scholarly journals Pharmaceutical Cocrystal Development of TAK-020 with Enhanced Oral Absorption

Crystals ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 211 ◽  
Author(s):  
Kouya Kimoto ◽  
Mitsuo Yamamoto ◽  
Masatoshi Karashima ◽  
Miyuki Hohokabe ◽  
Junpei Takeda ◽  
...  
Keyword(s):  
Solid State ◽  
Oral Absorption ◽  
Kinase Inhibitor ◽  
Physicochemical Characterization ◽  
Water Soluble ◽  
Amorphous Solid Dispersion ◽  
Pharmacokinetic Studies ◽  
Stoichiometric Ratio ◽  
Enhanced Absorption ◽  
Pharmaceutical Cocrystal

The objective of this study was to improve the solubility of poorly water-soluble drugs by pharmaceutical cocrystal engineering techniques and select the best pharmaceutical forms with high solubility and solubilized formulations for progress from the early discovery stage toward the clinical stage. Several pharmaceutical cocrystals of TAK-020, a Bruton tyrosine kinase inhibitor, were newly discovered in the screening based on the solid grinding method and the slurry method, considering thermodynamic factors that dominate cocrystal formation. TAK-020/gentisic acid cocrystal (TAK-020/GA CC) was selected based on a physicochemical property of enhanced dissolution rate. TAK-020/GA CC was proven to be a reliable cocrystal formation with a definitive stoichiometric ratio by a variety of analytical techniques—pKa calculation, solid-state nuclear magnetic resonance, and single X-ray structure analysis from the view of regulation. Furthermore, its absorption was remarkable and beyond those achieved in currently existing solubilized formulation techniques, such as nanocrystal, amorphous solid dispersion, and lipid-based formulation, in dog pharmacokinetic studies. TAK-020/GA CC was the best drug form, which might lead to good pharmacological effects with regard to enhanced absorption and development by physicochemical characterization. Through the trials of solid-state optimization from early drug discovery to pharmaceutical drug development, the cocrystals can be an effective option for achieving solubilization applicable in the pharmaceutical industry.

scholarly journals Bioavailability Improvement of Carbamazepine via Oral Administration of Modified-Release Amorphous Solid Dispersions in Rats

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1023
Author(s):  
Houli Li ◽  
Meimei Zhang ◽  
Lilong Xiong ◽  
Weiyi Feng ◽  
Robert O. Williams
Keyword(s):  
Controlled Release ◽  
Oral Absorption ◽  
Solid Dispersions ◽  
Amorphous State ◽  
Amorphous Solid ◽  
Water Soluble ◽  
Pharmacokinetic Studies ◽  
Modified Release ◽  
Capsule Formulation ◽  
Amorphous Solid Dispersions

The purpose of this study was to improve the bioavailability of carbamazepine (CBZ), a poorly water-soluble antiepileptic drug, via modified-release amorphous solid dispersions (mr-ASD) by a thin film freezing (TFF) process. Three types of CBZ-mr-ASD with immediate-, delayed-, and controlled-release properties were successfully prepared with HPMC E3 (hydrophilic), L100-55 (enteric), and cellulose acetate (CA, lipophilic), defined as CBZ-ir-ASD, CBZ-dr-ASD, and CBZ-cr-ASD, respectively. A dry granulation method was used to prepare CBZ-mr-ASD capsule formulations. Various characterization techniques were applied to evaluate the physicochemical properties of CBZ-mr-ASD and the related capsules. The drug remained in an amorphous state when encapsulated within CBZ-mr-ASD, and the capsule formulation progress did not affect the performance of the dispersions. In dissolution tests, the preparations and the corresponding dosage forms similarly showed typical immediate-, delayed-, and controlled-release properties depending on the solubility of the polymers. Moreover, single-dose 24 h pharmacokinetic studies in rats indicated that CBZ-mr-ASD significantly enhanced the oral absorption of CBZ compared to that of crude CBZ. Increased oral absorption of CBZ was observed, especially in the CBZ-dr-ASD formulation, which showed a better pharmacokinetic profile than that of crude CBZ with 2.63- and 3.17-fold improved bioavailability of the drug and its main active metabolite carbamazepine 10,11-epoxide (CBZ-E).

scholarly journals Formulation, In Vitro and In Vivo Evaluation of Gefitinib Solid Dispersions Prepared Using Different Techniques

