Journal of pharmaceutical sciences最新文献

Biopharmaceutical Classification Systems (BCS) class II drugs show poor solubility and high permeability in the body. Fenofibrate (FF) is a classic example of a BCS class II drug, used to treat high cholesterol and triglyceride (fat-like substances) levels in the blood. Atomic layer coating (ALC) is a surface engineering technology adapted from the semiconductor industry, where metal oxides are coated one atomic layer at a time over the active pharmaceutical ingredients (API) particles. ALC coating was proven to improve the processability, alter the hydrophilicity, improve the stability, and fine-tune the release of drugs. Herein, we report the intervention of ALC coating in enhancing the bioavailability of a poorly water-soluble drug (fenofibrate) in the animal model. The physical properties of uncoated fenofibrate were compared with those of zinc oxide-coated and silicon oxide-coated fenofibrate. Following the application of the coatings, the structural integrity (both chemical stability and solid-state stability) of the active pharmaceutical ingredient (API) remained uncompromised, as corroborated by ¹H NMR and powder X-ray diffraction analyses. Notably, zinc oxide-coated fenofibrate exhibited favorable flow characteristics, whereas no discernible enhancement in flow behavior was observed for silicon oxide-coated fenofibrate. The results from contact angle measurements suggest that the silicon oxide-coated fenofibrate exhibits superior wetting behavior, as indicated by a contact angle nearing 0°. The application of ALC demonstrates an enhanced dissolution rate when compared to the uncoated active pharmaceutical ingredient (API) while leaving its equilibrium solubility unaffected. Coating the API with silicon oxide improves particle hydrophilicity and wetting properties, whereas zinc oxide coating aids in particle de-agglomeration, thereby enhancing their interaction with an aqueous medium. In vivo bioavailability studies conducted on rodents and larger animal (dog) models indicate a substantial increase in bioavailability (approximately 2 times) for the silicon oxide-coated API in comparison to the uncoated API, as determined by the area under the curve (AUC). Furthermore, the C_max values for the silicon oxide-coated API also demonstrate a significant increase (approximately 3 times) over the uncoated API. Notably, an oral subacute toxicity study of ALC silicon-coated fenofibrate revealed no toxic effects attributable to the coating. This study underscores the potential of ALC in augmenting the bioavailability of BCS(II) drugs.

In early drug development, amorphous spray-dried dispersions (SDDs) applied to enhance the bioavailability of poorly water-soluble compounds are typically administered to preclinical species via oral gavage in the form of suspensions. The liquid formulations are usually prepared on the same day of dosing to minimize the exposure of the amorphous material to the aqueous vehicle, thereby reducing the risk of crystallization. Dose-ability (e.g. syringe-ability) of the suspensions is also a critical factor for the administration, particularly when high doses, thus concentrations, are required for toxicology studies. As a result, it is standard practice during early formulation screening to assess the stability and the maximum feasible concentration of SDDs in various vehicles. In this study, we evaluated the impact of different vehicles on the performance of a model SDD in-vitro and in-vivo settings, to mitigate the risks associated with its administration in liquid form. A poorly water-soluble compound (GEN-A) was selected to screen various SDDs and generate the SDD model at 30 % drug load with HPMCAS-MF polymer carrier. The SDD was suspended in selected aqueous vehicles after a careful vehicle components screening, that included suspending agents (HPC-SL), solubilizers (PEG400, Propylene glycol), surfactants (Vitamin E TPGS, SLS, Tween 80, Poloxamer 188), and complexing agents (HP-β-CD, SBE-β-CD). The suspensions were characterized for stability, dose-ability and dissolution in biorelevant media, prior administration in pre-clinical species. The SDD dissolution profile revealed that the drug's supersaturation level was positively impacted by the presence of a surfactant (SLS) and a complexing agent (SBE-β-CD) with respect to a suspending agents (HPC-SL) in the vehicle. Similarly, the pharmacokinetics profiles of the drug following the administration of the SDD in a vehicle with a complexing agent (SBE-β-CD) achieved greater exposure compare to the SDD in a vehicle with a suspending agent (HPC-SL). These findings confirm a synergistic effect between the SDD and the vehicles, suggesting that this combination could be leveraged to maximize the advantages of the amorphous approach.

