Comparative measurements of pressurised metered dose inhaler (pMDI) stem displacement

A technique was developed to enable direct measurement of a pressurised metered dose inhaler actuation cycle. Three commercially available 250 microg.dose(-1) beclomethasone diproprianate formulations were chosen for analysis; Becloforte (Glaxosmithkline, Sussex), Clenil Forte (Chiesi, Parma, Italy), and BDP-Modulite (Chiesi-Glaxosmithkline). The compression cycle of each device was analyzed and the point of drug actuation (force at which drug was released as an aerosol) was determined. Quantitative analysis of three devices from each product suggested no significant variation in inter-batch actuation force (ANOVA, p < 0.05) (N = 3). Interestingly, a significant variation between product type actuation force was observed (ANOVA, p < 0.05) (N = 3). Actuation forces ranged from 22.33 N +/- 1.44 N for Becloforte to 31.12 N +/- 2.73 N for Clenilforte. In general, such observations suggested a maximum difference of 8.7 N between the two extremes, equivalent to a 39% increase in force required to receive a dose.     

Outcomes of Severe Methanol Intoxication Treated with Hemodialysis: Report of Seven Cases and Review of Literature

To identify factors associated with the outcome of severe methanol intoxication treated with hemodialysis, we analyzed the clinical course of 7 patients admitted with serum methanol level higher than 50 mg/dL, and therefore requiring hemodialysis. Four patients (group A) had adverse outcomes (1 death, 3 severe neurological deficits and/or blindness) and 3 patients (group B) had no adverse outcomes. Compared to group B, group A appeared to have a longer delay between ingestion of methanol and arrival at the emergency department (ED), a longer wait in the ED until ethanol infusion was started (3.6 ± 2.7 vs 1.3 ± 0.9 hr, p < 0.05), and, on admission, higher serum methanol (504 ± 219 vs 321 ± 228 mg/dL, p < 0.05), higher serum osmolality (460.5 ± 98.2 vs 397.6 ± 52.3 mOsm/kg, p < 0.05), higher serum osmolal gap (162.6 ± 76.7 vs 105.6 ± 52.9 mOsm/kg, p < 0.05), lower arterial pH (6.86 ± 0.08 vs 7.38 ± 0.16, p < 0.01), lower serum bicarbonate (4.6 ± 1.6 vs 19.9 ± 5.7 mmol/L, p < 0.01), and higher serum anion gap (36.5 ± 1.3 vs 14.3 ± 6.7 mEq/L, p < 0.01). Delay in the ED until hemodialysis was started did not differ (group A 6.4 ± 2.6 hr, group B 5.3 ± 3.5 hr), while duration of hemodialysis until serum methanol levels became permanently undetectable was longer in group A (15.0 ± 0.5 vs 8.4 ± 4.4 hr, p < 0.01). The ingested dose of methanol and the delay between ingestion and initiation of therapy to block methanol metabolism (ethanol infusion) and remove methanol from the body (hemodialysis) appear to be the critical factors influencing the outcome of methanol intoxication. Early diagnosis and initiation of treatment before substantial parts of the ingested methanol have been metabolized are of paramount importance in ensuring a favorable outcome.     

