Efficacy and safety of oral insulin compared to subcutaneous insulin: a systematic review and meta-analysis.

INTRODUCTION: A systematic review and meta-analysis of interventional studies was conducted to compare the efficacy and safety of oral insulin versus subcutaneous (SC) insulin in diabetic patients. METHODS: Medline, Scopus, ISI Web of Knowledge and Cochrane Central Register of Controlled Trials were searched. Two independent reviewers evaluated studies for eligibility and quality and extracted the data. The primary outcomes were fasting blood glucose (FBG), 1h and 2h postprandial blood glucose, HbA1c, AUC of insulin, C max and T max of insulin, and T max of glucose infusion rate. Secondary outcomes were adverse events. RESULTS: Eleven studies (n = 373) met the inclusion criteria. Meta-analyses showed that there is no significant difference between oral and SC insulin in controlling HbA1c, FBG, 1 and 2 h postprandial blood glucose and producing C max of insulin (P > 0.05); however oral insulin had faster action as indicated by the shorter T max, compared to SC insulin (P < 0.05). The most included studies were varied in their methodological quality. CONCLUSION: This systematic review and meta-analysis showed that oral insulin is comparable to SC insulin with regard to glycemic efficacy and safety. However, is necessary to conduct additional studies in which oral insulin administered to large number of patients for long enough periods of time.

Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design.

Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7(®) software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 µm, and 2.98 µm; respectively. Our results provide fundamental data for the application of SLNs in pulmonary delivery system of budesonide.

Prolonged hypocalcemic effect by pulmonary delivery of calcitonin loaded poly(methyl vinyl ether maleic acid) bioadhesive nanoparticles.

The purpose of the present study was to design a pulmonary controlled release system of salmon calcitonin (sCT). Therefore, poly(methyl vinyl ether maleic acid) [P(MVEMA)] nanoparticles were prepared by ionic cross-linking method using Fe(2+) and Zn(2+) ions. Physicochemical properties of nanoparticles were studied in vitro. The stability of sCT in the optimized nanoparticles was studied by electrophoretic gel method. Plasma calcium levels until 48 h were determined in rats as pulmonary-free sCT solution or nanoparticles (25 µg · kg(-1)), iv solution of sCT (5 µg · kg(-1)), and pulmonary blank nanoparticles. The drug remained stable during fabrication and tests on nanoparticles. The optimized nanoparticles showed proper physicochemical properties. Normalized reduction of plasma calcium levels was at least 2.76 times higher in pulmonary sCT nanoparticles compared to free solution. The duration of hypocalcemic effect of pulmonary sCT nanoparticles was 24 h, while it was just 1 h for the iv solution. There was not any significant difference between normalized blood calcium levels reduction in pulmonary drug solution and iv injection. Pharmacological activity of nanoparticles after pulmonary delivery was 65% of the iv route. Pulmonary delivery of P(MVEMA) nanoparticles of sCT enhanced and prolonged the hypocalcemic effect of the drug significantly.

Synthesis and characterization of folate-targeted dextran/retinoic acid micelles for doxorubicin delivery in acute leukemia.

Folate and retinoic acid grafted/dextran (FA-RA/DEX) copolymers with different molecular weight of DEX were synthesized using carbonyldiimidazole and dimethylaminopyridine for targeted delivery of doxorubicin (DOX) in acute myelogenous leukemia (AML). The copolymers structure was confirmed by (1)H NMR and FTIR. Critical micelle concentration (CMC) of each copolymer was determined using pyrene as a fluorescent probe. DOX was loaded in micelles by the direct dissolution method. Physical properties of micelles, including particle size, zeta potential, drug loading efficiency, and drug release profiles, were examined. The orientation of the folate ligand on the surface of the micelles was studied by X-ray photoelectron spectroscopy (XPS) technique. The cytotoxicity of micelles loaded with DOX at different concentrations was studied in KG1 cells using MTT assay and their cellular uptake by flow cytometry technique. FTIR and (1)H NMR spectra confirmed successful production of the targeted micelles and XPS spectra showed the surface orientation of folate. R15D10F7 copolymer produced micelles with particle size of 82.86 nm, polydispersity index of 0.3, zeta potential of -4.68 mV, drug loading efficiency of 96%, and release efficiency of 63%. DOX loaded in folate-targeted micelles of RA/DEX was more toxic than that in nontargeted micelles and free drug and seems promising in reducing drug resistance in AML.