The purpose of the present study was to compare the dissolution profiles of high-dose salt-form drugs in bicarbonate buffer (BCB) and phosphate buffer (PPB) focusing on the pH changes in the bulk phase. The pH titration curves of BCB and PPB (pH 6.5, buffer capacity (β) = 4.4 mmol/L/pH unit) were first theoretically calculated and experimentally validated. For dissolution tests, six drug salts with an acid counterion, one drug salt with a weak base counterion, and one free acid drug were employed (125-800 mg clinical dose). The dose/fluid volume ratio (Dose/FV) was aligned with the clinical condition. In the pH titration study, the pH value decreased below pH 6.0 by adding HCl > 2.8 mmol/L (BCB) or > 1.6 mmol/L (PPB) and increased above pH 7.0 by adding NaOH > 2.0 mmol/L (BCB) or > 2.4 mmol/L (PPB). In the dissolution test, even though the initial pH and β values were the same, the pH value at 4 h was lower in PPB than in BCB in all cases. For the drug salts with an acid counterion, the area under the dissolution curve was 1.2 to 2.6-fold lower in BCB than in PPB. A marked precipitation process was observed in BCB, but less pronounced or absent in PPB. The results of this study suggest the use of BCB and a clinically equivalent Dose/FV may be valuable in predicting the oral absorption of high-dose drug salts.

Developing a controlled release (CR) formulations is a complex and iterative process, often requiring preclinical or clinical studies to establish in vitro-in vivo correlations. This can be particularly challenging for poorly soluble drugs due to the non-sink conditions encountered in vitro. Although compendial dissolution methods (e.g., USP II, IV) have historically been used to understand the dissolution performance of CR formulations, there is increasing interest in more physiologically relevant experimental techniques to improve the predictive ability. In this study, traditional USP apparatus as well as the biorelevant absorptive dissolution apparatus were employed to understand the impact of apparatus type and sink condition on the release mechanisms of CR formulations and in turn evaluate the application of absorptive dissolution apparatus for dissolution testing of CR formulations. Release mechanisms were further analyzed using the Peppas equations, providing additional mechanistic insights. The release behavior showed a strong dependence on sink conditions for drugs with low intrinsic solubility, while highly soluble drugs were unaffected by dissolution conditions. Interestingly, the dissolution mechanism was found to be independent of the apparatus type. The study clearly underscores the importance of considering the sink conditions in developing more predictive and biorelevant dissolution testing methods for CR formulations. Furthermore, the study highlights the potential impact on the sink and resultant differences in the drug release mechanisms as a function of the dose.

Some citrus fruits are known to cause clinically significant drug interactions by inhibiting intestinal cytochrome P450 (CYP) enzymes. This in vitro study aimed to investigate the kinetics of the inhibition of CYP3A4 and CYP2C19 by the juice of jabara, a Japanese citrus fruit that does not contain furanocoumarins such as 6',7'-dihydroxybergamottin, and to identify the inhibitory compound(s). CYP3A4 and CYP2C19 activity levels were determined in vitro using recombinant CYP preparations and their respective substrates. The ethyl acetate extract (EAE) of jabara juice was separated to isolate and identify the compound(s) that inhibited CYP3A4. Then, the time-dependent kinetics of the inhibition of CYP3A4 and CYP2C19 by the EAE and its inhibitory compound(s) were analyzed. The EAE of jabara juice was found to inhibit CYP3A4 in a time-dependent manner. Two flavonoids, 3,3',4',5,6,7,8-heptamethoxyflavone (HpMF) and 3,3',4',5,6,7-hexamethoxyflavone (HxMF), were identified as the responsible compounds. HpMF and HxMF inhibited CYP3A4 activity in a concentration- and time-dependent manner, with inhibition constants (K_I) of 10.0 and 7.90 µM and maximal inactivation rate constants (k_inact,max) of 0.00856 and 0.0134 min^-1, respectively. The EAE did not inhibit CYP2C19, even when preincubation was employed. These findings imply that jabara juice may cause food-drug interactions via time-dependent inhibition of intestinal CYP3A4.