The Clinical Impact of Increasing the Hemodialysis Dose

Good evidence suggests that improvements in dialysis efficiency reduce morbidity and mortality of hemodialysis (HD) patients. Dialysis efficiency has also been related to better control of arterial blood pressure (BP), anemia, and serum phosphorus levels, and to improvement in patients' nutritional status. Over a 2‐year period, the present self‐controlled study of 34 HD patients (23 men, 11 women; age, 52.6 ± 14.5 years; HD duration, 55.9 ± 61.2 months) looked at the effect on clinical and laboratory parameters of increasing the delivered dialysis dose under a strict dry‐weight policy. Dialysis dose was increased without increasing dialysis time and frequency. A statistically significant increase was seen in delivered HD dose: the urea reduction ratio (URR) increased to 60% ± 10% from 52% ± 8%, and then to 71% ± 7% (p < 0.001); Kt/V_urea increased to 1.22 ± 0.28 from 0.93 ± 0.19, and then to 1.55 ± 0.29 (p < 0.001). A statistically significant increase in hemoglobin concentration also occurred—to 10.8 ± 1.9 g/dL from 10.4 ± 1.7 g/dL, and then to 11.0 ± 1.3 g/dL (p < 0.05 as compared to baseline)—with no significant difference in weekly erythropoietin dose. Statistically significant decreases occurred in the systolic and diastolic blood pressures during the first year; they then remained unchanged. Systolic blood pressure decreased to 131 ± 23 mmHg from 147 ± 24 mmHg (p < 0.001); diastolic blood pressure decreased to 65 ± 11 mmHg from 73 ± 12 mmHg (p < 0.001). Serum albumin increased insignificantly to 4.4 ± 0.4 g/dL from 4.3 ± 0.4 g/dL, and then significantly to 4.6 ± 0.3 g/dL (p = 0.002 as compared to both previous values). Normalized protein catabolic rate increased significantly to 1.16 ± 0.15 g/kg/day from 0.93 ± 0.16 g/kg/ day (p < 0.001), and then to 1.20 ± 0.17 g/kg/day (p < 0.001 as compared to baseline). We conclude that the increases achieved in average Kt/V_urea per hemodialysis session by increasing dialyzer membrane area, and blood and dialysate flows, without increasing dialysis time above 4 hours, in patients hemodialyzed thrice weekly, coupled with strict dry‐weight policy, resulted in improvements in hypertension, nutritional status, and anemia.     

To investigate the influence of machine operating variables on formulations derived from lactose types in capsule filling: part 2

Abstract

This study is the second in a series that examines the characterizing and selection of suitable grades of lactose for capsule formulation development. Based upon the previous study, four grades were selected for further study. The effects of drug load and operational variables on formulations derived from these four lactose types were evaluated for physicochemical and mechanical attributes of plugs and their capsules on an instrumented dosing-disc capsule filling machine (H&H KFM/3) using acetaminophen as a model, highly soluble and poorly compressible drug. The results obtained were as follows: (1) flowability reduced upon increasing drug load; (2) powder bed height (PBH) and compression force (CF) had positive significant effect on plug weight (p?<?0.05); (3) ejection force was positively and significantly correlated with increasing speed and CF (p?<?0.05); (4) AL capsule plugs had the highest plug crushing force which was followed by DCL15; (5) the crushing strength of plugs made from DCL11 increased with increasing acetaminophen concentration; (6) higher CF had a significant negative impact on acetaminophen release at 15?min time point (p?<?0.05); (7) at 10% and 40% drug load, formulations containing AL showed the quickest drug release; and (8) increased drug load had a significant negative impact on the release rate at 15 and 45?min time points (p?<?0.05). Overall, the results from this study provides information on risk based assessment of filler selection based on drug load and the range of machine operating variables which will help in defining criteria for meeting key quality attributes for capsule formulation development.     

Application of Flow-Through Dissolution Method for the Evaluation of Oral Formulations of Nifedipine

