An alternative method to the evaluation of similarity factor in dissolution testing

This paper addresses an alternative method to the evaluation of similarity factor f₂ as a criterion for assessment of similarity between two in-vitro dissolution profiles as proposed in the SUPAC-IR Guidance (1995). Diltiazem hydrochloride Sustained-Release (SR) tablets were tested and the following independent-model dissolution parameters were used: t_10% dissolution time, t_25% dissolution time, t_50% dissolution time, mean dissolution time (MDT), dissolution efficiency (DE) at t₁₂₀, and at t₃₆₀. To compare the dissolution profiles, several release models were tested such as Higuchi, zero order, first order, Baker-Lonsdale, Hixson-Crowell, Weibull and Korsmeyer-Peppas. The similarities between two in-vitro dissolution profiles were assessed by pair-wise independent-model procedures such as difference factor (f₁), similarity factor (f₂) and Rescigno index (ξ₁ and ξ₂). The in vitro release kinetics of diltiazem hydrochloride sustained release tablets were evaluated using USP apparatus 2.     

Sucrose stearate-based proniosome-derived niosomes for the nebulisable delivery of cromolyn sodium

A Novel approach was developed for the preparation of controlled release proniosome-derived niosomes, using sucrose stearates as non-ionic biocompatible surfactants for the nebulisable delivery of cromolyn sodium. Conventional niosomes were prepared by a reverse phase evaporation method followed by the preparation of proniosomes by spraying the optimized surfactant–lipid mixture of sucrose stearate, cholesterol and stearylamine in 7:3:0.3 molar ratio onto the surface of spray dried lactose powder. Proniosome-derived niosomes were obtained by hydrating proniosomes with 0.9% saline at 50 °C and mixing for approximately 2 min. All vesicles were evaluated for their particle size, morphological characteristics, entrapment efficiency, in vitro drug release, nebulisation efficiency and physical stability at 2–8 °C. In addition, coating carrier surface with the surfactant–lipid mixture, during preparation of proniosomes, resulted in smaller, free flowing, homogenous and smooth vesicles with high drug entrapment efficiency. Compared to a standard drug solution, a successful retardation of the drug release rate was achieved with the proniosome-derived niosomes, where the t_50% value of the release profile was 18.1 h compared to 1.8 h. Moreover, high nebulisation efficiency percentage and good physical stability were also achieved. The results are very encouraging and offer an alternative approach to minimize the problems associated with conventional niosomes like degradation, sedimentation, aggregation and fusion.     

(3)H]Alvimopan binding to the micro opioid receptor: comparative binding kinetics of opioid antagonists

Alvimopan is a novel peripheral μ opioid antagonist in clinical development for the management of post-operative ileus and opioid-induced bowel dysfunction. We hypothesized that the long duration of action of alvimopan might be related to a slower dissociation rate from the μ opioid receptor compared to other shorter acting antagonists. The dissociation rate of alvimopan from the μ opioid receptor (t_1/2 = 30–44 min) was comparable to that of the long acting partial agonist buprenorphine (t_1/2 = 44 min), but was slower than those of the antagonists naloxone (t_1/2 = 0.82 min) and N-methylnaltrexone (t_1/2 = 0.46 min). Also, increases in the apparent affinities and potencies of buprenorphine and alvimopan, but not of naloxone and methylnaltrexone, were observed upon preincubation with the μ opioid receptor. Consistent with its long duration of action, alvimopan has a slow dissociation rate from the μ opioid receptor compared to other shorter acting antagonists and may be more potent if administered prior to dosing with exogenous opioids.     

