Drug–Drug Coamorphous Systems: Characterization and Physicochemical Properties of Coamorphous Atorvastatin with Carvedilol and Glibenclamide

Purpose

In this study, coamorphous form of atorvastatin calcium (ATC) with two drugs, i.e., carvedilol (CVD) and glibenclamide (GLN) in 1:1 stoichiometry, were prepared from solvent evaporation method and they were characterized and their physicochemical properties determined.

Methods

The coamorphous forms were characterized using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD). The kinetic solubility of coamorphous form of ATC with CVD (ATC–CVD) and GLN (ATC–GLN) were determined along with stability of supersaturated state of coamorphous forms using developed accurate and precise UV-net analyte signal standard addition method (chemometrics-based approach) and HPLC.

Results

The results of DSC and analysis of glass transition temperatures (T _g), PXRD, and FT-IR indicated that the crystalline studied drugs were converted to coamorphous forms, with unique thermal behaviors, revealing a molecular interaction between two components. The kinetic solubility data revealed that coamorphous forms have better metastable solubility than those of crystalline state. In addition, these systems showed greater solution stability than those for amorphous form of single components reported in the literature.

Conclusion

Coamorphous ATC–CVD and ATC–GLN were shown to have improved physicochemical and solution stability properties as compared to crystalline components.     

Ibuprofen-β-cyclodextrin Inclusion Complex:Preparation,Characterization,Physico-Chemical Properties and

本文对布洛芬（ＩＢＦ）和βＣＤ包合物的性质进行了研究。相溶试验表明在室温２３℃及３７℃下包合物中ＩＢＦ和βＣＤ的比例分别为１：３及２：３。本文采用均匀共沉淀法制备了固体包合物，并采用了扫描电镜、差热扫描、红外光谱及Ｘ线衍射来考察包合物的性质。包合物的溶解度及溶出速度较之它们的物理混合物及药物本身有了明显的提高，由此表明βＣＤ在布洛芬的溶解性中发挥了重要作用。     

Preparation and Characterization of Apo2L/TNF-Related Apoptosis-Inducing Ligand–Loaded Human Serum Albumin Nanoparticles with Improved Stability and Tumor Distribution

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received considerable attention as a potential anticancer agent. However, recombinant Apo2L/TRAIL has several limitations, which include a weak pharmacokinetic profile, namely, a short biological half-life and rapid renal clearance, and an inability to form a homotrimeric structure. In this research, we attempted to develop a sustained release nanoparticle (NP) formulation that stabilizes Apo2L/TRAIL and preserves its antitumor activity. Apo2L/TRAIL-loaded human serum albumin (HSA) NPs were prepared using a desolvation technique optimized by particle size, zeta-potential, and entrapment efficiency. Apo2L/TRAIL in HSA-NPs continuously released over 24 h at 37°C in phosphate buffered saline and rat plasma condition, and the biological activity of Apo2L/TRAIL-HSA-NPs was preserved (IC₅₀ = 67.2 ng/mL versus Apo2L/TRAIL IC₅₀ = 55.4 ng/mL) with negligible activity loss. Furthermore, in vivo pharmacokinetic profiles and tumor distribution demonstrated the superiority of Apo2L/TRAIL-HSA-NPs over Apo2L/TRAIL. The circulating half-life period was significantly prolonged from 9.8 to 90.7 min (9.2-fold enhancement), and drug bioavailability was clearly enhanced on the basis of area under the curve analysis (2.7-fold). And tumor distribution of Apo2L/TRAIL-HSA-NPs was also increased at 1 h after injection, which was about 14-fold (1-h point) over that of Apo2L/TRAIL. These results show that Apo2L/TRAIL-loaded HSA-NPs should be considered as potential long-acting cancer agents.     