Abstract

The drug release characteristics of three oral formulations (one conventional and 2 extended-release) of nifedipine were evaluated using a flow-through apparatus. The experiments were conducted for 4 to 24 hours using water or phosphate buffer (0.05 or 0.1 M; pH 7.4) with or without solubilizing agent, Tween, as a dissolution medium at a flow rate of 12.5 mL/min. The drug concentrations were determined using an HPLC method based on ratios of peak heights corresponding to UV absorbances at 254 nm for nifedipine and nitrendipine (internal standard). Dissolution characteristics in various media correspond to the nifedipine solubility in the medium. Peak nifedipine concentrations with 0.05 M phosphate buffer containing 0.5% Tween were significantly higher than those in the medium without Tween (21.5±1.0 vs 8.3±0.2 μg/mL, p c 0.001). Using a 0.05 M phosphate buffer with no Tween, the products tested showed distinct dissolution profiles representative of the respective formulation type. The conventional release product (10 mg) showed a higher mean peak nifedipine concentration (C_max,d) of 49.5±2.4 pg/mL (p < 0.001) attained at (t_max,d) 0.46±0.05 h as compared to those of modified-release products. The corresponding mean values for the modified-release tablets were 8.3±0.2 and 2.6±.3 μg/mL for C_max,d, and 0.28±0.03 and 12.0±3.8 h for t_max,d for the 20 and 30 mg tablets, respectively. Area under the concentration-time curves (AUC_o-t,d) for the 10, 20 and 30 mg formulations were 12.3±0.4,20.5±2.6 and 32.6±3.7 μg.h/mL, respectively (p < 0.001). As the dissolution profiles are similar to those of plasmakerum drug concentrations-time profiles obtained from clinical studies, application of this dissolution method, along with the derived in vitro drug-release kinetics parameters for potential correlation with in vivo parameters are discussed. The results of this study show that, compared to the USP dissolution method using apparatus 1 or 2, the flow-through dissolution system offers a potentially better alternative to assess drug release characteristics for different types of formulations, especially for drugs of low aqueous solubility such as nifedipine.     

Effects of direct spiking of silicone oil into a model pMDI formulation

Context: Silicone oil is used as a valve lubricant in pressurized metered dose inhalers (pMDIs). Its possible impact on drug delivery, through such effects as particle aggregation, has recently been discussed.

Objective: To examine the effects of a range of directly spiked silicone oil amounts on pMDI performance.

Materials and methods: pMDI canisters containing a corticosteroid medicinal compound, HFA134a and accurately measured amounts of silicone oil (0, 200, 400 and 550 µg) were prepared. Samples were characterized for actuation weight, aerodynamic size (by Andersen cascade impaction, ACI), charge (by electrical low-pressure impaction, ELPI) and product appearance by visual imaging.

Results and discussion: Actuation weights were unaffected by silicone oil. A small increase in aerodynamic size was observed in the presence of silicone oil as a shift from stage 5 to impactor throat. No significant change in medicinal compound recovery was seen (t-tests, p > 0.05). Fine particle fraction as a percentage of dose delivered (FPF) was unchanged, as was particle size distribution derived from charge measurements, with the addition of silicone oil (t-tests, p > 0.05). Canister opening did not indicate container interaction but that sedimentation occurred in the presence of silicone oil. Decanted suspensions containing silicone oil were more transparent. Possible interactions inside and outside the pMDI canister are described.

Conclusion: As demonstrated previously with an alternative experimental design the study showed that silicone oil has little effect on product performance, when added to a model pMDI formulation at levels that could potentially be observed as a leachable from the metering valve.     

Bond strength of resin composite to differently conditioned amalgam

Bulk fracture of teeth, where a part of the amalgam restoration and/or the cusp is fractured, is a common clinical problem. The aim of this study was to evaluate the effect of different surface conditioning methods on the shear bond strength of a hybrid resin composite to fresh amalgam. Amalgams (N = 84) were condensed into acrylic and randomly assigned to one of the following treatments (N = 6): (1) Alloy primer + opaquer, (2) Air-particle abrasion (50 μ m Al₂O₃) + alloy primer + opaquer, (3) Silica coating (30 μ m SiO_x) + silanization + opaquer, (4) Opaquer + pre-impregnated continuous bidirectional E-glass fibre sheets, (5) Silica coating + silanization + fibre sheets, (6) Silica coating + silanization + opaquer + fibre sheet application. Non-conditioned amalgam surfaces were considered as control group (7). The mean surface roughness depth (R_Z) was measured from the control group and air-abraded amalgam surfaces. The resin composite was bonded to the conditioned amalgam specimens using polyethylene molds. All specimens were tested under dry and thermocycled (6.000, 5–55 ^∘C, 30 s) conditions. The shear bond strength of resin composite to amalgam substrates was measured in a universal testing machine (1 mm/min). Surface roughness values for the non-conditioned control group (R_Z∼ 0.14 μ m) and for air-particle abraded surfaces with either Al₂O₃ or SiO_x (R_Z∼ 0.19 μ m and R_Z∼ 0.16 μ m, respectively) did not show significant differences (p = 0.23) (One-way ANOVA). In dry conditions, silica coating and silanization followed by fibre sheet application exhibited significantly higher results (14.8 ± 5.6 MPa) than those of the groups conditioned with alloy primer (2.2 ± 0.7 MPa) (p < 0.001), air-particle abrasion+alloy primer (4.4 ± 2.0 MPa, p < 0.001), silica coating + silanization alone (6.2 ± 0.8 MPa, p = 0.009) or non-conditioned group (1.4 ± 0.6, p < 0.001). Silica coating and silanization followed by additional fibre sheets with opaquer application (23.6 ± 6.9 MPa) increased the bond strength significantly compared to those of other groups (group 5 vs group 6, p = 0.007; other groups vs group 6, p < 0.001). Thermocycling decreased the bond strengths significantly for all of the conditioning methods tested (for group 1, p < 0.001; for group 2, p = 0.013; for group 3, p = 0.002; for group 4, p = 0.026; for group 5, p = 0.002; for group 6, p < 0.001 and for group 7, p < 0.001).     

