Inclusion complex of aprepitant with cyclodextrin: evaluation of physico-chemical and pharmacokinetic properties

Objective: Aprepitant (APR) is a water insoluble drug approved for the treatment of chemotherapy induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV). The innovator Emend^® is a formulation incorporating drug nanoparticles with good bioavailability (~67%). The objective of the current work was to evaluate the feasibility of formulating a cyclodextrin complex of APR with enhanced solubility/dissolution rate and concomitantly bioavailability.

Methods: The complex was prepared using two approaches: kneading and slurry method. The formulated complex was evaluated using DSC, XRPD and FT-IR studies.

Results: DSC, XRPD and FT-IR studies confirmed the interaction of β-cyclodextrin with APR indicating formation of a true complex wherein the drug was encapsulated in the cyclodextrin cavity (inclusion phenomenon). In addition to inclusion complexation, non inclusion phenomenon viz., interaction among hydroxyl groups of cyclodextrin and APR was also observed. The saturation solubility and dissolution rate of drug complex was higher than that of aprepitant API. The rate (C_max) and extent of absorption (AUC) of APR from the complex were found to be comparable to that of Emend^® (Reference product).

Conclusion: These studies established that cyclodextrin complexation may provide another viable and cost effective option for enhancing solubility and bioavailability of APR.     

In vivo brain microdialysis as a formulation-screening tool for a poorly soluble centrally acting drug

Objective: Efficacy of a formulation of a poorly soluble centrally acting drug was evaluated by measuring dopamine responses using in vivo brain microdialysis.

Methods: Co-crystals (1:1) of carbamazepine and nicotinamide (CBZ–NCT) were complexed with cyclodextrins (γ-CDs) using supercritical fluid processing. Phase solubility and intrinsic dissolution were studied. Pharmacodynamic studies were performed on rats divided into three groups getting either CBZ–NCT in CD (20?mg/kg CBZ), pure CBZ solution or vehicle. A guide cannula was implanted to attach the microdialysis probe. Dialysate samples were analyzed for dopamine levels, which were compared between groups.

Results: The optimized CBZ formulation (5% w/w in γ-CD) with solubility – 10?mg/mL showed stepwise increase in dopamine response (maximum 250% of baseline) compared to neat CBZ or vehicle (p?Conclusion: Hence, brain microdialysis was successfully used to evaluate a dissolution rate enhancing formulation.     

A phospholipid complex to improve the oral bioavailability of flavonoids

Aim: A phospholipid complex (TFH-PC) was prepared to increase the oral bioavailability of isorhamnetin, kaempferol, and quercetin from TFH (total flavones of Hippophae rhamnoides L.).

Methods: Solvent evaporation was used to prepare TFH-PC. Relevant parameters were investigated based on the complexation rate of isorhamnetin, kaempferol, and quercetin. Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray power diffraction (X-RPD), and scanning electron microscopy (SEM) were used for characterization. Solubility, octanol–water partition coefficient (log P), dissolution rate, and in vivo pharmacokinetics were also investigated.

Results: TFH-PC was successfully prepared in tetrahydrofuran with a drug to phospholipid ratio of 1:1, reaction temperature of 20?°C, and a reaction time of 1?h. The complexation rates of isorhamnetin, kaempferol, and quercetin were 97.7%, 95.97%, and 92.23%, respectively. FT-IR, DSC, X-RPD, and SEM confirmed the formation of TFH-PC. The aqueous solubilities of the three flavonoids in TFH-PC increased 22.0–26.8-fold compared with TFH. The dissolution of isorhamnetin, kaempferol, and quercetin in TFH-PC was 84.32%, 90.77%, and 100% within 10?min, respectively, greatly improved over TFH. After oral administration of TFH-PC in rats, the bioavailability of isorhamnetin, kaempferol, and quercetin in TFH-PC relative to TFH was 223%, 172%, and 242%, respectively.

Conclusion: The oral absorption of isorhamnetin, kaempferol, and quercetin was significantly improved in TFH-PC, mainly due to increased solubility and dissolution rate. This phospholipid complex shows potential for oral delivery of the flavonoids in TFH.     

Enhancement of oral bioavailability of anti-HIV drug rilpivirine HCl through nanosponge formulation*

Objective: To synthesize β cyclodextrin nanosponges using a novel and efficient microwave mediated method for enhancing bioavailability of Rilpivirine HCl (RLP).

