Patient Centricity Driving Formulation Innovation: Improvements in Patient Care Facilitated by Novel Therapeutics and Drug Delivery Technologies.

Innovative formulation technologies can play a crucial role in transforming a novel molecule to a medicine that significantly enhances patients' lives. Improved mechanistic understanding of diseases has inspired researchers to expand the druggable space using new therapeutic modalities such as interfering RNA, protein degraders, and novel formats of monoclonal antibodies. Sophisticated formulation strategies are needed to deliver the drugs to their sites of action and to achieve patient centricity, exemplified by messenger RNA vaccines and oral peptides. Moreover, access to medical information via digital platforms has resulted in better-informed patient groups that are requesting consideration of their needs during drug development. This request is consistent with health authority efforts to upgrade their regulations to advance age-appropriate product development for patients. This review describes formulation innovations contributingto improvements in patient care: convenience of administration, preferred route of administration, reducing dosing burden, and achieving targeted delivery of new modalities.

Surface Dissolution UV Imaging for Investigation of Dissolution of Poorly Soluble Drugs and Their Amorphous Formulation.

The aim of this study is to investigate the dissolution properties of poorly soluble drugs from their pure form and their amorphous formulation under physiological relevant conditions for oral administration based on surface dissolution ultraviolet (UV) imaging. Dissolution of two poorly soluble drugs (cefuroxime axetil and itraconazole) and their amorphous formulations (Zinnat® and Sporanox®) was studied with the Sirius Surface Dissolution Imager (SDI). Media simulating the fasted state conditions (compendial and biorelevant) with sequential media/flow rate change were used. The dissolution mechanism of cefuroxime axetil in simulated gastric fluid (SGF), fasted state simulated gastric fluid (FaSSGF) and simulated intestinal fluid (SIF) is predominantly swelling as opposed to the convective flow in fasted state simulated intestinal fluid (FaSSIF-V1), attributed to the effect of mixed micelles. For the itraconazole compact in biorelevant media, a clear upward diffusion of the dissolved itraconazole into the bulk buffer solution is observed. Dissolution of itraconazole from the Sporanox® compact is affected by the polyethylene glycol (PEG) gelling layer and hydroxypropyl methylcellulose (HPMC) matrix, and a steady diffusional dissolution pattern is revealed. A visual representation and a quantitative assessment of dissolution properties of poorly soluble compounds and their amorphous formulation can be obtained with the use of surface dissolution imaging under in vivo relevant conditions.

Designing biorelevant dissolution tests for lipid formulations: case example--lipid suspension of RZ-50.

Biorelevant dissolution test methods for lipid formulations of RZ-50, an experimental Roche compound, were developed and compared with standard compendial methods in terms of their in vivo predictability. Release of RZ-50, a poorly soluble weakly acidic drug, from lipid suspensions filled in soft gelatin capsules was studied in compendial and biorelevant media using the USP Apparatus 2 (paddle method) and the USP Apparatus 3 (Bio-Dis method). Pharmacokinetic data were obtained in dogs after oral administration of a single 2.5mg dose of RZ-50 soft gelatin capsules in the postprandial state. Level A IVIVC analysis and curve comparison of fraction drug dissolved vs. absorbed using the Weibull distribution were used to evaluate the in vitro methods in terms of their ability to fit the in vivo plasma profiles. Very low drug release was observed with the paddle method owing to poor dispersibility of the lipids in the dissolution media, whereas the Bio-Dis method hydrodynamics facilitated release of the drug by emulsifying the formulation in the medium. The best IVIVC was obtained using a dissolution medium representing fed gastric conditions in combination with the Bio-Dis method. Curve comparisons of the fraction drug absorbed and the fraction drug dissolved profiles based on Weibull distribution fits yielded similar results. The Bio-Dis/biorelevant in vitro method appears to be suitable for this type of lipid formulation.

Evaluation of solid state properties of solid dispersions prepared by hot-melt extrusion and solvent co-precipitation.

The solid state properties of solid dispersions of Compound A in hypromellose acetate succinate (HPMC-AS) prepared by hot-melt extrusion (HME) and solvent co-precipitation (CP) processes were evaluated using powder X-ray diffractometry (PXRD), thermal analysis, optical microscopy, scanning electron microscopy (SEM), FT-IR and Raman spectroscopy, water vapor sorption analyzer, and surface area by BET. PXRD indicated that both processes converted the crystalline drug into amorphous solid dispersions with a glass transition temperature around 104-107 degrees C and both products have similar spectroscopic and hygroscopic properties. The two products have similar true densities; however, the CP product is more porous and has a larger specific surface area than the HME product, as indicated by the BET results and SEM micrographs. Dissolution study using USP apparatus 2 showed that the CP product had a faster dissolution profile, but slower intrinsic dissolution rate than the HME product. The two products have acceptable physical stability after storage in 40 degrees C/75% RH chamber for 3 months. However, the HME product is more stable than the CP product in aqueous suspension formulation.

