Mechanistic Investigation of Pluronic® Based Nano-crystalline Drug-polymer Solid Dispersions

Purpose

To understand the mechanism of nano-crystalline drug formation in Pluronic® (i.e., poly(ethylene oxide-block-propylene oxide) triblock copolymers) based drug-polymer solid dispersions.

Materials and Methods

Four polymers, Pluronic® F127, F108, F68 and PEG 8000, which have different poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) ratio and chain length, were co-spray dried with BMS-347070, a COX-2 inhibitor, to form 50/50 (w/w) drug-polymer solid dispersions. The solid dispersions were analyzed by powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), and hot-stage microscopy. Average size of drug crystallites in different polymers was calculated by the Scherrer equation based on peak-broadening effect in PXRD. Two other drug compounds, BMS-A and BMS-B, were also spray dried with Pluronic® F127, and the solid dispersions were analyzed by PXRD and mDSC.

Results

The average size of BMS-347070 crystallites in PEG 8000, F127, F108 and F68 polymers was 69, 80, 98 and 136 nm, respectively, and the degree of BMS-347070 crystallinity is the lowest in PEG 8000. Hot-stage microscopy showed that 50/50 drug-polymer dispersions crystallized in a two-step process: a portion of the polymer crystallizes first (Step 1), followed by crystallization of drug and remaining polymer (Step 2). The T _g value of the BMS-347070/Pluronic® dispersions after Step 1 (i.e., T _g1) was measured and/or calculated to be 15–26°C, and that of BMS-347070/PEG 8000 was 60°C. Solid dispersions of BMS-A and BMS-B in Pluronic® F127 have T _g1 of 72 and 3°C, respectively; and PXRD showed BMS-A remained amorphous after ～3 weeks under ambient condition, while BMS-B crystallized in F127 with an average crystallite size of 143 nm.

Conclusions

The size of drug crystallites in the drug-polymer solid dispersions is independent of polymer topology, but is caused kinetically by a combined effect of nucleation rate and crystal growth rate. When drug-Pluronic® solid dispersions crystallize at room temperature, that is close to the T _g1 of the systems, a fast nucleation rate and a relatively slow crystal growth rate of the drug synergistically produced small crystallite size. While the much higher T _g1 value of drug-PEG 8000 led to a slower nucleation rate and an even slower crystal growth rate at room temperature, therefore, small crystallite size and low drug crystallinity were observed. Results from BMS-A/Pluronic® and BMS-B/Pluronic® systems confirmed this kinetic theory.

     

Supramolecular Chitosan Micro-Platelets Synergistically Enhance Anti-<Emphasis Type="BoldItalic">Candida albicans</Emphasis> Activity of Amphotericin B Using an Immunocompetent Murine Model

Purpose

The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity.

Methods

Micro-platelets were obtained by mixing oleoyl chitosan and α-cyclodextrin in water. The formulation is specifically-engineered for mucosal application by dispersing chitosan micro-platelets into thermosensitive pluronic^® F127 20 wt% hydrogel.

Results

The formulation completely cured C. albicans vaginal infection in mice and had a superior activity in comparison with AmB-DOC without addition of chitosan micro-platelets. In vitro studies showed that the platelets significantly enhance AmB-DOC antifungal activity since the IC₅₀ and the MIC₉₀ decrease 4.5 and 4.8-times. Calculation of fractional inhibitory concentration index (FICI?=?0.198) showed that chitosan micro-platelets act in a synergistic way with AmB-DOC against C. albicans. No synergy is found between spherical nanoparticles composed poly(isobutylcyanoacrylate)/chitosan and AmB-DOC.

Conclusion

These results demonstrate for the first time the ability of flattened chitosan micro-platelets to have synergistic activity with AmB-DOC against C. albicans candidiasis and highlight the importance of rheological and mucoadhesive behaviors of hydrogels in the efficacy of the treatment.

     

Probing the Distribution of Water in a Multi-Component System by Solid-State NMR Spectroscopy

Purpose

To characterize the distribution of water among various components in a powder blend using solid-state NMR spectroscopy.

