Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation.

Local delivery of biotherapeutics to the lung holds great promise for treatment of lung diseases, but development of physically stable, biologically active dry powder formulations of large molecules for inhalation has remained a challenge. Here, spray drying was used to manufacture a dry powder pulmonary formulation of bevacizumab, a monoclonal antibody approved to treat non-small cell lung cancer (NSCLC) by intravenous infusion. By reformulating bevacizumab for local delivery, reduced side effects, lower doses, and improved patient compliance are possible. The formulation had aerosol properties suitable for delivery to the deep lung, as well as good physical stability at ambient temperature for at least 6 months. Bevacizumab's anti-VEGF bioactivity was not impacted by the manufacturing process. The formulation was efficacious in an in vivo rat model for NSCLC at a 10-fold decrease in dose relative to the intravenous control.

5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming.

BACKGROUND: Epigenetic therapy through demethylation of 5-methylcytosine has been largely ineffective in treating lung cancer, most likely due to poor tissue distribution with oral or subcutaneous delivery of drugs such as 5-azacytidine (5AZA). An inhalable, stable dry powder formulation of 5AZA was developed. METHODS: Pharmacokinetics of inhaled dry powder and aqueous formulations of 5AZA were compared to an injected formulation. Efficacy studies and effect of therapy on the epigenome were conducted in an orthotopic rat lung cancer model for inhaled formulations. RESULTS: Inhaled dry powder 5AZA showed superior pharmacokinetic properties in lung, liver, brain and blood compared to the injected formulation and for all tissues except lung compared to an inhaled aqueous formulation. Only dry powder 5AZA was detected in brain (~4-h half-life). Inhaled dry powder was superior to inhaled aqueous 5AZA in reducing tumour burden 70-95%. Superiority of inhaled 5AZA dry powder was linked to effectively reprogramming the cancer genome through demethylation and gene expression changes in cancer signalling and immune pathways. CONCLUSIONS: These findings could lead to widespread use of this drug as the first inhaled dry powder therapeutic for treating local and metastatic lung cancer, for adjuvant therapy, and in combination with immunotherapy to improve patient survival.

Novel High-Drug-Loaded Amorphous Dispersion Tablets of Posaconazole; In Vivo and In Vitro Assessment.

Amorphous solid dispersions (ASDs) can increase the bioavailability of drugs with poor aqueous solubility. However, concentration-sustaining dispersion polymers (CSPs) incorporated in ASDs can result in low drug loading and, therefore, a large dosage-form size or multiple units to meet dose requirements, potentially decreasing patient compliance. To address this challenge, a high-loaded dosage-form (HLDF) architecture for ASDs was developed, in which a drug is first spray-dried with a high glass-transition temperature (Tg) dispersion polymer to facilitate high drug loading while maintaining physical stability. The ASD is then granulated with a CSP designed to extend supersaturation in solution. The HLDF differs from traditional ASD architectures in which the dispersion polymer inside the ASD acts as the CSP. By strategically combining two different polymers, one "inside" and one "outside" the ASD, solubilization performance, physical stability, and overall drug loading are maximized. This study demonstrates in vivo performance of the HLDF architecture using posaconazole as a model drug. Two sizes of HLDF tablets were tested in beagle dogs, along with traditional ASD architecture (benchmark) tablets, ASD tablets without a CSP, and a commercial crystalline oral suspension (Noxafil OS). HLDF tablets performed equivalently to the benchmark tablets, the smaller HLDF tablet being 40% smaller (by mass) than the benchmark tablet. The HLDF tablets doubled the blood plasma AUC relative to Noxafil OS. In line with the in vivo outcome, in vitro results in a multicompartment dissolution apparatus demonstrated similar area under the curve (AUC) values in the intestinal compartment for ASD tablets. However, the in vitro data underpredicted the relative in vivo AUC of Noxafil OS compared to the ASD tablets. This study demonstrated that the HLDF approach can increase drug loadings while achieving good performance for ASD drug products.

Solvent-Assisted Secondary Drying of Spray-Dried Polymers.

