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Objective To measure changes to the perineal bare area, local tissue reaction and healing responses of young sheep, following intradermal administration of cetrimide and polyvinylpyrrolidone (PVP), with and without ethanol, to the breech and tail. Method A needle-less injector was used to deposit formulations containing 40 g/L cetrimide and 30 g/L PVP (group 2) or 20 g/L cetrimide, 30 g/L PVP and 15 g/L ethanol (group 3), within the dermis of the tail and the region surrounding the perineal bare breech area of groups (N = 8) of Merino weaner sheep. The dimensions of the perineal bare area (length, width and diagonal distances left and right) and tail width were recorded before and at intervals after treatment for 60 days. Observations of swelling and bruising and scab formation at the treatment sites were recorded for up to 35 days after treatment. Rectal temperatures were monitored for up to 35 days after treatment and bodyweight for up to 60 days after treatment. An untreated control group (group 1) was included. Results Comparison of day -3 and day 35 measurement data showed that both treated groups had significantly (P < 0.05) wider breech bare areas compared to the untreated controls and that group 2 sheep had significantly (P < 0.05) longer breech bare areas compared to group 3 sheep or to the untreated controls, which were not significantly different. At this time scabs were still firmly in place on many treated sheep. At day 35 there was no increase in tail bare area caused by either treatment. By day 60 there was no significant difference between the treated and control groups in either the breech or tail regions indicating that the changes present at day 35, were not permanent. Mean weight gain in the groups throughout the 60-day interval was unaffected by treatment. Intradermal treatment was associated with a significant elevation in body temperature. This effect lasted for 3 days and was associated with signs of discomfort and depressed appearance in at least some of the treated sheep. Bruising was mild to severe in all treated sheep within two days of treatment but was not evident in any sheep by day 21. Mild to moderate swelling was also associated with treatment but was not uniform across sheep in the groups. The tail of one sheep was severely swollen for several days. Swelling remained obvious in most treated sheep until day 14 but was not present at day 21. Conclusion Under the conditions of this study intradermal injection of cetrimide had no permanent effect on bare area measurements on the breech or the amount of wool-bearing skin on the tail. It also caused signs of discomfort and pain that raise welfare concerns.

The aim of present work was to produce fine elongated crystals of salbutamol sulphate (SS) by sonocrystallization for pulmonary delivery and compare with micronized and spray dried SS (SDSS) for in vitro aerosolization behavior. Application of ultrasound during anti-solvent crystallization resulted in fine elongated crystals (sonocrystallized SS; SCSS) compared to aggregates of large irregular crystals obtained without sonication. Higher sonication amplitude, time, concentration and lower processing temperatures favored formation of smaller crystals with narrow particle size distribution (PSD). SCSS was separated from dispersion by spray drying in the form of loose aggregates (SD-SCSS). The fine particle fraction (FPF) of formulations with coarse lactose carrier in cascade impactor increased from 16.66% for micronized SS to 31.12% for SDSS (obtained by spray drying aqueous SS solution) and 44.21% for SD-SCSS, due to reduced cohesive/adhesive forces and aerodynamic size by virtue of elongated shape of crystals. SD-SCSS was stable without any change in crystallinity and aerodynamic behavior for 3 months at 40 degrees C/75% RH, but amorphous SDSS showed recrystallization with poor aerosolization performance on storage. Sonocrystallization, a rapid and simple technique is reported for production of SS crystals suitable for inhalation delivery.

During the last few decades microporous and mesoporous materials have been considered for medical use due to biological properties and stability in biological environment. Zeolites have been investigated as drug carriers, and as adjuvants in anticancer therapy, dietetic supplements or antimicrobial agents. This review gives a brief overview of the major aspects of molecular sieves applications in medicine.

Room temperature ionic liquids (RTILs) are organic salts which are liquids at ambient temperature. Composed of relatively large asymmetric organic cations and inorganic or organic anions, they have generated interest as 'green' solvents. Here we report on the solvency of alkyl imidazolium salts (PF(6)(-)Br(-)Cl(-)) for poorly water-soluble model drugs, albendazole and danazol, indicating their potential application as pharmaceutical solvents/cosolvents. The solubility of albendazole, for example, is increased by more than 10,000 times by 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF(6)(-)). Ionic liquids can be water-miscible or water-immiscible. The aqueous miscibility of a poorly water-miscible RTIL such as of [bmim]PF(6)(-) can be improved by the inclusion of a second more miscible RTIL (e.g. 1-hexyl-3-methylimidazolium bromide ([hmim]Br(-))). The extent of improvement in water miscibility was found to correlate with the hydrophilicity of the second RTIL. This ability to modulate RTILs' aqueous miscibility increases their usefulness as pharmaceutical solvents.

Purpose The aim of this study was to develop and evaluate a novel three-layered oral delivery system for insulin in vivo . Methods The patch system consisted of a mucoadhesive layer, a water insoluble backing layer made of ethylcellulose and an enteric coating made of Eudragit ® . Drug release studies were performed in media mimicking stomach and intestinal fluids. For in vivo studies patch systems were administered orally to conscious non-diabetic rats. Orally administered insulin in aqueous solution was used as control. After the oral administration of the patch systems a decrease of glucose and increase of insulin blood levels were measured. Results The mucoadhesive layer, exhibiting a diameter of 2.5 mm and a weight of 5 mg, comprised polycarbophil-cysteine conjugate (49%), bovine insulin (26%), gluthatione (5%) and mannitol (20%). 74.8 ± 4.8% of insulin was released from the delivery system over 6 h. Six hours after administration of the patch system mean maximum decrease of blood glucose level of 31.6% of the initial value could be observed. Maximum insulin concentration in blood was 11.3 ± 6.2 ng/ml and was reached 6 h after administration. The relative bioavailability of orally administered patch system versus subcutaneous injection was 2.2%. Conclusion The results indicate that the patch system provides enhancement of intestinal absorption and thereby offers a promising strategy for peroral peptide delivery.

Pharmacokinetic profiles of probucol were evaluated after oral administration of the various nanosuspensions in rats. Probucol nanoparticles were prepared by co-grinding with various molecular weights of polyvinylpyrrolidone (PVP K12, PVP K17 and PVP K30) and sodium dodecyl sulfate (SDS). The average particle sizes of probucol after dispersing the ternary ground mixtures (GMs), probucol/PVP K12/SDS, probucol/PVP K17/SDS and probucol/PVP K30/SDS into water were 28, 75 and 89 nm respectively. The ternary GM suspensions with PVP K17/SDS and PVP K30/SDS were stable at 25 degrees C. However the particle size of probucol from the ternary GM with PVP K12/SDS gradually increased. Pharmacokinetic profiles of probucol indicated that variation in particle surface condition covered with PVP and SDS in addition to the particle size affected the improvement of in vivo absorption of probucol. The ternary GM with PVP K12/SDS exhibited a superior improvement of probucol absorption compared to the GMs with PVP K17/SDS and PVP K30/SDS. The binary GM with PVP or SDS and physical mixtures with PVP and/or SDS did not show significant differences in the area under the plasma concentration-time curve compared to the unprocessed probucol. In conclusion, preparation of probucol nanoparticles by co-grinding with PVP K12 and SDS could be a promising method for bioavailability enhancement.