Processes ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 1210
Author(s):  
Sultan Alshehri ◽  
Abdullah Alanazi ◽  
Ehab M. Elzayat ◽  
Mohammad A. Altamimi ◽  
Syed S. Imam ◽  
...  
Keyword(s):  
Oral Absorption ◽  
Solid Dispersions ◽  
Water Soluble ◽  
In Vitro Dissolution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
In Vivo Evaluation ◽  
Significant Release

Gefitinib (Gef) is a poorly water-soluble antitumor drug, which shows poor absorption/bioavailability after oral administration. Therefore, this study was carried out to develop Gef solid dispersions (SDs) using different carriers and different techniques in order to enhance its dissolution and oral absorption/bioavailability. Various SD formulations of Gef were established using fusion and microwave methods utilizing Soluplus, Kollidone VA64, and polyethylene glycol 4000 (PEG 4000) as the carriers. Developed SDs of Gef were characterized physicochemically and evaluated for in vitro dissolution and in vivo pharmacokinetic studies. The physicochemical evaluation revealed the formation of Gef SDs using fusion and microwave methods. In vitro dissolution studies indicated significant release of Gef from all SDs compared to the pure Gef. Optimized SD of Gef (S2-MW) presented significant release of Gef (82.10%) compared with pure Gef (21.23%). The optimized Gef SD (S2) was subjected to in vivo pharmacokinetic evaluation in comparison with pure Gef in rats. The results indicated significant enhancement in various pharmacokinetic parameters of Gef from an optimized SD S2 compared to the pure Gef. In addition, Gef-SD S2 resulted in remarkable improvement in bioavailability compared to the pure Gef. Overall, this study suggested that the prepared Gef-SD by microwave method showed marked enhancement in dissolution and bioavailability.

scholarly journals Solubility enhancement, physicochemical characterization and formulation of fast-dissolving tablet of nifedipine-betacyclodextrin complexes

2012 ◽  
Vol 48 (1) ◽  
pp. 131-145 ◽  
Author(s):  
Swati Changdeo Jagdale ◽  
Vinayak Narhari Jadhav ◽  
Aniruddha Rajaram Chabukswar ◽  
Bhanudas Shankar Kuchekar
Keyword(s):  
Physicochemical Characterization ◽  
Inclusion Complexation ◽  
Water Soluble ◽  
In Vitro Dissolution ◽  
Phase Solubility ◽  
Binary Complex ◽  
Stoichiometric Ratio ◽  
Dissolution Profile ◽  
Weight Variation

The main objective of the study was to enhance the dissolution of nifedipine, a poorly water soluble drug by betacyclodextrin complexation and to study the effect of the preparation method on the in vitro dissolution profile. The stoichiometric ratio determined by phase solubility analysis for inclusion complexation of nifedipine with β-cyclodextrin was 1:1. Binary complex was prepared by different methods and was further characterized using XRD, DSC and FT-IR. A saturation solubility study was carried out to evaluate the increase in solubility of nifedipine. The optimized complex was formulated into fast-dissolving tablets by using the superdisintegrants Doshion P544, pregelatinized starch, crospovidone, sodium starch glycolate and croscarmellose sodium by direct compression. Tablets were evaluated for friability, hardness, weight variation, disintegration and in vitro dissolution. Tablets showed an enhanced dissolution rate compared to pure nifedipine.

Solid Dispersions: A Review

2014 ◽  
Vol 4 (2) ◽  
Author(s):  
Sumant Saini ◽  
Yashwant .
Keyword(s):  
Solid Dispersions ◽  
Physicochemical Characterization ◽  
Water Soluble ◽  
Absolute Minimum ◽  
Technology Transfers ◽  
Molecular Arrangement ◽  
Water Soluble Drugs ◽  
Carrier Solvent ◽  
Preparation Techniques ◽  
Selection Of

Solid dispersions are one of the most promising strategies to improve the oral bioavailability of poorly water soluble drugs. By reducing drug particle size to the absolute minimum, and hence improving drug wettability, bioavailability may be significantly improved. This article reviews the various preparation techniques for solid dispersion and compiles some of the recent technology transfers. The different types of solid dispersions based on the molecular arrangement have been highlighted. Some of the practical aspects to be considered for the preparation of solid dispersions, such as selection of carrier, solvent and methods of physicochemical characterization, along with an insight into the molecular arrangement of drugs in solid dispersions are also discussed. In this review, it is intended to discuss the recent advances related on the area of solid dispersions.