Sustained Release of Theophylline from Eudragit RLPO and RSPO Tablets

Abstract

Newer polymeric grades of Eudragit, RLPO and RSPO, were explored for their utilities by formulating a sustained-release tablet of theophylline as a model drug. Formulations selected on the basis of their lower polymer content and drug release content, over the period of 12 hr, were compared with the marketed formulation. These were evaluated for dissolution characteristics. In vitro release showed zero-order kinetics (r = 0.9879-0.994.5; p < 0.001). In vivo evaluations were carried out on healthy human volunteers (23 ± 2.68 years old; 48.64 ± 6.31 kg). Dissolution rate constant (k), C_max, T_max, AUC_0-12, AUC_0-24, and t_1/2 were evaluated statistically by two-way ANOVA. Upon t test, a highly significant difference between test products and the marketed product was observed. Wagner-Nelson analysis of the in vivo data revealed controlled-release absorption profiles for selected formulations. Linear regression analysis of the mean % of dose absorbed versus mean in vitro release, resulted in statistically significant correlation. Coefficient of correlation values between AUC_0-12 and k, and AUC_0-24 and k were found to be 0.991 (p < 0.01) and 0.984 (0.01 < p < 0.05), respectively. These data support a level-A correlation between in vitro release rate profiles and the in vivo absorptions for theophylline.     

Scopolamine Sublingual Spray: An Alternative Route of Delivery for the Treatment of Motion Sickness

ABSTRACT

The purpose of this study was to develop a sublingual drug delivery spray formulation of scopolamine hydrobromide (L-(-)-hyoscine hydrobromide) and to determine the absolute bioavailability of scopolamine hydrobromide following sublingual delivery and to investigate the effect of a bioadhesive on the pharmacokinetic parameters of this drug in a rabbit model. Rabbits received a single scopolamine free base equivalent sublingual dose of 100 μg/kg and this was compared to intravenous administration of the drug. Blood samples were collected at different time points, and plasma scopolamine concentrations were determined using a new sensitive and specific LC/MS analytical method which utilized electrospray ionization detection. The bioavailability of sublingual scopolamine was determined by comparing plasma concentrations after sublingual spray delivery with equivalent intravenous doses. Following delivery of the sublingual spray dose, the average C_max was 1024.4 ± 177 ng/mL, and the AUC value was found to be 61067.6 ± 9605 ng.min/mL. Relative to the intravenous dose (100% bioavailability), the bioavailability was 79.8% after sublingual spray administration. The addition of 2% chitosan, a bio-adhesive material and an absorption enhancer, showed a significant improvement in scopolamine sublingual absorption (p < 0.05) was observed. Considering the limitations of delivering scopolamine orally or transdermally to patients who experience motion sickness, the sublingual route of administration using a spray delivery dosage form, is a potential alternative modality for the prevention of nausea and vomiting associated with motion sickness.     