Significance: Belonging to BCS class II RLP has pH dependent solubility and poor oral bioavailability. However, a fatty meal enhances its absorption hence the therapy indicates that the dosage form be consumed with a meal. But then it becomes tedious and inconvenient to continue the therapy for years with having to face the associated gastric side effects such as nausea.

Method: Microwave synthesizer was used to mediate the poly-condensation reaction between β-cyclodextrin and cross-linker diphenylcarbonate. Critical parameters selected were polymer to cross-linker ratio, Watt power, reaction time and solvent volume. Characterization studies were performed using FTIR, DSC, SEM, ¹H-NMR and PXRD. Molecular modeling was applied to confirm the possibility of drug entrapment. In vitro drug dissolution followed by oral bioavailability studies was performed in Sprawley rats. Samples were analyzed using HPLC.

Results: Microwave synthesis yields para-crystalline, porous nanosponges (～205?nm). Drug entrapment led to enhancement of solubility and a two-fold increase in drug dissolution (P?C_max and AUC_0-∞ increases significantly (C_max of NS～ 586?±?5.91?ng/mL; plain RLP ～310?±?5. 74?ng/mL).

Conclusion: The approach offers a comfortable dosing zone for AIDs patients, negating the requirement of consuming the formulation in a fed state due to enhancement in drugs’ oral bioavailability.     

Carbamazepine and Polyethylene Glycol Solid Dispersions: Preparation,in Vitro Dissolution,and Characterization

Abstract

The objective of this study was to prepare solid dispersions of carbamazepine (CBZ) using polyethylene glycol (PEG) 4000 and PEG 6000, measure the dissolution, and characterize using x-ray diffraction, DSC, and IR spectroscopy. Solid dispersions were prepared by either the melt or solvent methods. A comparison of dissolution profiles of the solid dispersions indicated dramatic increases in the rate and extent of CBZ dissolution from solid dispersions. The dissolution of physical mixtures provided evidence of the solubilizing effects of PEGs. Untreated CBZ exhibited 10.09 ± 2.92% dissolution in 10 min (D_l0); whereas, a melt of PEG 6000 and CBZ at a ratio of 6: 1 provided 36.49 ± 1.97% and a melt of PEG 4000 and CBZ at a ratio of 6: 1 gave a D₁₀ of 23.59 ± 1.45%. The rate and extent of dissolution of CBZ were significantly higher when blends of the PEGs were employed to prepare solid dispersion. The melt method provided significantly higher rate and extent of dissolution of CBZ than the solvent method. Also, the rate and extent of dissolution of CBZ were significantly greater when the solid dispersion was cooled at room temperature as opposed to with ice (faster). X-ray diffractometry revealed almost a complete loss of crystallinity of CBZ in solid dispersions. IR spectrometry indicated an increase in amorphocity of the PEGs after melting. IR spectra suggested that no complexation occurred between the PEGs and CBZ. Alterations in the crystallinity of the system were also supported by the DSC thermograms. Decreasing heats of fusion implied decrease in crystallinity, which would be expected to provide greater dissolution rates. Peak melting temperatures obtained from the thermograms ruled out the possibility of the formation of a eutectic mixture. However, the formation of solid solution could also be a possible mechanism for the increase in dissolution.     

In vitro and in vivo evaluation of cyclodextrin-based nanosponges for enhancing oral bioavailability of atorvastatin calcium

The aim of this study was to explore the feasibility of complexing the poorly water-soluble drug atorvastatin calcium (AC) with β-cyclodextrin (β-CD) based nanosponges (NS), which offer advantages of improving dissolution rate and eventually oral bioavailability. Blank NS were fabricated at first by reacting β-CD with the cross-linker carbonyldiimidazole at different molar ratios (1:2, 1:4, and 1:8), then NS of highest solubilization extent for AC were complexed with AC. AC loaded NS (AC-NS) were characterized for various physicochemical properties. Pharmacokinetic, pharmacodynamics and histological finding of AC-NS were performed in rats. The prepared AC-NS showed particles size ranged from 408.7?±?12.9 to 423?±?15.9?nm while zeta potential values varied from ?21.7?±?0.90 to ?22.7?±?0.85?mV. The loading capacity varied from 17.9?±?1.21 to 34.1?±?1.16%. DSC, FT–IR, and PXRD studies confirmed the complexation of AC with NS and amorphous state of the drug in the complex. AC-NS displayed a biphasic release pattern with increase in the dissolution rate of AC as compared to plain AC. Oral administration of AC-NS (1:4 w/w, drug: NS) to rats led to 2.13-folds increase in the bioavailability as compared to AC suspension. Pharmacodynamics studies in rats with fatty liver revealed significant reduction (p?in vivo performance of AC.     

