Search

The purpose of this study was to investigate the in vitro dissolution performance of the different sized spray-dried nano-crystalline powders of naproxen. A DoE approach was used to formulate and optimize nano-crystalline suspensions. The critical wet milling operation parameters were i.e., drug concentration, drug-to-stabilizer ratio, stabilizer type (HPMC E15 or Tween 80) and milling intensity. The nano-crystalline suspensions were optimized for size and physical stability and then spray-dried to obtain nano-crystalline powders. Trehalose and lactose were investigated as spray-drying auxiliary excipients to achieve non-aggregating powders. Particle size, DSC and PXRD were utilized for characterization of powder formulations. A modified USP apparatus II was utilized to determine the in vitro release/dissolution of powder formulations. The size of the nano-crystalline suspensions was dependent on drug concentration and milling intensity. HPMC E15 containing formulations were better in terms of the spray-dried powder yield compared to Tween 80 containing formulations. Trehalose was selected to formulate non-aggregating nano-crystalline powders. No polymorphic changes were observed following the wet milling and spray-drying processes. Size dependent in vitro dissolution profiles, utilizing a dialysis sac method were obtained for the crystalline powders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

To develop a novel solid dispersion of clopidogrel napadisilate monohydrate (CNM) with improved stability and oral bioavailability, surface-modified solid dispersions were prepared by spray-drying using water as a solvent, Tween 80 as a surfactant, and hydroxypropylmethyl cellulose (HPMC) as a hydrophilic polymer, and optimized according to drug solubility. Its solid-state characterization was evaluated by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The stability study was performed at 50°C/75% RH over a period of 6 weeks. Its dissolution profiles and oral bioavailability in rats were also compared with that of CNM and clopidogrel bisulfate (CB). The solid dispersion, composed of CNM/HPMC/Tween80 at a weight ratio of 10/2.5/2.5, in which CNM was in the crystalline state, increased the drug solubility approximately 4.6-fold. It showed a significantly better dissolution profile than that of CNM in all the dissolution media, and gave either similar or higher dissolution compared to that of CB. This solubility and dissolution enhancement was attributed to improved wetting and solubilization of CNM crystals due to hydrophilic carriers attached on the drug surface. It had excellent stability, thereby addressing the stability problem of CB powder. Furthermore, it increased the area under curve (AUC) values by about 4-fold and 1.6-fold compared to CNM and CB, respectively, suggesting that it improved the oral bioavailability of the drug in rats. Thus, this solid dispersion system prepared with water, HPMC and Tween 80 can be used to enhance the bioavailability of CNM as well as to solve the stability problem of CB.

In this present research work, we have designed a pulsincap formulation comprising mini-tablets, which to the best of our knowledge this combination has not been reported yet. We successfully combined the advantages of mini-tablets technology to meet the optimized requirements of our pulsincap formulation. Our main aim was to target lornoxicam to treat rheumatoid arthritis as per the chronotherapeutic pattern of the disease. Directly compressing method was used to prepare mini-tablets. The drug, polymers and combine mixtures of drug and polymers was evaluated for pre-formulation testing. Prepared mini-tablets were also evaluated for physicochemical, dissolution and stability studies. From FTIR and DSC evaluation, we found no interaction between the drug and polymers used. For mini-tablets, all the physico-chemical parameters were in limit. The mini-tablets of lornoxicam were filled into an insoluble body of capsule, and its opening was sealed by plugging it with a polymer. The complete capsule body after sealing with a cap was given enteric coating. Different polymers in various concentrations were used as a plug, to identify the most suitable which gives a complete lag time of 5 hours when combined with 5% CAP coating. HPMC-K100M in 30% and sodium alginate in 40% concentrations were identified as the most suitable plugs. Our optimized pulsincap formulations releases lornoxicam after a lag time of 5 hrs and maximum portion of the drug will be released in the early morning hours. It was also found to be stable for a period of 6 months as per ICH guidelines.

Invasive pulmonary aspergillosis is a life threatening fungal infection mainly caused by Aspergillus species. Available treatment strategy against pulmonary aspergillosis is having very limited applicability, due to its toxicity and low circulation half-life. Pulmonary drug delivery is one of the strategies that can minimize these pitfalls. In the present study, polymeric and lipidic nanoparticles of amphotericin B were prepared by spray drying technique using hydroxypropylmethylcellulose (HPMC) and stearylamine with oleic acid respectively. Formulations were characterized for particle size, zeta potential, entrapment efficiency, in-vitro release studies, uptake analysis and in-vivo bio distribution studies. Developed polymeric and nanostructured lipid carriers (NLCs) were found in submicron size (600-700nm) and spherical in shape. Studies suggested that NLCs have better entrapment efficiency (77.1±5.5 %) as compared to HPMC carrier (71.28±5.22 %). Both formulations provided sustained drug release (HPMC, 82.05% releases up to 32 hrs and NLC, 88.2 % up to 40 hrs) and reduced dose dumping that may be helpful to reduce the toxicity and improve patient compliance. In-vitro antifungal studies suggested that stearylamine formulations exhibited better antifungal activity over control and HPMC formulations. Pharmacokinetic and organ distribution studies also support our hypothesis i.e. localized drug delivery for prolong period, improving the therapeutic effectiveness of the encapsulated drug against pulmonary aspergillosis. Studies suggested that drug delivery by pulmonary route is beneficial for local action in lungs.

Solid dispersions of artemether and polyethylene glycol 6000 (PEG6000) were prepared in ratio 12 : 88 (group-1). Self-emulsified solid dispersions of artemether were prepared by using polyethylene glycol 6000, Cremophor-A25, olive oil, Transcutol, and hydroxypropyl methylcellulose (HPMC) in ratio 12 : 75 : 5 : 4 : 2 : 2, respectively (group-2). In third group, only Cremophor-A25 was replaced with Poloxamer 188 compared to group-2. The solid dispersions and self-emulsified solid dispersions were prepared by physical and freeze dried methods, respectively. All samples were characterized by X-ray diffraction, attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimeter, scanning electron microscopy, and solubility, dissolution, and stability studies. X-ray diffraction pattern revealed artemether complete crystalline, whereas physical mixture and freeze-dried mixture of all three groups showed reduced peak intensities. In attenuated total reflectance Fourier transform infrared spectroscopy spectra, C-H stretching vibrations of artemether were masked in all prepared samples, while C-H stretching vibrations were representative of polyethylene glycol 6000, Cremophor-A25, and Poloxamer 188. Differential scanning calorimetry showed decreased melting endotherm and increased enthalpy change (ΔH) in both physical mixture and freeze-dried mixtures of all groups. Scanning electron microscopy of freeze-dried mixtures of all samples showed glassy appearance, size reduction, and embedment, while their physical mixture showed size reduction and embedment of artemether by excipients. In group-1, solubility was improved up to 15 times, whereas group-2 showed up to 121 times increase but, in group-3, when Poloxamer 188 was used instead of Cremophor-A25, solubility of freeze-dried mixtures was increased up to 135 times. In fasted state simulated gastric fluid at pH 1.6, the dissolution of physical mixture was increased up to 12 times and freeze-dried mixtures up to 15 times. The stability of artemether was substantially enhanced in freeze-dried mixtures by using polyethylene glycol 6000, Cremophor-A25, and Poloxamer 188 of self-emulsified solid dispersions of artemether in Hank's balanced salt solution at pH 7.4.

