Pharmaceutical Sciences News

Carboxymethyl starch and Lecithin complex as matrix for targeted drug delivery: I. Monolithic Mesalamine forms for colon delivery [European Journal of Pharmaceutics and Biopharmaceutics]

2013-04-03T04:00:00Z

Available online 3 April 2013
Publication year: 2013
Source:European Journal of Pharmaceutics and Biopharmaceutics

For drugs expected to act locally in the colon, and for successful treatment, a delivery device is necessary, in order to limit the systemic absorption which decreases effectiveness and causes important side effects. Various delayed release systems are currently commercialized; most of them based on pH-dependent release which is sensitive to gastrointestinal pH variation. This study proposes a novel excipient for colon delivery. This new preparation consists in the complexation between carboxymethyl-starch (CMS) and Lecithin (L). As opposed to existing excipients, the new complex is pH-independent, inexpensive, easy to manufacture and allows a high drug loading. FTIR, X-Ray and SEM structural analysis all support the hypothesis of the formation of a complex. By minor variation of the excipient content within the tablet, it is possible to modulate the release time and delivery at specific sites of the gastro-intestinal tract. This study opens the door to a new pH-independent delivery system for mesalamine targeted administration. Our novel formulation fits well with the posology of mesalamine, used in the treatment of Inflammatory Bowel Disease (IBD), which requires repeated administrations (1 g orally 4 times a day) to maintain a good quality of life.

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Increased dissolution and oral absorption of itraconazole/Soluplus extrudate compared with itraconazole nanosuspension [European Journal of Pharmaceutics and Biopharmaceutics]

2013-04-03T04:00:00Z

Available online 3 April 2013
Publication year: 2013
Source:European Journal of Pharmaceutics and Biopharmaceutics

The purpose of this article was to compare the in vitro and in vivo profiles of itraconazole(ITZ) extrudates and nanosuspension separately prepared by two different methods. And it was proved truly to form nanocrystalline and amorphous ITZ characterized by differential scanning calorimetry(DSC), x-ray powder diffraction (XRD) analysis, Fourier transform infrared spectrum(FTIR), transmission electron microscope(TEM) and scanning electron microscope (SEM).The release of ITZ/Soluplus solid dispersions with amorphous ITZ were almost complete while only 40% release was obtained with ITZ nanocrystals. The amorphous state needn’t to cross over the crystal lattice energy upon dissolution while the crystalline need to overcome it. In the in vivo assay, the AUC(0-t) and C max of ITZ/Soluplus were 6.9- and 11.6-time higher than those of pure ITZ. The formulation of the extrudate had an AUC(0-t) and C max similar to those of ITZ and also OH-ITZ compared with the commercial capsule(Sporanox^®). The relative bioavailability values with their 95% confidence limit were calculated to be 98.3%(92.5%∼104.1%)and 101.3%(97.9%∼104.1%), respectively. The results of this study showed increased dissolution and bioavailability of the solid dispersion of Soluplus-based carrier loading ITZ prepared by HME compared with the ITZ nanosuspension prepared by wet milling.

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Poly(N-isopropylacrylamide-co-hydroxyethylacrylamide) thermosensitive microspheres: the size of microgels dictates the pulsatile release mechanism [European Journal of Pharmaceutics and Biopharmaceutics]

2013-04-03T04:00:00Z

Available online 3 April 2013
Publication year: 2013
Source:European Journal of Pharmaceutics and Biopharmaceutics

