Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics

Many gaps exist in our understanding of species differences in gastrointestinal (GI) fluid composition and the associated impact of food intake and dietary composition on in vivo drug solubilization. This information gap can lead to uncertainties with regard to how best to formulate pharmaceuticals for veterinary use or the in vitro test conditions that will be most predictive of species-specific in vivo oral product performance. To address these challenges, this overview explores species-specific factors that can influence oral drug solubility and the formulation approaches that can be employed to overcome solubility-associated bioavailability difficulties. These discussions are framed around some of the basic principles associated with drug solubilization, reported species differences in GI fluid composition, types of oral dosage forms typically given for the various animal species, and the effect of prandial state in dogs and cats. This basic information is integrated into a question-and-answer section that addresses some of the formulation issues that can arise in the development of veterinary medicinals.

Preparation and Optimization of Garlic Oil/Apple Cider Vinegar Nanoemulsion Loaded with Minoxidil to Treat Alopecia

Alopecia areata is a scarless, localized hair loss disorder that is typically treated with topical formulations that ultimately only further irritate the condition. Hence, the goal of this study was to develop a nanoemulsion with a base of garlic oil (GO) and apple cider vinegar (APCV) and loaded with minoxidil (MX) in order to enhance drug solubilization and permeation through skin. A distance coordinate exchange quadratic mixture design was used to optimize the proposed nanoemulsion. Span 20 and Tween 20 mixtures were used as the surfactant, and Transcutol was used as the co-surfactant. The developed formulations were characterized for their droplet size, minoxidil steady-state flux (MX Jss) and minimum inhibitory concentration (MIC) against Propionibacterium acnes. The optimized MX-GO-APCV nanoemulsion had a droplet size of 110 nm, MX Jss of 3 μg/cm2 h, and MIC of 0.275 μg/mL. The optimized formulation acquired the highest ex vivo skin permeation parameters compared to MX aqueous dispersion, and varying formulations lacked one or more components of the proposed nanoemulsion. GO and APCV in the optimized formulation had a synergistic, enhancing activity on the MX permeation across the skin membrane, and the percent permeated increased from 12.7% to 41.6%. Finally, the MX-GO-APCV nanoemulsion followed the Korsmeyer–Peppas model of diffusion, and the value of the release exponent (n) obtained for the formulations was found to be 1.0124, implying that the MX permeation followed Super case II transport. These results demonstrate that the MX-GO-APCV nanoemulsion formulation could be useful in promoting MX activity in treating alopecia areata.

Supersaturation and Solubilization upon In Vitro Digestion of Fenofibrate Type I Lipid Formulations: Effect of Droplet Size, Surfactant Concentration and Lipid Type

Lipid-based formulations (LBF) enhance oral drug absorption by promoting drug solubilization and supersaturation. The aim of the study was to determine the effect of the lipid carrier type, drop size and surfactant concentration on the rate of fenofibrate release in a bicarbonate-based in vitro digestion model. The effect of the lipid carrier was studied by preparing type I LBF with drop size ≈ 2 µm, based on medium-chain triglycerides (MCT), sunflower oil (SFO), coconut oil (CNO) and cocoa butter (CB). The drop size and surfactant concentration effects were assessed by studying MCT and SFO-based formulations with a drop size between 400 nm and 14 µm and surfactant concentrations of 1 or 10%. A filtration through a 200 nm filter followed by HPLC analysis was used to determine the aqueous fenofibrate, whereas lipid digestion was followed by gas chromatography. Shorter-chain triglycerides were key in promoting a faster drug release. The fenofibrate release from long-chain triglyceride formulations (SFO, CNO and CB) was governed by solubilization and was enhanced at a smaller droplet size and higher surfactant concentration. In contrast, supersaturation was observed after the digestion of MCT emulsions. In this case, a smaller drop size and higher surfactant had negative effects: lower peak fenofibrate concentrations and a faster onset of precipitation were observed. The study provides new mechanistic insights on drug solubilization and supersaturation after LBF digestion, and may support the development of new in silico prediction models.

Drug Solubilization by Surfactants: Experimental Methods and Theoretical Perspectives

: This mini review will give an insight into the need and usefulness of investigating the solubilization of poorly soluble drugs. Commonly used experimental and theoretical models are outlined to study the efficacy of the carrier or excipient for the poorly soluble drugs. Furthermore, the use of surface active agents for drug solubilization is discussed in correlation with the mathematical models suggested from time to time. A few experimental techniques are also discussed which would be very helpful in elucidating the interactions prevailing in the mixed systems of poorly soluble drugs and surface active agents.

Possibilities of microemulsion application in rectal administration of indomethacin

Rectal administration is a suitable route of administration for drugs that are either very irritating to the intestine (e.g., indomethacin) or are more effective when the first-pass effect in the liver is circumvented. Microemulsions are a tool for the improvement of penetration of sparingly soluble drugs. They are mainly used in topical and transdermal drug delivery. However, they find application also in other routes of administration, mainly due to their ability to solubilize sparingly soluble drugs. The selection of a suppository base depends on the physical properties of the drug. The study focused on evaluating the effect of the microemulsion as the solubilizer of sparingly soluble indomethacin in hydrophilic and lipophilic suppository bases compared with Polysorbate 80 as the excipient contained in the microemulsion. The reference suppositories were prepared by the traditional moulding technique from Adeps solidus or Macrogol suppository base without the previous drug solubilization. The microemulsion-based suppositories were prepared after the initial solubilization of the drug in the microemulsion or Polysorbate 80, followed by the addition of suppository base to maintain the same drug/solubilizer ratio. The suppositories were tested for softening time, hardness, and uniformity of mass. The dissolution test was performed using the dialysis tubing method in the basket apparatus. The amount of indomethacin released into the dissolution medium was determined spectrophotometrically at 320 nm. The results indicate that solubilization of indomethacin in the microemulsion had a positive effect on in vitro drug release but not as significant as in the case of Polysorbate 80 used alone. The enhancement ratio for Polysorbate 80 in Adeps suppositories was 2.9, for the microemulsion in Adeps suppositories was 1.1, and for Polysorbate 80 in Macrogol suppositories was 7.4 after 3 hours. The test of uniformity of mass had shown that all suppositories (reference, solubilizer-containing) are within the permitted limits. The softening time was reduced by adding the solubilizer to each type of suppository base.