The aim of this study is to obtain swelling controlled release matrix tablets of captopril using the Quality by Design methodology (ICH Q8) and to know the transport mechanisms involved in captopril release. To obtain the area of knowledge, the design of experiments studying the effect of two components (HPMC K15M and ethylcellulose) at different levels has been applied, with the captopril dissolution profile as the product's most important critical quality attribute (CQA). Different dissolution profiles have been obtained with the design of experiments performed, which is a key factor in the development of controlled release matrix tablets. Kinetic analysis according to the equations of Higuchi and Korsmeyer-Peppas demonstrates that the release mechanism is a mechanism of erosion when the whole percentage of the polymer is ethylcellulose, and a diffusion mechanism when the whole percentage of the polymer is HPMC K15M. The physico-chemical characteristics of the gel layer determine the release rate of captopril. The thickness of the gel layer, the porosity which is formed in the matrix upon contact with water, pore size, the swelling rate, the erosion rate of the matrix, and the physico-chemical characteristics of captopril, are factors related to the kinetic equations described and that allow us to predict the release mechanism of captopril. A new relationship of the kinetic equations governing the in vitro behavior with the physical characteristics of the gel layer of the different formulations has been established. This study shows that the size of water-filled pores and the degree of crosslinking between the chains of HPMC K15M of the matrix are related to the exponent n of the Korsmeyer-Peppas equation and the type of transport of the captopril from within the matrix to the dissolution medium, that is, if the transport is only through water-filled pores, or if a combination of diffusion occurs through water-filled pores with a transport through continuous polymeric networks., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The purpose of this work was to explore the feasibility of using Soluplus(®) in preparing a fenofibrate (FBT) nanosuspension adopting wet media milling technology. HPMC and Soluplus(®) were used as stabilizers to prepare FBT/HPMC nanosuspension (F1) and FBT/Soluplus(®) nanosuspension (F2), respectively. The nanosuspensions were subjected to evaluations involving particle size, dissolution, preliminary stability and pharmacokinetic behavior. A marked reduction in particle size was achieved by nanosuspensions (from 17.55 μm to 642 nm (F1) and 344 nm (F2)). The nanosuspensions displayed almost complete dissolution while percentages of 30% and 13% were obtained by physical mixtures and coarse FBT separately. Soluplus(®) could stabilize the nanosuspension more effectively due to a weaker Ostwald ripening effect resulting from a slower diffusion of micelles formed by Soluplus(®) entrapping dissolved FBT than FBT exposed to pure water directly. In the in vivo evaluation, larger AUC0-72h and Cmax, and shorter Tmax were obtained by the nanosuspensions. Significant differences were observed between the physical mixtures. The phenomenon of double peaks was present in this study. The major factor may be the multiple absorption sites of FBT. The current work indicated that Soluplus(®) is well suited for preparation of a nanosuspension with good stability and improved dissolution and bioavailability., (Copyright © 2014. Published by Elsevier B.V.)

Therapeutic efficacy of some orally administered molecules is often conditioned by their solubility in physiological fluids as well as their absorption. The last aspect becomes more limitative and conditioning drug plasmatic profiles when the active ingredient is preferentially absorbed in a specific region of the gastrointestinal tract. A case is represented by furosemide (FURO) preferentially absorbed in the stomach, site in which, because of its acidic nature, is poorly soluble. To solve this problem new oral solid formulations have been developed. The inorganic-organic hybrid MgAl-HTlc-FURO has been formulated in tablet in which floating and mucoadhesion properties have been combined. Swellable (Methocel K4, Methocel K15, Methocel K100 M, hydroxypropyl methyl cellulose) or swellable/erodible polymers (Methocel E50 LV, Methocel K100 LV), used to obtain the floating, were combined to Carbopol(®) (971P or 974P) to confer mucoadhesion capacity. Prepared tablets were deeply characterized in terms of hydration capacity, erosion %, buoyancy lag time/floating time and mucoadhesion. The most suitable tablets selected from these preliminary tests, submitted to in vitro release studies, showed a sustained release of FURO. This is useful to maintain the therapeutic concentrations for a long time, in comparison to conventional dosage forms, thanking to the enhancement of formulation residence time in the stomach., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In the present study, we have synthesized a biocompatible hybrid carrier of hypromellose (HY) and poly(vinyl alcohol) (PVA) for immobilization of Burkholderia cepacia lipase (BCL). The immobilized biocatalyst HY:PVA:BCL was subjected to determination of half-life time (τ) and deactivation rate constant (K(D)) in various organic solvents. Biocatalyst showed higher τ-value in a nonpolar solvent like cyclohexane (822 h) as compared to that of a polar solvent such as acetone (347 h), which signifies better compatibility of biocatalyst in the nonpolar solvents. Furthermore, the K(D)-value was found to be less in cyclohexane (0.843 × 10(-3)) as compared to acetone (1.997 × 10(-3)), indicating better stability in the nonpolar solvents. Immobilized-BCL (35 mg) was sufficient to achieve 99% conversion of phenethyl butyrate (natural constituent of essential oils and has wide industrial applications) using phenethyl alcohol (2 mmol) and vinyl butyrate (6 mmol) at 44 °C in 3 h. The activation energy (E(a)) was found to be lower for immobilized-BCL than crude-BCL, indicating better catalytic efficiency of immobilized lipase BCL. The immobilized-BCL reported 6-fold superior biocatalytic activity and 8 times recyclability as compared to crude-BCL. Improved catalytic activity of immobilized enzyme in nonpolar media was also supported by thermodynamic activation parameters such as enthalpy (ΔH(⧧)), entropy (ΔS(⧧)) and Gibb's free energy (ΔG(⧧)) study, which showed that phenethyl butyrate synthesis catalyzed by immobilized-BCL was feasible as compared to crude-BCL. The present work explains a thermodynamic investigation and superior biocatalytic activity for phenethyl butyrate synthesis using biocompatible immobilized HY:PVA:BCL in nonaqueous media for the first time.

The pervasiveness of tribo-electric charge during pharmaceutical processing can lead to the exacerbation of a range of problems including segregation, content heterogeneity and particle surface adhesion. The excipients, hydroxypropyl methylcellulose (HPMC) and methylcellulose (MC), are often used in drug delivery systems and so it is important to understand the impact of associated factors on their charging and adhesion mechanisms, however, little work has been reported in this area. Such phenomena become more prominent when excipients are introduced to a powder mixture alongside the active pharmaceutical ingredient(s) (APIs) with inter- and intra-particulate interactions giving rise to electrification and surface adhesion of powder particles. The aim of this study was to understand the impact of material attributes (particle size, hydroxypropyl (Hpo) to methoxyl (Meo) ratio and molecular size) on the charging and adhesion characteristics of cellulose ethers. Furthermore, a poorly compactible and highly electrostatically charged drug, flurbiprofen, was used to develop binary powder mixtures having different polymer to drug ratios and the relationship between tribo-electric charging and surface adhesion was studied. Charge was induced on powder particles and measured using a custom built device based on a shaking concept, consisting of a Faraday cup connected to an electrometer. The diversity in physicochemical properties has shown a significant impact on the tribo-electric charging and adhesion behaviour of MC and HPMC. Moreover, the adhesion and electrostatic charge of the API was significantly reduced when MC and HPMC were incorporated and tribo-electric charging showed a linear relationship (R(2)=0.81-0.98) with particle surface adhesion, however, other factors were also involved. It is anticipated that such a reduction in charge and particle surface adhesion would improve flow and compaction properties during processing., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The objective of the present study was to develop fast dissolving oral film of the antipsychotic drug, flupentixol dihydrochloride, to enhance its bioavailability, optimize its therapeutic effect when used to treat depression with anxiety, and increase the convenience and compliance by the mentally ill, developmentally disable, elderly, and pediatric patients. Six formulae were prepared with different concentrations of water-soluble polymers vis. hydroxypropyl methylcellulose (HPMC E5) and carboxymethyl cellulose (CMC) by solvent casting technique. The prepared films were subjected to characterization for folding endurance, weight variations, thickness, disintegration time, drug release pattern, and drug content. Physical compatibility between the drug and excipients was guaranteed in the selected formulation (2% HPMC) by means of differential scanning calorimetry analysis and Fourier-transform infrared spectroscopy. This formulation revealed high stability after testing according to the International Conference on Harmonisation guidelines. In vivo studies based on single phase parallel design were carried out for the optimized formulation in healthy human volunteers. The concentration of flupentixol dihydrochloride in plasma samples was analyzed by a developed validated LC-MS/MS assay method and the pharmacokinetic parameters of the established formulation were compared with the commercially available oral tablets. Faster rate of absorption of flupentixol could be obtained from the oral film formulation and the relative bioavailability was found to be 151.06% compared to the marketed product.