Poly(N-isopropylacrylamide-co-N-hydroxyethylacrylamide) (poly(NIPAAm-co-HEAAm)) was prepared as a new thermosensitive copolymer possessing a sharp phase transition around the human body temperature. The effect of the copolymer concentration on the lower critical solution temperature (LCST) was determined under physiological conditions by cloud point (CP) and differential scanning calorimetric (DSC) methods. Then, thermosensitive microspheres were prepared from preformed copolymers by chemical cross-linking of hydroxyl groups with glutaraldehyde at a temperature situated slightly below LCST of the copolymer solution. The volume phase transition temperature (VPTT) of corresponding cross-linked microspheres was determined from swelling degree-temperature curve. The microspheres were loaded with model drug indomethacin by the solvent evaporation method. The DSC analysis proved that the drug is molecularly dispersed in the polymer network. Finally, the influence of the microsphere size on drug release was investigated. It was established that microspheres with the diameter ranging between 5 and 60 μm release the drug with almost the same rate below (in the swollen state) and above the VPTT (in the collapsed state). On the contrary, microspheres with the diameter ranging between 125 and 220 μm release a significantly higher amount of indomethacin below than above the VPTT. This different behavior is enough to assure a pulsatile release mechanism when the temperature changes cyclically below and above the VPTT. However, both small and large microspheres release a large amount of the drug during the collapsing process.

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2013-04-03T00:00:00Z

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2013-04-01T00:00:00Z

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Formulation of carbenoxolone for delivery to the skin [International Journal of Pharmaceutics]

2013-04-02T11:23:00Z

Available online 29 March 2013
Publication year: 2013
Source:International Journal of Pharmaceutics

Carbenoxolone (CEX), a semi-synthetic derivative of glycyrrhetinic acid, has previously been used as a disodium salt for the management of dyspepsia and peptic ulcer because of its anti-inflammatory properties. Although glycyrrhetinic acid is available in pharmaceutical and personal care products for skin care, the topical use of the free acid form of CEX, has not previously been reported. In this work we investigated the percutaneous penetration of CEX. Solubility and permeability studies were conducted using a range of solvents or skin permeation enhancers (SPEs) commonly used for skin delivery. Binary combinations of dimethyl isosorbide (DMI) and Transcutol™ (TC) with isopropyl myristate (IPM) were effective in promoting skin permeation of CEX although individual solvents were not. Alternative fatty acid esters to IPM were subsequently investigated with the most promising formulation consisting of TC and propylene glycol laurate (PGL). Interestingly, propylene glycol monolaurate (PGML) did not demonstrate comparable efficacy when combined with TC. A ternary formulation consisting of TC, PGL and IPM demonstrated the best permeation enhancement of CEX compared with all other vehicles. The findings confirm (i) the feasibility of promoting CEX penetration across the skin (ii) the synergistic effect of combinations of solvents and SPEs on dermal and transdermal delivery (iii) the necessity for more fundamental studies to explain the differential effects of fatty acid esters on the skin barrier.

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Thermodynamic study of binary system Propafenone Hydrocloride with Metoprolol Tartrate: Solid-Liquid Equilibrium and compatibility with α-lactose monohydrate and corn starch [International Journal of Pharmaceuticsα-lactose monohydrate and corn starch]

2013-04-02T11:23:00Z

Available online 29 March 2013
Publication year: 2013
Source:International Journal of Pharmaceutics

Solid-liquid equilibrium (SLE) for binary mixture of Propafenone Hydrocloride (PP) with Metoprolol Tartrate (MT) was investigated using differential scanning calorimetry (DSC) and corresponding activity coefficients were calculated. Simple eutectic behavior for this system was observed. The excess thermodynamic functions: G ^E and S ^E for the pre-, post-, and eutectic composition, have been obtained using the computed activity coefficients data of the eutectic phase with their excess chemical potentials μ i ^E (i = 1, 2). The experimental solid-liquid phase temperatures were compared with predictions obtained from available eutectic equilibrium models. The results indicate non-ideality in this mixture. Also, the compatibility of each component and their eutectic mixture with usual excipients was investigated, and the DSC experiments indicate possible weak interactions with α-lactose monohydrate and compatibility with corn starch. The results obtained were confirmed by FT-IR measurements.