PURPOSE: The purpose of this work is to introduce solvent-assisted secondary drying, a method used to accelerate the residual solvent removal from spray dried materials. Spray-drying is used to manufacture amorphous solid dispersions, which enhance the bioavailability of active pharmaceutical ingredients (APIs) with low aqueous solubility. In the spray-drying process, API and excipients are co-dissolved in a volatile organic solvent, atomized into droplets through a nozzle, and introduced to a drying chamber containing heated nitrogen gas. The product dries rapidly to form a powder, but small amounts of residual solvent (typically, 1 to 10 wt%) remain in the product and must be removed in a secondary-drying process. For some spray-dried materials, secondary drying by traditional techniques can take days and requires balancing stability risks with process time. METHODS: Spray-dried polymers were secondary dried, comparing the results for three state-of-the-art methods that employed a jacketed, agitated-vessel dryer: (1) vacuum-only drying, (2) water-assisted drying, or (3) methanol-assisted drying. Samples of material were pulled at various time points and analyzed by gas chromatography (GC) and Karl Fischer (KF) titration to track the drying process. RESULTS: Model systems were chosen for which secondary drying is slow. For all cases studied, methanol-assisted drying outperformed the vacuum-only and water-assisted drying methods. CONCLUSIONS: The observation that methanol-assisted drying is more effective than the other drying techniques is consistent with the free-volume theory of solvent diffusion in polymers.

NMR Relaxometry to Characterize the Drug Structural Phase in a Porous Construct.

Nuclear magnetic resonance (NMR) frequency spectra and T2 relaxation time measurements, using a high-power radio frequency probe, are shown to characterize the presence of an amorphous drug in a porous silica construct. The results indicate the ability of non-solid-state NMR methods to characterize crystalline and amorphous solid structural phases in drugs. Two-dimensional T1- T2 magnetic relaxation time correlation experiments are shown to monitor the impact of relative humidity on the drug in a porous silica tablet.

Millisecond Self-Assembly of Stable Nanodispersed Drug Formulations.

We report the development of a new spray-drying and nanoparticle assembly process (SNAP) that enables the formation of stable, yet rapidly dissolving, sub-200 nm nanocrystalline particles within a high Tg glassy matrix. SNAP expands the class of drugs that spray-dried dispersion (SDD) processing can address to encompass highly crystalline, but modestly hydrophobic, drugs that are difficult to process by conventional SDD. The process integrates rapid precipitation and spray-drying within a custom designed nozzle to produce high supersaturations and precipitation of the drug and high Tg glassy polymer. Keeping the time between precipitation and drying to tens of milliseconds allows for kinetic trapping of drug nanocrystals in the polymer matrix. Powder X-ray diffraction, solid state 2D NMR, and SEM imaging shows that adding an amphiphilic block copolymer (BCP) to the solvent gives essentially complete crystallization of the active pharmaceutical ingredient (API) with sub-200 nm domains. In contrast, the absence of the block copolymer results in the API being partially dispersed in the matrix as an amorphous phase, which can be sensitive to changes in bioavailability over time. Quantification of the API-excipient interactions by 2D 13C-1H NMR correlation spectroscopy shows that the mechanism of enhanced nanocrystal formation is not due to interactions between the drug and the BCP, but rather the BCP masks interactions between the drug and hydrophobic regions of the matrix polymers. BCP-facilitated SNAP samples show improved stability during aging studies and rapid dissolution and release of API in vitro.

Enhancing the Oral Absorption of Kinase Inhibitors Using Lipophilic Salts and Lipid-Based Formulations.

The absolute bioavailability of many small molecule kinase inhibitors (smKIs) is low. The reasons for low bioavailability are multifaceted and include constraints due to first pass metabolism and poor absorption. For smKIs where absorption limits oral bioavailability, low aqueous solubility and high lipophilicity, often in combination with high-dose requirements have been implicated in low and variable absorption, food-effects, and absorption-related drug-drug interactions. The current study has evaluated whether preparation of smKIs as lipophilic salts/ionic liquids in combination with coadministration with lipid-based formulations is able to enhance absorption for examples of this compound class. Lipophilic (docusate) salt forms of erlotinib, gefitinib, ceritinib, and cabozantinib (as example smKIs demonstrating low aqueous solubility and high lipophilicity) were prepared and isolated as workable powder solids. In each case, the lipophilic salt exhibited high and significantly enhanced solubility in lipidic excipients (>100 mg/g) when compared to the free base or commercial salt form. Isolation as the lipophilic salt facilitated smKI loading in model lipid-based formulations at high concentration, increased in vitro solubilization at gastric and intestinal pH and in some cases increased oral absorption (∼2-fold for cabozantinib formulations in rats). Application of a lipophilic salt approach can therefore facilitate the use of lipid-based formulations for examples of the smKI compound class where low solubility limits absorption and is a risk factor for increased variability due to food-effects.

Development of a Biorelevant, Material-Sparing Membrane Flux Test for Rapid Screening of Bioavailability-Enhancing Drug Product Formulations.

