid-based excipients in order to anticipate a possible impact on drug stability or variation of excipient functionality. The introduction presents the chemistry of natural lipids, fatty acids and their properties in relation to the extraction and refinement processes. Then, the key parameters during the manufacturing process influencing the quality of lipid-based excipients are provided. Finally, their critical characteristics are discussed in relation with their intended functionality and ability to interact with APIs and others excipients within the formulation.