Preparation and Evaluation of Piroxicam–HPMCAS Solid Dispersions for Ocular Use

The aim of the study was in vitro evaluation of piroxicam solid dispersions containing hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF, -HF) as a carrier. Binary (piroxicam–HPMCAS) and ternary (piroxicam–HPMCAS–Carbopol 940) solid dispersions were prepared by spray-drying method. The morphological characteristics were investigated by scanning electron microscopy. X-ray diffraction and differential scanning calorimetry were employed to study physical and chemical properties. In vitro release was studied using a flow-through cell technique. Studies of dissolution rate of piroxicam from solid dispersions were carried out in comparison with corresponding physical mixtures and drug alone. The dissolution profiles depend on the presence of Carbopol 940 in solid dispersions.     

Physicochemical Characterization of Hot Melt Extruded Bicalutamide–Polyvinylpyrrolidone Solid Dispersions

Solid molecular dispersions of bicalutamide (BL) and polyvinylpyrrolidone (PVP) were prepared by hot melt extrusion technology at drug‐to‐polymer ratios of 1:10, 2:10, and 3:10 (w/w). The solid‐state properties of BL, physical mixtures of BL/PVP, and hot melt extrudates were characterized using differential scanning calorimetry (DSC), powder X‐ray diffractometry (PXRD), Raman, and Fourier transform infrared (FTIR) spectroscopy. Drug dissolution studies were subsequently conducted on hot melt extruded solid dispersions and physical mixtures. All hot melt extrudates had a single T_g between the T_g of amorphous BL and PVP indicating miscibility of BL with PVP and the formation of solid molecular dispersions. PXRD confirmed the presence of the amorphous form of BL within the extrudates. Conversely, PXRD patterns recorded for physical mixtures showed sharp bands characteristic of crystalline BL, whereas DSC traces had a distinct endotherm at 196°C corresponding to melting of crystalline BL. Further investigations using DSC confirmed solid‐state plasticization of PVP by amorphous BL and hence antiplasticization of amorphous BL by PVP. Experimentally observed T_g values of physical mixtures were shown to be significantly higher than those calculated using the Gordon–Taylor equation suggesting the formation of strong intermolecular interactions between BL and PVP. FTIR and Raman spectroscopy were used to investigate these interactions and strongly suggested the presence of secondary interaction between PVP and BL within the hot melt extrudates. The drug dissolution properties of hot melt extrudates were enhanced significantly in comparison to crystalline BL and physical mixtures. Moreover, the rate and extent of BL release were highly dependent on the amount of PVP present within the extrudate. Storage of the extrudates confirmed the stability of amorphous BL for up to 12 months at 20°C, 40% RH whereas stability was reduced under highly humid conditions (20°C, 65% RH). Interestingly, BL recrystallization after storage under these conditions had no effect on the dissolution properties of the extrudates. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1322–1335, 2010     

Preparation and Characterization of Clopidogrel Bisulfate-hydroxypropyl-β-Cyclodextrin Mixed Inclusion Complex for Improved Intestinal Solubility and Anti-Thrombotic Efficacy

The study aimed to increase the intestinal solubility and absorption of orally bioavailable clopidogrel-bisulfate (CPB) by complexing with hydroxypropyl-β-cyclodextrin (HCD) to form a binary inclusion complex that was stabilized by Tween 80 (T80) resulting into mixed inclusion complex. The results of phase solubility studies and molecular docking of CPB with β-cyclodextrin (β-CD) and HCD suggested higher solubility and binding energy of the stable CPB: HCD complex in the presence of T80 as compared to the CPB: β-CD complex. The D-Optimal mixture design was used to optimize the formulation containing the CPB: HCD: T80 mixed inclusion complex. The results suggest the enhanced stability of the CPB: HCD inclusion complex in the presence of T80. The spectral attributes confirmed the inclusion complexation and pointed out the central position of CPB in a hydrophilic cavity of HCD. Further, the prepared soft gelatin capsule successfully confirmed the importance of obliterating the intestinal precipitation associated problem of CPB through an in-vitro release study. The anticoagulant activity in rabbits confirmed that soft gelatin capsules showed 1.2 folds and 1.3 folds increase in clotting time, 1.2 fold and 1.5 folds increase in bleeding time when compared to marketed formulation and pure drug, respectively. Conclusively, soft gelatin capsules exhibit the potential to enhance the oral bioavailability of CPB, leading to reduction of the dose and dose-related side effects.     