Characterization and evaluation of β-glucan formulations as injectable implants for protein and peptide delivery

Context: Injectable implants are biodegradable, syringeable formulations that are injected as liquids, but form a gel inside the body due to a change in pH, ions or temperature.

Objective: To investigate the effect of polymer concentration, pH, ions and temperature on the gel formation of β-glucan, a natural cell-wall polysaccharide derived from barley, with particular emphasis on two-phase system formation after addition of dextran or PEG.

Materials and methods: Oscillation viscometry was used to evaluate the gel character by measuring flow index (N), storage (G′) and loss (G″) moduli. Two-phase systems were further characterized for hardness and syringeability using a texture analyzer. Finally, in vitro release characteristics were determined using Franz diffusion cells.

Results: Oscillation viscometry revealed that only addition of dextran or PEG resulted in distinct gel formation. This was seen by a decrease in N after polymer addition. Moreover, hardness (in g) of the gels increased significantly (p?<?0.001) from 3.65?±?0.43 to 34.30?±?8.90 (dextran) and 805.80?±?5.30 (PEG) 24?h after polymer addition. In vitro release profiles showed significantly (p?<?0.05) reduced AUC_{0–8 h}, k and percentage of drug released from two-phase systems compared to β-glucan dispersions, with the PEG system resulting in the lowest amount released over 8?h (15.1?±?1.6%).

Discussion: The unfavorable mixing enthalpy and higher water affinity of PEG resulted in the formation of a dense β-glucan gel.

Conclusion: 1.5% (w/w) β-glucan combined with PEG at a ratio of 1:3 seemed to be the most promising injectable formulation with respect to fastest gel formation, increased hardness and sustained release.     

Production and Characterization of Hot-Melt Extruded Films Containing Clotrimazole

Abstract

Hot-melt extrusion technology (HME) was used to prepare muco-adhesive matrix films containing 10% w/w clotrimazole (CT) intended for local drug delivery applications for the oral cavity. This study was aimed at the production and characterization of these drug delivery systems for the prophylaxis and treatment of oral candidiasis. The film system's formulation contained hydroxypropyl cellulose and poly(ethylene oxide) as polymeric carriers, the bioadhesive polycarbophil, and other excipients. The CT formulation was processed at a temperature range of 125–130°C utilizing a Killion extruder (Model KLB-100) equipped with a 6-inch flex-lip die. The films were evaluated for postextrusion drug content, physical and chemical content uniformity, drug release, thermal and crystalline behavior, and bioadhesive strength. The extruded films demonstrated excellent content uniformity and a postprocessing drug content of 93.3% (± 1.0). The degradation product, (o-chlorophenyl)diphenyl methanol, was also identified and quantitated using high performance liquid chromatography. The films were determined to exhibit desirable and consistent release properties and bioadhesive strength (p<0.05). The results of this study indicate that HME is a viable technique for the preparation of muco-adhesive films containing clotrimazole for oral candidiasis.     

Pharmacokinetic and pharmacodynamic evaluation of floating microspheres of metformin hydrochloride

Metformin hydrochloride (MH), a biguanide antidiabetic, is the drug of choice in obese patients. It is well absorbed from the upper part of gastrointestinal tract and has oral bioavailability of 50% to 60%. The objective of this study was to formulate MH into floating microspheres in order to increase its residence time at the site of absorption and thus improve its bioavailability; and to extend the duration of action along with possibilities of dose reduction. Microspheres were prepared by emulsion solvent evaporation method and evaluated for particle size, entrapment efficiency, buoyancy, and in vitro release; and further characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and differential scanning calorimetry. The pharmacokinetic and pharmacodynamic evaluation of selected formulation was carried out in male Wistar diabetic rats. The data was statistically analyzed by unpaired t-test. A 3.5-fold increase in relative bioavailability was observed. The prolongation of half-life (t_1/2) from 4.5 ± 2.41 h to 14.12 ± 4.81 h indicated extended duration of action. Oral glucose tolerance test (OGTT) was analyzed by one-way analysis of variance followed by Dunnet multiple comparison test, a significant decrease (p < 0.05) in the blood glucose levels was observed when formulations were compared with control rats. Hence, MH floating microspheres were tested at 50 mg/kg and 100 mg/kg body weight, OGTT data showed nonsignificant difference (p >0.05). In conclusion, an effective oral antidiabetics treatment can be achieved by formulating MH into floating microspheres which results in increase in bioavailability along with extended duration of action resulting in possible reduction in dose.     