Designing novel pH-sensitive non-phospholipid vesicle: Characterization and cell interaction

In an effort to enhance the oral bioavailability of scutellarin, ethyl, benzyl and N,N-diethylglycolamide ester of scutellarin were synthesized. The hydrolysis of the prodrugs follows first-order kinetics in aqueous solution, and produced a V-shaped pH profile. The N,N-diethylglycolamide ester is highly susceptible to enzymatic hydrolysis in human plasma (t_1/2 ≈ 7 min) with a high stability in aqueous solution (t_1/2 ≈ 16 day, pH 4.2). Compared with the solubility of scutellarin, the solubility of glycolamide ester was about ten times in pH 4.0 buffer, and about thirty five times in water. Its apparent partition coefficient increased significantly from −2.56 to 1.48. Glycolamide ester of scutellarin was chosen to investigate the intestinal metabolism and in vivo bioavailability. Degradation studies in the intestinal tract content and homogenates indicated intestinal metabolism before absorption was a crucial obstacle for the prodrug. N,N-Diethylglycolamide ester can be protected from the degradation in the intestinal lumen by an emulsion. A significant increase in the plasma AUC and C_max of the prodrug emulsion was observed in rats, compared with that of the scutellarin–cyclodextrin complex (P < 0.01). The emulsion of N,N-diethylglycolamide ester produces a 1.58-fold enhancement in apparent bioavailability and 1.4-fold increase in the absolute bioavailability compared to the scutallarin–cyclodextrin complex.     

Methyl-β-cyclodextrin and doxorubicin pharmacokinetics and tissue concentrations following bolus injection of these drugs alone or together in the rabbit

The purpose of this work was to determine the pharmacokinetics and the tissue concentrations of methyl-β-cyclodextrin (MEBCD) and doxorubicin (DOX) in rabbits following administration of MEBCD and DOX, alone or in combination. MEBCD (200 mg/kg) and DOX (1 mg/kg) were intravenously injected to white New Zealand rabbits and blood samples were obtained over a 48-h period after administration. After this period, administration was repeated and animals were killed 1, 2 or 4 h after injection. Heart, liver and kidney were then removed. MEBCD and DOX analysis in plasma and tissues was performed using two HPLC methods with fluorimetric detection. MEBCD pharmacokinetic profile was consistent with a two-compartment model (t_1/2 : 30 min; t_1/2 β: 7 h). Co-administration with DOX did not modify the main pharmacokinetic parameters of MEBCD. However, C_5 min, t_1/2 , t_1/2 β and AUC_∞ were decreased by the co-administration of DOX with MEBCD compared to DOX alone. Assays of excised tissues showed that DOX enhanced the cardiac, renal and hepatic concentrations of MEBCD. On the other hand, MEBCD did not alter the cardiac distribution of DOX, while renal and hepatic distribution profiles were modified. In this study, the pharmacokinetic parameters of MEBCD injected intravenously were determined for the first time. DOX did not enhance MEBCD pharmacokinetic profile but MEBCD reduced the distribution half-life of DOX. Tissue determination showed that MEBCD did not enhanced the cardiac accumulation of DOX, which is auspicious for further in vivo experiments using the co-administration of DOX and MEBCD.     

Evaluation of gatifloxacin pharmacokinetics and pharmacodynamics in severely ill adults in a medical Intensive Care Unit

A prospective, open-label study investigated the steady-state pharmacokinetics of gatifloxacin in 20 adult patients in a medical Intensive Care Unit (ICU). Twelve patients had normal or moderately impaired renal function (creatinine clearance (CrCL) ≥40 mL/min) and received gatifloxacin 400 mg intravenously once daily. Eight patients had CrCL < 40 mL/min and received 200 mg doses. Gatifloxacin plasma and urine concentrations were determined by validated high-performance liquid chromatography. Mean ± standard deviation gatifloxacin elimination half-life (t_1/2), systemic clearance and volume of distribution in patients with CrCL ≥ 40 mL/min were 10.8 ± 1.5 h, 156 ± 29 mL/min and 1.8 ± 0.2 L/kg, respectively. Maximum and minimum serum concentrations (C_max and C_min) and area under the serum concentration–time curve from 0–24 h (AUC_0–24) in these patients were 4.77 ± 0.76 mg/L, 1.08 ± 0.28 mg/L and 44.4 ± 9.2 mg h/L, respectively. Observed t_1/2, C_max and AUC_0–24 following 200 mg doses in patients with poor renal function (CrCL < 40 mL/min) were 18.2 ± 3.3 h, 2.85 ± 0.76 mg/L and 36.6 ± 3.4 mg h/L, respectively. Statistically significant (P < 0.05) increase in AUC_0–24 and decreases in t_1/2 and clearance (total and renal) were observed in ICU patients administered intravenous gatifloxacin compared with previous data in healthy volunteers. Pharmacodynamic evaluation by Monte Carlo simulation indicated that approved gatifloxacin dosage regimens appear to be adequate for most pathogens (minimum inhibitory concentration (MIC) ≤0.5 μg/mL) associated with community-acquired infections in severely ill ICU patients; less susceptible pathogens (MIC ≥ 1 μg/mL) do not appear to be optimally treated with currently approved doses.     