Gastrointestinal Responsive Polymeric Nanoparticles for Oral Delivery of Insulin: Optimized Preparation,Characterization, and In Vivo Evaluation

Gastrointestinal responsive polymeric nanospheres (NPs) based on hydroxypropyl methylcellulose phthalate were prepared using spontaneous emulsification solvent diffusion method for improved oral administration of insulin. The NPs prepared under optimized conditions have an encapsulation efficiency of 90% and a particle size of about 200 nm. In vitro drug release experiments demonstrated that the NPs exhibited a gradient release profile of loaded drug when the pH value gradually increased from 3.0 to 7.4. Enzyme resistance experiments showed that under simulated gastrointestinal conditions, the NPs protected more than 60% of the drug from being degraded by trypsin. The oral hypoglycemic experiments revealed that insulin-loaded NPs could significantly reduce blood glucose levels in diabetic rats with a relative bioavailability of 8.6%. Ex vivo imaging investigation of rat tissues showed that the drug-loaded NPs could promote the absorption of insulin in the ileum and colon. The work described here suggests that the gastrointestinal responsive polymeric NPs may be promising candidates for improving gastrointestinal tract delivery of hydrophilic biomacromolecules. Accordingly, the results indicated that hydroxypropyl methylcellulose phthalate NPs with gastrointestinal stimuli responsiveness could be a promising candidate for oral insulin delivery.     

Dielectric Study of Equimolar Acetaminophen–Aspirin,Acetaminophen–Quinidine,and Benzoic Acid–Progesterone Molecular Alloys in the Glass and Ultraviscous States and Their Relevance to Solubility and Stability

Equimolar mixtures of acetaminophen–aspirin, acetaminophen–quinidine, and benzoic acid–progesterone have been vitrified and dielectric properties of their glassy and ultraviscous alloys have been studied. For 20 K/min heating rate, their T_gs are 266, 330, and 263 K, respectively. The relaxation has an asymmetric distribution of times, and the distribution parameter increases with increase in temperature. The dielectric relaxation time varies with T according to the Vogel–Fulcher–Tammann equation, log₁₀(τ₀) = A_VFT + [B_VFT/(T ? T₀)], where A_VFT, B_VFT, and T₀ are empirical constants. The equilibrium permittivity is highest for the aspirin–acetaminophen and lowest for the benzoic acid‐progesterone alloy, indicating a substantial interpharmaceutical hydrogen bonding that makes the alloy more stable against crystallization than the pure components. The benzoic acid–progesterone alloy is thermodynamically the most nonideal. It showed cold crystallization on heating, which is attributed to its relatively greater magnitude of the JG relaxation in relation to its α‐relaxation. It is argued that the difference between the free energy of an alloy and the pure components would have an effect on the solubility. Studies of solution thermodynamics of a glassy molecular alloy may be useful for optimizing choice of components and composition to form molecular alloys and to impact drug delivery. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1358–1374, 2010     

Inclusion Complexes of Nateglinide with HP–β–CD and L-Arginine for Solubility and Dissolution Enhancement: Preparation,Characterization, and Molecular Docking Study

Purpose

The objective of present study was to increase solubility and dissolution performance of a poorly water soluble antidiabetic drug, Nateglinide (NAT), through formation of inclusion complexes with hydroxypropyl-beta-cyclodextrin (HP–β–CD). The effect of L-arginine (ARG), an amino acid, on the complexation efficiency and solubility enhancing power of HP–β–CD was investigated by preparing ternary inclusion complexes.