This study was the first investigation into the potential of a fixed dose combination of ritonavir and darunavir in the form of dispersible powders prepared by spray drying. A common polymer (hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone-vinyl acetate 64) was formulated with either ritonavir or darunavir or a combination of ritonavir and darunavir. The influence of these polymers on the supersaturation level of ritonavir and darunavir was investigated. The concentration levels of ritonavir and darunavir during these tests dropped instantly to a plateau which could be considered as amorphous solubility. Besides, the presence of darunavir always decreased the supersaturation level of ritonavir and vice versa no matter which polymers were used. Moreover, the rate and extent of release of both ritonavir and darunavir from ternary spray-dried powders were less than the releases from binary spray-dried powders. Intermolecular interaction between ritonavir and darunavir was ruled out by (1)H NMR study which means that the decrease in supersaturation level or release must be at least partially attributed to the mediated solvent process. In order to restrict the mutual influence between darunavir and ritonavir, a complex of both ritonavir and darunavir with (2-hydroxypropyl)-β-cyclodextrin was prepared and improved the dissolution rate of both ritonavir and darunavir., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The combination of a highly soluble salt form of a drug with a polymeric precipitation inhibitor has the potential to prolong drug supersaturation even following salt disproportionation. In this study, dissolution profiles of ibuprofen sodium in the presence of various cellulosic polymers, including hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), and hydroxypropyl cellulose (HPC), were examined in order to assess degree and duration of supersaturation. In addition, the roles that the polymers played in altering drug solubility, media viscosity, physical form, and particle morphology were also assessed. A deep dive into the mechanisms of supersaturation revealed that intermolecular hydrogen bonding between ibuprofen and HPMC was driving supersaturation through nucleation inhibition and crystal growth modification. Polymer viscosity was proposed as the primary factor prolonging supersaturation of ibuprofen in the presence of MC, while mechanisms other than hydrogen bonding were likely to be attributed to supersaturation with the most hydrophobic polymer evaluated, HPC. Overall, the study suggested that induction of intermolecular interactions between ibuprofen and HPMC were more effective at inhibiting nucleation and maintaining prolonged supersaturation than physical modulation of solution properties, such as viscosity., (Copyright © 2014. Published by Elsevier B.V.)

The purpose of this work was to design and evaluate a vaginal film delivery system for UAMC01398, a novel non-nucleoside reverse transcriptase inhibitor currently under investigation for use as an anti-HIV microbicide. UAMC01398 (1mg) films consisting of hydroxypropylmethylcellulose (HPMC) and polyethylene glycol 400 (PEG400) in different ratios were prepared by solvent evaporation. Based on its flexibility, softness and translucent appearance, the 30% PEG400 and 70% HPMC containing film was selected for further assessment. The vaginal film formulation was fast-dissolving (<10 min in 1 mL of vaginal fluid simulant), stable up to at least one month and safe toward epithelial cells and lactobacilli. Furthermore, formulating UAMC01398 into the film dosage form did not influence its antiviral activity. Powder X-ray diffraction revealed the amorphous nature of the UAMC01398 film, resulting in enhanced compound permeation across the epithelial HEC-1A cell layer, presumably owing to the induction of supersaturation. The in vivo vaginal tissue uptake of UAMC01398 in rabbits, as measured by systemic concentrations, was increased compared to the previously established non-solubilizing gel (significant difference) and sulfobutyl ether-β-cyclodextrin (5%) containing gel. To conclude, we identified a film formulation suitable for the vaginal delivery of UAMC01398., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to fabricate valsartan composite nanoparticles by using the supercritical antisolvent (SAS) process, and to evaluate the correlation between in vitro dissolution and in vivo pharmacokinetic parameters for the poorly water-soluble drug valsartan. Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process. X-ray diffraction and thermal analyses indicated that valsartan was present in an amorphous form within the composite nanoparticles. The in vitro dissolution and oral bioavailability of valsartan were dramatically enhanced by the composite nanoparticles. Valsartan-hydroxypropyl methylcellulose-poloxamer 407 nanoparticles exhibited faster drug release (up to 90% within 10 minutes under all dissolution conditions) and higher oral bioavailability than the raw material, with an approximately 7.2-fold higher maximum plasma concentration. In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency. Therefore, the preparation of composite nanoparticles with valsartan-hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability.

The performance of hydroxypropyl methylcellulose (HPMC) as safe corrosion inhibitor for mild steel in aerated 0.5M H2SO4 solution was appraised by weight loss, impedance and polarization measurements. Results indicate that HPMC functions as a good inhibitor in the studied environment and inhibition efficiency increased with increasing concentration of inhibitor and temperature. Time-dependent effect of the inhibition efficiency reveals that inhibition efficiency increased with time up to the fourth day after which it waned, but improved on addition of KI. The synergism parameter evaluated confirmed the synergistic effect of KI and HPMC. Impedance results clearly show that HPMC inhibited the corrosion reaction via adsorption onto the metal/solution interface following Freundlich adsorption isotherm. Polarization results indicate that HPMC acts as a mixed-type inhibitor with predominant cathodic effect. Theoretical study using density functional theory was employed to establish the correlation between the structure (molecular and electronic) and the inhibition efficiency., (Copyright © 2014. Published by Elsevier Ltd.)

