Pharmacokinetics and Bioequivalence Estimation of Two Formulations of Alfuzosin Extended-Release Tablets.

Alfuzosin is a medication approved by the US Food and Drug Administration to treat benign prostatic hyperplasia symptoms. Bioequivalence studies are demanded by regulatory authorities to evaluate the expected in vivo biological similarity of 2 formulations of a medication. The aim of this study is to assess the bioavailability of the generic (test) and branded (reference) formulations of 10-mg alfuzosin extended-release tablets after oral administration to healthy adults under fed conditions. The study used a comparative randomized, single-dose, 2-way crossover open-label study design. Thirty-three participants were recruited and completed the clinical assessment. The pharmacokinetic parameters maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC0-t ), AUC extrapolated to infinity (AUC0-∞ ), time to maximum concentration, and elimination half-life were estimated to prove bioequivalence. The confidence intervals for the log-transformed test/reference ratios for alfuzosin 110.7% (98.0-124.9) and 112.0% (101.9-123.1) for Cmax and AUC0-t respectively, which are within the allowed limits specified by the regulatory authorities (80-125% for Cmax and AUC0-t ). The test formulation can therefore be prescribed as an alternative to the reference for symptomatic treatment of benign prostatic hyperplasia.

Evaluation of amorphous dispersion of a cellulose ester-colophony mix for ibuprofen controlled release processed by HME and spin coating.

Recently, there has been a rapid growth of using bio-based materials in pharmaceutical applications, due to their low cost and availability. In this study, natural composition of cellaburate (cellulose-ester) and colophony (pine-resin) was used to prepare films to control ibuprofen release from its amorphous solid dispersion. The effect of two preparation technologies of spin-coating and hot-melt-extrusion was studied on the physicochemical properties and in vitro dissolution/release behavior. Physical stability was evaluated for 12 w at 54 %RH/22 °C. Characterization involved using PLM/DSC/MTDSC/ATRFTIR/TGA/SEM and PXRD. Ibuprofen was amorphously-dispersed at 30 %(w/w) in 35:65 colophony:cellaburate films. Spin-films were more physically stable over 12 w; however, controlled release of ibuprofen was achieved mainly from hot-melt-extruded-films for 5 h. Both films have shown first-order release kinetics; whereby polymeric swelling and relaxation likely governed the release. The successful preparation of cellaburate-colophony platform that has achieved tunable release profiles of poorly water-soluble drug holds the potential for further drug delivery development.

Fabrication of Dissolvable Microneedle Patches Using an Innovative Laser-Cut Mould Design to Shortlist Potentially Transungual Delivery Systems: In Vitro Evaluation.

There has been a great interest towards transungual delivery systems due to limited drug penetration for the treatment of nail diseases. More important, antifungal oral medicaments used may cause serious side effects including liver damage. Therefore, we propose non-oral dissolvable microneedle (MN) patch to strike the poor permeability of the nail. We report the design of MN patch mould using a laser-cutting machine and solvent casting of several hydrophilic polymers to fabricate these MN patches. Formulations were evaluated for their in vitro release and penetration properties and selected based on physical characterization for compatibility (differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD)), dimension repeatability and drug content uniformity. A 72-array of cone-shaped MN patch mould was successfully constructed on polymethylmethacrylate sheets. Interval and frequency of laser exposure were pivotal to determine the needle sharpness, attained unexpectedly at a low level of circa 30 µm. F1 platform of polyvinyl alcohol, kollicoat IR®, ethylene glycol and gelatin showed circa 74% penetration of methylhydroxy-4-benzoate (F1(A)) over 24 h, whereas F2 (same as F1-A with the addition of poloxamer 338) resulted in an almost 42% of this drug retention in the bovine hoof (24 h). Both formulations are likely to be useful for onychomycosis treatment. F1 polymers also afford enhanced permeability (almost 73.5% after 24 h) of terbinafine hydrochloride into the hoof (F1(B)). However, F3 (chitosan, gelatin and ethylene glycol) presents the prospect of developing MN patch for this drug with almost complete hoof penetration (circa 96.3% after 24 h). All medicated formulations have shown similar mechanical properties after ageing for 1 year under dry conditions.

Solid-state compounding of immiscible PCL-PEO blend powders for molding processes.

Solid-state milling is a promising ecologically friendly method for fabricating polymeric blend and composite powder raw materials for several subsequent manufacturing processes. Biodegradable polymers, blends, and composites are expected to find extensive use by industry due to their environmental friendliness and acceptable mechanical and thermal properties for several applications. Poly-ε-caprolactone (PCL), poly-ethylene-oxide (PEO), and their blends have attracted so much attention to replace commodity polymers in future applications. Therefore, in the current research, bulk compounding of PCL-PEO blends with various compositions using solid-state cryomilling was investigated. Structural, mechanical, thermal, and hydrophilicity properties were examined on samples obtained by compression molding to explore the capabilities of the milling process for various applications. Morphology of the blends was explored by scanning electron microscopy (SEM), which showed a clear phase separation in blends after heating. Dispersed as well as co-continuous morphologies were achieved by varying composition. Differential scanning calorimetry (DSC) and x-ray diffraction (XRD) of the blends indicated insignificant amorphization by milling. Tensile strength, modulus, and percentage elongation at break of the blends demonstrated significant variations due to processing parameters.

