Improved Human Bioavailability of Vemurafenib, a Practically Insoluble Drug, Using an Amorphous Polymer-Stabilized Solid Dispersion Prepared by a Solvent-Controlled Coprecipitation Process

Shah, Navnit; Iyer, Raman; Mair, Hans-Juergen; Choi, Duk Soon; Tian, Hung; Diodone, Ralph; Fähnrich, Karsten; Pabst-Ravot, Anni; Tang, Kin; Scheubel, Emmanuel; Grippo, Joseph F.; Moreira, Sebastian; Go, Zenaida; Mouskountakis, James; Louie, Theresa; Ibrahim, Prabha; Sandhu, Harpreet; Rubia, Linda; Chokshi, Hitesh; Singhal, Dharmendra; Malick, Waseem

doi:10.1002/jps.23425

Cited by 177 publications

(114 citation statements)

References 48 publications

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“…The commonly observed gradual discontinuity in a DSC thermogram of conventional solid amorphous systems represents transition of a glassy state to a viscous liquid state. 25 The freshly prepared liquid salt formulations IBU IL, GEM IL and INDO IL did not exhibit discontinuity at glass transition temperatures as previously observed in pure drugs. The disappearance of the glass transitions is most likely due to dissolution of drugs in EMIM ES.…”

Section: Thermal Analysis By Differential Scanning Calorimetrysupporting

confidence: 68%

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2015

IJPSR

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As a result of tremendous efforts in past few decades, various techniques have been developed in order to resolve solubility issues. However, majority of these techniques offer benefits associated with certain drawbacks; majorly including low drug loading, physical instability on storage and excessive use of environmentally challenging organic solvents. Hence, current effort was to develop an eco-friendly technique using liquid salt, which can offer improvement in dissolution while maintaining long term stability. The liquid salt formulations of poorly soluble model drugs ibuprofen, gemfibrozil and indomethacin were developed using 1-Ethyl-3-methylimidazolium ethyl sulfate (EMIM ES) as a non-toxic and environmentally friendly alternate to organic solvents. Liquid medications containing clear solutions of drug, EMIM ES and polysorbate 20, were adsorbed onto porous carrier Neusilin US2 to form free flowing powder. Liquid loading as high as 70% w/w was achieved while maintaining good flowability and compressibility. The liquid salt based formulations (LSF) demonstrated greater rate and extent of dissolution compared to crystalline drugs. The LSF samples exposed to 40°C/80% RH for 8 weeks, demonstrated excellent physical stability without any signs of precipitation or crystallization. The liquid salt formulation technique served as compelling alternate to the conventional techniques for the development of poorly soluble compounds.

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Section: Thermal Analysis By Differential Scanning Calorimetrysupporting

confidence: 68%

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2015

IJPSR

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“…The marketed solid dispersion drugs include, but are not limited to, griseofulvin, nabilone, itraconazole, tacrolimus, and lopinavir/ritonavir. Roche's vemurafenib, a practically insoluble drug, has been successfully developed using an amorphous polymerstabilized solid dispersion prepared by a solvent-controlled co-precipitation process (45).…”

Section: Co-crystals and Amorphous Solid Dispersionmentioning

confidence: 99%

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

Wen¹,

Jung²,

2015

AAPS J

409

189

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Abstract. Various drug delivery approaches can be used to maximize therapeutic efficacy and minimize side effects, by impacting absorption, distribution, metabolism, and elimination (ADME) of a drug compound. For those drugs with poor water solubility or low permeability, techniques such as amorphous solid dispersion, liposomes, and complexations have been used to improve their oral bioavailability. Modified release (MR) formulations have been widely used to improve patient compliance, as well as to reduce side effects, especially for those drugs with short half-lives or narrow therapeutic windows. More than ten drugs using sterile long-acting release (LAR) formulations with clear clinical benefit have been successfully marketed. Furthermore, drug delivery systems have been used in delaying drug clearance processes. Additionally, modifying the in vivo drug distribution using targeted delivery systems has significantly improved oncology treatments. All the drug delivery approaches have their advantages and limitations. For both brand and generic drugs, the achievement of consistent quality and therapeutic performance using drug delivery systems can also pose serious challenges in developing a drug for the market, which requires close collaboration among industry, academia, and regulatory agencies. With the advent of personalized medicines, there will be great opportunities and challenges in utilizing drug delivery systems to provide better products and services for patients.

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“…Solid dispersions can be obtained from various techniques such as hot melt extrusion (HME), spray drying, and co-precipitation (3)(4)(5). However, HME is extremely suitable to prepare solid dispersion as this processing technique does not require any solvent or water, which avoids residual amounts of solvent and the accompanying stability risks during the shelf life of solid dispersion dosage form (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Development of Tablet Formulation of Amorphous Solid Dispersions Prepared by Hot Melt Extrusion Using Quality by Design Approach

et al. 2016

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ABSTRACT. The objective of the study was to identify the extragranular component requirements (level and type of excipients) to develop an immediate release tablet of solid dispersions prepared by hot melt extrusion (HME) process using commonly used HME polymers. Solid dispersions of compound X were prepared using polyvinyl pyrrolidone co-vinyl acetate 64 (PVP VA64), Soluplus, and hypromellose acetate succinate (HPMCAS-LF) polymers in 1:2 ratio by HME through 18 mm extruder. A mixture design was employed to study effect of type of polymer, filler (microcrystalline cellulose (MCC), lactose, and dicalcium phosphate anhydrous (DCPA)), and disintegrant (Crospovidone, croscarmellose sodium, and sodium starch glycolate (SSG)) as well as level of extrudates, filler, and disintegrant on tablet properties such as disintegration time (DT), tensile strength (TS), compactibility, and dissolution. Higher extrudate level resulted in longer DT and lower TS so 60-70% was the maximum amount of acceptable extrudate level in tablets. Fast disintegration was achieved with HPMCAS-containing tablets, whereas Soluplus-and PVP VA64-containing tablets had higher TS. Crospovidone and croscarmellose sodium were more suitable disintegrant than SSG to achieve short DT, and MCC was a suitable filler to prepare tablets with acceptable TS for each studied HME polymer. The influence of extragranular components on dissolution from tablets should be carefully evaluated while finalizing tablet composition, as it varies for each HME polymer. The developed statistical models identified suitable level of fillers and disintegrants for each studied HME polymer to achieve tablets with rapid DT (<15 min) and acceptable TS (≥1 MPa at 10-15% tablet porosity), and their predictivity was confirmed by conducting internal and external validation studies.

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Improved Human Bioavailability of Vemurafenib, a Practically Insoluble Drug, Using an Amorphous Polymer-Stabilized Solid Dispersion Prepared by a Solvent-Controlled Coprecipitation Process

Cited by 177 publications

References 48 publications

Untitled

Untitled

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

Development of Tablet Formulation of Amorphous Solid Dispersions Prepared by Hot Melt Extrusion Using Quality by Design Approach

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