Stability of flavone-8-acetic acid (LM975) in aqueous solutions by high-performance liquid chromatography

A high-performance liquid chromatographic method has been developed to investigate the stability of solutions of flavone-8-acetic acid (LM975) during preparation and storage. LM975 (20 μg ml⁻¹ in PBS) was found to be completely stable for 10 days at 80°C as long as light was rigorously excluded. The drug showed no significant adsorption to containers of different materials or to two filtration units tested. Drug degradation did occur however, on exposure to light. In normal laboratory light the t_0.95 (5% degraded) was 30.3 min, in intense natural light (laboratory window sill) the t_0.95 was 3.3 min and in intense artificial light (100 W bulb at 10 cm) the t_0.95 was 13.8 min. NMR and mass spectral analysis of the isolated degradation product implied the formation of the decarboxylated product, 8-methyl flavone. It is suggested that care be taken to exclude light during the preparation, storage and infusion of solutions of flavone-8-acetic acid.     

Evaluation of microcrystalline chitosans for gastro-retentive drug delivery

In vivo absorption studies were carried out in human volunteers to evaluate whether microcrystalline chitosan (MCCh) granules would be gastro-retentive. Furosemide, which is site-specifically absorbed from the upper gastrointestinal tract, was used as model drug. The rate of release of furosemide in vitro could be prolonged by increasing the molecular weight (M_w) or amount of MCCh (150 to 240 kDa; 80 to 95%) in the granules, and also by addition of acidic excipients to the formulations. No marked changes in the in vivo absorption rate (t_max) were noted, but the amounts of furosemide absorbed (AUC_0–∞ and C_max) decreased as the in vitro release rate decreased, although this was not statistically significant in the case of AUC. The highest AUC_0–∞ (3050 μg l⁻¹ h) for furosemide (40 mg) was achieved with granules containing 80% MCCh of 150 kDa M_w. With MCCh of 240 kDa M_w AUC_0–∞ was 1890 μg l⁻¹ h. This kind of pharmacokinetic profile of furosemide suggests that the gastric retention time of the granules is too short in relation to the release rate, and a large amount of the drug passes its “absorption window” before being released. The in vivo study produced no evidence that the chitosan formulations studied can be used as mucoadhesive gastro-retentive drug delivery systems. The results of in vitro mucoadhesion studies did not predict the results of in vivo studies.     

High-performance liquid chromatographic method for the bioequivalence evaluation of desloratadine fumarate tablets in dogs

A simple HPLC method was developed for the determination of desloratadine in dog plasma and was used for evaluating the bioequivalence of desloratadine fumarate tablets and desloratadine tablets in dogs. Chromatographic separation was performed on a Hypersil CN column (150 mm×5.0 mm, 5 μm) using a mixture of methanol, acetonitrile and phosphate buffer (pH 5.5; 0.01 mol/l) (35:35:30, v/v/v) as mobile phase delivered at a flow rate of 0.8 ml/min. The detection was set at 241 nm. The limit of quantitation was 5.0 ng/ml. The calibration range was from 5.0 to 800.0 ng/ml. Inter- and intra-day precision ranged from 1.8 to 3.8% and from 2.2 to 9.0%, respectively. The recovery of desloratadine from dog plasma ranged from 78.8 to 82.0%. The developed method was applied to the bioequivalence studies of desloratadine fumarate tablets (test preparation) and desloratadine tablets (reference preparation) in five dogs. Pharmacokinetic parameters t_max, C_max, AUC_0–t, AUC_0–∞, t_1/2 were determined from plasma concentration-time profiles of both preparations. The analysis of variance (ANOVA) did not show any significant difference between the two preparations and 90% confidence intervals fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two preparations exhibited comparable pharmacokinetic profiles and that desloratadine fumarate tablets was bioequivalent to desloratadine tablets.     

