Enhanced bioavailability of poorly absorbed hydrophilic compounds through drug complex/in situ gelling formulation.

BCS class III hydrophilic compounds are often associated with low oral bioavailability due to their poor epithelial permeability in the gastrointestinal tract. In this study, we reported an approach of incorporating a drug complex into an in situ gelling muco-adhesive carrier to achieve an improved bioavailability of a poorly absorbed hydrophilic compound. A new molecular entity (RWJ-445167) from Johnson and Johnson was used as a model compound. The compound was first complexed with sodium lauryl sulfate (SLS). The complex was then incorporated into an in situ gelling muco-adhesive carrier Cremophor for formulation characterization and rat pharmacokinetic (PK) studies. The study results showed that RWJ-445167 bound to SLS at a stoichiometric ratio. By complexing with SLS, the compound became lipophilic. The aqueous solubility of RWJ-445167 dropped to 0.58 mg/mL for the complex from 61 mg/mL for the free compound, while the partitioning coefficient of the complex increased to 7.59, compared with 0.05 of the free compound. In the rat PK study, with duodenal administration, the complex in the in situ-gelling formulation achieved 28.24% of bioavailability, compared to 4.26% of the free compound solution. The enhanced bioavailability was also significantly higher than those in the RWJ-445167/SLS physical mixture in Cremophor (14.91%), the complex in non-gelling carrier PEG 400 (9.95%) and the RWJ-445167/SLS physical mixture in PEG 400 carrier (8.60%). The study demonstrates that incorporation of a drug complex into an in situ gelling formulation provides a new approach to improving bioavailability of BCS class III drugs.

Enhanced bioavailability of a poorly water-soluble weakly basic compound using a combination approach of solubilization agents and precipitation inhibitors: a case study.

Poorly water-soluble weakly basic compounds which are solubilized in gastric fluid are likely to precipitate after the solution empties from the stomach into the small intestine, leading to a low oral bioavailability. In this study, we reported an approach of combining solubilization agents and precipitation inhibitors to produce a supersaturated drug concentration and to prolong such a drug concentration for an extended period of time for an optimal absorption, thereby improving oral bioavailability of poorly water-soluble drugs. A weakly basic compound from Johnson and Johnson Pharmaceutical Research and Development was used as a model compound. A parallel microscreening precipitation method using 96-well plates and a TECAN robot was used to assess the precipitation of the tested compound in the simulated gastric fluid (SGF) and the simulated intestinal fluid (SIF), respectively, for lead solubilizing agents and precipitation inhibitors. The precipitation screening results showed vitamin E TPGS was an effective solubilizing agent and Pluronic F127 was a potent precipitation inhibitor for the tested compound. Interestingly, the combination of Pluronic F127 with vitamin E TPGS resulted in a synergistic effect in prolonging compound concentration upon dilution in SIF. In addition, HPMC E5 and Eudragit L100-55 were found to be effective precipitation inhibitors for the tested compounds in SGF. Furthermore, optimization DOE study results suggested a formulation sweet spot comprising HPMC, Eudragit L 100-55, vitamin E TPGS, and Pluronic F127. The lead formulation maintained the tested compound concentration at 300 µg/mL upon dilution in SIF, and more than 70% of the compound remained solubilized compared with the compound alone at <1 µg/mL of its concentration. Dosing of the solid dosage form predissolved in SGF in dogs resulted in 52% of oral bioavailability compared to 26% for the suspension control, a statistically significant increase (p = 0.002). The enhanced oral bioavailability of the tested compound could be attributed to generation and prolongation of a supersaturated drug concentration in vivo by the solubilizing agents and precipitation inhibitors. The study demonstrates that the combination approach of solubilization agents and precipitation inhibitors provides improved oral bioavailability for a poorly water-soluble weakly basic compound.

Combination of Pluronic/Vitamin E TPGS as a potential inhibitor of drug precipitation.

In this study, we screened surfactants and their combinations at low concentrations as potentially potent inhibitors of drug precipitation in an aqueous medium. Nine surfactants (including Pluronic F127, Pluronic F108, and Pluronic F68) were evaluated at concentrations below their critical micelle concentrations (CMCs) using an in vitro precipitation assay. A model compound used in this study showed a sharp pH-dependent solubility profile and was much more soluble in simulated gastric fluid (SGF) (pH 1.2) than in simulated intestinal fluid (SIF) (pH 7.4). The compound was first dissolved in SGF with each surfactant, and the solutions were dispensed into the wells of a 96-well microtiter plate by a TECAN robot and diluted 10-fold with SIF. After a preset incubation time at room temperature, the solutions were filtrated through a 96-well filter plate, and the compound concentration in the filtrate was measured using an HPLC method. At concentrations below their CMCs, Pluronic F127 and Pluronic F108, but not Pluronic F68, inhibited the compound precipitation in SIF. Combinations of Pluronic F127 or Pluronic F108 with Vitamin E TPGS showed significantly stronger inhibition than the individual surfactants, indicating synergistic effects on inhibition of drug precipitation.

Advanced screening assays to rapidly identify solubility-enhancing formulations: high-throughput, miniaturization and automation.