Methods

Water sorption behavior of theophylline anhydrate and excipients was determined by dynamic vapor sorption (DVS) and Karl Fischer Titration (KFT) after storing them in humidity chambers for 1 week at room temperature (RT) and calibration curves were generated for water content vs. ¹H T ₁ relaxation times. Powder blends (either with microcrystalline cellulose or lactose as diluent) were stored at different relative humidity (RH) conditions and analyzed periodically using solid-state NMR, powder X-ray diffraction, and KFT.

Results

Anhydrous theophylline converted to the hydrate at?≥?84% RH. Based on the calibration curves of water content vs. relaxation times, the distribution of water in the powder blends was estimated. The total water content calculated using ssNMR was in good agreement with values measured using KFT. In blends stored at 90% RH, theophylline anhydrate-to-hydrate conversion did not occur in 1 week.

Conclusions

The distribution of water in multi-component powder blends was successfully determined using correlation between ¹H T ₁ relaxation times and total water content. Excipient water sorption inhibited hydrate formation in theophylline at 90% RH. Water distribution was affected by excipient type. The extent of water sorbed by excipients in blends was found to be different than their standalone equilibrium water content.

     

Impact of Drug-Polymer Miscibility on Enthalpy Relaxation of Irbesartan Amorphous Solid Dispersions

Purpose

Drug-polymer miscibility has been proposed to play a critical role in physical stability of amorphous solid dispersions (ASDs). The purpose of the current work was to investigate the role of drug-polymer miscibility on molecular mobility, measured as enthalpy relaxation (ER) of amorphous irbesartan (IBS) in ASDs.

Methods

Two polymers, i.e. polyvinylpyrrolidone K30 (PVP K30) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), were used to generate ASDs with 10% w/w of the polymer. Drug-polymer miscibility was determined using melting point depression (MPD) method. Molecular mobility was assessed from ER studies at a common degree of undercooling (DOU) (T_g???13.0°C?±?0.5°C).

Results

IBS exhibited higher miscibility in PVP K30 as compared to HPMCAS at temperature?>?140°C. However, extrapolation of miscibility data to storage temperature (62°C) using Flory-Huggins (F-H) theory revealed a reversal of the trend. Miscibility of IBS was found to be higher in HPMCAS (2.6%) than PVP K30 (1.3%) at 62°C. Stretched relaxation time (τ^β) of 17.4365 h and 7.0886 h was obtained for IBS-HPMCAS and IBS-PVP K30 ASDs, respectively.

Conclusion

Miscibility of drug-polymer at storage temperature explained the behavior of the molecular mobility, while miscibility near the melting point provided a reverse trend. Results suggest that drug-polymer miscibility determined at temperatures higher than the storage temperature should be viewed cautiously.

     

Characterization of Heterogeneity and Spatial Distribution of Phases in Complex Solid Dispersions by Thermal Analysis by Structural Characterization and X-ray Micro Computed Tomography

Purpose

This study investigated the effect of drug-excipient miscibility on the heterogeneity and spatial distribution of phase separation in pharmaceutical solid dispersions at a micron-scale using two novel and complementary characterization techniques, thermal analysis by structural characterization (TASC) and X-ray micro-computed tomography (XμCT) in conjunction with conventional characterization methods.

Method

Complex dispersions containing felodipine, TPGS, PEG and PEO were prepared using hot melt extrusion-injection moulding. The phase separation behavior of the samples was characterized using TASC and XμCT in conjunction with conventional thermal, microscopic and spectroscopic techniques. The in vitro drug release study was performed to demonstrate the impact of phase separation on dissolution of the dispersions.

Results

The conventional characterization results indicated the phase separating nature of the carrier materials in the patches and the presence of crystalline drug in the patches with the highest drug loading (30% w/w). TASC and XμCT where used to provide insight into the spatial configuration of the separate phases. TASC enabled assessment of the increased heterogeneity of the dispersions with increasing the drug loading. XμCT allowed the visualization of the accumulation of phase separated (crystalline) drug clusters at the interface of air pockets in the patches with highest drug loading which led to poor dissolution performance. Semi-quantitative assessment of the phase separated drug clusters in the patches were attempted using XμCT.