Two steps modification for improvement of cyclobenzaprine transdermal delivery: releasing from patch and penetrating through skin

The aim of this study was to improve the transdermal delivery of cyclobenzaprine (CBZ) from drug-in-adhesive patch which showed less side effects and better compliance. CBZ base was prepared and then characterized using differential scanning calorimetry (DSC). The interaction between CBZ and pressure-sensitive adhesive (PSA) was determined by Fourier Transform Infrared Spectroscopy (FT-IR). The influences of PSAs, penetration enhancers, patch thickness and drug content on the transdermal delivery of CBZ were studied thoroughly in vitro. Both CBZ releasing from patch and penetrating through the skin showed very great effect on the transdermal delivery of CBZ. The percentage of drug released from patch was increased with the decreasing of patch thickness, and so did the permeation percentage. The stratum corneum (SC) contributed approximately 57% resistance of total skin permeation resistance, and Span 20 increased the transdermal permeation by approximately 1.59-fold. The pharmacokinetic parameters were obtained through in vivo experiments of the optimized formulation using rabbit. Furthermore, the in vitro skin permeation results of CBZ patch correlated well with the in vivo absorption results in rabbit.     

Enhanced solubility and dissolution rate of amiodarone by complexation with β-cyclodextrin through different methods

The aim of this work was to investigate the inclusion complexation between amiodarone (AMD), a practically water insoluble anti arrhythmic agent, and β-cyclodextrin (βCD) in order to improve the solubility and the dissolution rate of the drug, in an attempt to enhance its bioavailability. The complexation was done through different methods: physical mixture (PM), coevaporated (CV), freeze-drying (FD) and spray-drying (SD). The data analysis indicated that the complexes produced by freeze-drying and spray-drying techniques resulted in amorphous samples (data obtained by DSC and XRPD), and showed a possible chemical interaction between OH-βCD group and AMD tertiary amine (visualized by FT-IR). Also, they presented higher thermal stability (demonstrated by TG) and the improvement of the drug dissolution rate.     

Gefitinib–cyclodextrin inclusion complexes: physico-chemical characterization and dissolution studies

Background: Gefitinib, an anticancer drug, has an extremely low aqueous solubility, and its oral absorption is limited by its dissolution rate. The solubility and dissolution of gefitinib can be improved by complexation with cyclodextrins (CDs). Methods: Phase solubility studies of gefitinib with hydroxypropyl βCD (HPβCD) and randomly methylated βCD (RMβCD) in n various aqueous systems was conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were prepared by freeze-drying method and characterized by X-ray diffractometry (X-RD) and differential scanning calorimetry (DSC). Results: Gefitinib formed stable complexes with HPβCD and RMβCD in distilled water as indicated by the association rate constants (Ks) of 458.9 and 1096.2 M^?1 for HPβCD and RMβCD, respectively. The complexation of gefitinib with CDs in pH 4.5 acetate buffer indicated an A_N type of phase-solubility diagrams, whereas gefitinib and HPβCD in distilled water in the presence of polymers such as polyvinyl pyrrolidone K-30 (PVP) or hydroxypropyl methylcellulose E3 (HPMC) resulted in A_P-type phase-solubility diagrams. The solid-state amorphous complexes (as described by DSC and X-RD) showed substantial increases in the solubility and dissolution rate of gefitinib with both CDs. Further increases in the solubility and dissolution rate of the gefitinib-HPβCD freeze-dried complex were obtained by physically mixing the complex with PVP and HPMC. Conclusion: Gefitinib formed stable inclusion complexes with HPβCD and RMβCD, and the solubility and dissolution rate of the drug was significantly increased.     

