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.

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.

Clarithromycin laurate salt: physicochemical properties and pharmacokinetics after oral administration in humans.

OBJECTIVE: To prepare and characterize the physicochemical and pharmacokinetic properties of clarithromycin laurate (CLM-L), a fatty acid salt of clarithromycin (CLM). METHODS: CLM-L was prepared by a simple co-melting process. The formation of CLM-L was confirmed using FTIR, 1H NMR, and 13C NMR. Solubility, intrinsic dissolution rate (IDR), and partitioning properties of CLM-L were determined and compared to those of CLM. Bioavailability of CLM from CLM-L tablets was evaluated in healthy volunteers and compared to immediate release CLM tablets. RESULTS: CLM-L showed lower aqueous solubility, higher partitioning coefficient, and slower dissolution rate. Tablets of CLM-L also showed a significantly slower in vitro release in comparison to CLM tablets. Cmax, Tmax and AUC0→∞ of CLM-L tablets and immediate release CLM tablets did not show a significant difference. However, the AUC0→∞ for the CLM-L tablets tended to be higher than that of CLM tablets at all-time points. CONCLUSION: CLM-L was successfully prepared and its formation was confirmed. CLM-L was more hydrophobic than CLM. It exhibited a slight in vivo absorption enhancement in comparison to CLM. However, its pharmacokinetic behavior was comparable to that of CLM.

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.

Application of active layering and coating techniques in the development of a multiparticulate, controlled release dosage form of a high-dose, highly soluble drug.

CONTEXT: The success of the development of controlled release, multilayered, multiparticulate dosage form of a high-dose, highly-soluble drug is dependent upon proper material and processing choices. OBJECTIVE: To develop a controlled release dosage form of diltiazem hydrochloride using active layering and coating. METHODS: Active layering was achieved by spraying a drug solution onto sugar cores using polyvinyl alcohol - polyethylene glycol as a binder. Layered pellets with highest loading and lowest binder content were coated using aqueous dispersions of polyvinyl acetate (PVAc). The effects of the plasticizer and curing on drug release were evaluated. RESULTS AND DISCUSSION: The binder level had no effect on the process efficiency. Drug release from PVAc-coated pellets was slowed by increasing PVAc level. Plasticization slowed drug release in comparison to nonplasticized formulations. Curing affected drug release of nonplasticized formulations only. Protection against humidity was essential in stabilizing drug release under stability study conditions. CONCLUSION: Materials and process used were suitable to face the challenge posed by the high dose of the water-soluble drug on the success of the formulation. The effects of the plasticizer, curing and ability of packaging to protect against elevated humidity on the performance of the studied system should be considered in development.

Effects of thermal curing conditions on drug release from polyvinyl acetate-polyvinyl pyrrolidone matrices.

This study aimed to investigate the effects of dry and humid heat curing on the physical and drug release properties of polyvinyl acetate-polyvinyl pyrrolidone matrices. Both conditions resulted in increased tablet hardness; tablets stored under humid conditions showed high plasticity and deformed during hardness testing. Release from the matrices was dependent on the filler's type and level. Release profiles showed significant changes, as a result of exposure to thermal stress, none of the fillers used stabilized matrices against these changes. Density of neat polymeric compacts increased upon exposure to heat; the effect of humid heat was more evident than dry heat. Thermograms of samples cured under dry heat did not show changes, while those of samples stored under high humidity showed significant enlargement of the dehydration endotherm masking the glass transition of polyvinyl acetate. The change of the physical and release properties of matrices could be explained by the hygroscopic nature of polyvinyl pyrrolidone causing water uptake; absorbed water then acts as a plasticizer of polyvinyl acetate promoting plastic flow, deformation, and coalescence of particles, and altering the matrices internal structure. Results suggest that humid heat is more effective as a curing environment than dry heat for polyvinyl acetate-polyvinyl pyrrolidone matrices.

Development of a predictive in vitro dissolution for clarithromycin granular suspension based on in vitro-in vivo correlations.

The objective of this study was to evaluate the in vitro behavior of different clarithromycin granular suspensions based on a developed in vitro-in vivo correlation model, using one reference and two test formulations. In vitro release rate data were obtained for each product using the USP apparatus II, operated at 50 rpm under different pH conditions. The dissolution efficiency was used to analyze the dissolution data. In vivo study was performed on six healthy male volunteers under fasting condition. Correlation was made between in vitro release and in vivo absorption. A linear model was developed using percent absorbed data versus percent dissolved data from the three products. Dissolution condition of 0.1N HCl for 1 h and then phosphate buffer at pH 6.8 was found to be the most discriminating dissolution method. Rate of absorption for the reference as estimated by Wagner-Nelson deconvolution was correlated with in vitro release with a correlation coefficient of 0.99. The in vivo results for the two test products were compared to the predicted values using the reference model with a correlation coefficient of 0.94. Furthermore, multiple level C correlations were obtained for some pharmacokinetic parameters with the corresponding in vitro kinetic parameters with correlation coefficients exceeding 0.90. Moreover, the interpretation of the in vitro and in vivo data with reference to formulations was discussed.

Assessment of the bioequivalence of two formulations of clarithromycin extended-release 500-mg tablets under fasting and fed conditions: a single-dose, randomized, open-label, two-period, two-way crossover study in healthy Jordanian male volunteers.