Large osseous defects remain a difficult clinical problem in orthopedic surgery owing to the limited effective therapeutic options, and bone morphogenetic protein-2 (BMP-2) is useful for its potent osteoinductive properties in bone regeneration. Here we build a strategy to achieve prolonged duration time and help inducting new bone formation by using water-soluble polymers as a protective film. In this study, calcium phosphate cement (CPC) scaffolds were prepared as the matrix and combined with sodium carboxymethyl cellulose (CMC-Na), hydroxypropylmethyl cellulose (HPMC), and polyvinyl alcohol (PVA) respectively to protect from the digestion of rhBMP-2. After being implanted in the mouse thigh muscles, the surface-modified composite scaffolds evidently induced ectopic bone formation. In addition, we further evaluated the in vivo effects of surface-modified scaffolds in a rabbit radius critical defect by radiography, three dimensional micro-computed tomographic (μCT) imaging, synchrotron radiation-based micro-computed tomographic (SRμCT) imaging, histological analysis, and biomechanical measurement. The HPMC-modified CPC scaffold was regarded as the best combination for segmental bone regeneration in rabbit radius., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Development of in vitro-in vivo correlations (IVIVCs) for extended-release (ER) products is commonly pursued during pharmaceutical development to increase product understanding, set release specifications, and support biowaivers. This manuscript details the development of Level C and Level A IVIVCs for ER formulations of niacin, a highly variable and extensively metabolized compound. Three ER formulations were screened in a cross-over study against immediate-release niacin. A Multiple Level C IVIVC was established for both niacin and its primary metabolite nicotinuric acid (NUA) as well as total niacin metabolites urinary excretion. For NUA, but not for niacin, Level A IVIVC models with acceptable prediction errors were achievable via a modified IVIVC rather than a traditional deconvolution/convolution approach. Hence, this is in contradiction with current regulatory guidelines that suggest that when a Multiple Level C IVIVC is established, Level A models should also be readily achievable. We demonstrate that for a highly variable, highly metabolized compound such as niacin, development of a Level A IVIVC model fully validated according to agency guidelines may be challenging. However, Multiple Level C models are achievable and could be used to guide release specifications and formulation/manufacturing changes., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

To prepare swellable/erodible time-dependent colon delivery systems with improved efficiency in delaying drug release, the application of an outer Eudragit® NE film, which contained the superdisintegrant Explotab® V17 as a pore former, was attempted. Tablet cores were successively spray-coated with a hydroxypropyl methylcellulose (HPMC) solution and diluted Eudragit® NE 30 D, wherein fixed amounts of Explotab® V17 were present. The resulting two-layer systems yielded lag phases of extended duration as compared with formulations provided with the HPMC layer only. By raising the thickness of the outer film, longer lag times were generally observed, whereas the effectiveness in deferring the drug liberation was reduced by increasing the pore former content, which, however, also resulted in a lower data variability. The films containing 20% of Explotab® V17 effectively and consistently prolonged the in vitro lag phase imparted by HPMC as a function of their thickness. Stored for 3 years under ambient conditions, a two-layer system with this outer film composition pointed out unmodified release patterns. The same system proved to meet gastroresistance criteria when enteric coated. The results obtained indicated that the proposed strategy would enable the preparation of erodible delivery systems with reduced size, possibly suitable as multiple-unit dosage forms., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The commercial and clinical success of amorphous solid dispersions (ASD) in overcoming the low bioavailability of poorly soluble molecules has generated momentum among pharmaceutical scientists to advance the fundamental understanding of these complex systems. A major limitation of these formulations stems from the propensity of amorphous solids to crystallize upon exposure to aqueous media. This study was specifically focused on developing analytical techniques to evaluate the impact of polymers on the crystallization behavior during dissolution, which is critical in designing effective amorphous formulations. In the study, the crystallization and polymorphic conversions of a model compound, nifedipine, were explored in the absence and presence of polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and HPMC-acetate succinate (HPMC-AS). A combination of analytical approaches including Raman spectroscopy, polarized light microscopy, and chemometric techniques such as multivariate curve resolution (MCR) were used to evaluate the kinetics of crystallization and polymorphic transitions as well as to identify the primary route of crystallization, i.e., whether crystallization took place in the dissolving solid matrix or from the supersaturated solutions generated during dissolution. Pure amorphous nifedipine, when exposed to aqueous media, was found to crystallize rapidly from the amorphous matrix, even when polymers were present in the dissolution medium. Matrix crystallization was avoided when amorphous solid dispersions were prepared, however, crystallization from the solution phase was rapid. MCR was found to be an excellent data processing technique to deconvolute the complex phase transition behavior of nifedipine.

The goal of this investigation was to develop films containing insulin-coated nanoparticles and evaluate their performance in vitro as potential peptide delivery systems. To incorporate insulin into the films, a new antisolvent co-precipitation fabrication process was adapted to obtain insulin-coated nanoparticles (ICNPs). The ICNPs were embedded in polymeric films containing a cationic polymethacrylate derivative (ERL) or a combination of ERL with hydroxypropyl methylcellulose (HPMC). ICNP-loaded films were characterized for morphology, mucoadhesion, and insulin release. Furthermore, in vitro insulin permeation was evaluated using a cultured tridimensional human buccal mucosa model. The antisolvent co-precipitation method was successfully adapted to obtain ICNPs with 40% (w/w) insulin load, achieving 323±8nm particles with a high zeta potential of 32.4±0.8mV, indicating good stability. High yields were obtained after manufacture and the insulin content did not decrease after one month storage. ICNP-embedded films using ERL as the polymer matrix presented excellent mucoadhesive and insulin release properties. A high permeation enhancement effect was observed for ICNP-loaded ERL films in comparison with ICNP-loaded ERL-HPMC films and a control insulin solution. ICNP-loaded ERL formulations were found to be more effective in terms of film performance and insulin permeation through the human buccal mucosa model, and thus are a promising delivery system for buccal administration of a peptide such as insulin., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aim: Caffeic acid has been described as active against bacteria commonly isolated from wound infections. However, its low stability and poor solubility reduce caffeic acid applicability as a pharmaceutical product. These parameters can be enhanced by complexation with cyclodextrin. The main goal of the present work was to incorporate caffeic acid on cyclodextrin-based hydrogels capable of controlled delivery, in order to be used as antibacterial wound dressing., Materials & Methods: Cyclodextrin-based hydrogels were prepared by direct crosslinking of β-cyclodextrin or hydroxypropyl-β-cyclodextrin with 1,4-butanediol diglycidyl ether in the presence of hydroxypropyl methylcellulose., Results: The hydrogels obtained combine good physicochemical properties (viscoelasticity, superabsorbency and high ability to retain and deliver caffeic acid) with the preservation of caffeic acid' antibacterial activity and effect on fibroblasts, with gel-β-cyclodextrin the most suited., Conclusion: The hydrogels obtained could be useful as caffeic acid delivery-system devices for the treatment of wound infections.