Fabrication of solid lipid nanoparticles of lurasidone HCl for oral delivery: optimization,in vitro characterization,cell line studies and in vivo efficacy in schizophrenia

Objective: The aim of the present investigation was to investigate the efficacy of solid lipid nanoparticles (SLNs) to enhance the absorption and bioavailability of lurasidone hydrochloride (LH) following oral administration.

Methods: The LH loaded SLNs (LH-SLNs) were prepared by high pressure homogenization (HPH) method, optimized using box Behnken design and evaluated for particle size (PS), entrapment efficiency (EE), morphology, FTIR, DSC, XRD, in vitro release, ex vivo permeation, transport studies across Caco-2 cell line and in vivo pharmacokinetic and pharmacodynamic studies.

Results: The LH-SLNs had PS of 139.8?±?5.5?nm, EE of 79.10?±?2.50% and zeta potential of ?30.8?±?3.5?mV. TEM images showed that LH-SLNs had a uniform size distribution and spherical shape. The in vitro release from LH-SLNs followed the Higuchi model. The ex vivo permeability study demonstrated enhanced drug permeation from LH-SLNs (>90%) through rat intestine as compared to LH-suspension. The SLNs were found to be taken up by energy dependent, endocytic mechanism which was mediated by clathrin/caveolae-mediated endocytosis across Caco-2 cell line. The pharmacokinetic results showed that oral bioavailability of LH was improved over 5.16-fold after incorporation into SLNs as compared to LH-suspension. The pharmacodynamic study proved the antipsychotic potential of LH-SLNs in the treatment of schizophrenia.

Conclusion: It was concluded that oral administration of LH-SLNs in rats improved the bioavailability of LH via lymphatic uptake along with improved therapeutic effect in MK-801 induced schizophrenia model in rats.     

Budesonide/cyclodextrin complex-loaded lyophilized microparticles for intranasal application

Objective: Lyophilized microparticles composed of budesonide (BDS), hydroxypropyl-β-cyclodextrin (HP-β-CD), and hydroxypropylmethylcellulose (HPMC) or sodium carboxymethylcellulose (CMC-Na) were developed for intranasal delivery and their characteristics were evaluated.

Materials and methods: The particle size and morphology were assessed by mean diameter measurement and scanning electron microscopy (SEM) image, respectively. The solid-state of products was tested by X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). In vitro drug release and cytotoxicity to the primary human nasal epithelial (HNE) cells were also evaluated.

Results and discussion: Lyophilized microparticles exhibited vanishment of crystallinity of drug in XRPD analysis, the enfeeblement of carbonyl (C=O) stretching bands of carboxyl group in BDS in FT-IR spectra and the disappearance of endothermic peak of drug in the results of DSC study. Based on the results of solid-state studies, BDS was existed as an amorphous form in the lyophilized microparticles. CD complexation enhanced drug solubility and release rate, and HPMC or CMC-Na also improved drug dissolution rates. Cytotoxicity of developed microparticles to the HNE cells was measured and their safety to HNE cell was identified.

Conclusion: Developed microparticles can efficiently deliver insoluble drug, such as BDS, to the nasal epithelium and thus it may improve therapeutic efficacy in the respiratory tract.     

Carbamazepine and Polyethylene Glycol Solid Dispersions: Preparation, in Vitro Dissolution, and Characterization

The objective of this study was to prepare solid dispersions of carbamazepine (CBZ) using polyethylene glycol (PEG) 4000 and PEG 6000, measure the dissolution, and characterize using x-ray diffraction, DSC, and IR spectroscopy. Solid dispersions were prepared by either the melt or solvent methods. A comparison of dissolution profiles of the solid dispersions indicated dramatic increases in the rate and extent of CBZ dissolution from solid dispersions. The dissolution of physical mixtures provided evidence of the solubilizing effects of PEGs. Untreated CBZ exhibited 10.09 ± 2.92% dissolution in 10 min (D_l0); whereas, a melt of PEG 6000 and CBZ at a ratio of 6: 1 provided 36.49 ± 1.97% and a melt of PEG 4000 and CBZ at a ratio of 6: 1 gave a D₁₀ of 23.59 ± 1.45%. The rate and extent of dissolution of CBZ were significantly higher when blends of the PEGs were employed to prepare solid dispersion. The melt method provided significantly higher rate and extent of dissolution of CBZ than the solvent method. Also, the rate and extent of dissolution of CBZ were significantly greater when the solid dispersion was cooled at room temperature as opposed to with ice (faster). X-ray diffractometry revealed almost a complete loss of crystallinity of CBZ in solid dispersions. IR spectrometry indicated an increase in amorphocity of the PEGs after melting. IR spectra suggested that no complexation occurred between the PEGs and CBZ. Alterations in the crystallinity of the system were also supported by the DSC thermograms. Decreasing heats of fusion implied decrease in crystallinity, which would be expected to provide greater dissolution rates. Peak melting temperatures obtained from the thermograms ruled out the possibility of the formation of a eutectic mixture. However, the formation of solid solution could also be a possible mechanism for the increase in dissolution.     