Methods

The binary and ternary inclusion complexes were prepared by physical mixing, kneading, co-evaporation, and spray drying methods containing NAT, HP–β–CD, and ARG. The complexes were characterized by FTIR, DSC, PXRD, and ¹H–NMR. Molecular modeling study revealed that introduction of ternary agent ARG have improved the interactions of NAT and HP–β–CD.

Results

The complex prepared by spray drying method showed the highest increase in solubility and dissolution rate compared to other methods. Molecular docking study revealed that ARG interactions plays an essential role in increasing the stability and solubility of the complex.

Conclusions

The present study demonstrated increase in solubility and dissolution of NAT. Hence, ternary complexes of NAT can be used as an efficient tool for the delivery of insoluble drug, NAT.

     

The Physicochemical Properties,Plasma Enzymatic Hydrolysis,and Nasal Absorption of Acyclovir and Its 2′-Ester Prodrugs

A series of 2-(O-acyl) derivatives of 9-(2-hydoxyethoxymethyl)guanine (acyclovir) was synthesized by acid anhydride esterification. Aqueous solubilities in isotonic phosphate buffer (pH 7.4), partition coefficients in 1-octanol/phosphate buffer, and hydrolysis kinetics in rat plasma were determined. The ester prodrugs showed consistent increases in lipophilicity with corresponding decreases in aqueous solubility as a function of side-chain length. The bioconversion kinetics of the prodrugs appear to depend on both the apolar and the steric nature of the acyl substituents. When perfused through the rat nasal cavity using the in situ perfusion technique, acyclovir showed no measurable loss from the perfusate. Nasal uptake of acyclovir prodrugs, on the other hand, were moderately improved. Furthermore, the extent of nasal absorption appears to depend on the lipophilicity of the prodrugs in the descending order hexanoate > valerate > pivalate > butyrate. Simultaneous prodrug cleavage by nasal carboxylesterase was also noted in the case of hexanoate.     

Preparation and Characterization of Insulin–Surfactant Complexes for Loading into Lipid-Based Drug Delivery Systems

Insulin suffers from poor oral bioavailability, but lipid-based drug delivery systems (DDS) may constitute promising tools for improving this. Loading of protein drugs into lipid matrices may, however, be challenging, and different formulation approaches must be taken to achieve sufficient loading and preservation of native structure. The aim of the present study was to characterize insulin after complexation with biocompatible surfactants to improve loading into lipid-based DDS. Insulin–surfactant complexes were prepared by freeze-drying with distearyldimethylammonium bromide or soybean phospholipid as complexing surfactant and dimethyl sulfoxide (DMSO) as solvent. Significant change in secondary structure of insulin freeze dried from DMSO was observed using Fourier transform infrared spectroscopy. Changes were quantitatively smaller in the presence of surfactants, demonstrating both a stabilizing effect of surfactants, but also a nonnative secondary structure in the solid state. Finally, circular dichroism analysis of rehydrated complexes showed that the processing did not irreversibly alter the secondary structure of insulin. In short, the present study demonstrates changes in the secondary structure of insulin after freeze-drying from DMSO, constituting a potential generic issue with this technique for protein processing. In the specific case of insulin, the changes were found to be reversible, explaining the success of this strategy in previous studies.     

Evaluation of drug–drug interactions with fesoterodine

Purpose  To assess drug–drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Methods  Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Results  Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C_max; from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C_max (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Conclusions  Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives. Funding for this study was provided by Schwarz Biosciences GmbH, and Pfizer Inc.     

Synthesis,Physicochemical Properties,and Cytotoxicity of a Series of 5′-Ester Prodrugs of 5-Iodo-2′-deoxyuridine

Five aliphatic 5-esters of 5-iodo-2deoxyuridine (IDU) were synthesized via an acid chloride alcoholysis reaction. The solubility in pH 7.4 phosphate buffer, lipophilicity as determined by partition experiments in octanol/pH 7.4 buffer, and cytotoxicity of these potential prodrugs were evaluated. The esters showed a 43- to 250-fold increase in lipophilicity and a 1.6- to 14-fold decrease in aqueous solubility relative to IDU. At a concentration of 50 µM, all esters showed reduced cytotoxicity toward uninfected Vero cells relative to IDU.     