Enhancement of Solubility and Dissolution Rate of Poorly Water Soluble Drug using Cosolvency and Solid Dispersion Techniques

1970 ◽  
Vol 1 (4) ◽  
pp. 349-356
Author(s):  
Meka Lingam ◽  
Vobalaboina Venkateswarlu
Keyword(s):  
Dissolution Rate ◽  
Solid Dispersions ◽  
Physicochemical Characterization ◽  
Aqueous Solubility ◽  
Water Soluble ◽  
Scanning Calorimetry ◽  
Peg 400 ◽  
Water Soluble Drug ◽  
Poorly Water Soluble ◽  
Poorly Water Soluble Drug

The low aqueous solubility of celecoxib (CB) and thus its low bioavailability is a problem.    Thus, it is suggested to improve the solubility using cosolvency and solid dispersions techniques. Pure CB has solubility of 6.26±0.23µg/ml in water but increased solubility of CB was observed with increasing concentration of cosolvents like PEG 400, ethanol and propylene glycol. Highest solubility (791.06±15.57mg/ml) was observed with cosolvency technique containing the mixture of composition 10:80:10%v/v of water: PEG 400: ethanol. SDs with different polymers like PVP, PEG were prepared and subjected to physicochemical characterization using Fourier-transform infrared (FTIR) spectroscopy, X-ray diffractometry (XRD), differential scanning calorimetry (DSC), solubility and dissolution studies. These studies reveals that CB exists mainly in amorphous form in prepared solid dispersions of PVP, PEG4000 and PEG6000 further it can also be confirmed by solubility and dissolution rate studies. Solid dispersions of PV5 and PV9 have shown highest saturation solubility and dissolution rate

Nevirapine Pharmaceutical Cocrystal: Design, Development and Formulation

2019 ◽  
Vol 9 (3) ◽  
pp. 240-247
Author(s):  
Prabhakar Panzade ◽  
Priyanka Somani ◽  
Pavan Rathi
Keyword(s):  
Dosage Form ◽  
In Vitro Dissolution ◽  
Soluble Form ◽  
Ir Absorption ◽  
Stoichiometric Ratio ◽  
Design Development ◽  
Formulation Development ◽  
Scanning Calorimetry ◽  
Absorption Bands ◽  
Pharmaceutical Cocrystal

Background and Objective: The top approach to deliver poorly soluble drugs is the use of a highly soluble form. The present study was conducted to enhance the solubility and dissolution of a poorly aqueous soluble drug nevirapine via a pharmaceutical cocrystal. Another objective of the study was to check the potential of the nevirapine cocrystal in the dosage form. Methods: A neat and liquid assisted grinding method was employed to prepare nevirapine cocrystals in a 1:1 and 1:2 stoichiometric ratio of drug:coformer by screening various coformers. The prepared cocrystals were preliminary investigated for melting point and saturation solubility. The selected cocrystal was further confirmed by Infrared Spectroscopy (IR), Differential Scanning Calorimetry (DSC), and Xray Powder Diffraction (XRPD). Further, the cocrystal was subjected to in vitro dissolution study and formulation development. Results: The cocrystal of Nevirapine (NVP) with Para-Amino Benzoic Acid (PABA) coformer prepared by neat grinding in 1:2 ratio exhibited greater solubility. The shifts in IR absorption bands, alterations in DSC thermogram, and distinct XRPD pattern showed the formation of the NVP-PABA cocrystal. Dissolution of NVP-PABA cocrystal enhanced by 38% in 0.1N HCl. Immediate release tablets of NVP-PABA cocrystal exhibited better drug release and less disintegration time. Conclusion: A remarkable increase in the solubility and dissolution of NVP was obtained through the cocrystal with PABA. The cocrystal also showed great potential in the dosage form which may provide future direction for other drugs.

scholarly journals Synthesis, Characterization and Bactericidal Activity of a 4-Ammoniumbuthylstyrene-Based Random Copolymer

Polymers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1140
Author(s):  
Silvana Alfei ◽  
Gabriella Piatti ◽  
Debora Caviglia ◽  
Anna Maria Schito
Keyword(s):  
Antibacterial Activity ◽  
Bactericidal Activity ◽  
Antimicrobial Agents ◽  
Water Solubility ◽  
Physicochemical Characterization ◽  
Random Copolymer ◽  
Water Soluble ◽  
Cationic Polymers ◽  
Severe Infections