The main objective of the study was to investigate the effect of permeation enhancers and application of low frequency (LUS) and high frequency ultrasound (HUS) on testosterone (TS) transdermal permeation after application of testosterone solid lipid microparticles (SLM). SLM formulations contained 10% compritol and 5 mg TS /g of SLM. The permeation experiments were performed using Franz diffusion cells and abdomen rat skin. The examined permeation enhancers were 1% oleic acid (OA) or 1 % dodecylamine (DA). HUS (1 MHz) was applied in a continuous mode for 1h at intensity 0.5 W/cm(2). Different intensities and application time of pulsed LUS (20 kHz) were also examined. Additionally, the effect of combination of US and OA or DA was investigated. Skin irritation and histological changes were also evaluated. The results revealed that SLMs have an occlusive effect on the skin. Statistical analysis revealed the following order for the permeation of TS: 1% DA for 30 min>HUS +1% DA for 30 min= HUS=HUS + SLM containing 1% OA> SLM containing 1% OA=control. At total application time of LUS 6, 12, and 15 min the flux increased by 1.86, 4.63, and 4.77 fold, respectively. The enhancement effect of different intensities of LUS was not directly proportional to the magnitude of intensity. Skin exposure to HUS or LUS before application of 1% DA for 30 min had no superior enhancement effect over application of either LUS or HUS alone. Application of drug loaded SLM offered skin protection against the irritation effect produced by TS and 1% DA. Histological characteristics of the skin were affected to various extents by application of enhancers or ultrasound. In general, application of LUS gave higher TS permeation than HUS. However, safe application of LUS should be practiced by careful selection of exposure parameters.

The objective of the study was to design membrane-controlled transdermal therapeutic system (TTS) for trimetazidine. The optimization of (i) concentration of ethanol-water solvent system, (ii) HPMC concentration of drug reservoir and (iii) limonene concentration in 2% w/v HPMC gel was done based on the in vitro permeation of trimetazidine across excised rat epidermis. A limonene-based membrane-controlled TTS of trimetazidine was fabricated and evaluated for its in vivo drug release in rabbit model. The in vitro permeation of trimetazidine from water, ethanol and selected concentrations (25, 50 and 75% v/v) of ethanol-water co-solvent systems showed that 50% v/v of ethanol-water solvent system provided an optimal transdermal flux of 233.1+/-3.8 microg/cm(2.)h. The flux of the drug decreased to 194.1+/-7.4 microg/cm(2.)h on adding 2% w/v of HPMC to ethanolic (50% v/v ethanol-water) solution of trimetazidine. However, on adding selected concentrations of limonene (0, 2, 4, 6 and 8% w/v) to 2% w/v HPMC gel drug reservoir, the flux of the drug increased to 365.5+/-7.1 microg/cm(2.)h. Based on these results, 2% w/v HPMC gel drug reservoir containing 6% w/v of limonene was chosen as an optimal formulation for studying the influence of rate-controlling EVA2825 membrane and adhesive-coated EVA2825 membrane. The flux of the drug across EVA2825 membrane (mean thickness 31.2 microm) decreased to 285.8+/-2.2 microg/cm(2.)h indicating that the chosen membrane was effective as rate-controlling membrane. On applying an adhesive coat (mean thickness 10.2 microm) to EVA2825 membrane, the drug flux further decreased to 212.4+/-2.6 microg/cm(2.)h. However, the flux of the drug across adhesive-coated EVA2825 membrane-rat epidermis composite was 185.9+/-2.9 microg/cm(2.)h, which is about 2-times higher than the desired flux. The fabricated limonene-based TTS patch of trimetazidine showed a mean steady state plasma concentration of 71.5 ng/mL for about 14 h with minimal fluctuation when tested in rabbits. It was concluded from the investigation that the limonene-based TTS patch of trimetazidine provided constant drug delivery across the skin in rabbit model.

The physical stability, dissolution rate, and solubility enhancement of indomethacin amorphized by co-grinding with 6 pharmaceutical silicates were investigated. Mixtures of indomethacin and silicates were co-ground to amorphous states at room temperature and 75% relative humidity (RH) in a rolling jar mill. The fraction of indomethacin amorphized was higher than would be expected for monolayer coverage on the silicate, suggesting additional stabilization of the amorphous drug in the mesopores of the silicate. The co-ground amorphous indomethacin was physically stable for 3 to 6 months at 40 degrees C/75% RH. The physicochemical properties (surface area, crystallinity, presence and absence of metal ions such as Mg(2+), Al(3+), Ca(2+)) of the silicates affect the amorphization time, chemical stability, dissolution, and solubility.

Background: Povidone-iodine (PVP-I) is widely used in antiseptic agents. Immediate allergic reaction to PVP-I preparations is very rare and often overlooked, as it is difficult to diagnose. Polyvinylpyrrolidone (PVP) is thought to play a role in the underlying mechanism. We examined the usefulness of the histamine release test (HRT) for definite diagnosis of PVP allergy. Method: A 9-year-old boy with eosinophilia (1,500/µl) and elevated total IgE (1,376 IU/ml) was suspected clinically of having a PVP allergy, as he had anaphylaxis twice when he was administered a PVP-I solution for impetigo contagiosum. Skin prick tests (SPTs) were performed with a PVP-I solution, PVP (K30), gentamicin sulfate and 2 other medicines containing PVP. HRT was assessed using peripheral blood basophils. Results: SPTs to PVP-I solution, PVP-K30 and other medicines were all negative. Histamine release was observed on stimulation by PVP in the presence of autologous serum, although it was not observed in the absence of autologous serum. Conclusions: This observation was in line with the clinical findings that anaphylaxis had not developed despite the long use of PVP-I solution, but developed only when he received PVP-I solution treatment where basophils could contact PVP-I in the presence of serum, which was probably due to a broken skin and vessel condition. Furthermore, our results suggest the usefulness of HRT in the diagnosis of PVP allergy, and the possibility that negative SPT does not entirely rule out PVP allergy.

Topical microemulsion of capsaicin without surfactant was developed in this study. In these systems, the oil phase was benzyl alcohol, and the cosurfactant was propylene glycol and ethanol. The drop-size of the systems was measured by dynamic light scattering method in order to distinguish true solution from microemulsion. The transdermal performance of the microemulsions was evaluated in vitro by Franz diffusion cells fitted with rat skins. The results showed the drop-size of the microemulsions without surfactant was smaller than that of the systems with Tween 80 and the permeation rate of capsaicin decreased as the content of Tween 80 increased. In the system composed of water, benzyl alcohol and propylene glycol, the permeation rate increased with the enhancement of benzyl alcohol and water. But water content had little effect on the permeation rate in the microemulsions with ethanol as cosurfactant.

The effects of roller compaction process parameters, morphological forms of calcium carbonate and particle size of sorbitol on flow, compaction and compression properties were investigated. The morphology of the calcium carbonate and the sorbitol particle size were more influential on the compaction properties than the settings of the roller compactor. The roller compaction process was demonstrated to be robust and stable in regard to flowability and compactibility. The flowability of the granules was improved adequately to facilitate compression in a production scale rotary tablet press. By adding sorbitol to the calcium carbonate, the compressibility – characterized by the Walker coefficient W ID – and the compactibility C P were improved considerably. A correlation between the consolidation characteristics was demonstrated. Compactibility data from the compaction simulator correlated with the tablet press for two of the calcium carbonates, the cubic form and the ground quality.

