Extemporaneous preparation strategy for early phase clinical studies.

Extemporaneous preparations (EPs) of investigational drugs, which are compounded at the clinical study site by a pharmacist, are being increasingly used in early phase clinical studies to accelerate the development of new medicines. The successful application of EP strategies in clinical studies requires 'fit-for-purpose' formulation design and preparation processes, as well as administration procedures that are safe, flexible, cost-effective, and simple to adapt by a compounding pharmacist at the clinical site. DNS-7801 is a weakly basic investigational compound that exhibits a higher aqueous solubility at lower pH with its solubility dropping off precipitously with increase in pH. This phenomenon is known to result in potential risk of variable and decreased exposure in vivo. Combination of citrate buffer at pH 3.0 and hydroxypropylbetadex enabled formulation of DNS-7801 solutions that were stable as formulated and up on manipulation for oral administration. The solutions were compatible with apple juice, used to mask (blind) the potential taste differences between the placebo and DNS-7801 solutions when dosing study subjects. The oral administration of the solutions resulted in dose proportional Cmax, AUC0-24, and AUC0-∞ of DNS-7801 in non-elderly and elderly subjects. A key advantage of the use of an EP approach with DNS-7801 was the flexibility in dose selection that this approach offered because DNS-7801 concentration in the preparation and/or volume could be readily adjusted based on real-time cohort data.

Gelatin and Non-Gelatin Capsule Dosage Forms.

Capsules offer an alternate to tablets for oral delivery of therapeutic compounds. One advantage of capsules over tablets is their amenability to deliver not only solids but also nonaqueous liquids and semisolids as a unit dose solid dosage form. Shell component is an essential part of capsule dosage forms. Capsule shells, available as hard or soft shells, are formulated from gelatin or a non-gelatin polymeric material such as hypromellose and starch, water, and with or without a nonvolatile plasticizer. The capsule shells may also be formulated to modify the release of their fill contents in a site-specific manner in the gastrointestinal tract. The goal of the current review is to provide an in-depth discussion on polymeric film-forming materials and manufacturing technologies used in the production of capsule shells.

Polyethylene glycols in oral and parenteral formulations--A critical review.

Polyethylene glycols (PEGs) are frequently employed as vehicles in oral and parenteral dosage forms. PEGs have low toxicity, are miscible with aqueous fluids in all proportions, and dissolve many poorly aqueous soluble compounds. Compounds with poor aqueous solubility and resulting poor bioavailability and considerable individual variability in the absorption were shown to provide exceptionally high bioavailability and reduced inter-subject variability in plasma concentrations when dosed as solutions or suspensions in PEGs. The advantages offered by PEGs, however, are not without potential challenges that must also be considered and which are the focus of this review. First, PEGs often may have high solubilizing power for some poorly aqueous soluble compounds, the high affinity of these vehicles for water can potentially lead to precipitation of the dissolved compounds when the formulations encounter an aqueous environment in vitro or in vivo, resulting in reduced bioavailability of the compounds. Second, PEGs, due to the presence of hydroxyl groups in their structures, are reactive with compounds dissolved within, resulting in the formation of degradation products. Third, PEGs, due to the presence of recurring ether groups in their polymer chains, are also inherently susceptible to autooxidative reactions, resulting in the formation of highly reactive products, which degrade several compounds formulated with PEGs. The objective is to review the applications and limitations of PEGs in pharmaceutical dosage forms and discuss solutions to mitigate challenges that may potentially arise from their use.

Development of ALZET® osmotic pump compatible solvent compositions to solubilize poorly soluble compounds for preclinical studies.

CONTEXT: Hydrophilic, non-aqueous solvents are frequently used to solubilize poorly water soluble compounds for use in ALZET® osmotic pumps used during the discovery and preclinical stages. Though these solvents exhibit the potential to solubilize several poorly soluble compounds, the solubilized compounds are prone to crystallization up on contact with aqueous fluids in vitro and in vivo. Crystallization of a compound can potentially cause pain at the release site, erratic blood levels, and uneven or delayed pharmacokinetic profiles. OBJECTIVE: In this study, we discussed the development of ALZET® pump compatible hydrophilic, non-aqueous vehicles that solubilized two poorly soluble model compounds (ELND006 and ELN 481594) and prevented their crystallization from solutions in vitro and in vivo. METHODS: The selected formulations were filled into the pumps at three concentrations for each model compound and investigated for their compatibility with the pumps and the subcutaneous tissue of mice where the pump was inserted. RESULTS AND DISCUSSION: The results showed that the formulations were stable physically with no crystallization and chemically with no degradation and were compatible with the pump and animal tissue. The plasma concentration of ELND006 decreased with time at each dose. The extent of the time-dependent decrease in ELND006 plasma levels increased as the amount of dose delivered increased. This time and dose dependent decrease in ELND006 plasma concentrations was attributed to the known auto-induction of hepatic enzymes by the compound. In contrast, the plasma concentration of ELN 481594 increased significantly at higher dose, likely due to accumulation of the compound.

A formulation strategy for gamma secretase inhibitor ELND006, a BCS class II compound: development of a nanosuspension formulation with improved oral bioavailability and reduced food effects in dogs.

ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimer's disease. ELND006 shows poor solubility and has moderate to high permeability, suggesting it is a Biopharmaceutics Classification System Class II compound. The poor absolute oral bioavailability of the compound in fasted dogs (F ∼11%) is attributed to poor aqueous solubility. In addition, inhibiting amyloid precursor protein but not Notch cleavage is an important goal for gamma secretase inhibitors; therefore, significant variation in bioavailability resulting from food consumption is a potential liability for this class of compounds. The objective of the present study was to determine if an ELND006 nanocrystalline formulation would offer improved and predictable pharmacokinetics. ELND006 was formulated as a nanosuspension with a mean particle size of less than 200 nm, which was stable in particle size and crystallinity for over 1 year. In addition, ELND006 nanosuspension exhibited rapid dissolution in comparison with reference active pharmaceutical ingredient (API). The in vivo performance of the ELND006 nanosuspension was tested in fed and fasted beagle dogs and compared with a gelatin capsule containing reference API. The results show that nanosizing ELND006 profoundly improved the oral bioavailability and virtually eliminated variation resulting from food intake.

Soft gelatin capsules (softgels).

It is estimated that more than 40% of new chemical entities (NCEs) coming out of the current drug discovery process have poor biopharmaceutical properties, such as low aqueous solubility and/or permeability. These suboptimal properties pose significant challenges for the oral absorption of the compounds and for the development of orally bioavailable dosage forms. Development of soft gelatin capsule (softgel) dosage form is of growing interest for the oral delivery of poorly water soluble compounds (BCS class II or class IV). The softgel dosage form offers several advantages over other oral dosage forms, such as delivering a liquid matrix designed to solubilize and improve the oral bioavailability of a poorly soluble compound as a unit dose solid dosage form, delivering low and ultra-low doses of a compound, delivering a low melting compound, and minimizing potential generation of dust during manufacturing and thereby improving the safety of production personnel. However, due to the very dynamic nature of the softgel dosage form, its development and stability during its shelf-life are fraught with several challenges. The goal of the current review is to provide an in-depth discussion on the softgel dosage form to formulation scientists who are considering developing softgels for therapeutic compounds.