Preparation, characterization and optimization of glipizide controlled release nanoparticles.

The purpose of the present study was to develop glipizide controlled release nanoparticles using alginate and chitosan thorough ionotropic controlled gelation method. Glipizide is a frequently prescribed second generation sulfonylurea which lowers the blood glucose in type-two diabetics. Quick absorption of the drug from the gastrointestinal tract along with short half- life of elimination makes it a good candidate for controlled release formulations. Alginate-chitosan nanoparticles (ACNP) are convenient controlled delivery systems for glipizide, due to both the release limiting properties of the system, and the bioadhesive nature of the polymers. In the present study, glipizide loaded alginate-chitosan nanoparticles (GlACNP) were prepared, and the particle characteristics including particle size (PS), zeta potential (ZP), entrapment efficiency (EE%), loading percent (LP), and mean release time (MRT), as well as the morphology of the nanoparticles, the drug-excipient compatibility, and the release kinetics along with the drug diffusion mechanism were evaluated. The results suggested that ionotropic controlled gelation method offers the possibility of preparing the nanoparticles in mild conditions in an aqueous environment, and can lead to the preparation of particles with favorable size, controlled release characteristics, and high entrapment efficiency, serving as a convenient delivery system for glipizide. The particle and release characteristics can be efficiently optimized using the Box-Behnken design. Based on the findings of the present study, it is expected that this novel formulation be a superior therapeutic alternative to the currently available glipizide delivery systems.

Preparation and characterization of a sustained release buccoadhesive system for delivery of terbutaline sulfate.

Terbutaline sulfate exhibits extensive first pass metabolism and a short elimination half life which makes frequent oral administration of the drug inevitable. A novel buccoadhesive controlled delivery system of the drug can easily overcome the problem. A two-layered core tablet composed of a fast release layer made of mannitol, lactose, PEG and the drug attached to a sustained release layer composed of drug, varying ratios of HPMC, Carbomer 934 (CP), and lactose capped with a buccoadhesive cup coated with an impermeable backing layer was developed. Buccoadhesive cup initially optimized for bioadhesion strength using HPMC and CP with various ratios. Drug transport through buccal membrane indicated a high permeability coefficient (0.00105 cm/sec). All tablets were acceptable with regard to drug contents, thickness, weight variations, hardness and drug content uniformity. The CP:HPMC 2:1 mixture showed the best mucoadhesion properties and was selected as excipient for the cup layer. Swelling index was higher for formulations containing greater amount of lactose and lower percentage of polymers. Fast release layer released its entire content within 15 min while sustained release layer lasted for 12 h. Drug release controlled by a combination of diffusion and chain relaxation mechanism.

Biodistribution of amikacin solid lipid nanoparticles after pulmonary delivery.

The main purpose of the present work was studying the biodistribution of amikacin solid lipid nanoparticles (SLNs) after pulmonary delivery to increase its concentration in the lungs for treatment of cystic fibrosis lung infections and also providing a new method for clinical application of amikacin. To achieve this aim, (99m)Tc labelled amikacin was loaded in cholesterol SLNs and after in vitro optimization, the desired SLNs and free drug were administered through pulmonary and i.v. routes to male rats and qualitative and biodistribution studies were done. Results showed that pulmonary delivery of SLNs of amikacin by microsprayer caused higher drug concentration in lungs than kidneys while i.v. administration of free drug caused reverse conditions. It seems that pulmonary delivery of SLNs may improve patients' compliance due to reduction of drug side effects in kidneys and elongation of drug dosing intervals due to the sustained drug release from SLNs.