Preparation of stable micron-sized crystalline irbesartan particles for the enhancement of dissolution rate

Purpose: In this study, micron-sized crystalline drug particles of irbesartan (IBS) were prepared to improve its stability and dissolution rate.

Method: The approach to crystalline particles was based on the liquid precipitation process by which the amorphous particles were prepared. Pharmaceutical acceptable additives were used as the crystallization agent to convert the amorphous drug into crystalline particles. High pressure homogenization (HPH) process has been employed to reduce the size of the crystalline particles, and the micron-sized particles were obtained by the freeze-drying process.

Results: Different additives show different influences on the polymorphic form of IBS. Polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) were effective in stabilizing amorphous particles instead of converting amorphous drug into crystalline particles, while poloxamer407 (F127) and tween80 (T80) could convert the amorphous drug into crystalline particles. T80 was also effective in controlling the particle size than that of F127. After HPH, crystalline particles with an average of 0.8 μm were obtained. The freeze-dried micron-sized crystalline particles exhibited significantly enhanced in vitro dissolution rate when compared to the raw drug. SEM, FT-IR, XRD, DSC and dissolution rate studies indicated that the micron-sized particles were stable during 6 months storage.

Conclusion: The preparation of micron-sized crystalline drug particles is an effective way to improve the stability and dissolution rate of irbesartan.     

Preparation of curcumin-hydroxypropyl-β-cyclodextrin inclusion complex by cosolvency-lyophilization procedure to enhance oral bioavailability of the drug

Abstract

The curcumin (CUR)-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex (CUR-HP-β-CD) was prepared to erase its therapeutic restrictions of poor aqueous solubility and low oral bioavailability. CUR-HP-β-CD was prepared by a simple procedure of water-ethanol cosolvent incubation-lyophilization which may be suitable for scale up production, and characterized by Fourier transform-infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), phase solubility method and dissolution study; the in vitro cytotoxicity was assayed by MTT, whereas the in vivo pharmacokinetics was tested by HPLC in rats receiving formulations via intravenous and oral administration, respectively. CUR was successfully encapsulated in HP-β-CD with a loading capacity of about 1:7 of CUR to HP-β-CD mole ratio, which remarkably enhanced drug water solubility and maintained well the antitumour activity of CUR. The CUR-HP-β-CD and free CUR have a similar pharmacokinetic behaviour in rats after intravenous administration; however, the oral bioavailability of CUR was enhanced to 2.77-fold by the HP-β-CD. The CUR-HP-β-CD can be successfully prepared by a simple method, which may be feasible for industrial scaling up, to remarkably increase drug water solubility and oral bioavailability while maintaining its bioactivity and may be a promising therapeutic preparation.     

Complexation as an approach to entrap cationic drugs into cationic nanoparticles administered intranasally for Alzheimer's disease management: preparation and detection in rat brain

Abstract

Objective: Complexation was investigated as an approach to enhance the entrapment of the cationic neurotherapeutic drug, galantamine hydrobromide (GH) into cationic chitosan nanoparticles (CS-NPs) for Alzheimer’s disease management intranasally. Biodegradable CS-NPs were selected due to their low production cost and simple preparation. The effects of complexation on CS-NPs physicochemical properties and uptake in rat brain were examined.