Conclusion

TASC and XμCT can provide unique information regarding the phase separation behavior of solid dispersions which can be closely associated with important product quality indicators such as heterogeneity and microstructure.

     

Predicting Pulmonary Pharmacokinetics from <Emphasis Type="Italic">In Vitro</Emphasis> Properties of Dry Powder Inhalers

Purpose

The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed for mometasone furoate, budesonide and fluticasone propionate.

Methods

Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived. In approach 1, the rate of in vivo drug dissolution/absorption was predicted for the included ICSs from in vitro aerodynamic particle size distribution and in vitro drug solubility estimates measured in an in vivo predictive dissolution medium. Approach 2 derived a first order absorption rate from the mean dissolution time (MDT), determined for the test formulations in an in vitro Transwell^® based dissolution system.

Results

Approach 1 suggested PK profiles which agreed well with the published pharmacokinetic profiles. Similarly, within approach 2, input parameters for the pulmonary absorption rate constant derived from dissolution rate experiments were able to reasonably predict the pharmacokinetic profiles published in literature.

Conclusion

Approach 1 utilizes more complex strategies for predicting the dissolution/absorption process without providing a significant advantage over approach 2 with regard to accuracy of in vivo predictions.

     

Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis

Purpose

Analog development of existing drugs and direct drug delivery to the lungs by inhalation as treatments for multiple and extensively drug resistant (MDR and XDR) tuberculosis (TB) represent new therapeutic strategies. Pyrazinamide (PZA) is critical to drug sensitive TB therapy and is included in regimens for MDR TB. However, PZA-resistant Mycobacterium tuberculosis (Mtb) strains threaten its use. Pyrazinoic acid esters (PAEs) are PZA analogs effective against Mtb in vitro, including against the most common PZA resistant strains. However, PAEs require testing for TB efficacy in animal models.

Methods

PAEs were delivered daily as aqueous dispersions from a vibrating mesh nebulizer to Mtb infected guinea pigs for 4 weeks in a regimen including orally administered first-line TB drugs.

Results

PAEs tested as a supplement to oral therapy significantly reduced the organ bacterial burden in comparison to infected, untreated control animals. Thus, PAE aerosol therapy is a potentially significant addition to the regimen for PZA resistant MDR-TB and XDR-TB treatment. Interestingly, low dose oral PZA treatment combined with standard therapy also reduced bacterial burden. This observation may be important for PZA susceptible disease treatment.

Conclusion

The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB.

     

A Comparative Study of Orally Delivered PBCA and ApoE Coupled BSA Nanoparticles for Brain Targeting of Sumatriptan Succinate in Therapeutic Management of Migraine

Purpose

The present investigation aimed at brain targeting of sumatriptan succinate (SS) for its optimal therapeutic effect in migraine through nanoparticulate drug delivery system using poly (butyl cyanoacrylate) (PBCA) and bovine serum albumin linked with apolipoprotein E3 (BSA-ApoE).

Method

The study involved formulation optimization of PBCA nanoparticles (NPs) using central composite design for achieving minimum particle size, maximum entrapment efficiency along with sustained drug release. SS incorporated in BSA-ApoE NPs (S-AA-NP) were prepared by desolvation technique and compared with SS loaded polysorbate 80 coated optimized PBCA NPs (FP_opt) in terms of their brain uptake potential, upon oral administration in male Wistar rats. The NPs were characterized by FTIR, thermal, powder XRD and TEM analysis.

Results

The in vivo studies of FP_opt and S-AA-NP on male Wistar rats demonstrated a fairly high brain/plasma drug ratio of 9.45 and 12.67 respectively 2 h post oral drug administration. The behavioural studies on male Swiss albino mice affirmed the enhanced anti-migraine potential of S-AA-NP than FP_opt (P?<?0.001).

Conclusion

The results of this work, therefore, indicate that BSA-ApoE NPs are significantly better than polysorbate 80 coated PBCA NPs for brain targeting of SS (P?<?0.05) and also offer an improved therapeutic strategy for migraine management.

     

A Comparison of Two Methods for the Preparation Cefquinome-Loaded Gelatin Microspheres for Lung Targeting

Purpose

The aim of this study was to prepare CEQ-loaded gelatin microspheres and compare two preparation methods, evaluate targeting to the lungs.