BACKGROUND: Clarithromycin extended-release tablets are indicated for the treatment of adults with acute maxillary sinusitis caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae; acute bacterial exacerbation of chronic bronchitis due to H influenzae, Haemophilus parainfluenzae, M catarrhalis, or S pneumoniae; or community acquired pneumonia due to H influenzae, H parainfluenzae, M catarrhalis, S pneumoniae, Chlamydia pneumoniae, or Mycoplasma pneumoniae. OBJECTIVE: This study was conducted to assess the bioequivalence of test and reference formulations of clarithromycin extended-release 500-mg tablets under fasting and fed conditions. METHODS: This was a single-dose, randomized, open-label, 2-period, 2-way crossover study with a 1-week washout period between doses. Separate bioequivalence studies (fasting and fed) were performed in 2 groups of healthy male Jordanian volunteers. Eighteen blood samples were obtained from each volunteer over 38 hours after drug administration. Clarithromycin concentrations were determined in plasma using a validated high-performance liquid chromatography method with electrochemical detection. Pharmacokinetic parameters of clarithromycin (C(max), T(max), AUC(0-t), AUC(0-infinity), lambda(z) [first-order elimination rate constant], and t((1/2))) were calculated and analyzed statistically. Tolerability was assessed based on changes in vital signs and laboratory tests, and by questioning subjects about adverse events. RESULTS: Thirty-eight volunteers each participated in the fasting and fed studies. The mean ages of participants in the fasting and fed studies were 26.7 and 27.6 years, respectively; their mean weight was 71.2 and 70.9 kg and mean height was 171.3 and 179.0 cm. Under fasting conditions, the arithmetic mean (SD) C(max) was 569.4 (189.3) ng/mL for the test formulation and 641.2 (202.0) ng/mL for the reference formulation, with a geometric mean ratio of 0.88. The arithmetic mean AUC(0-t) was 8602.9 (4105.1) and 8245.3 (4122.4) ng . h/mL in the respective formulations, with a geometric mean ratio of 1.06. The arithmetic mean T(max) was 8.0 (5.6) and 6.1 (3.8) hours. In the fed study, the C(max) and AUC of both formulations were significantly increased relative to the fasting study (P < 0.05). The arithmetic mean C(max) of the 2 formulations was 1183.0 (637.5) and 1199.6 (496.3) ng/mL, with a geometric mean ratio of 0.93. The arithmetic mean AUC(0-t) was 12,981.2 (7849.0) and 11,822.9 (5790.2) ng . h/mL, with a geometric mean ratio of 1.06. The arithmetic mean T(max) was 5.7 (2.8) and 6.7 (2.5) hours. The 90% CI for the ratio (test:reference) of log-transformed C(max) and AUC values was within the acceptance range of 0.80 to 1.25. The 2 formulations were both well tolerated, and no adverse events were reported during the study. CONCLUSIONS: In these fasting and fed studies in healthy male Jordanian volunteers, the 2 formulations of clarithromycin extended-release 500-mg tablets were found to be bioequivalent according to the US Food and Drug Administration regulatory definition. Administration with food significantly increased the rate and extent of absorption of both products, with no significant effect on their bioequivalence.

Modulation of buspirone HCl release from hypromellose matrices using chitosan succinate: implications for pH-independent release.

Chitosan succinate (CS) was synthesized through the acylation of chitosan with succinic anhydride. The interaction of CS with buspirone HCl (BUSP) was evaluated using dialysis experiments and shown to result in complex with a stability constant of 2.26 mM and a capacity of 0.0362 micromol BUSP/mg CS. The extent of complexation upon dry and wet mixing of CS and BUSP was determined quantitatively using differential scanning calorimetry. The extent of the interaction was highest in wet mixtures and was found to be dependent on the pH of the granulation liquid. CS was incorporated in BUSP-containing hypromellose (HPMC) tablets using dry mixing and wet granulation with BUSP. Tablet dissolution was tested in 0.1N HCl and phosphate buffer, pH 6.8. According to f(2) and mean dissolution time results, the similarity of profiles increased as CS content increased with the highest f(2) value observed when CS was wet granulated with BUSP. Dissolution was also tested in deionized water and 5% NaCl; where increased ionic strength resulted in faster dissolution suggesting an ion exchange involvement in drug release. CS was proved effective in modulating BUSP release from HPMC matrices for pH-independent release through ionic complex formation.

A comparative study of first-derivative spectrophotometry and column high-performance liquid chromatography applied to the determination of repaglinide in tablets and for dissolution testing.

A fast and reliable method for the determination of repaglinide is highly desirable to support formulation screening and quality control. A first-derivative UV spectroscopic method was developed for the determination of repaglinide in tablet dosage form and for dissolution testing. First-derivative UV absorbance was measured at 253 nm. The developed method was validated for linearity, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ) in comparison to the U.S. Pharmacopeia (USP) column high-performance liquid chromatographic (HPLC) method. The first-derivative UV spectrophotometric method showed excellent linearity [correlation coefficient (r) = 0.9999] in the concentration range of 1-35 microg/mL and precision (relative standard deviation < 1.5%). The LOD and LOQ were 0.23 and 0.72 microg/mL, respectively, and good recoveries were achieved (98-101.8%). Statistical comparison of results of the first-derivative UV spectrophotometric and the USP HPLC methods using the t-test showed that there was no significant difference between the 2 methods. Additionally, the method was successfully used for the dissolution test of repaglinide and was found to be reliable, simple, fast, and inexpensive.