Lipid-containing formulations

Abstract The major enzymatic barrier to the absorption of macromolecules, particularly therapeutic peptides, is the pancreatic enzymes the peptidases, nucleases, lipases and esterases that are secreted in considerable quantities into the intestinal lumen and rapidly hydrolyse macromolecules and lipids. In the case of the peptidases, they work in a co-ordinated fashion, whereby the action of the pancreatic enzymes is augmented by those in the brush borders of the intestinal cells. The sloughing-off of mucosal cells into the lumen also furnishes a mixture of enzymes that are a threat to macromolecules. As the specificity and activity of the enzymes are not always predictable, during pharmaceutical development it is important to test the stability of therapeutic macromolecules, and novel macromolecular-containing or lipid-containing formulations, in the presence of mixtures of pancreatic enzymes and bile salts, or in animal intestinal washouts or ideally, aspirates of human intestinal contents. 

As detailed in Part I, the two most important mechanisms that give rise to chemical instability of the components in lipid-based formulations are hydrolysis (for those components containing ester bonds) and oxidation (for unsaturated lipids and oxygen labile cosolvents and surfactants, for example, PEG 400 and LabriLfl/12125 CS). The use of PEG-based surfactants and unsaturated lipids in lipid-based formulations make lipid peroxidation especially likely. While the products of lipid peroxidation can give rise to drug instability, a chief concern is that aldehyde products can... 

In the case of amorphous systems, absence of crystallinity upon tableting or over the shelf-life of the product must be ascertained to avoid potential slow down in dissolution, reduction in bioavailability, and loss of elegance. For lipid containing products, minimizing oxidation during manufacture and storage must be planned for by processing under inert conditions and incorporation of antioxidants in the formulation. ... 

The simplest lipid-based formulations contain only one excipient such as Gelucire 44/14, oleic acid, o -tocopherol, corn oil, peanut oil, sesame oil, medium-chain triglyceride, or medium-chain mono- and diglycerides. There are at least 10 commercially available one-lipid excipient oral formulations, and they all happen to be in soft capsules. 

The next level of complexity in lipid-based formulations is those that contain two excipients. Some typical combinations are sesame oil with a-tocopherol, medium-chain triglyceride with ethanol, and propylene glycol esters of fatty acids with glyceryl monooleate. There are at least 6 commercially available oral formulations with two lipid excipients. 

Ascending the level of complexity of lipid-based formulations are those that contain mixtures of three excipients. Typical examples of such combinations include 1) medium-chain triglycerides, PEG, and PG 2) TPGS, PEG 400, and PG 3) oleic acid, cremophor EL, and ethanol or PG 4) Polysorbate 20, PEG... 

The next level of complexity of lipid-based formulations currently marketed contain mixtures of four excipients, which can be SEDDS formulations or mixtures such as beeswax, soybean oil, hydrogenated vegetable oils and hydrogenated soybean oil. There are at least two commercially available four-excipient lipid-based oral formulations and both are delivered in soft gelatin capsules. Aptivus soft gelatin capsule (tipranavir) is a SEDDS formulation with ethanol and PG as the polar solvents, cremophor EL as the surfactant, and medium-chain mono-and-diglycerides as the oily phase. 

The highest level of complexity of lipid-based formulations in currently marketed products can be illustrated by three cyclosporin A products, which contain mixtures of five or six excipients and are microemulsion preconcentrates. Gengraf , Neoral , and Sandimmune soft gelatin capsules are all stored at room temperature. 

After intraperitoneal injection into a murine disseminated peritoneal tumor model, however, folate lipoplex formulations produced an approximately 10-fold increase in tumor-associated gene expression, compared with conventional complex [68]. When gene expression was measured in tumors and various peritoneal organs after intraperitoneal administration, the highest gene expression was observed in tumor cell ascites, followed by solid tumors. Thus, intraperitoneal administration of the folate-PEG-lipid-containing liposome complex may be more suitable for peritoneal dissemination. 

In the case of edible composite films and coatings containing a biopolymer and a lipid, the formulation requires to heat the lipid above its melting point, to homogenate both phases, degas, and cast on the plate or product surface, with the final evaporation of the solvent (Krochta, 2002). Some drying methods that have been studied include... 

Figure 2 Optimization of the cationic lipidxolipid ratio in vitro. Variable molar (in nucleotides) amounts of plasmid DNA containing a reporter gene (p-galactosidase) were mixed with the cationic lipid GL67 formulated with different mole ratios (boxes) of the neutral lipid dioleoylphosphatidylethanolamine (DOPE) and used to transfect CFTl epithelial cells in a 96-well plate. Expression levels were determined 2 days later, and indicate an optimal ratio of GL67 DOPE 1 2 (mohmol).

Functional Nail-Care Products. Cuticle removers are solutions of dilute alkaHes that faciHtate removal, or at least softeniag, of the cuticle. Formulations containing as much as 5% potassium hydroxide have been reported. Such preparations may contain about 10% glycerine to reduce dryiag, and thickeners, such as clays, to reduce mnoff Lipids and other conditioners are iacluded to reduce damage to tissues other than the cuticle. 

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