A preformulation study on the kinetics of HI-6 in concentrated solution

The degradation kinetics of HI-6 have been investigated at various temperatures and at different pHs at a concentration of 200 mg/ml. Both aqueous and other hydrophilic solvents (glycols and glycerol-water mixtures) have been used. The degradation of HI-6 follows pseudo-first-order kinetics with respect to HI-6. The observed rate seems to depend on a hydroxyl ion-catalyzed reaction (k_OH) and an un/water catalyzed reaction (k₀) which show influence at pH below 3. The pH profile shows a positive slope less than one, which seems to depend on an error in the determination of the rate constants at higher pH. k_OH was determined to be 1 · 10⁹ andk₀ to be 0 · 011 h⁻¹ at 60° C. The observed rate seems to be independent of the dielectric constant of the solvent. The activation energy k₀ has been determined to be 82.0 kJ mol⁻¹. Based upon these data the predicted shelf life (t_90%) at pH 0 will not be long than 13 days at 25 ° C and 9 months at 0°C. Thus, the systems studied seem to be unsuitable to formulate a stable intramuscular formulation of HI-6.     

Hydration in hyaluronic acid and its esters using differential scanning calorimetry

Differential scanning calorimetry (DSC) was used to distinguish three types of water of hydration in sodium hyaluronate and ethyl, benzyl, and partial benzyl esters of hyaluronic acid. These three types were defined as follows: type I: free, freezing water (freezing temperature ≈ 0 ° C); type II: weakly bound, freezing water (freezing temperature < 0 ° C); and type III: strongly bound, non-freezing water. Samples were scanned from (−) 50 to 20 ° C at a rate of 2.5 ° C/min. In the case of sodium hyaluronate, the onset temperature of melting deviated from that of pure water; such deviation was not observed for the esters of hyaluronic acid. 9–21 mol type III water were associated with each polymer repeat unit, with the value depending on the type of ester and degree of esterification. Hydrated sodium hyaluronate powder samples stored at (−) 50 ° C for up to 29 h did not show any changes in onset temperature and heat of fusion values, suggesting that the kinetics of freezing did not greatly influence the results. In hydrated benzyl ester and partial benzyl ester membranes, a good correlation was found between the percent of freezable water and permeability coefficients for various model compounds, suggesting that these solutes may be transported primarily in freezable water.     

Comparative in vitro-in vivo study of two quinine rectal gel formulations

The main objective of this work was to develop and evaluate rectal quinine paediatric formulations to treat acute uncomplicated malaria attack in some African countries. Developed dosage forms must be able to assure a prolonged release in the rectum but not too much so as to avoid product expulsion by the child anus. Two quinine rectal gels, namely mucoadhesive (MA) gel and thermosensitive (TS) gel, containing 20 mg quinine base/g were developed and evaluated in vitro and in vivo in the rabbit. The MA and the TS gels contained hydroxypropyl methylcellulose 4000 (HPMC) and poloxamer 407, respectively. The calculated in vitro release exponent (n) values suggested that drug was released from both gels by non-Fickian diffusion. Both gels exhibit practically similar efficient of dissolution (ED%) which was not reflected in the plasma and, therefore, quinine bioavailability from MA gel was found to be higher than that obtained from TS gel and their AUC_0–∞ were statistically different (P = 0.0006). The t_1/2 values of quinine were significantly higher for Hydrogels than for IV and rectal solutions. MRT values displayed by TS gel and MA gel were not statistically different but were about 3.8- and 1.3-fold, respectively, larger than those obtained for IV solution and rectal solution, respectively. These results confirm the sustained-release behaviour of both hydrogels in the rabbit. Tolerability study of hydrogels didn’t show any damage on the rectal mucosa of the rabbit.     