Methods

Gelatin microspheres containing CEQ were prepared by an emulsion cross-linking method (ECLM) and a spray-drying method (SDM) and were characterized in terms of morphology, size, drug-loading coefficient, encapsulation ratio and in vitro release.

Results

The microspheres prepared by ECLM gave a drug loading (DL) of 19.4?±?2.4% and an entrapment efficiency (EE) of 80.8?±?3.2%. The microspheres prepared by SDM resulted in a DL value of 20.8?±?2.7% and an EE of 95.3?±?3.8%. The average particle size of microspheres was 7-30 μm by both methods and both preparations sustained CEQ release for 36 h in the target tissue (lungs). The in vitro release profile of the microspheres matched the Korsmeyer-Peppas release pattern. In vivo studies identified the lung as the target tissue and the region of maximum CEQ release. Histopathological examination showed a partial lung inflammation that disappeared spontaneously as the microspheres were biodegraded. In general, the formulations were safe.

Conclusion

The well-sustained CEQ release from the microspheres revealed its suitability as a drug delivery vehicle that minimized injury to healthy tissues while achieving the accumulation of therapeutic drug for lung targeting. The intravenous administration of CEQ gelatin microspheres prepared by SDM is of potential value in treating lung diseases in animals.

     

Optimization of Weight Ratio for DSPE-PEG/TPGS Hybrid Micelles to Improve Drug Retention and Tumor Penetration

Purpose

To enhance therapeutic efficacy and prevent phlebitis caused by Asulacrine (ASL) precipitation post intravenous injection, ASL-loaded hybrid micelles with size below 40 nm were developed to improve drug retention and tumor penetration.

Methods

ASL-micelles were prepared using different weight ratios of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethyleneglycol-2000 (DSPE-PEG₂₀₀₀) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) polymers. Stability of micelles was optimized in terms of critical micelle concentration (CMC) and drug release properties. The encapsulation efficiency (EE) and drug loading were determined using an established dialysis-mathematic fitting method. Multicellular spheroids (MCTS) penetration and cytotoxicity were investigated on MCF-7 cell line. Pharmacokinetics of ASL-micelles was evaluated in rats with ASL-solution as control.

Results

The ASL-micelles prepared with DSPE-PEG₂₀₀₀ and TPGS (1:1, w/w) exhibited small size (~18.5 nm), higher EE (~94.12%), better sustained in vitro drug release with lower CMC which may be ascribed to the interaction between drug and carriers. Compared to free ASL, ASL-micelles showed better MCTS penetration capacity and more potent cytotoxicity. Pharmacokinetic studies demonstrated that the half-life and AUC values of ASL-micelles were approximately 1.37-fold and 3.49-fold greater than that of free ASL.

Conclusions

The optimized DSPE-PEG₂₀₀₀/TPGS micelles could serve as a promising vehicle to improve drug retention and penetration in tumor.

     

Optimization,Biopharmaceutical Profile and Therapeutic Efficacy of Pioglitazone-loaded PLGA-PEG Nanospheres as a Novel Strategy for Ocular Inflammatory Disorders

Purpose

The main goal of this study was to encapsulate Pioglitazone (PGZ), in biodegradable polymeric nanoparticles as a new strategy for the treatment of ocular inflammatory processes.

Methods

To improve their biopharmaceutical profile for the treatment of ocular inflammatory disorders, nanospheres (NSs) of PGZ were formulated by factorial design with poly (lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG). Interactions drug-polymer have been carried out by spectroscopic (X-ray spectroscopy, FTIR) and thermal methods (DSC). The PGZ-NSs were tested for their in vitro release profile, cytotoxicity, and ocular tolerance (HET-CAM® test); ex vivo corneal permeation, and in vivo inflammatory prevention and bioavailability.

Results

The optimized system showed a negative surface charge of ?13.9 mV, an average particle size (Z_av) of around 160 nm, a polydispersity index (PI) below 0.1, and a high encapsulation efficiency (EE) of around 92%. According to the DSC results, the drug was incorporated into the NSs polymeric matrix. The drug release was sustained for up to 14 h. PGZ-NSs up to 10 μg/ml exhibited no retinoblastoma cell toxicity. The ex vivo corneal and scleral permeation profiles of PGZ-NSs showed that retention and permeation through the sclera were higher than through the cornea. Ocular tolerance in vitro and in vivo demonstrated the non-irritant character of the formulation.