Design and in vitro characterization of buccoadhesive tablets of timolol maleate

Objective: The purpose of this work was to develop and evaluate buccoadhesive tablets of timolol maleate (TM) due to its potential to circumvent the first-pass metabolism and to improve its bioavailability.

Methods: The tablets were prepared by direct compression using two release modifying polymers, Carbopol 974P (Cp-974p) and sodium alginate (SA). A 3² full factorial design was employed to study the effect of independent variables, Cp-974p and SA, in various proportions in percent w/w, which influences the in vitro drug release and bioadhesive strengths. Physicochemical properties of the drug were evaluated by ultraviolet, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction (P-XRD). Tablets were evaluated for hardness, thickness, weight variation, drug content, surface pH, swelling index, bioadhesive force and in vitro drug release.

Results: The FTIR and DSC studies showed no evidence of interactions between drug, polymers and excipients. The P-XRD study revealed that crystallinity of TM remain unchanged in optimized formulation tablet. Formulation F9 achieves an in vitro drug release of 98.967%?±?0.28 at 8?h and a bioadhesive force of 0.088 N?±?0.01211.

Conclusion: We successfully developed buccal tablet formulations of TM and describe a non-Fickian-type anomalous transport as the release mechanism.     

Sigma-2 receptor ligand anchored telmisartan loaded nanostructured lipid particles augmented drug delivery,cytotoxicity, apoptosis and cellular uptake in prostate cancer cells

Recently, the anticancer activity of telmisartan (TEL) has been discovered against prostate cancer. Nevertheless, despite favorable therapeutic profile, poor aqueous solubility and suboptimal oral bioavailability hamper the anticancer efficacy of TEL. Therefore, in this investigation, sigma-2 receptor ligand, 3-(4-cyclohexylpiperazine-1-yl) propyl amine (CPPA) anchored nanostructured lipid particles of telmisartan (CPPA-TEL-NLPs) were engineered using stearic acid for targeting prostate cancer, PC-3 cells. The mean particle size of TEL-NLPs was measured to be 25.4?±?3.2?nm, significantly (p?p?p?In vitro drug release study was conducted to determine the drug delivery potential of tailored nanoparticles. TEL-NLPs released 93.36% of drug significantly (p?50 of CPPA-TEL-NLPs was measured to be 20.3?µM significantly (p?50 of 41.3?µM, significantly (p?>?0.05) not different from 43.4?µM, exhibited by TEL-NLPs in PNT-2 cells. We elucidated that CPPA-TEL-NLPs entered the PC-3 cells via receptor mediated endocytosis pathway and thus exhibited superior cytotoxicity, apoptosis and greater extent of cellular uptake in PC-3 cells. In conclusion, CPPA-TEL-NLPs may be a promising nanomedicine and warrant further in vivo investigations for gaining clinical success.     

Damage morphology produced in low-cycle high-load indentations of feldspar porcelain and leucite glass ceramic

This paper reports on damage morphology created in low-cycle high-load spherical indentations of feldspar porcelain and leucite glass ceramic to mimic teeth clenching or grinding. Maximum contact stresses were evaluated as functions of cycle numbers and applied loads using a Hertz model. The surface damage of the two materials after low-cycle high-load indentation testing was viewed using scanning electron microscopy to understand the relations between crack propagation and microstructures. The results indicate that the maximum contact stresses for both materials reduced significantly with the cycles (ANOVA, p < 0.05) but did not show a significant change with the applied loads (ANOVA, p > 0.05). Feldspar porcelain can endure much less maximum contact stress than leucite glass ceramic. Low-cycle high-load spherical indentations induced extensive ring cracks, wedging of crack faces by debris, fragmentation, and pulverization on feldspar porcelain surfaces. In contrast, leucite glass ceramic surfaces yielded only minimum microcracks at 500 N load and localized fractures and cracks at the higher loads of 600 and 700 N. This study shows that leucite glass ceramic had much higher resistance to low-cycle high-load fatigue impacts than feldspar porcelain and it can be a better choice for restorations under teeth clenching and grinding conditions.     