Use of magnetic folate-dextran-retinoic acid micelles for dual targeting of doxorubicin in breast cancer.

Amphiphilic copolymer of folate-conjugated dextran/retinoic acid (FA/DEX-RA) was self-assembled into micelles by direct dissolution method. Magnetic iron oxide nanoparticles (MNPs) coated with oleic acid (OA) were prepared by hydrothermal method and encapsulated within the micelles. Doxorubicin HCl was loaded in the magnetic micelles. The characteristics of the magnetic micelles were determined by Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), transmission electron microscopy (TEM), and vibrating sample magnetometer (VSM). The crystalline state of OA-coated MNPs and their heat capacity were analyzed by X-ray diffraction (XRD) and differential scanning calorimetry (DSC) methods, respectively. The iron content of magnetic micelles was determined using inductively coupled plasma optical emission spectrometry (ICP-OES). Bovine serum albumin (BSA) was used to test the protein binding of magnetic micelles. The cytotoxicity of doxorubicin loaded magnetic micelles was studied on MCF-7 and MDA-MB-468 cells using MTT assay and their quantitative cellular uptake by fluorimetry method. TEM results showed the MNPs in the hydrophobic core of the micelles. TGA results confirmed the presence of OA and FA/DEX-RA copolymer on the surface of MNPs and micelles, respectively. The magnetic micelles showed no significant protein bonding and reduced the IC50 of the drug to about 10 times lower than the free drug.

Stability evaluation of freeze-dried Lactobacillus paracasei subsp. tolerance and Lactobacillus delbrueckii subsp. bulgaricus in oral capsules.

Freeze-drying is a common preservation technology in the pharmaceutical industry. Various studies have investigated the effect of different cryoprotectants on probiotics during freeze-drying. However, information on the effect of cryoprotectants on the stability of some Lactobacillus strains during freeze-drying seems scarce. Therefore, the aim of the present study was to establish production methods for preparation of oral capsule probiotics containing Lactobacillus paracasei subsp. tolerance and Lactobacillus delbrueckii subsp. Bulgaricus. It was also of interest to examine the effect of various formulations of cryoprotectant media containing skim milk, trehalose and sodium ascorbate on the survival rate of probiotic bacteria during freeze-drying at various storage temperatures. Without any cryoprotectant, few numbers of microorganisms survived. However, microorganisms tested maintained higher viability after freeze-drying in media containing at least one of the cryoprotectants. Use of skim milk in water resulted in an increased viability after lyophilization. Media with a combination of trehalose and skim milk maintained a higher percentage of live microorganisms, up to 82%. In general, bacteria retained a higher number of viable cells in capsules containing freeze-dried bacteria with sodium ascorbate after three months of storage. After this period, a marked decline was observed in all samples stored at 23°C compared to those stored at 4°C. The maximum survival rate (about 72-76%) was observed with media containing 6% skim milk, 8% trehalose and 4% sodium ascorbate.

Pharmacokinetic study of niosome-loaded insulin in diabetic rats.

BACKGROUND AND THE PURPOSE OF THE STUDY: Encapsulation of human insulin in lipid vesicular systems such as niosomes was sought as a route to protect this protein against proteolytic enzymes and to improve its oral bioavailability. The purpose of this study was to assess the effect of insulin encapsulation in niosomes on oral bioavailability in diabetic rats. METHODS: Recombinant human insulin was entrapped in multilamellar niosomes composed of polyoxyethylene alkyl ether surfactants (Brij 52 and Brij 92) or sorbitan monostearate (Span 60) and cholesterol. The amount of insulin released in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF) were measured at 37°C. The protection of entrapped insulin against pepsin, α-chymotrypsin and trypsin were evaluated in comparison with free insulin solution. Diabetes was induced by IP injection of streptozotocin (65 mg/kg) in male wistar rats and effects of orally administered niosomes and subcutaneously injected insulin on hypoglycemia and elevation of insulin levels in serum were compared. RESULTS AND CONCLUSION: The extent and rate of insulin release from Brij 92 and Span 60 vesicles were lower than that of Brij 52 niosomes (P<0.05). Vesicles protected insulin in comparison with free insulin solution against proteolytic enzymes (P<0.05) significantly. Animals treated with oral niosome-encapsulated insulin (100 IU/kg) showed decreased levels of blood glucose and elevated serum insulin, which in the case of Brij 92 niosomes, hypoglycemic effect was significant (P<0.05). Niosomes were also stable in solubilizing bile salt solutions and could effectively prolong the release of insulin in both SGF and SIF. Results of this study showed that niosomes may be utilized as oral carriers of insulin; however, to increase bioavailability of insulin, further studies on the protease inhibitor co-encapsulation in niosomal formulations might be helpful.