The growing resistance of bacteria to current chemotherapy is a global concern that urgently requires new and effective antimicrobial agents, aimed at curing untreatable infection, reducing unacceptable healthcare costs and human mortality. Cationic polymers, that mimic antimicrobial cationic peptides, represent promising broad-spectrum agents, being less susceptible to develop resistance than low molecular weight antibiotics. We, thus, designed, and herein report, the synthesis and physicochemical characterization of a water-soluble cationic copolymer (P5), obtained by copolymerizing the laboratory-made monomer 4-ammoniumbuthylstyrene hydrochloride with di-methyl-acrylamide as uncharged diluent. The antibacterial activity of P5 was assessed against several multi-drug-resistant clinical isolates of both Gram-positive and Gram-negative species. Except for strains characterized by modifications of the membrane charge, most of the tested isolates were sensible to the new molecule. P5 showed remarkable antibacterial activity against several isolates of genera Enterococcus, Staphylococcus, Pseudomonas, Klebsiella, and against Escherichia coli, Acinetobacter baumannii and Stenotrophomonas maltophilia, displaying a minimum MIC value of 3.15 µM. In time-killing and turbidimetric studies, P5 displayed a rapid non-lytic bactericidal activity. Due to its water-solubility and wide bactericidal spectrum, P5 could represent a promising novel agent capable of overcoming severe infections sustained by bacteria resistant the presently available antibiotics.

scholarly journals Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 889
Author(s):  
Kaijie Qian ◽  
Lorenzo Stella ◽  
David S. Jones ◽  
Gavin P. Andrews ◽  
Huachuan Du ◽  
...  
Keyword(s):  
Solid Dispersion ◽  
Oral Drug Delivery ◽  
Drug Product ◽  
Amorphous Solid ◽  
Water Soluble ◽  
Nucleation Theory ◽  
Product Development Process ◽  
Classical Nucleation Theory ◽  
Oral Drug ◽  
Amorphous Solid Dispersion

Among many methods to mitigate the solubility limitations of drug compounds, amorphous solid dispersion (ASD) is considered to be one of the most promising strategies to enhance the dissolution and bioavailability of poorly water-soluble drugs. The enhancement of ASD in the oral absorption of drugs has been mainly attributed to the high apparent drug solubility during the dissolution. In the last decade, with the implementations of new knowledge and advanced analytical techniques, a drug-rich transient metastable phase was frequently highlighted within the supersaturation stage of the ASD dissolution. The extended drug absorption and bioavailability enhancement may be attributed to the metastability of such drug-rich phases. In this paper, we have reviewed (i) the possible theory behind the formation and stabilization of such metastable drug-rich phases, with a focus on non-classical nucleation; (ii) the additional benefits of the ASD-induced drug-rich phases for bioavailability enhancements. It is envisaged that a greater understanding of the non-classical nucleation theory and its application on the ASD design might accelerate the drug product development process in the future.

scholarly journals In Vitro Drug Release, Permeability, and Structural Test of Ciprofloxacin-Loaded Nanofibers

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 556
Author(s):  
Luca Éva Uhljar ◽  
Sheng Yuan Kan ◽  
Norbert Radacsi ◽  
Vasileios Koutsos ◽  
Piroska Szabó-Révész ◽  
...  
Keyword(s):  
Amorphous State ◽  
Physical Mixture ◽  
Water Soluble ◽  
Vinyl Pyrrolidone ◽  
Amorphous Solid Dispersion ◽  
Release Mechanism ◽  
Dissolution Studies ◽  
In Vitro Diffusion ◽  
Poly Vinyl Pyrrolidone

Nanofibers of the poorly water-soluble antibiotic ciprofloxacin (CIP) were fabricated in the form of an amorphous solid dispersion by using poly(vinyl pyrrolidone) as a polymer matrix, by the low-cost electrospinning method. The solubility of the nanofibers as well as their in vitro diffusion were remarkably higher than those of the CIP powder or the physical mixture of the two components. The fiber size and morphology were optimized, and it was found that the addition of the CIP to the electrospinning solution decreased the nanofiber diameter, leading to an increased specific surface area. Structural characterization confirmed the interactions between the drug and the polymer and the amorphous state of CIP inside the nanofibers. Since the solubility of CIP is pH-dependent, the in vitro solubility and dissolution studies were executed at different pH levels. The nanofiber sample with the finest morphology demonstrated a significant increase in solubility both in water and pH 7.4 buffer. Single medium and two-stage biorelevant dissolution studies were performed, and the release mechanism was described by mathematical models. Besides, in vitro diffusion from pH 6.8 to pH 7.4 notably increased when compared with the pure drug and physical mixture. Ciprofloxacin-loaded poly(vinyl pyrrolidone) (PVP) nanofibers can be considered as fast-dissolving formulations with improved physicochemical properties.

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