Taurolidine is an experimental antibacterial and antiendotoxic compound whose clinical utility as an antitumor agent is being investigated in human clinical trials. Taurolidine in aqueous solution exists in equilibrium with taurultam. Taurultam is subsequently transformed to taurinamide. The pharmacokinetic profiles of these metabolites are not well established. In this study, 18 healthy volunteers were administered 5.0 g of taurolidine in 250 mL of 5% polyvinylpyrrolidone in water over 2, 1, or 0.5 hours by intravenous infusion in a parallel-group design. All subjects noted discomfort at the infusion site, although there were no serious adverse events. t(max) generally occurred at the end of infusion for taurinamide, whereas that of taurultam was reached before completion of infusion. The taurolidine metabolite taurultam demonstrated a shorter half-life and lower systemic exposure than taurinamide. Shortening of infusion duration increased the C(max) and AUC of taurultam. Changes in infusion rate did not substantially change the pharmacokinetic parameters of taurinamide.

Spherical crystals of celecoxib to improve solubility, dissolution rate and micromeritic propertiesCelecoxib spherical agglomerates were prepared with polyvinylpyrrolidone (PVP) using acetone, water and chloroform as solvent, non-solvent and bridging liquid, respectively. The agglomerates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), IR spectroscopic studies and scanning electron microscopy (SEM). The IR spectroscopy and DSC results indicated the absence of any interactions between drug and additives. XRD studies showed a decrease in crystallinity in agglomerates. The crystals exhibited significantly improved micromeritic properties compared to pure drug. The loading efficiency (% or mg drug per 100 mg crystals) was in the range of 93.9 ± 2.3 and 97.3 ± 1.3% (n = 3) with all formulations. The aqueous solubility and dissolution rate of the drug from crystals was significantly (p < 0.05) increased (nearly two times). The solubility andin vitrodrug release rates increased with an increase in PVP concentration (from 2.5 to 10%). The SEM studies showed that the crystal posseses a good spherical shape with smooth and regular surface.

Spectral peak area analysis has in this study been shown to be a viable method in near-infrared spectroscopy (NIRS) moisture assays. The study also shows that the required number of calibration samples can be minimized, and the method is, therefore, especially suitable for moisture assays in early formulation development and in-situ process monitoring. Diffuse NIRS was utilized in the development of moisture assays for the model compounds polyvinylpyrrolidone and hydroxypropyl-beta-cyclodextrin and also for a lyophilized formulation. Reference data were obtained using coulometric Karl Fischer titration. The NIRS measurements were performed through the bottoms of the sample vials using either a Fourier Transform-Near-Infrared (FT-NIR) spectrometer fitted with a diffuse reflectance probe or a dispersive single beam spectrometer. The ratios of the peak areas of a water peak at 5200 cm(-1) and a reference peak were evaluated using linear regression analysis. The spectral peak area analysis method was compared with a conventional partial least squares regression method. The moisture assays were verified using independent test sets. The investigated moisture range was 0-22% for the samples of PVP, 0-8.5% for the samples of hydroxypropyl-beta-cyclodextrin and 0.5-8.5% for the samples of the lyophilized formulation. The results of the spectral peak area analysis and the conventional partial least squares regression were similar, but the peak area method was more robust and could also make accurate predictions for lyophilized PVP samples, although the calibration set consisted of non-lyophilized samples. The peak area method required fewer calibration samples than the conventional partial least squares regression method.

The C60-fullerene derivatives are expected, as novel and potent anti-oxidants, to more effectively protect skin cells against oxidative stress. UVA-induced oxidative stress is considered to promote melanogenesis and serious skin damage. The effect of any fullerene derivatives on UVA-induced melanogenesis is still unknown. Here, we evaluated effects of a water-soluble polyvinylpyrrolidone (PVP)-wrapped fullerene derivative (named “Radical Sponge®” because of its anti-oxidant ability) on melanogenesis, which was promoted by UVA-irradiation to human melanocytes and skin tissues. Radical Sponge® markedly scavenged UVA-induced reactive oxygen species (ROS) inside human melanocytes as shown by fluorometry using the redox indicator CDCFH-DA. After treatment with Radical Sponge® or other agents, human melanocytes and skin tissues were irradiated by UVA. Then, cellular melanin content, tyrosinase activity and the ultrastructural change of skin melanosomes were examined. Radical Sponge® showed to significantly inhibit UVA-promoted melanogenesis in normal human epidermis melanocytes (NHEM) and human melanoma HMV-II cells within a non-cytotoxicity dose range. As compared with two whitening agents, arbutin and l-ascorbic acid, Radical Sponge® demonstrated the stronger anti-melanogenic potential according to spectrophotometric quantification for extracted melanin. In human skin cultures also, UVA-promoted melanin contents were repressed by Radical Sponge® according to Fontana–Masson stain, suggesting its ability to repress UVA-induced tanning. Transmission electron microscopic ultrastructural images also proved that UVA-increased melanosomes in human skin tissue were obviously reduced by Radical Sponge®. The UVA-enhanced tyrosinase enzymatic activity in NHEM melanocytes was inhibited by Radical Sponge® more markedly than by arbutin and l-ascorbic acid. The UVA-enhanced tyrosinase protein expression, together with cell-size fatness and dendrite-formation, was also inhibited more markedly by Radical Sponge® according to immunostain and flow cytometry using anti-tyrosinase antibody. Thus the depigmentating action of Radical Sponge® might be due to its down-regulating effect on the tyrosinase expression, which is initiated by UVA-caused ROS generation.

Topical treatment of acne rosacea, a chronic condition characterized by recurrent course for many years, is primarily based on metronidazole preparations. The aim of this study was to evaluate the effect of various acrylic acid polymers, in composition with methylcellulose on metronidazole release rate from hydrogels proposed for the treatment of acne rosacea. Viscosity and release studies using "Paddle over Disk" system with semipermeable membrane of MWCO 3500 were performed. Compositions of Carbopol 971P and methylcellulose revealed an increase in viscosity with increasing concentration of methylcellulose in the range of 17200-26166 mPa.s. In all the examined formulations, the release process was characterized by a two-stage course. Among bipolymeric formulations, the highest first-stage release rate of 9.18 x 10(-3) min(-1) was determined for the gel consisting of 2.00% Carbopol 980NF with 1.00% methylcellulose. The second-stage release rates ranged between 2.88 x 10(-3) and 8.00 x 10(-3) min(-1). Two-stage release course can thus be attributed to metronidazole distribution into two compartments of hydrogel matrix. Proposed gels, with similar rheological properties, may be used for ex vivo and in vivo studies to obtain a suitable drug activity of metronidazole in the treatment of acne rosacea.

The major indication for testosterone (T) treatment is male hypogonadism that is characterized by low serum T concentrations. Although a recently developed hydroalcoholic gel, Androgel, containing 1% T addresses many of the problems associated with the more conventional formulations, the bioavailability of T is only 10% requiring 5 to 10 g of gel to be applied daily. The present study was performed to investigate the effect of isopropyl alcohol (IPA) content as a penetration enhancer based on its ability to prevent skin dryness and in turn to increase T permeation from hydroalcoholic gels. Five different hydroalcoholic gel formulations, containing 1% T and carbopol as the gel-forming polymer, were formulated by varying the amount of IPA. The release of T from each gel, including Androgel, was studied in vitro on Franz diffusion cells using cellulose ester and Celgard 2400 as synthetic membranes and hairless guinea pig skin as a natural membrane. The amount of drug released from the gels was analyzed using an HPLC-UV method. The results of release/permeation studies on guinea pig skin showed that all the gels were similar to Androgel, indicating that the addition of IPA does not affect the release of T from hydroalcoholic gels. Although no statistical significant difference was seen, the release profiles of the gels showed a trend of increasing release of T with increasing concentration of IPA. Thus, IPA does have a potential to increase the bioavailability of T from hydroalcoholic gels.