Development of novel budesonide pellets based on CODES(TM) technology: In vitro/in vivo evaluation in induced colitis in rats.

BACKGROUND AND THE PURPOSE OF THE STUDY: Budesonide is the drug of choice for treatment of active inflammatory bowel disease (IBD). The aim of this study was to develop budesonide pellets based on a novel colon drug delivery system (CODES). METHODS: Pellet cores containing lactulose or mannitol were prepared by extrusion/spheronization and coated with an acid soluble polymer (Eudragit E100), hydroxypropylmethyl cellulose (HPMC) and an enteric coat (Eudragit FS 30D) sequentially. In vitro drug release of coated pellets was studied using USP dissolution apparatus type II in buffers of pH 1.2 (2 hrs), pH of 7.4 (4 hrs) and pH of 6.8 containing 8% rat cecal contents (RCC) (18 hrs). The efficacy of the optimized formulation (containing 50% lactulose coated with Eudragit E (30% w/w) and Eudragit FS 30D (12% w/w)) was evaluated against 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. RESULTS: The results of the kind of bacteria in vitro dissolution tests indicated absence of drug release in pHs of 1.2 and 7.4 and controlled release in buffer of pH 6.8 containing RCC. It was found that release rate was controlled by the type and amount of polysaccharide and the thickness of the acid soluble layer. The prepared formulation showed promising results in alleviating the conditions of experimental model of colitis. CONCLUSION: The results of this study suggest that pellets based on CODES technology could be useful for colonic delivery of budesonide.

Development and validation of a rapid HPLC method for simultaneous analysis of budesonide and its novel synthesized hemiesters in colon specific formulations.

A simple and reliable reversed-phase high performance liquid chromatographic (HPLC) method was developed, validated and applied for determination of budesonide and its novel synthesized hemiesters in colon specific formulations and dissolution media. The method was employed on a µ-Bondapak C(18) column (250 mm × 4.6 mm, 5 µm) at ambient temperature. The mobile phase consisted of acetonitrile: monobasic potassium phosphate containing orthophosphoric acid (55:45, pH 3.2) at a flow rate of 1 ml/min. The UV detection wavelength was set at 244 nm and 50 µL of sample was injected into the HPLC system. Dexamethasone was used as the internal standard. The retention times for internal standard and budesonide were 4.5 and 7.2 min, respectively. The method was linear in the concentration range of 1-20 µg/ml of budesonide (R(2)>0.999). Limit of detection and limit of quantitation were 0.05 and 0.5 µg/ml, respectively. The method presented the requisite accuracy, selectivity, sensitivity and precision and showed good resolution for separation of the drug and related derivatives in the presence of excipients. The proposed method was successfully used for analysis of the drug and its derivatives in dissolution media and oral colon specific formulations prepared in our laboratory with enough reproducibility.

Mg2+ substituted calcium phosphate nano particles synthesis for non viral gene delivery application.