Comparative Randomized, Single-Dose, Two-Way Crossover Open-Label Study to Determine the Bioequivalence of Two Formulations of Dalfampridine Tablets.

Dalfampridine is a medication that is approved by the US Food and Drug Administration to improve walking impairments in patients with multiple sclerosis (MS). The branded dalfampridine is enormously expensive; hence, the availability of generic dalfampridine will provide better access to the medication, especially for uninsured patients with MS. Bioequivalence studies are demanded by the regulatory authorities to allow the marketing of new generics of dalfampridine. The aim of this study was to assess the bioavailability of the generic (test) and branded (reference) formulations of 10 mg dalfampridine of extended-release tablets after oral administration to healthy adults under fed conditions. The current report methodology was based on a comparative, randomized, single-dose, 2-way crossover open-label study design. Twenty-seven subjects were given a single dose of the test dalfampridine tablet and completed the clinical study. The pharmacokinetic parameters Cmax and AUC0→t, Kel , AUC0→∞ , tmax , and t1/2el were estimated to prove bioequivalence. The confidence intervals for the log-transformed test/reference ratios for dalfampridine 100.96% (97.09%-104.97%) and 99.77% (95.81%-103.87%) for Cmax and AUC0→∞ , respectively, were within the allowed limit specified by the regulatory authorities (80%-125%). Hence, clinically, the test tablet can be prescribed as an alternative to the reference for the indication of improving walking impairments in patients with MS.

Fabrication of Hierarchical Polymeric Thin Films by Spin Coating Toward Production of Amorphous Solid Dispersion for Buccal Drug Delivery System: Preparation, Characterization, and In Vitro Release Investigations.

The landscape of thin films is continuously evolving as an attractive self-administration mean to drive patient compliance. This work reports incorporation of drugs into various polymeric compositions using spin coating technology to screen amorphous solid dispersion film formation for buccal applications. Polarized light microscopy and differential scanning calorimetry were used for characterization. Physical stability was assessed after films storage at 0% RH/25°C for 6 months. Chlorpheniramine maleate, theophylline, and famotidine were used as model drugs and mixed with Opadry amb II® or Kollicoat IR®. Acryl-EZE II® or Zein was also used as surface (design I) or surface and base polymers (design II). Of all the drug-Opadry combinations, only chlorpheniramine was amorphously dispersed up to 25% (w/w). In contrast, Kollicoat IR® resulted in amorphous dispersions of all the tested drugs, suggesting that it has a better solubilization capacity. Drugs prepared in design II achieved higher in vitro release compared to respective design I, indicating that lower content of Acryl-EZE II® or Zein can decrease drug release over 3 h. It has been also revealed that Zein could improve physical stability of the aged theophylline solid-dispersed films. Release kinetics of model drugs were satisfactory when described by first-order kinetics, facilitated through anomalous transport of both diffusion and polymer swelling.

Hot melt extruded transdermal films based on amorphous solid dispersions in Eudragit RS PO: The inclusion of hydrophilic additives to develop moisture-activated release systems.

A series of Eudragit RS PO-based hot melt extruded films were evaluated as potential transdermal systems, with particular emphasis on the inclusion of hydrophilic excipients to allow water sorption, which in turn would allow drug release on application to the skin. More specifically, sucrose, methyl cellulose, xanthan gum (Xantural®75), poloxamer (Pluronic®F127), Gelucire 44/14 were added to Eudragit RS PO and assessed in terms of physical structure (modulated temperature DSC (MTDSC), thermogravimetric analysis (TGA), powder XRD (PXRD), scanning electron microscopy(SEM)) and in vitro drug release and permeation properties. In addition, the effect of prior hydration on drug permeation was studied for selected systems. Phase separation was noted for sucrose, methylcellulose (high loading), xanthan gum (high loading), poloxamer and Gelucire 44/14 (high loading) using both visual observation and MTDSC. PXRD studies indicated drug crystallization within the phase separated systems. SEM studies broadly followed the same pattern. Dissolution studies indicated that the hydrophilic excipients considerably enhanced the release rate, while Franz diffusion cell studies showed a much greater variability in effectiveness, which we ascribe to the paucity of water of hydration present which would not allow swellable additives such as xanthan to release the drug. However, films containing Gelucire 44/14 emerged as the most satisfactory systems, despite the higher additive loaded systems showing drug phase separation. This may be related to emulsification rather than swelling on contact with water, as noted for the permeation studies involving pre-hydration. This strategy therefore presents a promising approach for triggered transdermal drug delivery, activated by hydration from the skin itself.