The aim of this study was to investigate the effect of two different types of high-flux dialysis membranes on insulin resistance among patients who are receiving hemodialysis (HD) due to end-stage renal failure (ESRF).Forty-six (21 female, 25 male) patients were included in the study, who were on HD treatment due to stage-5 chronic renal failure. Prior to the study, fasting insulin resistance via Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) and fractioned urea clearance (Kt/V) values were calculated using the urokinetic model. The polysulfone (PS) dialysis membrane of all patients included in the study was replaced with "polyarylethersulfone, polyvinylpyrrolidone, polyamide (PPP)" high-flux membrane that has the same surface area over 12 weeks. At the end of the 12-week period, HOMA and Kt/V values were recalculated.At the end of the 12-week period, Kt/V values rose statistically significant from 1.575 to 1.752 (p = 0.002). HOMA-IR values declined, though not statistically significant, from 3.268 to 2.926 (p = 0.085). PPP high-flux membrane increased the Kt/V values significantly compared to the PS membrane, while it decreased the insulin resistance and increased insulin sensitivity.The two different types of high-flux dialysis membranes used for HD have different effects on insulin sensitivity. Compared to the PS membrane, PPP high-flux membrane decreased insulin resistance by increasing insulin sensitivity among non-diabetic ESRF patients.

Virus safety of cell-based medicinal products is a particular challenge. These products are frequently manufactured using various human- or animal-derived starting and raw materials (serum and feeder-cells) in cell culture, which are possible sources for viral contamination. For living or proliferating cells, no methods for virus inactivation (such as heat or chemical treatment) can be used and the options for testing these medicinal products for all possible viral contaminations are very limited. As a consequence, other safety measures, in particular careful selection and testing of starting and raw materials, are very important. For raw materials, attention should be paid to cell-culture additives of biological origin, such as human and bovine serum and porcine trypsin. Whenever possible, manufacturing steps for inactivation and removal of viruses should be introduced as an additional safety measure. In addition, recombinant products from animal cell cultures (such as growth factors, monoclonal antibodies for cell sorting, viral vectors) are used and have to be tested for virus safety.

Polymeric film-forming systems (FFSs) are potential drug delivery systems for topical application to the skin. The FFSs form thin and transparent polymeric films in situ upon solvent evaporation. Their application convenience and cosmetic attributes, superior to conventional semi-solids, may offer improved patient compliance. This study represents the first phase of an investigation into the use of FFSs for prolonged dermal drug delivery. FFS formulations were distinguished based on their ability to sustain the release of betamethasone 17-valerate (BMV) in vitro over 72 h. The effect of film-forming polymer (hydrophilic: hydroxypropyl cellulose (Klucel™ LF); hydrophobic: polymethacrylate copolymers (Eudragit® NE and Eudragit® RS), and polyacrylate copolymer (Dermacryl® 79) was first determined, and then the impact of incorporation of plasticisers (triethyl citrate, tributyl citrate, and dibutyl sebacate) was examined. The Klucel film released a significantly higher amount of BMV than the hydrophobic FFS, 42 versus 4 μg/cm2, respectively. The release was increased when a plasticiser was incorporated, and with higher enhancement ratios achieved with the more lipophilic plasticisers. In conclusion, the results show that FFSs can sustain drug release (hence representing useful systems for prolonged dermal therapy) and emphasise the importance of the formulation on drug delivery, with the type of polymer being of greatest significance.

Pharmacists are required to ensure the quality of services provided to each patient. Good Pharmacy Practice (GPP) is a tool of clarifying and fulfilling this commitment. The role of International Pharmaceutical Federation (FIP) is to guide the national pharmaceutical organizations, which, in turn, should initiate the establishment of national standards. A key element is the obligation imposed by the profession throughout the world - to promote different activities for the benefit of those we serve. GPP is recommended to be considered as a list of occupational tasks, the implementation of which would serve the interests of patients or customers in the pharmacy. Ultimately, the quality of pharmaceutical care system will help to ensure not only the commercial interests of the pharmacy, but also the security requirements as those services and products, as well as professionals and patients.

GOAL OF THE WORK: Oral mucositis (OM) is a functionally destructive complication of aggressive head and neck cancer therapy, often resulting in intense pain, an inability to eat and drink and secondary malnutrition and dehydration. The barrier-forming properties of Gelclair have shown promise in relieving such symptoms. The aim of this randomised-controlled trial was to evaluate the efficacy of Gelclair, as compared to standard therapy, as a means of short-term symptom control for patients suffering from radiotherapy-induced OM.Twenty patients, with radiotherapy-induced OM seen in two oncology centres in Devon, were randomised to either standard therapy (Sucralfate and Mucaine) or Gelclair and assessed over 24 h. Both treatments were taken four times during the 24-h period, 30 min before meals.No significant difference was found between the Gelclair and standard therapy arms in terms of general pain (F = 1.512, df = 1, 17, ns). There did appear to be a trend towards pain improvement initially after the use of Gelclair, but this did not last for the full 24-h assessment period. There was no significant reduction in pain on speaking (F = 0.261, df = 1, 17, ns) nor an improvement in capacity to eat and drink, although the effects of standard therapy did appear to last longer than the Gelclair.This study indicates that Gelclair is no more effective than current standard practice in relieving the pain associated with radiotherapy-induced OM. Nevertheless, observations from this preliminary study warrant further investigation, with a view to shaping the way forward for head and neck cancer practice on a national level.

To test the hypothesis that the molecular motions associated with chemical degradation in glassy amorphous systems are governed by the molecular motions associated with structural relaxation. The extent to which a chemical process is linked to the motions associated with structural relaxation will depend on the nature of the chemical process and molecular motion requirements (e.g., translation of a complete molecule, rotational diffusion of a chemical functional group). In this study the chemical degradation and molecular mobility were measured in model systems to assess the degree of coupling between chemical reactivity and structural relaxation. The model systems included pure amorphous cephalosporin drugs, and amorphous molecular mixtures containing a chemically labile drug and an additive expected to moderate molecular mobility.Amorphous drugs and mixtures with additives were prepared by lyophilization from aqueous solution. The physical properties of the model systems were characterized using optical microscopy and differential scanning calorimetry. The chemical degradation of the drugs alone and in mixtures with additives was measured using high-performance liquid chromatography (HPLC). Molecular mobility was measured using isothermal microcalorimetry to measure enthalpy changes associated with structural relaxation below T (g).A weak correlation between the rates of degradation and structural relaxation times in pure amorphous cephalosporins suggests that reactivity in these systems is coupled to molecular motions in the glassy state. However, when sucrose was added to one of the cephalosporin drugs stability improved even though this addition reduced T (g) and the relaxation time constant, tau(D)(beta), suggesting that there was no correlation between reactivity and structural relaxation in the cephalosporin mixtures. In contrast, the rate of ethacrynate sodium dimer formation in mixtures was more strongly coupled to the relaxation time constant, tau(D)(beta).These studies suggest that the extent to which chemical degradation is coupled to structural relaxation in glasses motions is determined by how closely the motions of the rate controlling step in chemical degradation are associated with structural relaxation. Moderate coupling between the rate of dimer formation for ethacrynate sodium in mixtures with sucrose, trehalose and PVP and structural relaxation constants suggests that chemical changes that require more significant molecular motion, and includes at least some translational diffusion, are more strongly coupled to the molecular motions associated with structural relaxation. The observation that sucrose stabilizes cefoxitin sodium even though it lowers T (g) and reduces the relaxation time constant, tau(D)(beta) is perhaps a result of the importance of other kinds of molecular motions in determining the chemical reactivity in glasses.