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Chloroaluminium Phthalocyanine Polymeric Nanoparticles as Photosensitisers: Photophysical and Physicochemical Characterisation, Release and Phototoxicity IN VITRO [European Journal of Pharmaceutical Sciences]

2013-04-02T14:06:00Z

Available online 29 March 2013
Publication year: 2013
Source:European Journal of Pharmaceutical Sciences

Nanoparticles of poly(D,L-lactide-co-glycolide), poly(D,L-lactide) and polyethylene glycol-block-poly(D,L-lactide) were developed to encapsulate chloroaluminium phthalocyanine (AlClPc), a new hydrophobic photosensitiser used in photodynamic therapy (PDT). The mean nanoparticle size varied from 115 to 274 nm, and the encapsulation efficiency ranged from 57 to 96% due to drug precipitation induced by different types of polymer. All nanoparticle formulations presented negative zeta potential values (–37 mV to –59 mV), explaining their colloidal stability. The characteristic photophysical parameters were analysed: the absorption spectrum profile, fluorescence quantum yield and transient absorbance decay, with similar values for free and nanoparticles of AlClPc. The time-resolved spectroscopy measurements for AlClPc triplet excited state lifetimes indicate that encapsulation in nanocapsules increases triplet lifetime, which is advantageous for PDT efficiency. A sustained release profile over 168 hours was obtained using external sink method. An in vitro phototoxic effect higher than 80% was observed in human fibroblasts at low laser light doses (3 J/cm²) with 10 μM of AlClPc. The AlClPc loaded within polymeric nanocapsules presented suitable physical stability, improved photophysical properties, sustained released profile and suitable activity in vitro to be considered a promising formulation for PDT.

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In vitro and in vivo characterization of meloxicam nanoparticles designed for nasal administration [European Journal of Pharmaceutical Sciences]

2013-04-02T14:06:00Z

Available online 28 March 2013
Publication year: 2013
Source:European Journal of Pharmaceutical Sciences

The nasal pathway represents a non-invasive route for delivery of drugs to the systemic circulation. Nanonization of poorly soluble drugs offers a possibility to increase dissolution properties, epithelial permeability or even bioavailability. The aim of the present study was to use in vitro methods to screen formulations which were intended for nasal application, and to perform animal experiments for recognizing the differences in plasmakinetics of intranasal- and oral-administered meloxicam nanoparticles. Due to nanonization the solubility of meloxicam elevated up to 1.2 mg/mL, additionally the extent of dissolution also increased, complete dissolution was observed in 15 min. Favourable in vitro diffusion profile of meloxicam nanoparticles was observed and their epithelial permeability through human RPMI 2650 cells was elevated. The pharmacokinetic parameters were significantly increased when meloxicam was administered as nanoparticles to rats either nasally (increase of Cmax 2.7-fold, AUC 1.5-fold) or orally (increase of Cmax 2.4-fold, AUC 2-fold) as compared to physical mixture of the drug and the excipients.

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Oily nanosuspension for long-acting intramuscular delivery of curcumin didecanoate prodrug: preparation, characterization and in vivo evaluation [European Journal of Pharmaceutical Sciences]

2013-04-02T14:06:00Z

Available online 29 March 2013
Publication year: 2013
Source:European Journal of Pharmaceutical Sciences

The objective of this study was to prepare the nanocrystals of curcumin didecanoate (CurDD) by wet ball milling and to investigate the comparative pharmacokinetics of oily nano- and micro-suspensions after intramuscular (i.m.) administration to rats. Upon optimizing the wet ball milling parameters, CurDD nanocrystals were produced with median particle size of ∼ 500 nm and the freeze-dried nanocrystals were readily dispersed in peanut oil to form stable nanosuspensions. Although the nanosuspension appeared to exhibit slower clearance from the injection site after i.m. injection, compared to microsuspension (∼5 μm), a significantly higher maximum plasma curcumin concentration (69.0 ng/ml) was observed for the former than that for the latter (18.5 ng/ml). In addition, the nanosuspension provided significant higher plasma curcumin concentrations and brain CurDD contents for at least 15 days than the microsuspension, except for the initial times. A single i.m. injection of nanosuspension appeared to achieve reversal effect on reserpine-induced hypothermia for at least 13 days. This study demonstrates that CurDD nanosuspension may act as a long-acting i.m. injectable for sustained delivery of curcumin, potentially applicable to elicit a long-lasting antidepressant effect.