The aim of the present study was to show that the physiological variability of fasted gastric pH and tablet gastric retention time contributes to the overall variability of simulated plasma profiles of diclofenac. Those two parameters were implemented into dissolution study and plasma profiles were simulated under assumptions that in vitro dissolution well represents that occurring in vivo, and that absorption profiles are identical to dissolution profiles, as diclofenac is a highly permeable drug. Dissolution experiments were performed using USP 2 apparatus and two consecutive dissolution media, namely, an acidic medium of various pH (ranging from 1-3), where tablets were kept for a certain time (10-200 min), and phosphate buffer (pH 6.8). It was shown that the acid pH value and acid retention time of tablets affect in vitro drug release, and consequently also influence the simulated plasma profiles. Lower acid pH resulted in lower plasma peaks at each studied acid retention time. Longer acid retention time caused lower plasma concentrations at lower acid pH values, whereas at pH 3 higher plasma concentrations were noted. Additionally, it was demonstrated that the variability of both parameters represents an important contribution to the overall variability of plasma profiles., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to improve the physicochemical properties and oral absorption of poorly water-soluble everolimus via preparation of a solid dispersion (SD) system using a solvent wetting (SW) technique. The physicochemical properties, drug release profile, and bioavailability of SD prepared by SW process were also compared to SD prepared by the conventional co-precipitation method. Solid state characterizations using scanning electron microscopy, particle size analysis and X-ray powder diffraction indicated that drug homogeneously dispersed and existed in an amorphous state within the intact polymeric carrier. Whereas, a film-like mass was obtained by a co-precipitation method and further pulverization step was needed for tabletization. The drug release from the SD tablet prepared by SW process at a ratio of drug to hydroxypropyl methylcellulose of 1:15 was markedly higher than the drug alone and equivalent to the marketed product (Afinitor(®), Novartis Pharmaceuticals), a SD tablet prepared by co-precipitation method, archiving over 75% the drug release after 30 min. At the accelerated (40°C/75% R.H.) and stress (80°C) stability tests, the novel formula was more stable than drug powder and provided comparable drug stability with the commercially available product, which contains a potentially risky antioxidant, butylated hydroxyl toluene. The pharmacokinetic parameters after single oral administration in beagles showed no significant difference (P>0.01) between the novel SD-based tablet and the marketed product. The results of this study, therefore, suggest that the novel SD system prepared by the solvent wetting process may be a promising approach for improving the physicochemical stability and oral absorption of the sirolimus derivatives., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Several molecular inheritances have severely restrained the peroral delivery of taxanes. The main objective of the present investigation was to develop a paclitaxel (PTX) formulation which can circumvent the hurdles of its extremely poor solubility and permeability, Pgp efflux and high pre-systemic metabolism. Positively charged PTX nanocrystals of 209 nm were prepared by sonoprecipitation with high pressure homogenization technique, wherein an arginine based surfactant was explored as a stabilizer. The BET surface area analysis revealed that the surface area of PNC was 8.53 m(2)/gm, reflecting significant rise in surface area with nanonization of PTX. The DSC and XRD pattern suggested that the PTX is in the form of the most stable dihydrate crystal. The PNC showed very rapid dissolution profile compared to plain PTX in both sinks and non-sink conditions. Clarithromycin (CLM) was evaluated as a better alternative to cyclosporin A in improving PTX permeability. The PNC-CLM showed remarkable enhancement of 453% in relative bioavailability along with maintaining the therapeutic concentration of PTX for 8h. Efficacy data in B16 F10 melanoma tumor bearing mice showed substantial reduction in tumor volume and improvement in percentage survival compared to the control group., (Copyright © 2014. Published by Elsevier B.V.)

ZnS nanoparticles stabilized by a carbohydrate-based matrix, hypromellose (hydroxypropyl methylcellulose) were prepared via a wet chemical method. The nanocomposite was characterized by X-ray diffraction, transmission electon microscopy and Fourier transform infrared spectroscopy. X-Ray diffraction patterns revealed a zinc blende structure. Thermogravimetric analysis suggested that polymer attached to the surface decomposes at 700 °C. Absorption measurements were carried out and calculation of the diameter polydispersity index (DPI) suggests the formation of monodisperse nanoparticles. The optical properties of the as-prepared samples were studied by UV/vis spectroscopy and steady-state photoluminescence (PL) spectroscopy. The PL studies indicate the applicability of these nanoparticles as biocompatible sensors or luminescence markers in future., (Copyright © 2013 John Wiley & Sons, Ltd.)

Purpose: The aim of this work was to investigate the influence of hydroxypropyl methylcellulose (HPMC) on the phase transformation and release profile of carbamazepine-nicotinamide (CBZ-NIC) cocrystal in solution and in sustained release matrix tablets., Methods: The polymorphic transitions of the CBZ-NIC cocrystal and its crystalline properties were examined by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Raman spectroscopy, and scanning electron microscopy (SEM)., Results: The apparent CBZ solubility and dissolution rate of CBZ-NIC cocrystal were constant in different concentrations of HPMC solutions. In a lower percentage of HPMC in the matrix tablets, the CBZ release profile of the CBZ-NIC cocrystal was nonlinear and declined over time. With an increased HPMC content in the tablets, the CBZ-NIC cocrystal formulation showed a significantly higher CBZ release rate in comparison with the other two formulations of CBZ III and the physical mixture., Conclusions: Because of a significantly improved dissolution rate of the CBZ-NIC cocrystal, the rate of CBZ entering into solution is significantly faster than the rate of formation of the CBZ-HPMC soluble complex in solution, leading to a higher supersaturation level of CBZ and subsequently precipitation of CBZ dihydrate.

This work presents the use of attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and spectroscopic imaging to study the stability and dissolution behaviour of amorphous solid dispersions (ASDs). ASDs are employed to improve the bioavailability of drugs which are poorly soluble in aqueous solutions. Selecting the appropriate polymeric excipients for use in pharmaceutical tablets is crucial to control drug stability and subsequent release. In this study, indomethacin was used as a model poorly-aqueous soluble drug since the amorphous-form has improved dissolution properties over its crystalline forms. ASDs of indomethacin/polyethylene glycol (PEG) and indomethacin/hydroxypropyl methylcellulose (HPMC) in a 1:3 wt ratio were compared. Firstly, ATR-FTIR spectroscopy was employed to monitor the stability of indomethacin in the ASDs over 96 h. While the indomethacin/HPMC ASD showed the ability to maintain the amorphous indomethacin form for longer periods of time, ATR-FTIR spectra revealed that indomethacin in the drug/PEG ASD crystallised to the stable γ-form, via the α-form. Secondly, ATR-FTIR spectroscopic imaging was used to study the dissolution of ASD tablets in a phosphate buffer (pH 7.5). Crystallisation of amorphous indomethacin was characterised in the spectra collected during the dissolution of the indomethacin/PEG ASD which consequently hindered release into the surrounding solution. In contrast, release of amorphous indomethacin was more effective from HPMC., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Coating thickness is the most important attribute of coated pharmaceutical pellets as it directly affects release profiles and stability of the drug. Quality control of the coating process of pharmaceutical pellets is thus of utmost importance for assuring the desired end product characteristics. A visual imaging technique is presented and examined as a process analytic technology (PAT) tool for noninvasive continuous in-line and real time monitoring of coating thickness of pharmaceutical pellets during the coating process. Images of pellets were acquired during the coating process through an observation window of a Wurster coating apparatus. Image analysis methods were developed for fast and accurate determination of pellets' coating thickness during a coating process. The accuracy of the results for pellet coating thickness growth obtained in real time was evaluated through comparison with an off-line reference method and a good agreement was found. Information about the inter-pellet coating uniformity was gained from further statistical analysis of the measured pellet size distributions. Accuracy and performance analysis of the proposed method showed that visual imaging is feasible as a PAT tool for in-line and real time monitoring of the coating process of pharmaceutical pellets., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Four different hydrophilic matrix formulations based on hydroxypropyl methylcellulose (HPMC) were investigated for erosion properties in vivo. Three formulations contained a fixed amount of HPMC (40%) with varying proportions of two HPMC grades with different molecular weights (Methocel K100LV and K4M), and a fourth formulation contained a lower amount of the HPMC of lower molecular weight (20%). The effect of food on the in vivo erosion behavior was investigated on two formulations containing different contents of the same HPMC grade. The in vivo erosion behavior and gastrointestinal transit were investigated using magnetic marker monitoring (MMM). The in vitro and in vivo erosion-time profiles show that the erosion was strongly dependent on the composition of the formulation. The formulations containing a larger proportion of high molecular weight HPMC or higher content of HPMC exhibit relatively slower erosion rate and vice versa. In vivo erosion rates were significantly higher under postprandial administration as compared to fasted state administration. No rapid disintegration of any of the formulations (i.e. formulation failure that can potentially cause dose dumping) was observed., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to develop a novel valsartan-loaded spray-dried emulsion based on hydroxypropylmethyl cellulose (HPMC) with enhanced oral absorption. The valsartan-loaded redispersible dry emulsion was prepared by using a high-pressure homogenization and spray-drying process with water, Capryol 90, HPMC, and different surfactants, based on the results of the solubility study. The spray-dried emulsions formed small and homogeneous emulsions with a mean droplet emulsion size ranging from 133.5 to 152.5nm at the dispersion state in water. The valsartan-loaded redispersible dry emulsion with HPMC/poloxamer 407 showed enhanced pH-independent valsartan release, resulting in a dramatically enhanced oral bioavailability of valsartan compared to the raw material and commercial product. Therefore, a formulation strategy using the redispersible dry emulsion with HPMC/poloxamer 407 is very effective for the development of a new dosage form containing valsartan., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Context: Alternating Current Biosusceptometry is a magnetically method used to characterize drug delivery systems. This work presents a system composed by an automated ACB sensor to acquire magnetic images of floating tablets., Objective: The purpose of this study was to use an automated Alternating Current Biosusceptometry (ACB) to characterize magnetic floating tablets for controlled drug delivery., Materials and Methods: Floating tablets were prepared with hydroxypropyl methylcellulose (HPMC) as hydrophilic gel material, sodium bicarbonate as gas-generating agent and ferrite as magnetic marker. ACB was used to characterize the floating lag time and the tablet hydration rate, by quantification of the magnetic images to magnetic area. Besides the buoyancy, the floating tablets were evaluated for weight uniformity, hardness, swelling and in vitro drug release., Results: The optimized tablets were prepared with equal amounts of HPMC and ferrite, and began to float within 4 min, maintaining the flotation during more than 24 h. The data of all physical parameters lied within the pharmacopeial limits. Drug release at 24 h was about 40%., Conclusions: The ACB results showed that this study provided a new approach for in vitro investigation of controlled-release dosage forms. Moreover, using automated ACB will also be possible to test these parameters in humans allowing to establish an in vitro.in vivo correlation (IVIVC).