The objective of this study was to investigate thermodynamic and kinetic factors contributing to differences in the isothermal nucleation rates of two structurally related calcium channel blockers, nifedipine and felodipine, both alone and in the presence of poly(vinylpyrrolidone) (PVP).Thin films of amorphous systems were cast onto glass slides and the nucleation rate was determined using optical microscopy. Enthalpy, entropy, and free energy of crystallization of the pure compounds were measured using differential scanning calorimetery (DSC). Molecular mobility and glass transition temperature of each amorphous system were characterized using DSC and hydrogen bonding patterns were analyzed with infrared spectroscopy. The composition dependence of the thermodynamic activity of the amorphous drug in the presence of the polymer was estimated using Flory-Huggins lattice theory.Nifedipine crystallized more readily than felodipine from the metastable amorphous form both alone and in the presence of PVP despite having a similar glass transition temperature and molecular mobility. Nifedipine was found to have a larger enthalpic driving force for crystallization and a lower activation energy for nucleation.The properties of the metastable form alone did not explain the greater propensity for nifedipine crystallization. When considering the physical stability of amorphous systems, it is important to also consider the properties of the crystalline counterpart.

The distribution of drugs between water, oil and mixed micelles after the oral application of lipid-based drug delivery systems affects their absorption rate. Since it has not been previously possible to monitor this process online during in vitro lipolysis, it was our aim to develop a suitable real-time method.To follow the fate of a co-administered drug during fat digestion, the spin probe tempol benzoate was incorporated as a lipophilic model drug into a long-chain triglyceride (olive oil) and an in vitro digestion test was combined with electron paramagnetic resonance (EPR) spectroscopy (X-Band). Additionally the progression of digestion was determined by means of high performance thin layer chromatography (HPTLC).The spectral shape of the EPR spectrum changed significantly during the digestion process. EPR spectra at all times could be simulated with three species indicating a redistribution of the lipophilic model drug between olive oil, phosphate buffer and mixed micelles formed by bile salts and phospholipids.This in vitro real-time analysis could be a very helpful tool to monitor the digestibility of novel lipid-based drug nanocarriers which is an important step to optimize and to predict drug delivery processes. In future the EPR monitoring of fat digestion will be transferred to in vivo experiments.

Polyvinylpyrrolidone (PVP), a polymer of the monomer N-vinylpyrrolidone with various molecular weights, was originally developed as a plasma expander. Currently, it is widely used in hair sprays, skin care products, fruit juices, and as a retarding agent in drugs such as procaine and hormones. PVP polymers with a molecular weight greater than 20,000 cannot be excreted by the kidneys and therefore are phagocytosed and permanently stored in the reticular endothelial system, leading to the so-called PVP storage disease. We report a case of localized cutaneous PVP storage disease presenting with persistent upper lip swelling and mimicking cheilitis granulomatosa, which has never been reported before.

OBJETIVO: Avaliar a presença de conservantes, corantes, adoçantes e aromatizantes em 73 apresentações farmacêuticas de 35 medicamentos para uso oral, e as informações da bula sobre excipientes. MÉTODOS: Selecionamos 35 medicamentos, de venda livre ou sob prescrição médica, comercializados no Brasil. A amostra incluiu: analgésicos/antitérmicos, antimicrobianos, mucolíticos, antitussígenos, descongestionantes, anti-histamínicos, broncodilatadores, corticosteróides, antiinflamatórios e suplementos vitamínicos. Foram analisadas 73 apresentações desses fármacos, anotando-se as informações da bula sobre conservantes, corantes, adoçantes e aromatizantes. RESULTADOS: A bula de um medicamento (1,3%) não mencionava os ingredientes inativos. Os conservantes mais encontrados nos medicamentos foram metilparabeno e propilparabeno (43% e 35,6% respectivamente). Os adoçantes mais usados foram: sacarose (açúcar) (53,4%), sacarina sódica (38,3%) e sorbitol (36,9%). Vinte e um produtos (28,7%) continham dois adoçantes. Predominaram os medicamentos sem corante (43,8%), seguidos pelos coloridos por amarelo crepúsculo (amarelo FD&C no. 6) (15%). Cinco produtos (6,8%) continham mais de um corante. A tartrazina (amarelo FD&C no. 5) foi encontrada em sete formulações (9,5%). Os aromatizantes mais usados foram os de frutas (83%). Constatamos a freqüente omissão das bulas sobre o teor exato de açúcar dos produtos (77%). Duas das quatro bulas de medicamentos contendo aspartame não mencionavam as precauções no uso por fenilcetonúricos. CONCLUSÕES: A omissão e a imprecisão das informações da bula sobre os excipientes farmacêuticos expõem os indivíduos suscetíveis ao risco de reações adversas dos conservantes e corantes. Também podem ocorrer complicações do uso inadvertido de medicamentos contendo açúcar pelos pacientes diabéticos, ou de fármacos adoçados com aspartame pelos fenilcetonúricos.AIM: to evaluate the presence of preservatives, dyes, sweeteners and flavouring substances in 73 pharmaceutical preparations of 35 medicines for oral administration, according to drug labeling information about the excipients. METHODS: 35 medications were selected, both over-the-counter and prescription durgs, marketed in Brazil. The sample included: analgesic/antipyretic, antimicrobial, mucoregulatory, cough and cold, decongestant, antihistamine, bronchodilator, corticosteroid, antiinflammatory and vitamin medications. We collected data on 73 preparations of these drugs, according to drug labeling information regarding preservatives, dyes, sweeteners and flavourings. RESULTS: Methylparaben and propylparaben were the most common preservatives found (43% and 35.6% respectively). The most common sweeteners were: sucrose (sugar) (53.4%), sodium saccharin (38.3%) and sorbitol (36.9%). Twenty-one medicines (28,7%) contained two sweeteners. Colourless medicines predominated (43.8%), followed by those with sunset yellow dye (FD&C yellow no. 6) (15%). Five products (6.8%) contained more than one colour agent. Tartrazine (FD&C yellow no. 5) was present in seven preparations (9.5%). Fruit was the most common flavouring found (83%). Labelings of drugs which contained sugar frequently omitted its exact concentration (77%). Of the four labelings of medicines which contained aspartame, two did not warn patients regarding phenylketonuria. CONCLUSION: Omission and inacuracy of drug labeling information on pharmaceutical excipients may expose susceptible individuals to adverse reactions caused by preservatives and dyes. Complications of inadvertent intake of sugar-containing medicines by diabetics, or aspartame intake by patients with phenylketonuria may also occur.

Protecting proteins from aggregation is one of the most important issues in both protein science and protein engineering. In this research, the mechanism of enhancing the refolding of guanidine hydrochloride-denatured carbonic anhydrase B by polyvinylpyrrolidone 40 (PVP40) was studied by both kinetic and equilibrium refolding experiments. The reactivation and refolding kinetics indicated that the rate constant of refolding the first refolding intermediate (I(1)) to the second one (I(2)) is promoted by the addition of PVP. Fluorescence quenching studies further indicated that PVP could bind to the aggregation-prone species I(1), resulting in the protection of the exposed hydrophobic surface, a minimization of the protein surface, and more importantly, an increase of the refolding rate of I(1). These properties were quite different from those of poly(ethylene glycol) (PEG), which has been shown to have a strong and stoichiometric binding to I(1) and does not interfere with the refolding pathway. Unlike PEG, the binding of PVP to I(1) does not block the aggregation pathway directly but decreases the energy barrier for I(1) to refold to I(2) and thus reduces the accumulation of I(1). These results suggested that PVP works by a quite different mechanism from those well established ones in chaperones and chemical promoters. PVP is more like a folding catalyst rather than a chemical chaperone. The distinct mechanism of enhancing protein aggregation by PVP is expected to facilitate the attempt to develop new chemical compounds as well as new strategies to protect proteins from aggregation.