Conclusion

The in vivo anti-inflammatory efficacy of developed PGZ-NSs indicates this colloidal system could constitute a new approach to prevent ocular inflammation.

     

Polymorphic Transformation of Indomethacin during Hot Melt Extrusion Granulation: Process and Dissolution Control

Purpose

To study and elucidate the effect of the intensity and duration of processing stresses on the possible solid-state changes during a hot melt extrusion granulation process.

Methods

Blends of α-indomethacin and PEG 3350 (w/w 4:1) were granulated using various screw sizes/designs on the melt extruder under different temperature regimes. Differential Scanning Calorimetry and X-ray Powder Diffraction were employed for characterization. The dissolution behavior of the pure polymorphs and the resulting granules was determined using in-situ fiber optic UV testing system. An XRPD quantitation method using Excel full pattern fitting was developed to determine the concentration of each constituent (amorphous, α and γ indomethacin and PEG) in samples collected from each functioning zone and in granules.

Results

Analysis of in-process samples and granules revealed that higher temperature (≥130°C) and shear stress accelerated the process induced phase transitions from amorphous and/or the α form to γ indomethacin during heating stage. However, rapid cooling resulted in an increased percentage of the α form allowing isolation of the meta-stable form.

Conclusions

By determining the conditions that either prevent or facilitate process induced transformations of IMC polymorphs during melt granulation, a design space was developed to control the polymorph present in the resulting granules. This represents the conditions necessary to balance the thermodynamic relationships between the polymorphs of the IMC system and the kinetics of the possible transformations as a function of the processing stresses.

     

Detection and Specific Elimination of EGFR<Superscript>+</Superscript> Ovarian Cancer Cells Using a Near Infrared Photoimmunotheranostic Approach

Purpose

Targeted theranostics is an alternative strategy in cancer management that aims to improve cancer detection and treatment simultaneously. This approach combines potent therapeutic and diagnostic agents with the specificity of different cell receptor ligands in one product. The success of antibody drug conjugates (ADCs) in clinical practice has encouraged the development of antibody theranostics conjugates (ATCs). However, the generation of homogeneous and pharmaceutically-acceptable ATCs remains a major challenge. The aim of this study is to detect and eliminate ovarian cancer cells on-demand using an ATC directed to EGFR.

Methods

An ATC with a defined drug-to-antibody ratio was generated by the site-directed conjugation of IRDye®700 to a self-labeling protein (SNAP-tag) fused to an EGFR-specific antibody fragment (scFv-425).

Results

In vitro and ex vivo imaging showed that the ATC based on scFv-425 is suitable for the highly specific detection of EGFR⁺ ovarian cancer cell, human tissues and ascites samples. The construct was also able to eliminate EGFR⁺ cells and human ascites cells with IC₅₀ values of 45–66 nM and 40–90 nM, respectively.

Conclusion

Our experiments provide a framework to create a versatile technology platform for the development of ATCs for precise detection and treatment of ovarian cancer cells.

     

Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs

Purpose

Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa.

Methods

A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated.

Results

The previous murine study data were well replicated with fT?>?MIC selected as the best predictor. However, for increased dosing frequencies fAUC/MIC was found to be more predictive and the magnitude of the index was sensitive to drug susceptibility. With human PK fT?>?MIC and fAUC/MIC had similar predictive capacities with preference for fT?>?MIC when short t_1/2 and fAUC/MIC when long t_1/2.

Conclusions

A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than using a fixed PK/PD index target.

     

Synergistic Effect of Polyvinyl Alcohol and Copovidone in Itraconazole Amorphous Solid Dispersions

Purpose

The first objective is to evaluate the feasibility of melt-extruding polyvinyl alcohol-based amorphous solid dispersions for oral drug delivery. The second objective is to investigate the miscibility between polyvinyl alcohol 4-88 and copovidone, and to characterize the properties of ternary itraconazole amorphous solid dispersions comprising both polymers.