A pharmacological examination of venom from the Papuan taipan (Oxyuranus scutellatus canni).

The Papuan taipan (Oxyuranus scutellatus canni) is the third most venomous terrestrial snake in the world, however, little is know about the pharmacology of the venom. In the chick biventer cervicis muscle, venom (10 μg/ml) abolished nerve-mediated twitches (time to 90% inhibition (t₉₀) 44±5 min, n=9). This inhibition was unaffected by prior incubation of the venom with the phospholipase A inhibitor 4-bromophenacyl bromide (4-BPB; 0.72 mM) (t₉₀ 48±7 min, n=8). The mouse phrenic nerve diaphragm preparation displayed greater sensitivity to venom (10 μg/ml) (t₉₀ 25±1 min, n=6). In the chick biventer muscle, venom (10 μg/ml) significantly inhibited responses to acetylcholine (1 mM) and carbachol (20 μM), but not KCl (40 mM), indicating activity at post-synaptic nicotinic receptors. Venom (10 μg/ml) did not affect direct muscle stimulation. Venom (3–30 μg/ml) produced dose-dependant contractions of the guinea-pig ileum. Contractile responses were significantly inhibited by indomethacin (1 μM) or prior incubation of the venom with 4-BPB (0.72 mM) indicating involvement of a PLA component. In rat phenylephrine (0.3 μM) precontracted aortae, venom (3–100 μg/ml) produced endothelium-independent relaxation which was unaffected by prior incubation of venom (30 μg/ml) with 4-BPB (0.72 mM). In anaesthetised rats, 10 μg/kg (i.v.) venom produced rapid respiratory and cardiovascular collapse while 5 μg/kg (i.v.) venom produced only a small transient decrease in mean arterial blood pressure. Prior administration of 5 μg/kg (i.v.) venom enabled subsequent administration of 10 and 100 μg/kg (i.v.) venom without respiratory or cardiovascular collapse. Further work is required to identify specific toxins with the above pharmacological activity.     

In vivo pharmacokinetics in human volunteers: oral administered guar gum-based colon-targeted 5-fluorouracil tablets

The objective of the present study is to compare the guar gum-based colon-targeted tablets of 5-fluorouracil against an immediate release tablet by in vitro dissolution and in vivo pharmacokinetic studies in human volunteers. Twelve healthy volunteers participated in the study. 5-Fluorouracil was administered at a dose of 50 mg both in immediate release tablet and colon-targeted tablet. On oral administration of colon-targeted tablets, 5-fluorouracil started appearing in the plasma at 6 h, and reached the peak concentration (C_max of 216±15 ng/ml) at 7.6±0.1 h (T_max), whereas the immediate release tablets produced peak plasma concentration (C_max of 278±21 ng/ml) at 0.6±0.01 h (T_max). The AUC_0−∞ for 5-fluorouracil from colon-targeted tablet and immediate release tablet were found to be 617±39 and 205±21 ng/ml/h, respectively. Colon-targeted tablets showed delayed t_max, delayed absorption time (t_a), decreased C_max and decreased absorption rate constant when compared to the immediate release tablets.The results of the study indicated that the guar gum-based colon-targeted formulation did not release the drug in stomach and small intestine, but delivered it to the colon resulting in a slow absorption of the drug and making it available for local action in colon.     