Formulation and corneal permeation of ketorolac tromethamine-loaded chitosan nanoparticles

Abstract

The aim of this work was to formulate chitosan (CS)-based nanoparticles (NPs) loaded with ketorolac tromethamine (KT) intended for topical ocular delivery. NPs were prepared using ionic gelation method incorporating tri-polyphosphate (TPP) as cross-linker. Following the preparation, the composition of the system was optimized in terms of their particle size, zeta potential, entrapment efficiency (EE) and morphology, as well as performing structural characterization studies using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The data suggested that the size of the NPs was affected by CS/TPP ratio where the diameter of the NPs ranged from 108.0?±?2.4?nm to 257.2?±?18.6?nm. A correlation between drug EE and the corresponding drug concentration added to the formulation was observed, where the EE of the NPs increased with increasing drug concentration, for up to 10?mg/mL. FT-IR and DSC revealed that KT was dispersed within the NPs where the phosphate groups of TPP were associated with the ammonium groups of CS. The in vitro release profile of KT from CS NPs showed significant differences (p?<?0.05) compared to KT solution. Furthermore, mucoadhesion studies revealed adhesive properties of the formulated NPs. The KT-loaded NPs were found to be stable when stored at different storage conditions for a period of 3 months. The ex vivo corneal permeation studies performed on excised porcine eye balls confirmed the ability of NPs in retaining the drug on the eye surface for a relatively longer time. These results demonstrate the potential of CS-based NPs for the ocular delivery of KT.     

Formulation and in Vitro and in Vivo Availability of Diclofenac Sodium Enteric-Coated Beads

Abstract

Diclofenac sodium enteric-coated beads were prepared using the conventional pan coating technique. Eudragit L₁₀₀ was used as a pH-dependent release-controlling polymer. The beads were evaluated for their particle size distribution, drug loading efficiency, flowability, in vitro release in 0.1 N HCI (pH 1.2) and phosphate buffer (pH 6.8), and bioavailability in beagle dogs relative to the commercial enteric-coated tablets Voltaren®. The beads showed a narrow particle size distribution in which 83% of the beads were in the range of 1-2 mm. The actual yield of the beads was 90.5% and their drug loading was 92%. The beads released about 8% of the drug during 2 hr of dissolution in 0.1 N HCI, and the commercial tablets released no drug. In phosphate buffer (pH 6.8) both formulations released their drug content in 1 hr. Both formulations are, therefore, in compliance with the USP requirements for release from enteric-coated dosage forms.

The in vivo availability study in six beagle dogs revealed that the formulated enteric-coated beads filled in hard gelatin capsules had a 197.54% bioavailability relative to that of the commercial Voltaren tablets. The tablets showed a significantly lower (p < 0.05) area under curve for 0—8 hr (AUC_{0-8 hr}) of 13.44 ± 15.02 μg hr/ml compared to 26.55 ± 5.19 μg hr/ml for the capsules. The capsules showed a nonsignificantly (p > 0.05) higher peak plasma concentration (C^max) of 6.77 ± 0.67 μg/ml compared to 5.88 ± 7.38 μg/ml for the tablets. The time to reach peak (T_max) values were 2 ± 1.48 and 2.25 ± 1.08 hr for the capsules and tablets, respectively. The capsules showed less interdog variability with respect to C_max (CV% 34.6) and AUC (CV% 19.55) compared to CV% 79.9 and 111.76, respectively, for the commercial tablets     

Comparison and Validation of Drug Loading Parameters of PEGylated Nanoparticles Purified by a Diafiltration Centrifugal Device and Tangential Flow Filtration