Summary Background : Congenital obstruction of the lacrimal drainage system is present in approximately 6% of newborn. Syringing and probing is one of the common interventional modalities for this condition. Current literature states that syringing and probing is performed best with general anesthesia with tracheal intubation. We study a technique to improve the safety and efficacy of the laryngeal mask airway (LMA) in lacrimal duct surgery. Methods : Sixty-five ASA grade I-II patients between 6 months and 10 years scheduled for syringing and probing were included after informed consent was obtained from the parents. After induction of anesthesia and confirmation of LMA position, a transparent suction catheter was inserted into the hypopharynx. Continuous suction was applied to the catheter. A total of 2–3 ml of 0.01% povidone–iodine solution was used for syringing. Staining of the catheter was regarded as a sign of patency of the duct. Results : None of our patients had perioperative airway or respiratory complications. Conclusions : Based on the results of our study, we suggest that the LMA can safely be used in lacrimal duct procedures. Using 0.01% povidone–iodine as irrigation fluid further increases the margin of safety.

In photodynamic therapy (PDT), topically applied aminolevulinic acid (5-ALA) is converted to protoporphyrin IX (PpIX), which upon light excitation induces tumor destruction. To optimize 5-ALA-PDT via improving the highly hydrophilic 5-ALA limited penetration into the skin, we propose the use of the known skin penetration enhancer, oleic acid (OA). In vitro skin penetration and retention of 5-ALA (1% w/w) were measured in the presence or absence of OA (2.5, 5.0, and 10.0% w/w) in propylene glycol (PG) using porcine ear skin as the membrane. In vivo accumulation of PpIX, 4 h after application, was determined fluorometrically in healthy mice skin by chemical extracton of skin samples. In vivo PpIX fluorescence kinetics was also investigated by noninvasive techniques using an optical fiber probe, for 30 min up to 24 h after topical application of 1.0% 5-ALA + 10.0% OA in PG on hairless mice skins. The flux and in vitro retention of 5-ALA in viable epidermis increased in the presence of 10.0% (w/w) OA. The amounts of PpIX, evaluated both by chemical tissue extractions and in vivo measurements by an optical fiber probe, increased after applying 5-ALA formulations containing 5.0 or 10.0% OA. Moreover, in vivo kinetic studies showed an increase in skin PpIX accumulation when formulations containing 10% OA were used; PpIX accumulation was also maintained longer compared to controls. Both in vitro and in vivo results show the OA potential as an optimizer of 5-ALA skin delivery.

This study was conducted to demonstrate the use of differential scanning calorimetry (DSC) in detecting and measuring beta-relaxation processes in amorphous pharmaceutical systems.DSC was employed to study amorphous samples of poly(vinylpyrrolidone) (PVP), indomethacin (IM), and ursodeoxycholic acid (UDA) that were annealed at temperatures (T(a)) around 0.8 of their glass transition temperatures (T(g)). Dynamic mechanical analysis (DMA) was used to measure beta-relaxation in PVP.Reheating the annealed samples gives rise to annealing peaks that occur below T(g). The peaks cannot be generated when annealing below the low temperature limit of beta-relaxation. These limits are around 50 degrees C for PVP, -20 degrees C for IM, and 30 degrees C for UDA. The effective activation energy (E) of the sub-T(g) relaxation has been estimated for each T(a) and found to increase with T(a), reflecting increasing contribution of the alpha-process. Estimates of E for beta-relaxation have been obtained from the lowest T(a) data, and are as follows: 68 (PVP), 56 (IM), 67 (UDA) kJ mol(-1).DSC can be used for detecting beta-relaxation processes and estimating its low temperature limit, i.e., the temperature below which amorphous drugs would remain stable. It can also provide comparative estimates of low temperature stability of amorphous drugs in terms of the activation energies of the beta-relaxation.

The intricate problems associated with the delivery and various unnecessary in vivo transitions of proteins and drugs needs to be tackled soon to be able to exploit the myriad of putative therapeutics created by the biotechnology boom. Nanomedicine is one of the most promising applications of nanotechnology in the field of medicine. It has been defined as the monitoring, repair, construction and control of human biological systems at the molecular level using engineered nanodevices and nanostructures. These nanostructured medicines will eventually turn the world of drug delivery upside down. PEGylation (i.e. the attachment of polyethylene glycol to proteins and drugs) is an upcoming methodology for drug development and it has the potential to revolutionise medicine by drastically improving the pharmacokinetic and pharmacodynamic properties of the administered drug. This article provides a total strategy for improving the therapeutic efficacy of various biotechnological products in drug delivery. This article also presents an extensive analysis of most of the PEGylated proteins, peptides and drugs, together with extensive clinical data. Nanomedicines and PEGylation, the latest offshoots of nanotechnology will definitely pave a way in the field of drug delivery where targeted delivery, formulation, in vivo stability and retention are the major challenges.

Objectives: The aim of this study was to evaluate the efficacy of topical valdecoxib as an analgesic during chest tube removal in postcardiac surgical patients. Design: A prospective, randomized, double-blind, placebo-controlled study. Setting: The study was performed in the cardiac intensive care unit. Participants: Fifty-three patients undergoing elective cardiac surgery were randomized to receive either topical valdecoxib or liquid paraffin on the chest tube exit sites. Intervention: Topical valdecoxib was applied to 1 of the 2 chest tube sites (mediastinal or pericardial) in a randomized manner before drain removal. Liquid paraffin was used as the control on the other tube site. The patient and observer were blinded to the drug and control. Measurements and Main Results: Pain was assessed by using the visual analog scale. The heart rate and systolic blood pressure were recorded at each stage by the blinded observer. Statistical analysis of the obtained data was undertaken using the nonparametric Mann-Whitney U test. The median pain scores before, during, and after tube removal in the control group were 2, 5, and 4, respectively. The valdecoxib group had corresponding scores of 1, 2, and 2. The pain scores were significantly lower in the valdecoxib group. No differences were seen in the heart rate and systolic blood pressure between the 2 groups. No adverse effects were noted. Conclusions: Topical valdecoxib is a safe and effective topical analgesic for chest tube removal in cardiac patients.

Poly(vinyl pyrrolidone) (PVP) is widely used for bioengineering and pharmaceutical applications, and its adhesion characteristics are critical. When used as a binder in pharmaceutical granulation, it covers the resultant granules and governs their surface properties. The intrinsic adhesion forces of PVP toward common hydrophobic (magnesium stearate) and hydrophilic (lactose) pharmaceutical materials have been studied as a function of relative humidity (RH). The effect of RH on adhesion force was more significant for the PVP/hydrophilic material than the PVP/hydrophobic material. Adhesion was lowest between 20 and 40% RH, and it increased at RH above 40% and below 20%. This is likely to be due to the development of capillary and triboelectrification forces, respectively. In a nano-indentation experiment using a silicon tip at room temperature, the PVP surface underwent a glass transition at 70% RH. This result suggests that surface softening contributes to the increased PVP adhesion at RH above 70%. To adjust the adhesion properties of PVP, humidity control should be an essential part of research and development. Effect of humidity on the adhesion forces between PVP and lactose (LT) or magnesium stearate (MS).

ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional matrix tablets decreased with increasing pH-values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Three different polymers were used as matrix formers, the partly water-soluble and poorly swellable mixture of polyvinylacetate/polyvinylpyrrolidone, the water-insoluble and almost unswellable ethylcellulose (EC) and the water-soluble and highly swellable hydroxypropyl methylcellulose (HPMC). To solve the problem of pH-dependent solubility different organic acids, such as fumaric, tartaric, adipic, glutaric and sorbic acid were added to the drug-polymer system. The addition of organic acids to all three matrix formers was found to maintain low pH-values within the tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, the micro-environmental conditions for the dissolution of the weakly basic drug were kept almost constant. An extended release matrix tablet for ZK 811 752 consisting of drug, polymer and organic acid providing the desired pH-independent drug release has been developed.

This work explores the distribution of water and its effects on molecular mobilities in poly(vinylpyrrolidone) (PVP) glasses using molecular dynamics (MD) simulation technology.PVP glasses containing 0.5% and 10% w/w water and a small amount of ammonia and Phe-Asn-Gly were generated. Physical aging processes and associated structural and dynamic properties were monitored vs. time for periods up to 0.1 micros by MD simulation.Increasing water content from 0.5% to 10% w/w was found to reduce the Tg by about 90 K and increase the rates of volume and enthalpy relaxation. At 0.5% w/w, water molecules are mostly isolated and uniformly distributed while at 10% w/w, water distribution is markedly heterogeneous, with strands of water molecules occupying channels between the polymer chains. At 10% w/w, each water molecule has an average of 2.0 neighboring water molecules. The plasticization effects of water were revealed in diffusion coefficient increases of 3.7-, 7.3-, and 7.6-fold for water, ammonia, and the individual polyvinylpyrrolidone segments, respectively, and in shorter relaxation times (37- to 47-fold) for rotation of polymer segments with an elevation in water content from 0.5% to 10% w/w. Water diffusivity was found to linearly correlate with the number of neighboring water molecules. Rotation of the PVP segments is comprised of a fast wobble motion within a highly restrained cavity and a slow rotation over a wider angular space. Only the slow rotation was shown to be significantly affected by water content.Water distribution in the PVP glass is highly heterogeneous at 10% w/w water, reflecting the formation of water strands or small clusters rather than complete phase separation. Local enhancement of mobility with increasing water content has been demonstrated using MD simulations.

Purpose To investigate the effect of plasticizers on the stability of protein formulations in the solid state and to apply these results to a study of mechanisms of protein stabilization by sugars in the solid sate. Methods The IgG1 antibody was formulated with either sucrose or trehalose alone or a mixture of sorbitol with sucrose or trehalose. After lyophilization, the pure protein and sucrose formulations were equilibrated at different relative humidities giving residual moistures from less than 1% to 5% for sucrose systems and up to 17% for pure protein systems. All the samples were stored at 50°C for up to1 month and at 40 and 25°C for up to 6 months. Aggregation and chemical degradation were monitored by size exclusion chromatography (SEC) and ion exchange chromatography (IEX), respectively. The secondary structure was characterized by FTIR using second derivative analysis of Amide I region. Structural relaxation times, τ, an indication of molecular mobility in the glassy matrix, were characterized using the thermal activity monitor (TAM). The τ values of the recombinant human monoclonal antibody (rhuMab) formulation with various water contents were also measured in this study and compared with stability data taken from the literature (Breen ED, Curley JG, Overcashier DE, Hsu CC, Shire SJ, 2001, Pharm Res 18:1345–1353). Results The structural relaxation time, τ, decreased sharply with increasing water content. However, the stability data suggest a minimum in degradation rate at 2%–3% water content. Addition of a small amount of sorbitol to a sucrose-based formulation resulted in greater retention of native structure, smaller relaxation time, but improved stability. However, with the trehalose-based formulations, addition of sorbitol had no effect on protein structure (FTIR), but the decrease in relaxation time and the improvement in stability were qualitatively similar to the corresponding data obtained with the sucrose-based formulation. Conclusion Glass dynamics as measured by τ could not explain the stability results. Stability correlated best with the preservation of native structure for sucrose-based formulations, but with the trehalose-based formulation, neither structural relaxation time nor extent of native structure was predictive of stability. However, it is possible that the β-relaxations rather than the α-relaxation (i.e., the τ we measured) is critical to the stability. Plasticizers like glycerol may decrease τ for “α-motion” but increase τ for “β-motion” and stabilize proteins (Cicerone MT, Tellington A, Trost L, Sokolov A, 2003, BioProcess Inter 1:1–9). © 2005 Wiley-Liss, Inc. and the American Pharmacists Association

The purpose of the present study was to investigate the impact of intermolecular forces on the stability of the amorphous state of loperamide and two of its fragment molecules (4-dimethylamino-N,N-dimethyl-2,2-diphenyl-butyramide (F1) and 4-(4-chlorophenyl)-4-piperidinol (F2)) in solid dispersions with PVP-K30 and PVP-VA64. The stability of originally homogeneous and amorphous dispersions was investigated under different storage conditions. The chemical stability of the compounds was evaluated with HPLC. TGA-analysis was used in order to assess the amount of water in the samples, whereas MT-DSC-measurements were performed to investigate changes in the physical state of the compounds caused by the storage procedure. TGA-analysis reveals a higher uptake of water in humid conditions of the dispersions with PVP-K30 in comparison to those with PVP-VA64, hereby reflecting the more hydrophilic nature of the former polymer. This water acts as a plasticizing agent resulting in an increased mobility and decreased glass transition temperature. Since the degree of supersaturation and the molecular mobility have an influence on the stability of the amourphous state, both parameters were assessed. With respect to the degree of supersaturation of the compounds in the dispersions, the materials seem to be very much alike. Therefore it was postulated that the induction of crystallization in the F1/polymer dispersions stored at high RH (52%) is due to higher molecular mobility of this compound in the dispersions in comparison to F2. The hydrogen bonds that are being formed between F2 and the polymers reduce its mobility and secure this compound from crystallization upon storage, thus indicating the importance of specific interactions with respect to stability issues of solid dispersions. No hydrogen bonds are formed between F1 and the polymers. As a result, the stability of the amorphous state of the compound is being compromised and crystallization takes place. Loperamide, that also does not form hydrogen bonds with the polymers, is less susceptible to crystallization due to its intrinsic good glass forming properties.

Permeation enhancement of ketoprofen (KP) from supersaturated systems and the effects of antinucleant polymers on both stability and permeation of supersaturated KP were investigated using silicone membrane as a skin model. The supersaturation was prepared by the cosolvent technique with water and propylene glycol (PG). Saturated solubility of KP in water/PG cosolvent increased markedly with an increase in PG percentage. The time-profiles of the cumulative amount of released KP from supersaturated solutions through the membrane increased linearly, and this KP flux had a significant correlation with the degree of saturation (DS) in 80 : 20, 60 : 40, 50 : 50, and 40 : 60 (v/v) water/PG cosolvent systems. The influence of 1% solutions of antinucleant polymers, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and sodium carboxymethylcellulose (SCMC) on the DS and the stability of supersaturated KP was examined in 60 : 40 (v/v) water/PG cosolvent. The remaining DS for 24 h after mixing the solvents increased in the presence of HPMC and SCMC but not PVP. In the presence of SCMC, the physical stability of supersaturated KP was higher, however, the KP flux was lower than that in the control and in the presence of the other polymers. In conclusion, the supersaturation system can be applied to achieve higher transmembrane permeation of KP, and appropriate antinucleant polymers such as HPMC can optimize the physical stability and permeability of KP.