Inclusion Complex of Hydroxypropyl-β-Cyclodextrin with Carbamazepine: Preparation by Co-Dissolution,Characterization, and In Vivo Comparative Study of the Anticonvulsant Activity

Pharmaceutical Chemistry Journal - The inclusion complex of the antiepileptic drug carbamazepine with hydroxypropyl-β-cyclodextrin was prepared by co-dissolution in practically quantitative...     

Tamoxifen Citrate Loaded Solid Lipid Nanoparticles (SLN™): Preparation,Characterization, In Vitro Drug Release,and Pharmacokinetic Evaluation

Solid lipid nanoparticles (SLN) were prepared by emulsification and high pressure homogenization technique and characterized by size analysis and differential scanning calorimetry. The influence of experimental factors such as homogenization pressure, time, and surfactant concentration on the nanoparticle size and distribution were investigated to optimize the formulation. Homogenization at 15,000 psi for 3 cycles was found to be optimum and resulted in smaller sized nanoparticles. In case of tristearin SLN (TSSLN), tripalmitin SLN (TPSLN), and glycerol behenate SLN (GBSLN), the relatively smaller sized nanoparticles were obtained with 3% sodium tauroglycocholate. The SLN were loaded with an anticancer agent, tamoxifen citrate (TC). The TC-loaded TSSLN shown lower entrapment efficiency (78.78%) compared to the TPSLN (86.75%) and GBSLN (98.64%). Short term stability studies indicated a significant increase in size of nanoparticles when stored at 50°C, compared to those stored at 30°C and 4°C. The particle destabilization upon storage in case of all the types of nanoparticles studied was in the order of day light > artificial light > dark. An ultraviolet (UV) spectrophotometric method of estimation of tamoxifen in rat plasma was developed and validated. The TC‐loaded TSSLN was administered to the rats intravenously and the pharmacokinetic parameters in the plasma were determined. The t_1/2 and mean residence time of TC-loaded TSSLN in plasma was about 3.5-fold (p < 0.001) and 3-fold (p < 0.001) higher, respectively, than the free tamoxifen, indicating the potential of TC-loaded TSSLN as a long circulating system in blood. Thus the above mentioned solid lipid nanoparticles can be a beneficial system to deliver tamoxifen to cancer tissues through enhanced permeability and retention (EPR) effect.     

Preparation and Characterization of Silver Sulfadiazine–Loaded Polyvinyl Alcohol Hydrogels as an Antibacterial Wound Dressing

In this study, we prepared a series of silver sulfadiazine (AgSD)–loaded polyvinyl alcohol (PVA) hydrogels via electron beam (e-beam) irradiation. Our objective was to explore the influence of e-beam irradiation on the chemical structure and crystallinity of AgSD and the antibacterial properties of AgSD/PVA hydrogels. Prior to irradiation, we mixed AgSD in PVA solution in 2 forms, either suspended in water (WS) or dissolved in ammonia solution (AS). We noted that nano silver was released from AgSD/PVA-AS hydrogels immersed in deionized water, while it would not happen in AgSD/PVA-WS hydrogels. Both kinds of AgSD/PVA hydrogels exhibited good antibacterial activities against gram-negative Escherichia coli and gram-positive Staphylococcus aureus. And their antibacterial activity was not obviously affected by different dosages of e-beam irradiation. Moreover, the antibacterial activity of the AgSD/PVA-WS hydrogels was stronger than that of AgSD/PVA-AS. Accordingly, the cell cytotoxicity of the AgSD/PVA-WS hydrogels was higher than that of AgSD/PVA-AS. Our study results reveal that e-beam irradiation of PVA solution with dispersed AgSD is a simple and efficient way to prepare AgSD/PVA hydrogels, which might be an ideal antibacterial wound dressing.