This article describes drug loading validation of nanoparticles. Ultracentrifugation was avoided because of problems arising from small-sized particles. Ultrafiltration was adopted in two different modes followed by monitoring of polyvinyl alcohol (PVA), dextran sulfate (DS), and loperamide HCl contents. Diafiltration centrifugation removed all PVA at the fourth cycle and provided significantly (p = .000, .017) higher drug loading values compared with tangential flow filtration (TFF). This was due to residual PVA associated with the nanoparticles. TFF enabled satisfactory dry weight recovery (101.66 ± 4.45%, n = 3) of nanoparticles during extended purification. Indirect drug loading (from the purification curve) was not significantly different (p = .450, .487) to the direct drug loading values. Encapsulation parameters were obtained from the purification curve once quantitative estimation of the all formulation components was established.     

Biopolymeric mucoadhesive bilayer patch of pravastatin sodium for Buccal delivery and treatment of patients with atherosclerosis

Mucoadhesive bilayer buccal patch has been developed to improve the bioavailability and therapeutic efficacy along with providing sustained release of pravastatin sodium. Buccal patches comprising of varying composition of Carbopol 934P and HPMC K4M were designed and characterized for surface pH, swelling index, in vitro bioadhesion, mechanical properties, in vitro drug release and in vivo pharmacokinetic and pharmacodynamics performance. All formulations exhibited satisfactory technological parameters and followed non-fickian drug release mechanism. Bilayer buccal patch containing Carbopol 934P and HPMC K4M in 4:6 ratio (PBP5) was considered optimum in terms of swelling, mucoadhesion, mechanical properties and in vitro release profile. Pharmacokinetic studies in rabbits showed significantly higher (p < 0.05) Cmax (75.63 ± 6.98 ng/mL), AUC_0-8 (311.10 ± 5.89 ng/mL/h) and AUC_0-∞ (909.42 ± 5.89 ng/mL/h) than pravastatin oral tablet (Cmax – 67.40 ± 9.23 ng/mL, AUC_0-8-130.33 ± 10.25 ng/mL/h and AUC_0-∞-417.17 ± 5.89 ng/mL/h)). While, increased tmax of buccal patch indicated its sustained release property in comparison to oral tablet. Pharmacodynamic studies in rabbits showed statistically significant difference (p < 0.005) in the reduction of TG (131.10 ± 10.23 mg/dL), VLDL (26.00 ± 2.56 mg/dL) and LDL level (8.99 ± 3.01 mg/dL) as compared to oral conventional tablet. In conclusion, bioavailability from the developed buccal patch of pravastatin was 2.38 times higher than the oral dosage form, indicating its therapeutic potential in the treatment of atherosclerosis.     

Optimizing the dermal accumulation of a tazarotene microemulsion using skin deposition modeling

Abstract

Context: It is well known that microemulsions are mainly utilized for their transdermal rather than their dermal drug delivery potential due to their low viscosity, and the presence of penetration enhancing surfactants and co-surfactants.

Objective: Applying quality by design (QbD) principles, a tazarotene microemulsion formulation for local skin delivery was optimized by creating a control space.

Materials and methods: Critical formulation factors (CFF) were oil, surfactant/co-surfactant (SAA/CoS), and water percentages. Critical quality attributes (CQA) were globular size, microemulsion viscosity, tazarotene skin deposition, permeation, and local accumulation efficiency index.

Results and discussion: Increasing oil percentage increased globular size, while the opposite occurred regarding SAA/CoS, (p?=?0.001). Microemulsion viscosity was reduced by increasing oil and water percentages (p?<?0.05), due to the inherent high viscosity of the utilized SAA/CoS. Drug deposition in the skin was reduced by increasing SAA/CoS due to the increased hydrophilicity and viscosity of the system, but increased by increasing water due to hydration effect (p?=?0.009). Models with very good fit were generated, predicting the effect of CFF on globular size, microemulsion viscosity, and drug deposition. A combination of 40% oil and 45% SAA/CoS showed the maximum drug deposition of 75.1%. Clinical skin irritation study showed that the aforementioned formula was safe for topical use.

Conclusion: This article suggests that applying QbD tools such as experimental design is an efficient tool for drug product design.