Introduction: Gastroretentive drug delivery systems (GRDDS) play an important role in the delivery of drug substances to the upper part of the gastrointestinal tract; they offer a possibility to overcome the limited gastric residence time of conventional dosage forms., Aims: The aim of the study was to understand drug-release and floatation mechanisms of a floating GRDDS based on functionalized calcium carbonate (FCC). The inherently low apparent density of the excipient (approx. 0.6 g/cm(3)) enabled a mechanism of floatation. The higher specific surface of FCC (approx. 70 m(2)) allowed sufficient hardness of resulting compacts. The floating mechanism of GRDDS was simulated in silico under simulated acidic and neutral conditions, and the results were compared to those obtained in vitro., Methods: United States Pharmacopeia (USP) dissolution methods are of limited usefulness for evaluating floating behavior and drug release of floating dosage forms. Therefore, we developed a custom-built stomach model to simultaneously analyze floating characteristics and drug release. In silico dissolution and floatation profiles of the FCC-based tablet were simulated using a three-dimensional cellular automata-based model., Results: In simulated gastric fluid, the FCC-based tablets showed instant floatation. The compacts stayed afloat during the measurement in 0.1 N HCl and eroded completely while releasing the model drug substance. When water was used as dissolution medium, the tablets had no floating lag time and sank down during the measurement, resulting in a change of release kinetics., Conclusions: Floating dosage forms based on FCC appear promising. It was possible to manufacture floating tablets featuring a density of less than unity and sufficient hardness for further processing. In silico dissolution simulation offered a possibility to understand floating behavior and drug-release mechanism., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Women are very much susceptible for acquired immunodeficiency syndrome (AIDS) and other sexually transmitted diseases (STDs), mainly due to unprotected heterosexual vaginal intercourse and for some other social and economical disadvantages. Our aim was to formulate and optimize vaginal film of abacavir, a potent nucleoside reverse transcriptase inhibitor, for the treatment of AIDS and HIV. Abacavir films were prepared by solvent evaporation method using sodium alginate (Na-alginate) as the main polymer, Hydroxypropyl Methylcellulose E 15 (HPMC E 15) as the copolymer and glycerol as a humectant. Abacavir sulphate (ABC) was used here as a drug. Films were optimized for various physicochemical parameters such as tensile strength, % elongation at break, swelling capacity, drug content (mg/cm(2)), thickness, folding endurance, bioadhesion, pH, moisture content and SEM. Drug polymer interaction was studied by FTIR Spectra. The drug release study was accomplished in dissolution apparatus. In vivo study was also carried out. This newly formed film was one kind of sustain release type and can be considered as a novel drug carrier system for the treatment of AIDS and other STDs. It was suitable for local as well as systemic effect. The films showed good physicochemical property with good aesthetic appeal.

Context: The in vitro performance of floating mucoadhesive metformin tablets was optimized using different polymer ratios of polyvinylpyrrolidone (PVP) tamarind seed gum (TSG) and hydroxypropylmethylcellulose (HPMC)., Objective: The objectives of this investigation were to investigate the combinatorial effects of PVP, TSG and HPMC; to study the work of adhesion measured on stainless steel (Wss) and on rabbit gastric mucosa (Wgm); and a comparison of hydrophilic and more hydrophobic tablets., Material and Methods: In vitro performance was measured as tablet hardness (H), tablet floating lag time (FLT), time needed to release 60% of drug content (t60%), swelling thickness (S), Wss and Wgm. To compare the effects, a simplex lattice mixture design was used., Results and Discussion: H, FLT, Wss and Wgm were found dependent on polymer ratio. H was increased when PVP ratio was increased. FLT, Wss and Wgm were increased when HPMC ratio was increased. The p value for the lack of fit for all models were greater than 0.05. An approximate linear correlation between Wgm and Wss was established (R(2) = 0.71). The tablets containing PVP resulted in larger H, shorter FLT and t60%, whereas Wss and Wgm were enhanced., Conclusion: The different in vitro performance of tablets containing different water-soluble polymers could be explained partially by the differences in the hydrophilic properties of the polymers and the ability of PVP to interact with HPMC or TSG. An equation established is used to conclude mucoadhesion based on adhesion measurements on stainless steel.

In this work, one-dimensional population balance models (PBMs) have been developed to model a pulsed top-spray fluidized bed granulation. The developed PBMs have linked the key binder solution spray operating factors of the binder spray rate, atomizing air pressure and pulsed frequency of spray with the granule properties to predict granule growth behaviour in the pulsed spray fluidized bed granulation process at different operating conditions with accuracy. A multi-stage open optimal control strategy based on the developed PBMs was proposed to reduce the model mismatch, in which through adjusting the trajectory of the evolution of the granule size distribution at predefined sample intervals, to determine the optimal operating variables related to the binder spray including the spray rate of binding liquid, atomizing air pressure and pulsed frequency of spray. The effectiveness of the proposed modelling and multi-stage open optimal control strategies has been validated by experimental and simulation tests., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This study reports on the incorporation of the self-setting polysaccharide derivative hydrogel (silanized-hydroxypropyl methylcellulose, Si-HPMC) into the formulation of calcium phosphate cements (CPCs) to develop a novel injectable material for bone substitution. The effects of Si-HPMC on the handling properties (injectability, cohesion and setting time) and mechanical properties (Young's modulus, fracture toughness, flexural and compressive strength) of CPCs were systematically studied. It was found that Si-HPMC could endow composite CPC pastes with an appealing rheological behavior at the early stage of setting, promoting its application in open bone cavities. Moreover, Si-HPMC gave the composite CPC good injectability and cohesion, and reduced the setting time. Si-HPMC increased the porosity of CPCs after hardening, especially the macroporosity as a result of entrapped air bubbles; however, it improved, rather than compromised, the mechanical properties of composite CPCs, which demonstrates a strong toughening and strengthening effect. In view of the above, the Si-HPMC composite CPC may be particularly promising as bone substitute material for clinic application., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Matrix tablets are the most popular method of oral drug administration, and polymeric materials have been used broadly in matrix formulations to modify and modulate drug release rate. The main goal of the system is to extend drug release profiles to maintain a constant in vivo plasma drug concentration and a consistent pharmacological effect. Polymeric matrix tablets offer a great potential as oral controlled drug delivery systems. Cellulose derivatives, like hydroxypropyl methylcellulose (HPMC) are often used as matrix formers. However, also other types of polymers can be used for this purpose including: Kollidon SR, acrylic acid polymers such as Eudragits and Carbopols. Nevertheless, polymers of natural origin like: carragens, chitosan and alginates widely used in the food and cosmetics industry are now coming to the fore of pharmaceutical research and are used in matrix tablets technology. Modern polymers allow to obtain matrix tablets by 3D printing, which enables to develop new formulation types. In this paper, the polymers used in matrix tablets technology and examples of their applications were described.