Methods

Samples were prepared using a co-rotating, twin-screw extruder. A solution precipitation study was conducted to compare the precipitation inhibition of polyvinyl alcohol against other commonly used polymers for amorphous solid dispersions. Miscibility between polyvinyl alcohol 4-88 and copovidone was determined using DSC and XRD analyses. All extrudates were characterized using DSC, XRD, and non-sink dissolution.

Results

Polyvinyl alcohol demonstrated the highest capacity for inhibiting the precipitation of itraconazole. Itraconazole was found to be more soluble in copovidone (>30%) than in polyvinyl alcohol 4-88 (<5%) in binary extrudates. Polyvinyl alcohol and copovidone are miscible when the proportion of polyvinyl alcohol 4-88 does not exceed 30% (w/w). Compared to binary extrudates, the ternary extrudate demonstrated a higher degree of supersaturation and more sustained supersaturation of itraconazole in purified water and phosphate buffer pH 6.8 solution.

Conclusion

As a surface-active material, polyvinyl alcohol was effective in inhibiting precipitation of itraconazole in aqueous media. Solubility of itraconazole in polyvinyl alcohol in solid state was limited because of the high polarity of the polymer. Ternary systems comprising a mixture of polyvinyl alcohol and copovidone demonstrated better supersaturation in aqueous media than binary systems. Ternary systems benefited from both the high solubilizing capacity of copovidone and high precipitation inhibition capacity of polyvinyl alcohol.

     

Assessment of the Protein–Protein Interactions in a Highly Concentrated Antibody Solution by Using Raman Spectroscopy

Purpose

To investigate the protein–protein interactions of a highly concentrated antibody solution that could cause oligomerization or aggregation and to develop a better understanding of the optimization of drug formulations.

Methods

In this study, we used Raman spectroscopy to investigate the structure and interactions of a highly concentrated antibody solution over a wide range of concentrations (10–200 mg/mL) with the aid of a multivariate analysis.

Results

Our analysis of the amide I band, I ₈₅₆ /I ₈₃₀ of Tyr, and the relative intensity at 1004 cm^?1 of the Phe and OH stretching region at around 3000 cm^?1 showed that across this wide range of concentrations, the secondary structure of the IgG molecules did not change; however, short-range attractive interactions around the Tyr and Phe residues occurred as the distance between the IgG molecules decreased with increasing concentration. Analysis of the OH stretching region at around 3000 cm^?1 showed that these short-range attractive interactions correlated with the amount of hydrated water around the IgG molecules.

Conclusions

Our data show that Raman spectroscopy can provide valuable information of the protein–protein interactions based on conformational approaches to support conventional colloidal approaches, especially for analyses of highly concentrated solutions.

     

New Perspectives for Fixed Dose Combinations of Poorly Water-Soluble Compounds: a Case Study with Ezetimibe and Lovastatin

Purpose

Aiming to improve the dissolution rate of ezetimibe (EZE) and lovastatin (LOV) in a fixed dose combination (FDC), co-amorphous systems and ternary solid dispersions were prepared by quench cooling and spray drying, respectively.

Methods

Formulations were characterized through X-ray diffraction, modulated differential scanning calorimetry, infrared spectroscopy, scanning electron microscopy and laser diffraction, and evaluated by ‘in vitro’ dissolution. Stability studies were conducted at different conditions during 30 days with the ternary solid dispersion composed of 75% of Soluplus® (ELS 1:1 75%).

Results

Single phase co-amorphous systems made up of the pure drugs were not able to increase the dissolution rate of EZE and LOV. However, ternary solid dispersions achieved high dissolution for both compounds, especially when Soluplus® was used as carrier. The dissolution efficiency increased up to 18 (EZE) and 6 (LOV) times in ternary solid dispersions, compared to the crystalline drugs. ELS 1:1 75% preserved its amorphous state during 30 days, in different stability conditions.

Conclusions

A spray dried ternary solid dispersion able to enhance the dissolution rate of two poorly soluble, therapeutically complementary drugs, is reported for the first time. These promising results open new perspectives for the development of more advanced FDCs.