Bioavailability-enhancing formulations are often used to overcome challenges of poor gastrointestinal solubility for drug substances developed for oral administration. Conventional in vitro dissolution tests often do not properly compare such formulations due to the many different drug species that may exist in solution. To overcome these limitations, we have designed a practical in vitro membrane flux test, that requires minimal active pharmaceutical ingredient (API) and is capable of rapidly screening many drug product intermediates. This test can be used to quickly compare performance of bioavailability-enhancing formulations with fundamental knowledge of the rate-limiting step(s) to membrane flux. Using this system, we demonstrate that the flux of amorphous itraconazole (logD = 5.7) is limited by aqueous boundary layer (ABL) diffusion and can be increased by adding drug-solubilizing micelles or drug-rich colloids. Conversely, the flux of crystalline ketoconazole at pH 5 (logD = 2.2) is membrane-limited, and adding solubilizing micelles does not increase flux. Under certain circumstances, the flux of ketoconazole may also be limited by dissolution rate. These cases highlight how a well-designed in vitro assay can provide critical insight for oral formulation development. Knowing whether flux is limited by membrane diffusion, ABL diffusion, or dissolution rate can help drive formulation development decisions. It may also be useful in predicting in vivo performance, dose linearity, food effects, and regional-dependent flux along the length of the gastrointestinal tract.

Impact of Drug-Rich Colloids of Itraconazole and HPMCAS on Membrane Flux in Vitro and Oral Bioavailability in Rats.

Improving the oral absorption of compounds with low aqueous solubility is a common challenge that often requires an enabling technology. Frequently, oral absorption can be improved by formulating the compound as an amorphous solid dispersion (ASD). Upon dissolution, an ASD can reach a higher concentration of unbound drug than the crystalline form, and often generates a large number of sub-micrometer, rapidly dissolving drug-rich colloids. These drug-rich colloids have the potential to decrease the diffusional resistance across the unstirred water layer of the intestinal tract (UWL) by acting as rapidly diffusing shuttles for unbound drug. In a prior study utilizing a membrane flux assay, we demonstrated that, for itraconazole, increasing the concentration of drug-rich colloids increased membrane flux in vitro. In this study, we evaluate spray-dried amorphous solid dispersions (SDDs) of itraconazole with hydroxypropyl methylcellulose acetate succinate (HPMCAS) to study the impact of varying concentrations of drug-rich colloids on the oral absorption of itraconazole in rats, and to quantify their impact on in vitro flux as a function of bile salt concentration. When Sporanox and itraconazole/AFFINISOL High Productivity HPMCAS SDDs were dosed in rats, the maximum absorption rate for each formulation rank-ordered with membrane flux in vitro. The relative maximum absorption rate in vivo correlated well with the in vitro flux measured in 2% SIF (26.8 mM bile acid concentration), a representative bile acid concentration for rats. In vitro it was found that as the bile salt concentration increases, the importance of colloids for improving UWL permeability is diminished. We demonstrate that drug-containing micelles and colloids both contribute to aqueous boundary layer diffusion in proportion to their diffusion coefficient and drug loading. These data suggest that, for compounds with very low aqueous solubility and high epithelial permeability, designing amorphous formulations that produce colloids on dissolution may be a viable approach to improve oral bioavailability.

Inhaled PYY(3-36) dry-powder formulation for appetite suppression.

OBJECTIVE: Peptide YY3-36 [PYY(3-36)] has shown efficacy in appetite suppression when dosed by injection modalities (intraperitoneal (IP)/subcutaneous). Transitioning to needle-free delivery, towards inhalation, often utilizes systemic pharmacokinetics as a key endpoint to compare different delivery methods and doses. Systemic pharmacokinetics were evaluated for PYY3-36 when delivered by IP, subcutaneous, and inhalation, the systemic pharmacokinetics were then used to select doses in an appetite suppression pharmacodynamic study. METHODS: Dry-powder formulations were manufactured by spray drying and delivered to mice via nose only inhalation. The systemic plasma, lung tissue, and bronchoalveolar lavage fluid pharmacokinetics of different inhalation doses of PYY(3-36) were compared to IP and subcutaneous efficacious doses. Based on these pharmacokinetic data, inhalation doses of 70:30 PYY(3-36):Dextran T10 were evaluated in a mouse model of appetite suppression and compared to IP and subcutaneous data. RESULTS: Inhalation pharmacokinetic studies showed that plasma exposure was similar for a 2 × higher inhalation dose when compared to subcutaneous and IP delivery. Inhalation doses of 0.22 and 0.65 mg/kg were for efficacy studies. The results showed a dose-dependent (not dose proportional) decrease in food consumption over 4 h, which is similar to IP and subcutaneous delivery routes. CONCLUSIONS: The pharmacokinetic and pharmacodynamics results substantiate the ability of pharmacokinetic data to inform pharmacodynamics dose selection for inhalation delivery of the peptide PYY(3-36). Additionally, engineered PYY(3-36):Dextran T10 particles delivered to the respiratory tract show promise as a non-invasive therapeutic for appetite suppression.