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Gamma scintigraphy in the analysis of ketoprofen behaviour from matrix tablets [International Journal of Pharmaceutics]

2013-04-02T11:23:00Z

Available online 28 March 2013
Publication year: 2013
Source:International Journal of Pharmaceutics

The aim of this work was to study in vitro and in vivo the behaviour of matrix tablets (quick and extended release) containing ketoprofen (KTP) as a model drug and cellulose ether polymers, using gamma scintigraphy. The matrix tablets were prepared by the direct compression method and labelled by incorporating a drop of technetium (^99mTc). It was spectrophotometricaly confirmed that the radioisotope inclusion did not modify the kinetics of KTP release. In vitro studies were carried out for the tablets using the paddle method of the USP 35/NF30. The images were processed by defining regions of interest over the tablet ^99mTc and the percentage of remaining activity/time curves were generated for both formulations. In vitro gamma scintigraphy studies showed significant differences ( p < 0.05) between both formulations. Identical results were obtained from the in vivo studies. In vivo tests were performed on five healthy volunteers. The scintigraphy images were acquired during 2.5 and 7.5 h for quick and extended release formulations, respectively. The position of the extended release formulation tablet along the gastrointestinal tract (GIT) was assessed. The described results demonstrate the in vitro/in vivo correlation for the drug release profile and exhibit the importance of gamma scintigraphy for the drug location through the GIT.

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Influence of drug content, type of semi-solid vehicle and rheological properties on the skin penetration of the model drug fludrocortisone acetate [International Journal of Pharmaceutics]

2013-04-02T11:23:00Z

Available online 28 March 2013
Publication year: 2013
Source:International Journal of Pharmaceutics

Throughout Europe, topical creams containing corticosteroids are diluted with various neutral cream bases to meet the specific needs of patients. Even though this practice has been common for years, its effect has not been thoroughly investigated and so the effectiveness of the diluted topical steroidal creams is difficult to predict. In the present study, the model drug fludrocortisone acetate was incorporated into three cream bases of different hydrophilicity that are commonly used in Austria. Different final drug concentrations were chosen for comparative studies. Additionally, a semi-solid preparation developed by our group was investigated for comparison. These formulations were tested in diffusion and tape stripping experiments. Diffusion cell studies showed that changes in drug concentration do not necessarily change the skin permeation behaviour in vitro. The tape stripping protocol was successfully optimised for investigation of semi-solid preparations to provide reproducible and accurate results despite the challenges of investigating semi-solid formulations. The results showed that tape stripping experiments are more suitable to elucidate subtle differences between formulations. The composition of the cream bases exhibited stronger effects on the skin penetration of the steroidal drug irrespective of its concentration than the rheological properties. No correlation between formulation viscosity and skin penetration was found.

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Preformulation study of Methazolamide for topical ophthalmic delivery: Physicochemical properties and degradation kinetics in aqueous solutions [International Journal of Pharmaceutics]

2013-04-02T11:23:00Z

Available online 29 March 2013
Publication year: 2013
Source:International Journal of Pharmaceutics

Methazolamide (MTZ) is an anti-glaucoma drug. The present paper aims to characterize the physicochemical properties and degradation kinetics of MTZ to provide a basis for topical ophthalmic delivery. With the increase in pH (pH 5.5-8.0) of aqueous solution, the solubility of the compound increased while the partition coefficient (Ko/w) which was estimated in the system n-octanol/aqueous solution decreased. The degradation of MTZ in aqueous solution followed pseudo-ﬁrst-order kinetic. The degradation rate k pH is the rate in the absence of buffer catalysis. Plotting the natural logarithm of k pH versus the corresponding pH value gave a V-shaped pH-rate proﬁle with a maximum stability at pH5.0. The degradation rate constants as a function of the temperature obeyed the Arrhenius equation (R² = 0.9995 at pH 7.0 and R² = 0.9955 at pH 9.0, respectively). A decrease in ionic strength and buffer concentration displayed a stabilizing effect on MTZ. Buffer species also influenced the MTZ hydrolysis. Phosphate buffer system was more catalytic than tris and borate buffer systems. In brief, it is important to consider the physicochemical properties and the stability of MTZ during formulation.