Determination of drug-polymer binding constants by affinity capillary electrophoresis for aryl propionic acid derivatives and related compounds.

The binding constants (K(b)s) of 17 aryl propionic acid derivatives (APADs) and related compounds with polyvinylpyrrolidone (PVP K30) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) in aqueous media were determined by affinity capillary electrophoreses (ACE). The K(b)s of APAD to polymers increase with octanol-water partition coefficients of the compounds. Kollidon VA64 is a stronger binder than PVP K30 to APAD compounds. The K(b)s are greater at pH 4 than at pH 9. Both hydrophobic interaction and hydrogen bonding may be involved. However, hydrophobic interaction appears to be dominant. The ACE method is simple and fast, which could be used to study drug-polymer interaction in aqueous media.

Highly efficient miniaturized coprecipitation screening (MiCoS) for amorphous solid dispersion formulation development.

Microprecipitated bulk powder (MBP) is a novel solid dispersion technology to manufacture amorphous formulations of poorly soluble compounds that cannot be processed by spray drying or melt extrusion. An efficient high-throughput screening method has been developed to aid the selection of polymer type, drug loading and antisolvent to solvent ratio for MBP formulation development. With a 96-well platform, the miniaturized coprecipitation screening (MiCoS) includes mixing of drug and polymer in dimethylacetamide, controlled precipitation to generate MBP, filtration/washing, drying and high throughput characterization. The integrated MiCoS approach has been demonstrated with a model compound, glybenclamide. Based on the solid state stability and kinetic solubility of the MBP, hydroxypropylmethylcellulose acetate succinate polymer with 40% or lower drug loading, and antisolvent (0.01 N HCl) to solvent (dimethylacetamide) ratio of 5:1 or higher were selected to make glybenclamide MBP. MiCoS can be applied to both early and late stage formulation processing. In early stage research programs, the system can be used to enable efficacy, pharmacokinetics or mini-toxicology studies for poorly water soluble molecules using minimal amount of drug substance (2-10mg). In late stage development programs, MiCoS can be used to optimize MBP formulation by expanding the experimental design space to include additional formulation variants.

Dissolution media simulating the proximal canine gastrointestinal tract in the fasted state.

Human biorelevant media have been shown to be a useful tool in pharmaceutical development and to provide input for in silico prediction of pharmacokinetic profiles after oral dosing. Dogs, in particular Beagles, are often used as animal models for preclinical studies. Key differences in the composition of human and canine gastric and intestinal fluids are described in the literature and underscore the need to develop a discrete set of biorelevant media, adapted to the conditions of the proximal canine gastrointestinal (GI) tract, to improve forecast and interpretation of preclinical results using in vitro dissolution studies. Canine biorelevant media can also be used in the development of oral dosage forms for companion animals, which is a rapidly growing market. The compositions of Fasted State Simulated Gastric Fluid canine (FaSSGFc) and Fasted State Simulated Intestinal Fluid canine (FaSSIFc) are adapted to the physiological composition of the corresponding gastrointestinal fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid, and free fatty acid content (in terms of concentration and reported subtypes). It was demonstrated that canine Fasted State Simulated Intestinal Fluid (FaSSIFc) is superior in predicting the solubility of model compounds in Canine Intestinal Fluid (CIF) compared to the human biorelevant media (FaSSIF and FaSSIF-V2). Two different versions of FaSSGFc, composed at pH 1.5 and pH 6.5, offer the possibility to design in vitro studies which correspond to the in vivo study design, depending on whether pentagastrin is used to decrease the gastric pH in the dogs or not. Canine biorelevant media can therefore be recommended to achieve more accurate forecasting and interpretation of pharmacokinetic studies of oral drug products in dogs.

Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process.

The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP. The MBP provided a greater rate and extent of dissolution than crystalline drug, reaching an apparent drug concentration of 28-35 µg/mL, almost 30-fold higher than solubility of crystalline drug at 1 µg/mL. The supersaturation was also maintained for more than 4 h. Upon exposure to high temperature and humidity, the MBP was destabilized, resulting in crystallization and lower dissolution rate. The control of moisture and temperature is essential to maintain the stability of the MBP. In a relative human bioavailability study, vemurafenib MBP provided a four- to fivefold increase in exposure compared with crystalline drug. Improving solubility with an amorphous-solid dispersion is a viable strategy for the development of practically insoluble compounds.

Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs.

A novel method was developed to manufacture amorphous formulations of poorly soluble compounds that cannot be processed with existing methods such as spray drying and melt extrusion. The manufacturing process and the characterization of the resulting amorphous dispersion are presented via examples of two research compounds. The novel process is utilized N,N-dimethylacetamide (DMA) to dissolve the drug and the selected ionic polymer. This solution is then co-precipitated into aqueous medium. The solvent is extracted out by washing and the co-precipitated material is isolated by filtration followed by drying. The dried material is referred to as microprecipitated bulk powder (MBP). The amorphous form prepared using this method not only provides excellent in vitro and in vivo performance but also showed excellent stability. The stabilization of amorphous dispersion is attributed to the high T(g), ionic nature of the polymer that help to stabilize the amorphous form by possible ionic interactions, and/or due to the insolubility of polymer in water. In addition to being an alternate technology for amorphous formulation of difficult compounds, MBP technology provides advantages with respect to stability, density and downstream processing.

Prediction of the thermal phase diagram of amorphous solid dispersions by Flory-Huggins theory.

Miscibility of drug and polymer is one of the key parameters in amorphous formulation design. The purpose of this work is to provide a theoretical approach to evaluate miscibility between drug and polymer in amorphous solid dispersions. The model system is indomethacin and polyvinylpyrrolidone-vinyl acetate copolymer. The Flory-Huggins (F-H) interaction parameter, χ, of drug and polymer was estimated at different temperatures by two methods: melting point depression of drug in various polymer ratios at the melting temperature, and Hildebrand and Scott solubility parameter calculation at 25°C. The simplified first-order relation between the F-H interaction parameter and temperature was established. This allows the construction of a temperature-composition phase diagram of a two-component amorphous system. The spinodal curve was generated and provides an insight into the thermodynamic stability of an amorphous solid dispersion at various temperatures. The predicted stability of the model system was compared with the experimental data. The merits and deficiency of the proposed approach were fully discussed.

Size exclusion chromatography with Corona charged aerosol detector for the analysis of polyethylene glycol polymer.

A technique of using size exclusion chromatography (SEC) with the Corona charged aerosol detector (CAD) was developed and evaluated in comparison with refractive index (RI) and evaporative light scattering detection (ELSD) for fast screening of polyethylene glycol (PEG), a polymer used in preparing pegylated pharmaceutical compounds. These detection techniques were used in the analysis of multiple lots of PEG reagents. CAD was found to provide more accurate impurity and polydispersity profiles of PEG reagents that better differentiate their quality, while RI was not suitable for this application due to its low sensitivity and ELSD led to underestimation of the impurity and polydispersity. The accuracy of polydispersity determination by SEC-CAD was validated against a commercial reference standard of known polydispersity. The SEC-CAD technique and the observed differences between the three detectors can also be applied to polymer analysis in general.

Affinity purification and characterization of an anti-PEG IgM.

Anti-PEG IgM was purified by affinity chromatography using variable length PEG chains (5, 10, 20 and 30 kDa) as affinity ligands. Maximal binding of anti-PEG IgM was observed using the 30 kDa PEG-derivatized NuGel (single passage). Purified anti-PEG IgM was characterized for binding to PEG functionalized proteins/peptides by surface plasmon resonance, western blotting and ELISA. Anti-PEG IgM, in solution and adsorbed on 20 kDa PEG-derivatized NuGel, was subjected to pepsin digestion followed by affinity chromatography. SDS-PAGE analysis of eluates in both preparations yielded one fragment that was similar in size. However, an additional lower molecular weight band was observed in solution-digested affinity purified material that was not present in the eluate from the material subjected to pepsin digestion on the affinity matrix. The lower MW fragment could be eluted under milder conditions, suggesting loss of binding multiplicity. Analysis by mass spectrometry yielded molecular weights of 132 kDa (both) and 82 kDa (solution) for the respective fragments. N-terminal sequencing of both fragments resulted in primary sequences (heavy and light chains) that were not only identical to each other but also to those of native IgM. The anti-PEG IgM fragments were characterized for binding to pegylated interferon alfa-2a by ELISA. The results from these studies suggest that affinity purified anti-PEG IgM and fragments can be used as probes in detection assays for PEG functionalized biotherapeutics in pre-clinical and clinical studies.