This work focused on the control of the manufacturing process for a controlled release (CR) pellet product, within a Quality by Design (QbD) framework. The manufacturing process was Wurster coating: firstly layering active pharmaceutical ingredient (API) onto sugar pellet cores and secondly a controlled release (CR) coating. For each of these two steps, development of a Process Analytical Technology (PAT) method is discussed and also a novel application of automated microscopy as the reference method. Ultimately, PAT methods should link to product performance and the two key Critical Quality Attributes (CQAs) for this CR product are assay and release rate, linked to the API and CR coating steps respectively. In this work, the link between near infra-red (NIR) spectra and those attributes was explored by chemometrics over the course of the coating process in a pilot scale industrial environment. Correlations were built between the NIR spectra and coating weight (for API amount), CR coating thickness and dissolution performance. These correlations allow the coating process to be monitored at-line and so better control of the product performance in line with QbD requirements., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Despite rapid dissolution in compendial phosphate buffers, gastro resistant (enteric coated) products can take up to 2 h to disintegrate in the human small intestine, which clearly highlights the inadequacy of the in vitro test method to predict in vivo behaviour of these formulations. The aim of this study was to establish the utility of a novel pH 5.6 bicarbonate buffer, stabilized by an Auto pH™ System, as a better surrogate of the conditions of the proximal small intestine to investigate the dissolution behaviour of standard and accelerated release enteric double coating formulations. Prednisolone tablets were coated with 3 or 5 mg/cm(2) of partially neutralized EUDRAGIT(®) L 30 D-55, HP-55 or HPMC adjusted to pH 6 or 8. An outer layer of EUDRAGIT(®) L 30 D-55 was applied at 5mg/cm(2). For comparison purposes, a standard single layer of EUDRAGIT(®) L 30 D-55 was applied to the tablets. Dissolution was carried out using USP II apparatus in 0.1 M HCl for 2 h, followed by pH 5.6 bicarbonate buffer. EUDRAGIT(®) L 30 D-55 single-coated tablets showed a slow drug release with a lag time of 75 min in buffer, whereas release from the EUDRAGIT(®) L 30 D-55 double-coated tablets was accelerated. These in vitro lag times closely match the in vivo disintegration times for these coated tablets reported previously. Drug release was further accelerated from modified double coatings, particularly in the case of coatings with a thinner inner layer of HP-55 or HPMC (pH 8 and KH2PO4). This study confirms that the pH 5.6 bicarbonate buffer system offers significant advantages during the development of dosage forms designed to release the drug in the upper small intestine., (Copyright © 2014. Published by Elsevier B.V.)

In order to improve the in vitro dissolution rate and in vivo oral bioavailability of the poorly water soluble drug, felodipine (FELO), the wet-milling process was employed involving co-grinding with HPMC E5 and the in vitro release rate as investigated. After solidification by spray drying or freeze drying, the microsized powders were characterized in terms of their size, morphology, and in vitro dissolution rate. The oral bioavailability of this dry powder for suspension was evaluated in rats. After milling with 8% HPMC E5 and freeze drying, the powder mixture had an average particle size of 2.249 ± 1.497 μm and displayed an excellent dissolution rate of up to 93.2% within 10 minutes. DSC and PXRD investigations confirmed the absence of any crystal transformation during the wet-milling process. Using two different solidification methods, powders were stable for 6 months with regard to their in vitro dissolution rate. Significantly improved bioavailability was obtained for the wet-milled suspension before solidification and freeze dried powders with 6.8- (p < 0.001) and 3.6-fold (p < 0.01) increases, respectively, compared with that of the un-milled FELO. Also, no marked difference (p > 0.05) in bioavailability was seen for the spray dried powders. These effects suggest that the solidification method plays an important role in modifying the bioavailability of FELO after wet milling. Consequently, wet-milling is an effective technique to enhance the bioavailability of FELO and to maintain these benefits, freeze-drying is a feasible approach to solidifying the wet-milled suspension for industrial applications.