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A GLUE uncertainty analysis of a drying model of pharmaceutical granules [European Journal of Pharmaceutics and Biopharmaceutics]

2013-04-03T04:00:00Z

Available online 29 March 2013
Publication year: 2013
Source:European Journal of Pharmaceutics and Biopharmaceutics

A shift from batch processing towards continuous processing is of interest in the pharmaceutical industry. However, this transition requires detailed knowledge and process understanding of all consecutive unit operations in a continuous manufacturing line to design adequate control strategies. This can be facilitated by developing mechanistic models of the multi-phase systems in the process. Since modelling efforts only started recently in this field, uncertainties about the model predictions are generally neglected. However, model predictions have an inherent uncertainty (i.e. prediction uncertainty) originating from uncertainty in input data, model parameters, model structure, boundary conditions and software. In this paper, the model prediction uncertainty is evaluated for a model describing the continuous drying of single pharmaceutical wet granules in a six-segmented fluidized bed drying unit, which is part of the full continuous from-powder-to-tablet manufacturing line (Consigma^TM, GEA Pharma Systems). A validated model describing the drying behaviour of a single pharmaceutical granule in two consecutive phases is used. First of all, the effect of the assumptions at the particle level on the prediction uncertainty is assessed. Secondly, the paper focuses on the influence of the most sensitive parameters in the model. Finally, a combined analysis (particle level plus most sensitive parameters) is performed and discussed. To propagate the uncertainty originating from the parameter uncertainty to the model output, the Generalised Likelihood Uncertainty Estimation (GLUE) method is used. This method enables a modeller to incorporate the information obtained from the experimental data in the assessment of the uncertain model predictions and to find a balance between model performance and data precision. A detailed evaluation of the obtained uncertainty analysis results is made with respect to the model structure, interactions between parameters and uncertainty boundaries.

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2013-03-29T00:00:00Z

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Pulmonary DWCNT exposure causes sustained local and low-level systemic inflammatory changes in mice [European Journal of Pharmaceutics and Biopharmaceutics]

2013-04-03T04:00:00Z

Available online 28 March 2013
Publication year: 2013
Source:European Journal of Pharmaceutics and Biopharmaceutics

Carbon nanotubes (CNTs) represent promising vectors to facilitate cellular drug delivery and to overcome biological barriers, but some types may also elicit persistent pulmonary inflammation based on their fibre characteristics. Here, we show the pulmonary response to aqueous suspensions of block copolymer dispersed, double-walled carbon nanotubes (DWCNT, length 1-10 μm) in mice by bronchoalveolar lavage (BAL) analysis, and BAL and blood cytokine, and lung antioxidant profiling. The intratracheally instilled dose of 50 μg DWCNT caused significant pulmonary inflammation that was not resolved during a 7-day observation period. Light microscopy investigation of the uptake of DWCNT-agglomerates revealed no particle ingestion for granulocytes, but only for macrophages. Accumulating macrophage, multinucleated macrophage, and lymphocyte numbers in the alveolar region further indicated ineffective resolution with chronification of the inflammation. The local inflammatory impairment of the lung was accompanied by pulmonary antioxidant depletion and haematological signs of systemic inflammation. While the observed inflammation during its acute phase was dominated by neutrophils and neutrophil recruiting cytokines, the contribution of macrophages and lymphocytes with related cytokines, became more significant after day 3 of exposure. This study confirms that acute pulmonary toxicity can occur on exposure of high doses of DWCNT agglomerates and offers further insight for improved nanotube design parameters to avoid potential long- term toxicity.