Methods: Placebo CS-NPs were prepared by ionic gelation, and the parameters affecting their physicochemical properties were screened. The complex formed between GH and chitosan was detected by the FT-IR study. GH/chitosan complex nanoparticles (GH-CX-NPs) were prepared by ionic gelation, and characterized in terms of particle size, zeta potential, entrapment efficiency, in vitro release and stability for 4 and 25?°C for 3 months. Both placebo CS-NPs and GH-CX-NPs were visualized by transmission electron microscopy. Rhodamine-labeled GH-CX-NPs were prepared, administered to male Wistar rats intranasally, and their delivery to different brain regions was detected 1?h after administration using fluorescence microscopy and software-aided image processing.

Results: Optimized placebo CS-NPs and GH-CX-NPs had a diameter 182 and 190?nm, and a zeta potential of +40.4 and +31.6?mV, respectively. GH encapsulation efficiency and loading capacity were 23.34 and 9.86%, respectively. GH/chitosan complexation prolonged GH release (58.07%?±?6.67 after 72?h), improved formulation stability at 4?°C in terms of drug leakage and particle size, and showed insignificant effects on the physicochemical properties of the optimized placebo CS-NPs (p?>?0.05). Rhodamine-labeled GH-CX-NPs were detected in the olfactory bulb, hippocampus, orbitofrontal and parietal cortices.

Conclusion: Complexation is a promising approach to enhance the entrapment of cationic GH into the CS-NPs. It has insignificant effect on the physicochemical properties of CS-NPs. GH-CX-NPs were successfully delivered to different brain regions shortly after intranasal administration suggesting their potential as a delivery system for Alzheimer’s disease management.     

Physicochemical,pharmacokinetic and pharmacodynamic evaluations of novel ternary solid dispersion of rebamipide with poloxamer 407

This study was conducted primarily to improve the solubility of rebamipide, a poorly water-soluble anti-ulcer drug, using novel ternary solid dispersion (SD) systems and secondly to evaluate the effect of solubility enhancement on its pharmacokinetic (PK) and pharmacodynamic (PD) profile. After dissolving the three components in aqueous medium, ternary SD containing the drug, sodium hydroxide (NaOH) and PVP-VA 64 was achieved by spray drying method, which was used as primary SD. Poloxamer 407, a surfactant polymer, was incorporated in this primary SD by four different methods: co-grinding, physical mixing, melting or spray drying. SD was then characterized by dissolution test, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). The spray dried SD of poloxamer 407 together with primary SD displayed highest dissolution rate of the drug of about 70% after 2 h. DSC, PXRD and FT-IR characterized the amorphous state and molecular dispersion of the drug in the SD. PK and PD studies in Sprague–Dawley rats revealed that the bioavailability of the drug using optimal SD was about twofold higher than that of reference product, and the irritation area of stomach was significantly reduced in the ulcer-induced rat model using optimal SD as compared to the reference product.     

In vitro and in vivo studies on a novel solid dispersion of repaglinide using polyvinylpyrrolidone as the carrier

In order to improve the dissolution and absorption of the water insoluble drug repaglinide, a solid dispersion was developed by solvent method using polyvinylpyrrolidone K30 (PVP K30) as the hydrophilic carrier for the first time. Studies indicated that both solubility and the dissolution rate of repaglinide were significantly increased in the solid dispersion system compared with that of repaglinide raw material or physical mixtures. The repaglinide solid dispersions with PVP K30 solid state was characterized by polarizing microscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). DSC and XRD studies indicated that repaglinide existed in an amorphous form in the solid dispersion. FT-IR analysis demonstrated the presence of intermolecular hydrogen bonding between repaglinide and PVP K30 in the solid dispersion. In the in situ gastrointestinal perfusion experiment, solid dispersion was shown to remarkably enhance the absorption of repaglinide in stomach and all segments of intestine. In vivo pharmacokinetic study in rats showed that immediate and complete release of repaglinide from the solid dispersion resulted in rapid absorption that significantly increased the bioavailability and the maximum plasma concentration over repaglinide raw material. These results demonstrated PVP K30 was an appropriate carrier for solid dispersion of repaglinide, with increased dissolution and oral absorption.     