Development of solubility-enhancing formulations for poorly water-soluble compounds always poses a challenge. Conventional formulation screening assays are potentially time-consuming and labor-intensive and, moreover, require a large amount of a compound; they are not ideal when compound availability and testing time are limited. In recent years, in-vitro screening assays that are rapid, inexpensive, minimally labor-intensive, and require only small quantities of a compound have become available. These advanced assays allow high-throughput automation, miniaturization, and parallel processing, thereby enabling scientists to rapidly identify solubility-enhancing formulations with milligram or sub-milligram quantities of an active pharmaceutical ingredient (API). This article reviews these assays for rapidly screening the aqueous solubility of lead compounds and the solubility-enhancing formulations with limited quantities of API.

Evaluation of drug precipitation of solubility-enhancing liquid formulations using milligram quantities of a new molecular entity (NME).

A precipitation screening method using a 96-well microtiter plate was developed to evaluate in vitro drug precipitation kinetics of liquid formulations for poorly water-soluble compounds, using milligram quantities of compounds and milliliter volumes of biorelevant media. By using this method we identified three formulations showing distinct in vitro precipitation kinetics (fast, slow, and no precipitation) for a model new molecular entity (JNJ-25894934). The in vitro precipitation profiles in simulated intestinal fluid (SIF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) were compared with those measured by a USP dissolution method, and with in vivo absorption at the fasted and fed states in canine pharmacokinetic (PK) studies. The precipitation kinetics of all three formulations in the initial hours measured by the screening method correlated to those determined by the USP method (R(2) = 0.96). The PK results showed that the fast-precipitation formulation had the lowest bioavailability. However, a similar bioavailability was observed for the slow- and no-precipitation formulations. The oral bioavailability of JNJ-25894934 at the fed state was also significantly higher than that at the fasted state for all three formulations (p < 0.05). In addition, the in vitro precipitation profiles in FeSSIF correlated better with in vivo absorption than those in SIF and FaSSIF.

Nanosizing of a drug/carrageenan complex to increase solubility and dissolution rate.

In this study, we present a novel approach of nanosizing a drug/polymeric complex to increase both solubility and dissolution rate of poorly water-soluble compounds. A hydrophilic polymer, lambda-carrageenan, was first complexed with a model poorly water-soluble compound to increase the compound's aqueous solubility. The compound/carrageenan complex was further nanosized by wet-milling to enhance the dissolution rate. By complexing with carrageenan, the compound became amorphous in the complex. Using additional carrageenan as a stabilizer for nanosizing, a nanosuspension of a compound/carrageenan complex with a median particle size of about 0.3 microm was successfully developed. The particle size of the nanosuspension did not increase significantly during the lyophilization process and was stable for at least 39 days at room temperature after lyophilization. This approach of nanosizing a drug/carrageenan complex increased the aqueous solubility of the compound from less than 1 microg/mL to 39 microg/mL. In addition to increasing aqueous solubility, a nanosized compound/carrageenan complex had a faster dissolution rate than the complex, the free compound, and the nanosuspension of the free compound.

Characterization of physiochemical and biological properties of an insulin/lauryl sulfate complex formed by hydrophobic ion pairing.

An insulin/lauryl sulfate complex was prepared by hydrophobic ion pairing (HIP). The physiochemical and biological properties of the HIP complex were characterized using octanol/water partition measurement, isothermal titration calorimetry (ITC), ultraviolet-circular dichroism (UV-CD) and Fourier transform infrared spectroscopy (FTIR). Sodium dodecyl sulfate (SDS) bound to the insulin in a stoichiometric manner. The formed complex exhibited lipophilicity, and its insulin retained its native structure integrity. The in vivo bioactivity of the complex insulin was evaluated in rats by monitoring the plasma glucose level after intravenous (i.v.) injection, and the glucose level was compared with that for free insulin. The pharmacodynamic study result in rats showed that the complex insulin had in vivo bioactivity comparable to free insulin.

Parallel screening approach to identify solubility-enhancing formulations for improved bioavailability of a poorly water-soluble compound using milligram quantities of material.

In this article, we present a parallel experimentation approach to rapidly identify a solubility-enhancing formulation that improved the bioavailability of a poorly water-soluble compound using milligrams of material. The lead compound and a panel of excipients were dissolved in n-propanol and dispensed into the wells of a 96-well microtiter plate by a TECAN robot. Following solvent evaporation, the neat formulations were diluted with an aqueous buffer, and incubated for 24h. The solubilization capacity of the excipients for the compound at 24h (SC(24h)), was determined by HPLC, and compared with its solubility in the corresponding neat formulations determined by a bench-scale method. The ranking order of solubilization capacity of the five tested formulations for this compound by this microscreening assay is same as the ranking order of the compound solubility in the neat formulations. Several formulations that achieved the target aqueous solubility were identified using the screening method. One of the top formulations, an aqueous solution of the compound containing 20% Tween 80 by weight, increased the compound solubility from less than 2 microg/mL to at least 10mg/mL. In a rat pharmacokinetic (PK) study, the Tween 80 formulation achieved 26.6% of bioavailability, a significant improvement over 3.4% of bioavailability for the aqueous Methocel formulation (p<0.01). The results in the study suggest that this parallel screening assay can be potentially used to rapidly identify solubility-enhancing formulations for an improved bioavailability of poorly water-soluble compounds using milligram quantities of material.