Rheological properties of three component creams containing sorbitan monoesters as surfactants

The objectives of the present study were (1) to evaluate the effect of formulation ingredients on the release rate of Ubiquinone from its adsorbing solid compact; and (2) to prepare and evaluate an optimized self-nanoemulsified tablet formulation. A three factor, three-level Box–Behnken design was used for the optimization procedure, with the amounts of copolyvidone (X₁), maltodextrin (X₂) and microcrystalline cellulose (X₃) as the independent variables. The response variable was cumulative percent of Ubiquinone emulsified in 45 min with constraints on weight, flowability index, tensile strength, friability and disintegration time of the dry powdered emulsion and the resultant compact. Based on the experimental design, different Ubiquinone release rates and profiles were obtained. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative percent emulsified in 45 min was Y₆=64.10−12.32X₁−4.36X₂−25.53X₃+6.99X₁X₂+3.97X₁X₃+9.70X₂X₃−8.98X₁²−16.22X₂²+17.10X₃². The optimization model predicted an 85.4% release with X₁, X₂ and X₃ levels of 66.6, 560.1 and 100, respectively. A new formulation was prepared according to these levels. The observed responses were in close agreement with the predicted values of the optimized formulation.     

酮洛芬择时释药片Beagle犬体内的生物等效性

目的：研究酮洛芬择时释药片（受试制剂）和酮洛芬胶囊（参比制剂）在Beagle犬体内的药动学特征和生物等效性。方法：采用双周期双交叉试验，每只Beagle犬口服受试制剂和参比制剂，于相应时间点取静脉血检测酮洛芬血药浓度。采用DAS 2.1.1软件分别计算2种制剂的药动学参数，并计算受试制剂的相对生物利用度。通过统计学分析比较2种制剂的生物等效性。结果：受试制剂和参比制剂的主要药动学参数分别为t_1/2（4.28±1.59）h和（5.90±2.33）h，C_max（61.36±2.37）μg·mL^-1和（67.59±10.72）μg·mL^-1，t_max（5.83±0.61）h和（2.04±0.19）h，t_lag（3.46±0.25）h和（0.46±0.22）h，AUC_0-t（341.16±19.09）μg·h·mL^-1和（355.93±51.82）μg·h·mL^-1，AUC_0-∞（354.29±19.91）μg·h·mL^-1和（416.77±42.49）μg·h·mL^-1，受试制剂的相对生物利用度为85.01%。结论：受试制剂和参比制剂的AUC_0-t、C_max是生物等效性的，但在t_max、t_lag生物不等效。受试制剂在一定的时滞（约3.458h）后释药，符合择时释药制剂的释药要求。     

Bioreversible quaternary N-acyloxymethyl derivatives of the poorly soluble tertiary amine Lu 28-179—Synthesis, pharmaceutical chemical characterization and bioavailability studies in dogs

Quaternary prodrug types of poorly water-soluble tertiary amines have been shown to possess significantly enhanced solubilities as compared to the parent amine. In the present study, the N-acyloxymethylation approach to improve the aqueous solubility of Lu 28-179 a tertiary amine exhibiting an intrinsic solubility in the nanomolar range, have been investigated. The acetyl-, propanoyl-, butanoyl-, isobutanoyl- and pivaloyloxymethyl derivatives were isolated as chloride salts and the aqueous solubilities (S) far exceeded that of the parent tertiary amine (S₀). S/S₀ ratios in the range 2–4 × 10⁶ were found for the most soluble prodrugs. The prodrugs were reasonable stable to hydrolysis in aqueous buffer solutions (pH 0.1–7.4), but susceptible to undergo enzyme-mediated regeneration of Lu 28-179 after incubation in human plasma, simulated intestinal fluid and duodenum juice from pigs and dogs. Despite promising in vitro properties the prodrugs were unable to improve the oral bioavailability of Lu 28-179 as compared to that obtained after administration of a reference formulation of the parent drug in the dog.     

Interaction of naproxen with ionic cyclodextrins in aqueous solution and in the solid state