     

A Dose Ranging Pharmacokinetic Evaluation of IQP-0528 Released from Intravaginal Rings in Non-Human Primates

Purpose

Design of intravaginal rings (IVRs) for delivery of antiretrovirals is often guided by in vitro release under sink conditions, based on the assumption that in vivo release will follow a similar release profile.

Methods

We conducted a dose-ranging study in the female reproductive tract of pigtail macaques using matrix IVRs containing IQP-0528, a poorly soluble but highly potent antiretroviral drug with an IC₉₀ of 146 ng/mL. These IVRs consisted of drug-loaded segments, 15.6% IQP-0528 in Tecoflex 85A, comprising either all, half, or a quarter of the entire ring.

Results

In vitro release under sink conditions demonstrates loading-proportional release, with a cumulative 30-day release of 48.5 ± 2.2 mg for our 100% loaded ring, 24.8 ± .36 mg from our 50% loaded ring, and 13.99 ± 1.58 mg from our 25% loaded ring. In vivo, while drug concentration in vaginal fluid is well in excess of IQP-0528’s EC₉₀, we find no statistical difference between the different ring loadings in either swab drug levels or drug released from our rings.

Conclusions

We show that in vitro release may not accurately reflect in vivo release, particularly for poorly soluble drugs. All tested loadings of our IVRs are capable of delivering IQP-0528 well in excess of the IC₉₀.

     

Controlling Release of Integral Lipid Nanoparticles Based on Osmotic Pump Technology

Purpose

To achieve controlled release of integral nanoparticles by the osmotic pump strategy using nanostructured lipid carriers (NLCs) as model nanoparticles.

Methods

NLCs was prepared by a hot-homogenization method, transformed into powder by lyophilization, and formulated into osmotic pump tablets (OPTs). Release of integral NLCs was visualized by live imaging after labeling with a water-quenching fluorescent probe. Effects of formulation variables on in vitro release characteristics were evaluated by measuring the model drug fenofibrate. Pharmacokinetics were studied in beagle dogs using the core tablet and a micronized fenofibrate formulation as references.

Results

NLCs are released through the release orifices of the OPTs as integral nanoparticles. Near zero-order kinetics can be achieved by optimizing the influencing variables. After oral administration, decreased C _max and steady drug levels for as long as over 24 h are observed. NLC-OPTs show an oral bioavailability of the model drug fenofibrate similar to that of the core tablets, which is about 1.75 folds that of a fast-release formulation.

Conclusion

Controlled release of integral NLCs is achieved by the osmotic pump strategy.

     

Formulation and Evaluation of Chitosan-Based Buccal Bioadhesive Films of Zolmitriptan

Purpose

Therapeutic efficacy of zolmitriptan in oral therapy is primarily limited by the biopharmaceutical issues. The objective of this study is to design and optimize chitosan-based buccal bioadhesive system for the effective delivery of zolmitriptan in the treatment of migraine.

Methods

Factorial design (3²) is constructed and conducted in a fully randomized manner to study all nine possible experimental runs. The films were prepared by solvent casting method by varying the content of chitosan (X₁) and polyvinyl alcohol (X₂). The effect of these two independent variables on swelling index (Y1), percent drug release in 15 min (Y2) and 5 h (Y3), and mucoadhesive strength (Y4) of prepared films was evaluated.

Results

The physical and chemical characteristics displayed by the prepared films (F1–F9) were found to be optimal. It was observed that the factor X₁ has positive and X₂ has negative effect on response Y1. In contrast, factor X₁ showed negative effects on drug release at both time intervals (15 min and 5 h) while X₂ displayed positive responses for these variables (Y2 and Y3). However, the mucoadhesion increased with an increase in factor X₁ and decreased when the factor X₂ was increased. Indeed, the desirable characteristics exhibited by the film F7 are ideal for buccal application. Greater flux (63.93?±?12.51 μg/cm²/h) demonstrated in ex vivo studies substantiated the potential of optimized film to effectively deliver zolmitriptan across the buccal membrane.

Conclusions

This study concludes that the chitosan-based buccal film (F7) could be used in both prophylaxis and acute treatment of migraine, although need to be proved in vivo.