Gene therapy provides a unique approach to medicine as it can be adapted towards the treatment of both inherited and acquired diseases. Recently, calcium phosphate vectors as a new generation of the non viral gene delivery nano carriers have been studied because of their biocompatibility and DNA condensation and gene transfer ability. Substituting cations, like magnesium, affects physical and chemical properties of calcium phosphate nano particles. In this study, Mg(2+) substituted calcium phosphate nano particles have been prepared using the simple sol gel method. X-ray diffraction analysis, Fourier transform infra red spectroscopy, transmission electron microscopy, specific surface area analysis, zeta potential measurement and ion release evaluation were used for characterization of the samples. It was concluded that presence of Mg ions decrease particle size and crystallinity of the samples and increase positive surface charge as well as beta tricalcium phosphate fraction in chemical composition of calcium phosphate. These properties result in increasing the DNA condensation ability, specific surface area and dissolution rate of the samples which make them suitable particles for gene delivery application.

Applying the Taguchi design for optimized formulation of sustained release gliclazide chitosan beads: an in vitro/in vivo study.

Gliclazide is a second generation of hypoglycemic sulfonylurea and acts selectively on pancreatic beta cell to control diabetes mellitus. The objective of this study was to produce a controlled release system of gliclazide using chitosan beads. Chitosan beads were produced by dispersion technique using tripolyphosphate (TPP) as gelating agent. The effects of process variables including chitosan molecular weight, concentration of chitosan and TPP, pH of TPP, and cross-linking time after addition of chitosan were evaluated by Taguchi design on the rate of drug release, mean release time (MRT), release efficiency (RE(8)%), and particle size of the beads. The blood glucose lowering effect of the beads was studied in normal and streptozotocin-diabetic rats. The optimized formulation CL(2)T(5)P(2)t(10) with about 31% drug loading, 2.4 h MRT, and 69.16% RE(8)% decreased blood glucose level in normal rats for 24 h compared to pure powder of gliclazide that lasted for just 10 h.

Production and in vitro characterization of lisinopril-loaded nanoparticles for the treatment of restenosis in stented coronary arteries.

Lisinopril, an angiotensin converting enzyme (ACE) inhibitor drug, was encapsulated in poly(lactide-co-glicolide) (PLGA) nanoparticles (NP) for site-specific delivery by catheters in prevention of restenosis. NP were prepared by emulsification-diffusion method. The PLGA type, stabilizing agent type and its concentration were studied as process variables. The z-average particle size varied between 265-412 nm. The highest zeta potential was seen in NP prepared with Pluronic F-68. None of the studied variables or their interactions had a significant effect on the particle size while all had main effect on the zeta potential. The highest entrapment efficiency was 93% and all studied variables and their interactions except PLGA type and its interaction with the stabilizer type had significant effects on the loading. Baker-Lonsdale model was the most appropriate model for release of lisinopril from NP. Five per cent PLGA 75:25 and 5% Pluronic F-68 showed promising results for 21 days release of lisinopril as an anti-restenotic agent.

Development and characterization of floating microballoons for oral delivery of cinnarizine by a factorial design.

Cinnarizine (CN) is a pipperazine derivative with anti-histaminic activity and high affinity to H(1) receptors. The objective of this study was to produce floating microspheres (FM) of CN by diffusion solvent evaporation technique to increase drug solubility and hence its bioavailability. The effect of process variables such as: Eudragit type, stirring rate and time of stirring after addition of oily phase to the aqueous phase were evaluated on the yield, particle size, loading, release and floating behaviors of microspheres using a factorial design. Release of CN from microspheres was studied in pHs: 1.2 and 7.2 using paddle technique. The samples of dissolution test were analysed spectrophotometrically at 256.1 nm and 256.5 nm respectively. particle size of microspheres was studied using microscopic method and their floating behavior was studied in HCl (0.1 N, pH 1.2) medium with Tween 20 (0.5% w/v). Eight formulations were produced by changing 3 variables each at 2 levels: Eudragit S100 (Ps) or a combination of two Eudragits S100:RLPO (1:3) (P(SR)), stirring rate of 200 (R(2)) or 300 rpm (R(3)) and stirring time after addition of oily phase to the aqueous phase 0 (T(0)) or 1 hr (T(1)). The average size of microspheres was 300 microm. The highest yield efficiency (94%) was seen in P(SR)R(3)T(0) formulation and the greatest loading percentage was 8.5% in P(SR)R(2)T(1) formulation. The microspheres containing just Eudragit S100, didn't show suitable releasing profile during 8 hours in pH 1.2 but those containing combination of Eudragit S100:RL released approximately whole amount of CN during 10 hours (8 hours in pH 1.2 and 2 hours in pH 7.2). The highest floating percentage up to 6 hours was 77.5% in P(S)R(2)T(1) formulation. The type of Eudragit used seems to play an important role in producing sustained release floating microspheres. P(SR)R(3)T(0) formulation containing both types of Eudragit S100:RL (1.3) that releases 99.1% of the drug after 10 hours and 65% floating after 6 hr seems suitable for oral sustained delivery of CN.