The possible role of the cyclodextrin charge in the interaction with an acidic drug such as naproxen (pK_a 4.8) has been evaluated. Sulfobutylether-ß-cyclodextrin (SBE-ßCyd) and trimethylammonium-ß-cyclodextrin (TMA-ßCyd) were selected as, respectively, anionically and cationically charged carriers and their performance was compared with that of the parent ß-cyclodextrin (ßCyd) and of its methyl-derivative (MeßCyd) previously found as the best partner for the drug. Interactions in solution were investigated by phase-solubility, fluorescence and circular dichroism analyses. Equimolar drug–carrier products prepared by different techniques (blending, cogrinding, sealed-heating, colyophilization) were characterized by differential scanning calorimetry and X-ray powder diffractometry and tested for drug dissolution properties. Anionic charges of SBE-ßCyd did not negatively influence interactions in unbuffered aqueous solutions (pH ≈5) with the acidic drug. In fact, it was a very effective carrier, exhibiting solubilizing and complexing properties considerably better than the parent ßCyd and comparable to those of MeßCyd. On the contrary, the positive charges of TMA-ßCyd did not favour interactions with the counter-ionic drug (despite the presence of about 60% ionised drug) and it was less efficacious also than native ßCyd. Therefore, the role of the Cyd charge on the complexing and solubilizing properties towards naproxen was not important whereas other factors, such as steric hindrance effects and favourable hydrophobic interactions were significant in determining the drug affinity for the Cyd inclusion. Solid state studies evidenced similar amorphizing properties of both charged Cyds towards naproxen. On the other hand, dissolution tests, in agreement with solution studies, showed that all products with SBE-ßCyd exhibited significantly better dissolution properties than the corresponding ones with TMA-ßCyd. A clear influence of the preparation method of drug–Cyd solid systems on the performance of the end product was also observed. Colyophilization was the most effective technique, followed by the cogrinding one. Colyophilized product with SBE-ßCyd allowed a 10-times increase in drug dissolution efficiency (D.E.) (with respect to the five-times increase obtained with the corresponding coground product) and a reduction of t_50% from about 60 min (for the coground product) to less than 2 min.     

Microparticles prepared by grinding of polymeric films

Microparticles were prepared by a film grinding method, whereby thin drug-containing ethylcellulose films were cryogenically ground into microparticles. The particle size and shape of the microparticles could be controlled by the thickness of the films and by the milling time. The encapsulation efficiency as well as the in vitro drug release depended on the physical state of the drug in the ethylcellulose matrix (dispersed vs dissolved). Increased drug loadings and decreased particle size and film thickness increased the drug release. Microparticles prepared from cast films were more dense and had a slower drug release compared to microparticles prepared from sprayed films or from films prepared from an aqueous colloidal ethylcellulose dispersion, Aquacoat ECD. Lamination of the drug-containing film with a drug-free polymer layer on both sides resulted in a reduced drug release. Hydrophilic plasticizers acted as pore-formers and accelerated drug release, while lipophilic plasticizers reduced the drug release. The solubility of the drug in the organic polymer solution was one of the main parameters to achieve high encapsulation efficiencies and extended drug release, while dispersed drug was released much faster. The drug release from microparticles prepared by film grinding was faster than from microparticles prepared by the solvent evaporation method. The faster release was attributed to the fractured surface of the ground particles. Grinding of microparticles, which were prepared by the solvent evaporation, also resulted in a faster release.     

Pluronic gels for nasal delivery of Vitamin B12. Part I: preformulation study

Thermoreversible nasal gels of Vitamin B₁₂ using pluronic PF 127 were aimed to improve absorption and patient compliance. In the present research work, effects of Vitamin B₁₂ and gel additives, viz. PF concentration, osmolarity, polyethylene glycol (PEG 15000) on thermodynamic properties of phase transitions at gelation (T₁) and gel melting (T₂) is reported. Aqueous PF 127 gels prepared by cold method containing pluronic (20–24%, w/w), vitamin, sorbitol, PEG, and benzalkonium chloride. T₁ decreases and T₂ increases with vitamin and PF concentration. Gelation range narrows with sorbitol and PEG. Suppression of T₂ is significantly higher than T₁ with both the additives. The linearity was observed only for semilogarithmic plot of PF concentration and 1/T₂ for sorbitol and PEG, which reveals significant interaction of both at gel melting. Enthalpy of both transitions remains unchanged with vitamin indicating no interaction with polymer. Benzalkonium chloride decreased gelation onset temperature. Thermodynamic properties of PF 127 gels are significantly altered with polymer concentration and water-soluble formulation additives.