Lipid-based formulations, bioenhancers by nature

Oral bioavailability of drugs is often limited due to poor solubility and/or limited intestinal permeability. To overcome these issues numerous strategies have been developed, among which lipid-based formulations deserved a special place thanks to many benefits illustrated hereafter by selected examples. 

Addressing more challenges with an augmented range of bioenhancers

Gattefossé is a leading provider of lipid excipients and lipid-based drug delivery technologies. Pioneering in the field, with early concepts and patents, including the development of SEDDS (Self Emulsifying Drug Delivery System), Gattefossé continues to innovate with new excipients and applications. With strong expertise in the formulation of challenging drugs, we offer a complete portfolio of products for oral bioavailability enhancement. 

Unlocking oral bioavailability potential with lipid-based formulations 

Poor solubility, poor permeability, and pre-systemic elimination are factors that can limit absorption of some drugs. Lipid excipients have the capability to overcome these hurdles and to enhance oral bioavailability through different mechanisms:

• Lipid excipients solubilize a wide range of molecules. Drugs with limited water solubility have usually good solubility in lipid excipients, and many scientific publications highlight the high solubilizing capacity of lipid excipients. 
• Lipid-based formulations maintain drug in solubilized state throughout the digestion process. Upon action of enzymes and bile salts, the lipid-based formulation is digested and transformed in a series of colloidal structures: vesicles, mixed micelles, and crystalline lipid phases. They contribute to maintaining the drug in a solubilized state throughout the digestion process. Ultimately, fatty acids, monoglycerides and the drug partition out of the micelles and are absorbed.
• Medium chain fatty acid containing excipients favor intestinal permeation. The drugs whose absorption is limited by their permeation can advantageously be formulated with excipients derived from caprylic and capric acids such as Capryol^® 90, Labrafac™ MC60 or Labrasol^® ALF. The proposed mechanism of action is a combination of paracellular transport with the reversible opening of enterocytic tight junctions and transcellular transport due to membrane fluidization.
• Long chain fatty acid containing excipients favor lymphatic absorption. Drugs with high first-pass metabolism are best formulated with long chain fatty acid excipients such as Maisine^® CC and Peceol™ to enhance lymphatic absorption and hence bioavailability.
• Lipid-based formulations help mitigate food-effect. Food effect is a critical phenomenon that can occur, changing drastically the bioavailability of a drug when taken with food or drink. This phenomenon can be mitigated with lipid-based formulations, as upon ingestion they stimulate the secretion of bile and are digested similarly in fasted or fed states.

Getting inspired from marketed medicines

A review of marketed lipid-based formulations showed that soft gel capsules and oral solutions/suspensions are the predominant dosage forms, followed by hard gel capsules¹.

• Straightforward development with single excipient formulation in a softgel. This is the simplest development possible, when one single excipient can solubilize the entire therapeutic dose. The first case study to highlight is enzalutamide, which is soluble at 45 mg/mL in caprylocaproyl polyoxylglycerides, i.e. Labrasol². Therefore, this single excipient can solubilize the 40 mg dose in one capsule. The second example is dutasteride, whose therapeutic dose is 0.5 mg. It is soluble at about 20 mg/mL in mono and diglycerides of caprylic/capric acid, i.e. Labrafac™ MC60³. In another market reference, dutasteride is formulated in about 300 mg of propylene glycol monocaprylate, type II, i.e. Capryol® 90⁴ .
• Fast onset of action with oral solution/suspension. Celecoxib has advantageously been reformulated from a tablet to an oral suspension in the form of a lipid-based formulation (ethyl alcohol, glyceryl monocaprylate, lauroyl polyoxyl-32 glycerides, medium chain triglycerides, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil) for higher solubility and bioavailability and more effective treatment of acute migraine⁵. 
• Hard capsules for semi-solid and solid formulations. For semi-solid or solid formulations, capsule molding in a hard capsule is the easiest production process. Most famous examples consist in fenofibrate and ibuprofen formulated in the waxy self-emulsifying excipient lauroyl polyoxyl glycerides, i.e. Gelucire^® 44/14⁶. Another well-known example is isotretinoin, formulated as a SEDDS (stearoyl macrogol glycerides, soybean oil, sorbitan monooleate and propyl gallate). The viscous composition due to stearoyl macrogol glycerides, i.e. Gelucire^® 50/13, is poured in a hard capsule⁷.

¹ H. Bennett-Lenane, J.P. O'Shea, C.M. O'Driscoll, B.T. Griffin. J. Pharm. Sci. 109 (2020) 3248–3261
² https://www.tga.gov.au/sites/default/files/auspar-enzalutamide-141124.pdf
³ https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021319s032lbl.pdf
⁴ https://www.medicines.org.uk/emc/product/11305/smpc#PRODUCTINFO 
⁵ https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212157s000lbl.pdf 
⁶ Soraya Hengsawas Surasarang and Robert O. Williams. (2016), Co-solvent and Complexation Systems, Pages 215-256, in Formulating Poorly water-soluble drugs ISBN 2210-7371
⁷ https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021951s000lbl.pdf

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