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Quantification of protonation in organic solvents using solution NMR spectroscopy: Implication in salt formation [International Journal of Pharmaceutics]

2013-03-28T10:00:00Z

Available online 26 March 2013
Publication year: 2013
Source:International Journal of Pharmaceutics

Purpose Investigate the use of solution NMR spectroscopy to evaluate whether the general ΔpK a rule is valid in organic solvents. Such information may be useful in evaluation of acid-base reactions and solvent selection for salt formation. Methods ¹H NMR chemical shift changes in model bases during titration with acids, and separately, on the addition of acids at a molar ratio of 1:1 were determined in water, dimethyl sulfoxide, and methanol. The effect of acid strength on the fraction of ionized base was examined. Results ¹H NMR chemical shift changes indicated protonation (in situ salt formation). Different media affected the observed chemical shift changes. In all media investigated the data followed the ΔpK a (base-acid) general rule, that the pK a value of the acids should be 2 to 3 units lower than the pK a of the base to ensure proton transfer. The addition of water into organic solvents increased the fraction of ionized base. Conclusions Protonation, as measured by chemical shift changes using solution NMR spectroscopy, provided novel insight on potential salt formation in different media. Even though pK a values change with the solvent, the general ΔpKa rule can be applied in different solvent systems. Solution NMR spectroscopy appears to be a useful tool to evaluate salt formation reaction and process control in different solvent systems.

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Pharmacokinetic studies of protein drugs: Past, present and future [Advanced Drug Delivery Reviews]

2013-04-02T22:00:00Z

Available online 27 March 2013
Publication year: 2013
Source:Advanced Drug Delivery Reviews

Among the growing number of therapeutic proteins on the market, there is an emergence of biotherapeutics designed from our comprehension of the physiological mechanisms responsible for their peripheral and tissue pharmacokinetics. Most of them have been optimized to increase their half-life through glycosylation engineering, polyethylene glycol conjugation or Fc fusion. However, our understanding of biological drug behaviors is still its infancy compared to the huge amount of data regarding small molecular weight drugs accumulated over half a century. Unfortunately, therapeutic proteins share few resemblances with these drugs. For instance drug-targeted-mediated disposition, binding to glycoreceptors, lysosomal recycling, large hydrodynamic volume and electrostatic charge are typical critical characteristics that cannot be derived from our anterior knowledge of classical drugs. However, the numerous discoveries made in the two last decades have driven and will continue to drive new options in biochemical engineering and support the design of complex delivery systems. Most of these new developments will be supported by novel analytical methods for assessing in vitro or in vivo metabolism parameters.

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Development of PVP/PEG mixtures as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique and optimization of dissolution using artificial neural networks [European Journal of Pharmaceutics and Biopharmaceutics]

2013-03-29T05:00:00Z

Available online 26 March 2013
Publication year: 2013
Source:European Journal of Pharmaceutics and Biopharmaceutics

The effect of plasticizer’s (PEG) molecular weight (MW) on PVP based solid dispersions (SDs), prepared by melt mixing, was evaluated in the present study using Tibolone as a poorly water soluble model drug. PEGs with MW of 400, 600 and 2000 g/mol were tested and the effect of drug content, time and temperature of melt mixing on the physical state of Tibolone and the dissolution characteristics from SDs was investigated. PVP blends with PEG400 and PEG600 were completely miscible, while blends were heterogeneous. Furthermore, a single T g recorded in all samples, indicating that Tibolone was dispersed in a molecular lever (or in the form of nanodispersions), varied with varying PEG’s molecular weight, melt mixing temperature and drug content; while FTIR analysis indicated significant interactions between Tibolone and PVP/PEG matrices. All prepared solid dispersion showed long term physical stability (18 months in room temperature). The extent of interaction between mixture components was verified using Fox and Gordon-Taylor equations. Artificial neural networks, used to correlate the studied factors with selected dissolution characteristics, showed good prediction ability.