Preparation of three mucoadhesive formulations was optimized and pharmaceutically evaluated. Ofloxacin was radiolabeled with (99m)Tc and radiolabeled complex was characterized by HPLC. (99m)Tc-Ofloxacin was added as a tracer to the formulations namely Oflox C934, Oflox C940 and Oflox HPMC and the formulations were fed orally to rats. Imaging studies were carried out to assess the prolonged gastric retention of the formulations. (99m)Tc-Ofloxacin served as a good tracer for studying the pharmacokinetics of three controlled release mucoadhesive dosage forms by gamma scintigraphy studies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Current compendial dissolution and disintegrating testing is unable to mimic physiological conditions affecting gastric drug release from immediate release dosage forms. In order to obtain more realistic data, a novel test setup was developed that we term a 'dynamic open flow through test apparatus'. It is based on the previously described dissolution stress test device and attempts to simulate the intra-gastric dissolution conditions pertinent to immediate release dosage forms administered under fasting conditions with respect to flow rates, intra-gastric temperature profiles and gastric motility. The concept of the dynamic open flow through test apparatus has been tested using five different types of hard capsules: conventional hard gelatin capsules (HGC), three hypromellose based capsules (Vcaps, Vcaps Plus and DRcaps) and pullulan based capsules (Plantcaps). These were of different sizes but all contained 100mg caffeine in each formulation, adjusted to avoid buoyancy by addition of excipient. When the capsules were stressed in the apparatus under the dynamic flow conditions applying mild pressure simulating gastric motility, release from release from Vcaps Plus, Vcaps and Plantcaps capsules was very well comparable to HGC. Capsules are usually swallowed with cold water and the temperature dependency of release from gelatin was noted as a significant factor, since heat exchange in the stomach is slow., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Nanocrystal-based drug delivery systems provide important tools for ocular formulation development, especially when considering poorly soluble drugs. The objective of the study was to formulate ophthalmic, intraocular pressure (IOP) reducing, nanocrystal suspensions from a poorly soluble drug, brinzolamide (BRA), using a rapid wet milling technique, and to investigate their IOP reducing effect in vivo. Different stabilizers for the nanocrystals were screened (hydroxypropyl methylcellulose (HPMC), poloxamer F127 and F68, polysorbate 80) and HPMC was found to be the only successful stabilizer. In order to investigate both the effect of an added absorption enhancer (polysorbate 80) and the impact of the free drug in the nanocrystal suspension, formulations in phosphate buffered saline (PBS) at pH 7.4 and pH 4.5 were prepared. Particle size, polydispersity (PI), solid state (DSC), morphology (SEM) as well as dissolution behavior and the uniformity of the formulations were characterized. There was rapid dissolution of BRA (in PBS pH 7.4) from all the nanocrystal formulations; after 1 min 100% of the drug was fully dissolved. The effect was significantly pronounced at pH 4.5, where the dissolved fraction of drug was the highest. The cytotoxicity of nanocrystal formulations to human corneal epithelial cell (HCE-T) viability was tested. The effects of the nanocrystal formulations and the commercial product on the cell viability were comparable. The intraocular pressure (IOP) lowering effect was investigated in vivo using a modern rat ocular hypertensive model and elevated IOP reduction was seen in vivo with all the formulations. Notably, the reduction achieved in experimentally elevated IOP was comparable to that obtained with a marketed product. In conclusion, various BRA nanocrystal formulations, which all showed advantageous dissolution and absorption behavior, were successfully formulated., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The objective of this study was to investigate the effect of particle size on the dissolution and oral absorption of pranlukast microsuspensions and nanosuspensions stabilized by hydroxypropylmethyl cellulose. Four pranlukast suspensions with different mean particle sizes (0.16, 0.89, 3.13, and 18.21μm) were prepared by various top-down processes such as jet milling, high pressure homogenization, and bead milling. The dissolution rate and oral absorption of pranlukast suspensions were significantly affected by the particle size. The in vivo pharmacokinetic parameters of pranlukast suspensions were increased with decreasing mean particle size of suspensions. Especially, the AUC0→24h and Cmax values of pranlukast nanosuspension with a particle size of 0.16μm were approximately 3.5- and 6.3-fold greater, respectively, than that of pranlukast microsuspension with a particle size of 18.21μm. Therefore, the preliminary results from our study suggest that a pranlukast nanosuspension with a mean particle size of about 0.16μm may have significant potential for clinical application., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The purpose of this study is to identify critical physicochemical properties of hydroxypxropyl methylcellulose (HPMC) that impact the dissolution of a controlled release tablet and develop a strategy to mitigate the HPMC lot-to-lot and vendor-to-vendor variability. A screening experiment was performed to evaluate the impacts of methoxy/hydroxypropyl substitutions, and viscosity on drug release. The chemical diversity of HPMC was explored by nuclear magnetic resonance (NMR), and the erosion rate of HPMC was investigated using various dissolution apparatuses. Statistical evaluation suggested that the hydroxypropyl content was the primary factor impacting the drug release. However, the statistical model prediction was not robust. NMR experiments suggested the existence of structural diversity of HPMC between lots and more significantly between vendors. Review of drug release from hydrophilic matrices indicated that erosion is a key aspect for both poorly soluble and soluble drugs. An erosion rate method was then developed, which enabled the establishment of a robust model and a meaningful HPMC specification. The study revealed that the overall substitution level is not the unique parameter that dictates its release-controlling properties. Fundamental principles of polymer chemistry and dissolution mechanisms are important in the development and manufacturing of hydrophilic matrices with consistent dissolution performance., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Dabrafenib is a BRAF kinase inhibitor indicated for the treatment of BRAF V600E mutation-positive melanoma. The population pharmacokinetics of dabrafenib, including changes over time and relevant covariates, were characterized based on results from four clinical studies using a nonlinear mixed effects model with a full covariate approach. Steady-state exposures of dabrafenib metabolites (hydroxy-, carboxy-, and desmethyl-dabrafenib) were characterized separately. The pharmacokinetics of dabrafenib were adequately described by non-inducible and inducible apparent clearance that increased with dose and time. Total steady-state clearance (CL/F) at 150 mg BID dose was 34.3 L/h. Based on the induction half-life (67 hours), steady state should be achieved within 14 days of dosing. Capsule shell was the most significant covariate (55%) while sex and weight had only a small impact on exposure (<20%). The AUC ratio (hypromellose:gelatin capsule) is predicted to be 1.80 and 1.42 following single and repeat dosing, respectively. Age, renal (mild and moderate), and hepatic (mild) impairment were not significant covariates. Steady-state pre-dose concentration (%CV) of dabrafenib and of hydroxy-, carboxy-, and desmethyl-dabrafenib at 150 mg BID were 46.6 ng/mL (83.5%), 69.3 ng/mL (64.1%), 3608 ng/mL (14.7%), and 291 ng/mL (17.2%), respectively. Capsule shell, concomitant medications, older age, and weight were predictors of metabolite exposure., (© 2014, The American College of Clinical Pharmacology.)

Effect of different hydrophilic plasticizers on drug crystallinity of hydroxypropyl methylcellulose (HPMC) matrix film was studied. HPMC films containing telmisartan using different plasticizers were prepared by casting method. Drug crystallinity in the films was examined using polarized light microscopy (PLM), scanning electron microscopy (SEM), and x-ray diffractometry (XRD) to describe their phase behavior/solid state miscibility/crystal growth and drug-polymer-plasticizer interaction. HPMC and plasticizer were compatible with the drug and no phase separation was observed upon solvent evaporation. Plasticized-HPMC contributed a major role in the significant inhibition of crystal growth of the drug in the film. The triethanolamine film produced a relatively smooth surface in comparison to the other films in the submicron level. The films have not shown any significant changes even after exposure to stress (40°C/75% RH, 6 w). Triethanolamine as plasticizer brought about amorphization of telmisartan to the maximum extent in the film which is technologically more advantageous than the others owing to its anticipated better bioavailability., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The objective of the present study was to define a systematic approach to design and prepare solid dispersions of poorly water-soluble drug. The systematic approach can be defined in four phases. In the first phase, glass forming ability is assessed, and in the second phase, probable excipients are screened. The screened excipients are evaluated (third phase) for glass transition temperatures (Tg) and miscibility studies according to Florey-Huggins interaction parameter. The predicted excipients are used to prepare the solid dispersion and evaluated for Tg and any interactions using Fourier transfer infrared studies (fourth phase), and the findings are correlated with phase three predictions. For this investigation, cilostazol (CIL) was selected as model drug, which was classified as a poor glass former. As per the physical chemical properties of CIL, ten excipients, both polymeric and non-polymeric, were selected and screened. Out of these, povidone, copovidone, hypromellose and Eudragit EPO were found theoretically miscible with CIL. After going through phase 2 to phase 4, only povidone, copovidone and hypromellose were confirmed as polymer of choice for preparing the solid dispersion of CIL with a prediction of better physical solid-state stability on the basis of good miscibility between drug and carrier.

Hydroxypropyl methyl cellulose (HPMC) based hybrid nanocomposites reinforced with bacterial cellulose nanocrystals (BCNC) and silver nanoparticles (AgNPs) had been prepared and characterised. BCNC was capable of improving the tensile strength and modulus of HPMC, but they made the film more brittle. The addition of AgNPs along with BCNC, helped to regain some of the lost elongation properties without affecting other properties. Moisture sorption analysis proved that the hydrophilicity of the nanocomposite decreased considerably by the addition of these nanomaterials. Several mathematical models were also used to fit the experimental sorption results. A unique combination of two nanomaterials was highly effective in overcoming certain limitations of nanocomposites which uses only one type of nanomaterial. This type of hybrid nanocomposites with superior properties is expected to be useful in eco-friendly food packaging applications., (Copyright © 2014 Elsevier Ltd. All rights reserved.)