Biologic comparison of inhaled insulin formulations: Exubera™ and novel spray-dried engineered particles of dextran-10.

Inhaled peptides and proteins have promise for respiratory and systemic disease treatment. Engineered spray-dried powder formulations have been shown to stabilize peptides and proteins and optimize aerosol properties for pulmonary delivery. The current study was undertaken to investigate the in vitro and in vivo inhalation performance of a model spray-dried powder of insulin and dextran 10 in comparison to Exubera™. Dextrans are a class of glucans that are generally recognized as safe with optimum glass transition temperatures well suited for spray drying. A 70% insulin particle loading was prepared by formulating with 30% (w/v) dextran 10. Physical characterization revealed a "raisin like" particle. Both formulations were generated to produce a similar bimodal particle size distribution of less than 3.5 µm MMAD. Four female Beagle dogs were exposed to each powder in a crossover design. Similar presented and inhaled doses were achieved with each powder. Euglycemia was achieved in each dog prior and subsequent to dosing and blood samples were drawn out to 245 min post-exposure. Pharmacokinetic analyses of post-dose insulin levels were similar for both powders. Respective dextran 10-insulin and Exubera exposures were similar producing near identical area under the curve (AUC), 7,728 ± 1,516 and 6,237 ± 2,621; concentration maximums (C max), 126 and 121 (µU/mL), and concentration-time maximums, 20 and 14 min, respectively. These results suggest that dextran-10 and other dextrans may provide a novel path for formulating peptides and proteins for pulmonary delivery.

Simultaneous Spray Drying for Combination Dry Powder Inhaler Formulations.

Spray drying is a particle engineering technique used to manufacture respirable pharmaceutical powders that are suitable for delivery to the deep lung. It is amenable to processing both small molecules and biologic actives, including proteins. In this work, a simultaneous spray-drying process, termed simul-spray, is described; the process involves two different active pharmaceutical ingredient (API) solutions that are simultaneously atomized through separate nozzles into a single-spray dryer. Collected by a single cyclone, simul-spray produces a uniform mixture of two different active particles in a single-unit operation. While combination therapies for dry powder inhalers containing milled small molecule API are commercially approved, limited options exist for preparing combination treatments that contain both small molecule APIs and biotherapeutic molecules. Simul-spray drying is also ideal for actives which cannot withstand a milling-based particle engineering process, or which require a high dose that is incompatible with a carrier-based formulation. Three combination case studies are demonstrated here, in which bevacizumab is paired with erlotinib, cisplatin, or paclitaxel in a dry powder inhaler formulation. These model systems were chosen for their potential relevance to the local treatment of lung cancer. The resulting formulations preserved the biologic activity of the antibody, achieved target drug concentration, and had aerosol properties suitable for pulmonary delivery.

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets.

Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom-up approach (absolute average fold error of AUC0-inf < 2). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products.

Correction: Mudie et al. In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets. Pharmaceutics 2021, 13, 1257.

The authors wish to make the following corrections to this paper [...].

Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs.

Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug-drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required. In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration-time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance. In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.

Formulation development and in vivo evaluation of a new dry powder formulation of albuterol sulphate in beagle dogs.

PURPOSE: Study objectives were to develop, characterize, and evaluate a novel excipient for dry powder inhalation formulations in a canine model with a model compound. METHODS: Dry powder inhalation formulations of albuterol sulphate were developed and compared to a commercially available nebulizer albuterol solution formulation. In vitro analysis indicated a high fine-particle fraction (FPF, >70%) and a respirable particle size ( approximately 2.5 microm MMAD). Each inhalation formulation, including controls, was delivered targeting a deposited lung dose of 10 microg/kg albuterol. Active formulations were evaluated for pharmacokinetic (PK) profile and bronchodilatory effects in a ragweed-sensitized dog model of allergic airway responses. RESULTS: In vitro, the dextran spray-dried formulated materials showed that aerosol performance, including FPF, MMAD, glass transition temperature, and amorphous characteristics, were all largely unaffected by amount of drug loaded. Both the commercial and the dry powder formulations attenuated the ragweed-induced bronchoconstriction by 91.59 +/- 3.60 and 81.28 +/- 9.29%, respectively. The PK profiles for both albuterol formulations were similar, as were the corresponding T(max), C(max) and T(1/2). CONCLUSIONS: Results indicate that dextran 10 has promise as a novel excipient for dry powder inhalation drug delivery, in a preclinical setting, over a wide range of drug loadings.