Development of Amorphous Solid Dispersion (ASD) requires an in-depth characterization at different stages due to its structural and functional complexity. Various tools are conventionally used to investigate the processing, stability, and functionality of ASDs. However, many subtle features remain poorly understood due to lack of nano-scale characterization tools in routine practice. Atomic force microscopy (AFM) is a type of scanning probe microscopy, used for high resolution imaging and measuring features at the nano-scale. In recent years AFM has been used increasingly as a characterization tool in different areas of the development of ASD, including drug-polymer miscibility, localized characterization of the phase separated domains, lateral molecular diffusivity on ASD surface, crystallinity and crystallization kinetics in ASD, phase behavior of ASD during dissolution, and conformation of polymer during dissolution. In this review, we have highlighted the current applications of AFM in capturing critical aspects of stability and dissolution behavior of ASD. Potential areas of future development in this domain have been discussed.

A huge majority of new chemical entities (NCEs) advancing through the drug discovery pipeline often have poor aqueous solubility. This requires formulation scientists to search for solubility enhancement strategies, within the constraints of time and material. To address these challenges, a strategic platform formulation is often required for a rapid compound screening to enable early exploratory PK and toxicology studies. Through this work, we present an option of a material-sparing, high yielding and solubility-enabling amorphous API and HPMCAS-L co-loaded mesoporous silica-based formulation. The usability of this platform formation strategy was assessed for a physico-chemically diverse set of eleven compounds. The formulation approach was successful in stabilizing the model compounds mesoporous silica. Additionally, through the presence of HPMCAS-L, the precipitation risk in supersaturable aqueous environment was significantly reduced. Finally, this manuscript provides fundamental, computational and experimental molecular-properties based formulation guidance tree to a priori gauge the (1) possibility of generating solid-state stable amorphous formulations and (2) sustaining in vitro supersaturation in extreme non-sink dissolution conditions. This unique and conceptual formulation guidance tree is believed to be extremely beneficial to drug discovery formulators to triage NCEs and streamline solubility-enabling formulation efforts.

The oxidative degradation pathways of deflazacort (DFL) were investigated to address the gap in understanding its degradation products, focusing on reactions with oxidative stressors such as hydrogen peroxide and 4,4'-azobis (4-cyanovaleric acid) (ACVA). Using HPLC-PDA, high-resolution mass spectrometry (HRMS), NMR and IR spectroscopy, four novel degradation products were identified and structurally characterized. Two of these products were isolated using preparative HPLC before characterization. Hydrogen peroxide led to the formation of three novel products (DP-1, DP-2, and DP-3), while ACVA resulted in a single novel product (DP-4). Mechanistic and kinetic experiments supported the proposed degradation pathways under the various oxidative stress conditions studied, revealing distinct rates of formation for the degradation products during the time-course study. The identification and detailed structural elucidation of these degradation products provide critical insights into the chemical stability and potential reactivity of DFL under oxidative stress. These findings underscore the importance of comprehensive stability testing for ensuring drug safety and efficacy, and offer valuable data for future research on the toxicity and pharmacological impact of DFL degradation products.

Polymeric additives are widely used to delay drug crystallization from supersaturated solutions, which is critical for enhancing oral bioavailability by amorphous solid dispersion (ASD). The efficacy of these polymers relies on their capacity to inhibit nucleation and subsequent crystal growth. Drug nucleation is pivotal to crystallization; therefore, effective polymers are essential for suppressing nucleation from supersaturated solutions. We studied the performance of cellulose ω-carboxyalkanoates designed as crystallization inhibitors by measuring their influence on nucleation induction times of poorly soluble drugs celecoxib, posaconazole, and enzalutamide, from supersaturated solutions. In the absence of polymers, crystallization occurred within 5 to 15 minutes for all three drugs. Polymer hydrophobicity strongly influenced effectiveness in crystallization inhibition. Hydrophobic polymers prolonged induction times for up to 8 hours, while hydrophilic polymers were less effective, except for cellulose acetate glutarate (CA_1.18-GA_1.21; degrees of substitution acetate 1.18, glutarate 1.21). The cellulose ω-carboxyalkanoates had glass transition temperatures well above 100 °C, outstanding for ASD stability requirements. We investigated the impact of these designed polymers on surface tension and found that it only weakly influenced crystallization inhibition. Among the nine crafted cellulose derivatives, water-soluble CA_1.18-GA_1.21 emerged as a highly promising ASD polymer, preventing crystallization for 2-8 hours for all fast-crystallizing model compounds.