Because the therapeutic options for managing infections in neonates in developing countries are often limited, innovative approaches to preventing infections are needed. Topical therapy with skin barrier-enhancing products may be an effective strategy for improving neonatal outcomes, particularly among preterm, low birth weight infants whose skin barrier is temporarily but critically compromised as a result of immaturity.We tested the impact of topical application of sunflower seed oil 3 times daily to preterm infants34 weeks gestational age at the Kasr El-Aini neonatal intensive care unit at Cairo University on skin condition, rates of nosocomial infections and mortality.Treatment with sunflower seed oil (n = 51) resulted in a significant improvement in skin condition (P = 0.037) and a highly significant reduction in the incidence of nosocomial infections (adjusted incidence ratio, 0.46; 95% confidence interval, 0.26-0.81; P = 0.007) compared with infants not receiving topical prophylaxis (n = 52). There were no reported adverse events as a result of topical therapy.Given the low cost (approximately .20 dollars for a course of therapy) and technologic simplicity of the intervention and the effect size observed in this study, a clinical trial with increased numbers of subjects is indicated to evaluate the potential of topical therapy to reduce infections and save newborn lives in developing countries.

Correct oral hygiene is believed to be the basis of primary and secondary prevention. Sometimes, using a toothbrush or other mechanical instruments for oral hygiene may be difficult and it may become necessary to use an antiseptic. Chlorhexidine is an essential component in many available preparations on sale, because of its marked antiseptic qualities. One of the most frequent side-effects is the appearance of stains on the teeth and mucous membranes, which particularly disturbs the patient. A new mouthwash containing chlorhexidine has recently become available, besides maintaining its antiseptic qualities, also avoids the side-effect of staining. Objectives: The aim of this study was to check the capacity of the new mouthwash, which contains chlorhexidine and Anti Discoloration System (ADS), not only to prevent plaque formation like the other mouthwashes containing chlorhexidine but also to avoid staining that is one of the most frequent side-effects. Study design: The comparative study was carried out on a sample of 15 patients treated with two mouthwashes both containing 0.2% chlorhexidine, but different in that the first does not contain ADS, which is instead present in the second, a new product. The results obtained show that in the 15 patients treated, there is no statistically significant difference in the ability of the mouthwash to prevent bacterial plaque, however evidence of the stain was much less with the new mouthwash.

The purpose of this study was to investigate the transport mechanisms and causes of low bioavailability of leuprolide. The everted gut sac technique and Caco-2 cell monolayer were used to examine: (1) transport properties, enzyme degradation and apparent permeation coefficient (Papp); (2) the influence of trypsin inhibitor, EDTA, chitosan and alginate on drug transport; and (3) the effect of animal species on the intestinal transport. Results showed flux increased with increasing concentration of drug, showing a passive diffusion pathway. The enzyme degradation in rabbit gut was the highest. The Papp of (4.19 +/- 1.33) x 10(-5) cm/s in rat gut was the largest and the Papp of (5.20 +/- 0.20) x 10(-7) cm/s in Caco-2 cell the smallest. At a low concentration of drug, trypsin inhibitor had strong enhancement effect on the Papp by protecting enough drug for permeation. Chitosan had no effect on the activity of alpha-chymotrypsin. The increase in Papp was due to opening of the tight junctions and interaction with cells. In conclusion, both inhibition of proteolytic enzymes and opening the tight junctions to allow for paracellular transport improved the intestinal absorption. At low drug concentration, reduction of enzyme degradation is the most important factor.

The purpose of this study was to investigate the suitability of phase sensitive smart polymer-based protein formulations in order to deliver a model protein, lysozyme, in a conformationally stable and biologically active form at a controlled rate over extended period of time. Four different formulations, using d,l-poly(lactide) (d,l-PLA) and a solvent mixture of different ratios of benzyl benzoate (BB) and benzyl alcohol (BA), were prepared. Conformational stability and biological activity of lysozyme were studied by differential scanning calorimeter and enzyme activity assay, respectively. We found a significant (P

A tablet system consisting of cores coated with two layers of swelling and rupturable coatings was prepared and evaluated as pulsatile drug delivery system. Cores containing buflomedil HCl as model drug were prepared by direct compression of different ratios of spray-dried lactose and microcrystalline cellulose and were then coated sequentially with an inner swelling layer containing a superdisintegrant (croscarmellose sodium) and an outer rupturable layer of ethylcellulose. The effect of core composition, level of swelling layer and rupturable coating, and magnesium stearate in rupturable layer was investigated. Mechanical properties of ethylcellulose films in the dry and wet state were characterized with a puncture test. Rupture and dissolution tests were performed using the USP XXIV paddle method at 50 rpm in 0.1 N HCl. The lag time of the pulsatile release tablets decreased with increasing amount of microcrystalline cellulose in the cores and increased with increasing levels of both swelling layer and rupturable ethylcellulose coating. Increasing levels of the ethylcellulose coating retarded the water uptake and thus prolonged the lag time. Addition of magnesium stearate to the ethylcellulose coating lowered the mechanical strength of the film and improved the robustness of the system.

Common colds were shortened by 7 days in a 1984 clinical trial using zinc gluconate throat lozenges each 2 h. Between then and 2004, 10 other double-blind, placebo-controlled clinical trials showed widely varying results. This re-analysis of these trials presents solution chemistry methods to elucidate differences in efficacy. Statistically significant correlation was shown between total daily dosages of positively charged zinc species and reductions in median (p = 0.005) and mean duration (p < 0.02) of common colds in these trials.

The aim of this study was to investigate the potential of poly(vinylpyrrolidone) (PVP) to inhibit the crystallisation of amorphous lactose during storage of the composites up to 6 months. Short-term stability was assessed by microcalorimetry over 10 days and long-term stability by storage in desiccators with different relative humidities for 3 and 6 months. The solid-state structure of the particles after storage was analysed by differential scanning calorimetry. It was found that the presence of PVP increased the critical relative humidity (RH) for crystallisation relative to the pure lactose and both the proportion and the molecular weight of the PVP affected the stabilisation of the amorphous phase. The difference in critical RH between the materials increased over time. The T(g) of the materials was generally reduced due to the absorption of water and it is suggested that the inhibiting effect therefore is related mainly to a specific interaction between lactose and PVP, rather than to a counteracting effect of the polymer on the moisture induced depression of T(g).

Roller compaction of a milled botanical (Baphicacanthus cusia) with and without a binder, polyvinylpyrrolidone (PVP) was conducted. Effects of co-milling on binder function and flowability of the powder blend was also investigated. Flakes were comminuted, and the size and size distribution, friability, Hausner ratio, and Carr index of the granulations were determined. Crude herb should be reduced to a suitable size for it to be successfully roller compacted. Larger-sized and less friable granules were obtained with decreasing roller speed. Addition of PVP affected the flowability and binding capacity of the herbal powder blend, which influenced size and friability of the granules. Co-milling of PVP with the herbal powder enhanced the flow of the blends and the effectiveness of the binder, which contributed favorably to the roller-compacted product. Roller compaction is a convenient and cost-effective granulating technique suitable for milled botanicals. Co-milling can be used to improve the properties of roller-compacted products.