A novel architecture for achieving high drug loading in amorphous spray dried dispersion tablets.

Although Amorphous Solid Dispersions (ASDs) effectively increase bioavailability, tablet mass can be high due to the large fraction of excipients needed to stabilize the amorphous drug in the solid state, extend drug supersaturation in solution and achieve robust manufacturability. The aim of this work was to reduce tablet mass of an ASD tablet comprising a low glass transition temperature (Tg), rapidly crystallizing drug without compromising these key attributes. In this approach, erlotinib (Tg = 42 °C, Tm/Tg = 1.4 K/K) was spray dried with the high Tg polymer poly(methyl methacrylate-co-methacrylic acid) (Eudragit® L100, Evonik) (Tg = 187 °C) to facilitate high drug loading while maintaining physical stability. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) (AQOAT® HF, Shin-Etsu) was granulated with the ASD to extend supersaturation in solution. For comparison, a benchmark ASD was spray dried at a lower drug loading with HPMCAS-H (Tg = 119 °C). This High Loaded Dosage Form (HLDF) approach reduced tablet mass by 40%, demonstrated similar physical stability and in vitro performance as the benchmark and exhibited excellent downstream manufacturability. Strategically combining two different polymers in a tablet to maintain physical stability and sustain supersaturation in solution can decrease tablet mass of some low Tg, rapidly crystallizing amorphous drugs.

Mechanistic Study of Belinostat Oral Absorption From Spray-Dried Dispersions.

Spray-dried dispersions (SDDs) are an important technology for enhancing the oral bioavailability of poorly water-soluble drugs. To design an effective oral SDD formulation, the key rate-determining step(s) for oral drug absorption must be understood. This work combined in vivo and in vitro tests with in silico modeling to identify the rate-determining steps for oral absorption of belinostat SDDs made with 3 different polymers (PVP K30, PVP VA64, and HPMCAS-M). The goal was developing a belinostat SDD formulation that maximizes oral bioavailability (ideally matching the performance of a belinostat oral solution) and defining critical performance attributes for formulation optimization. The in vivo pharmacokinetic study with beagle dogs demonstrated that 1 of the 3 SDDs (PVP K30 SDD) matched the performance of the oral solution. In vitro data coupled with in silico modeling elucidated differences among the SDDs and supported the hypothesis that absorption of belinostat in the small intestine from the other 2 SDDs (PVP VA64 and HPMCAS-M) may be limited by dissolution rate or reduced drug activity (maximum concentration) in the presence of polymer. It was concluded that drug concentration in the stomach before emptying into the proximal intestine is a key factor for maximizing in vivo performance.

Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations.

Higher lipid solubility of lipophilic salt forms creates new product development opportunities for high-dose liquid-filled capsules. The purpose of this study is to determine if lipophilic salts of Biopharmaceutical Classification System (BCS) Class I amlodipine and BCS Class III fexofenadine, ranitidine, and metformin were better lipid formulation candidates than existing commercial salts. Lipophilic salts were prepared from lipophilic anions and commercial HCl or besylate salt forms, as verified by 1H-NMR. Thermal properties were assessed by differential scanning calorimetry and hot-stage microscopy. X-ray diffraction and polarized light microscopy were used to confirm the salt's physical form. All lipophilic salt forms were substantially more lipid-soluble (typically >10-fold) when compared to commercial salts. For example, amlodipine concentrations in lipidic excipients were limited to <5-10 mg/g when using the besylate salt but could be increased to >100 mg/g when using the docusate salt. Higher lipid solubility of the lipophilic salts of each drug translated to higher drug loadings in lipid formulations. In vitro tests showed that lipophilic salts solubilized in a lipid formulation resulted in dispersion behavior that was at least as rapid as the dissolution rates of conventional salts. This study confirmed the applicability of forming lipophilic salts of BCS I and III drugs to promote the utility of lipid-based delivery systems.

Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.