Development of paracetamol-caffeine co-crystals to improve compressional,formulation and in vivo performance

Paracetamol, a frequently used antipyretic and analgesic drug, has poor compression moldability owing to its low plasticity. In this study, new co-crystals of paracetamol (PCM) with caffeine (as a co-former) were prepared and delineated. Co-crystals exhibited improved compaction and mechanical behavior. A screening study was performed by utilizing a number of methods namely dry grinding, liquid assisted grinding (LAG), solvent evaporation (SE), and anti-solvent addition using various weight ratios of starting materials. LAG and SE were found successful in the screening study. Powders at 1:1 and 2:1 weight ratio of PCM/CAF by LAG and SE, respectively, resulted in the formation of co-crystals. Samples were characterized by PXRD, DSC, and ATR-FTIR techniques. Compressional properties of PCM and developed co-crystals were analyzed by in-die heckle model. Mean yield pressure (Py), an inverse measure of plasticity, obtained from the heckle plots decreased significantly (p?In vitro dissolution studies on tablets also showed enhanced dissolution profiles (～90–97%) in comparison to the tablets of PCM prepared by direct compression (～55%) and wet granulation (～85%) methods. In a single dose sheep model study, co-crystals showed up to twofold increase in AUC and C_max. A significant (p?in vitro and in vivo profile. Enhancement in AUC and C_max of PCM by co-crystallization might suggest the dose reduction and avoidance of side effects.     

Dry powders for the inhalation of ciprofloxacin or levofloxacin combined with a mucolytic agent for cystic fibrosis patients

Objective: This study aimed to design and characterize an inhalable dry powder of ciprofloxacin or levofloxacin combined with the mucolytics acetylcysteine and dornase alfa for the management of pulmonary infections in patients with cystic fibrosis.

Methods: Ball milling, homogenization in isopropyl alcohol and spray drying processes were used to prepare dry powders for inhalation. Physico-chemical characteristics of the dry powders were assessed via thermogravimetric analysis, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry and scanning electron microscopy. The particle size distribution, dissolution rate and permeability across Calu-3 cell monolayers were analyzed. The aerodynamic parameters of dry powders were determined using the Andersen cascade impactor (ACI).

Results: After the micronization process, the particle sizes of the raw materials significantly decreased. X-ray and DSC results indicated that although ciprofloxacin showed no changes in its crystal structure, the structure of levofloxacin became amorphous after the micronization process. FT-IR spectra exhibited the characteristic peaks for ciprofloxacin and levofloxacin in all formulations. The dissolution rates of micro-homogenized and spray-dried ciprofloxacin were higher than that of untreated ciprofloxacin. ACI results showed that all formulations had a mass median aerodynamic diameter less than 5?μm; however, levofloxacin microparticles showed higher respirability than ciprofloxacin powders did. The permeability of levofloxacin was higher than those of the ciprofloxacin formulations.

Conclusion: Together, our study showed that these methods could suitably characterize antibiotic and mucolytic-containing dry powder inhalers.     

Development of novel gastroretentive drug delivery system of gliclazide: hollow beads

Aim: The current communication deals with the development of hollow floating beads of gliclazide. The primary effect of this drug is to potentiate glucose-stimulated insulin release from pancreatic islet-β-cells by induction of a decrease in potassium efflux from these cells. Because of the poor aqueous solubility, its absorption is limited. Thus, an attempt was made to improve its release profile.

Methods: The hollow drug-loaded alginate beads in combination with low methoxyl pectin and hydroxypropylmethylcellulose (HPMC) were prepared by a simple ionotropic gelation method. The beads were evaluated for particle size and morphology using optical microscopy and scanning electron microscopy (SEM), respectively. Mucoadhesion test was done using goat stomach mucosal membrane. Release characteristics of the gliclazide-loaded hollow beads were studied in 0.1?N HCl (pH 1.2) and phosphate buffer (pH 5.8).

Results: The developed beads were spherical in shape with hollow internal structure and had a particle size in the range of 0.730?±?0.05 to 0.890?±?0.03?mm. The incorporation efficiency of alginate -pectin beads was higher than alginate -HPMC beads. The Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction analysis showed stable character of drug in the drug-loaded hollow beads and revealed the absence of any drug -polymer interactions. The beads remained buoyant for more than 12?h. The drug release from beads followed Fickian diffusion with swelling.

Conclusion: The preliminary results of this study suggest that the developed beads containing gliclazide could enhance drug entrapment efficiency, reduce the initial burst release and modulate the drug release.