Colon-specific delivery of mesalazine chitosan microspheres.

Mesalazine (5-ASA) is a cyclo-oxygenase inhibitor and anti-inflammatory drug effective in Crohn's disease and ulcerative-colitis. As 5-ASA is rapidly absorbed from the small intestine and it is necessary to develop a colon-specific delivery system for it. Coated chitosan microspheres were used for this purpose by an emulsion-solvent evaporation technique based on a multiple w/o/w emulsion. Four hundred milligrams of chitosan solution (3%) in dilute acetic acid (0.5 M) containing 12% 5-ASA was dispersed into 2 ml solution of cellulose acetate butyrate (CAB) in methylene chloride. The primary induced w/o emulsion was dispersed into a 1% PVA aqueous solution to produce a w/o/w multiple emulsion and was stirred for approximately 2.5 h. The produced microspheres were separated, washed and dried. Release of 5-ASA from microspheres was studied in different pHs 1.2, 7.4, 6.8 and 6.8 in the presence of caecal contents of rat. The average size of microspheres was 200 microm. The highest yield efficiency (80%) was seen in medium molecular weight (MW) chitosan with a 1 : 2 core/coat ratio and the greatest loading efficiency (85%) related to the microspheres of the same type of chitosan but with a 1 : 1 core/coat ratio. Decreasing the coat content and increasing chitosan Mw increased the bioadhesion significantly (p < 0.05). Microspheres of chitosan with medium Mw and 1 : 1 core/coat that showed the greatest release of drug (near 80%) in the presence of caecal secretions with a zero-order mechanism, near zero per cent in pH 1.2 after 2 h, max 20% in pH 7.4 after 3 h and near 60% in pH 6.8 after 8 h seem suitable for site-specific delivery of 5-ASA in vitro.

Nasal delivery of insulin using chitosan microspheres.

Nasal delivery of insulin is an alternative route for administration of this drug. The objective of this study was preparation of chitosan microspheres for insulin nasal delivery. After preparation of insulin chitosan microspheres by emulsification-cross linking process, the effect of chitosan quantity (200-400mg), cross-linker type (ascorbic acid or ascorbyl palmitate) and amount (70-140 mg) were studied on the morphology, particle size, loading efficiency, flow and release of insulin from the microspheres by a factorial design. Optimized formulation was administered nasally in four groups of diabetic rats and their serum insulin levels were analysed by the insulin enzyme immunoassay kit and the serum glucose by the glucose oxidase kits. Insulin loading in microspheres was between 4.7-6.4% w/w, preparation efficiency more than 65% and mean particle size was 20-45 microm. In most cases, drug released followed a Higuchi model. Ascorbic acid caused an increase in stability, particle size and T50%, while decreased the loading efficiency and production efficiency. Increasing the chitosan content, increased particle size, flow and insulin release rate form the microspheres. The increase of cross-linking percentage decreased the flow and size of the microspheres while increase of cross-linking percentage promoted the stability and decreased DE8% of insulin. Microspheres containing 400mg of chitosan and 70mg ascorbyl palmitate caused a 67% reduction of blood glucose compared to i.v. route and absolute bioavaliability of insulin was 44%. The results showed that chitosan microspheres of insulin are absorbable from nasal route.

High performance liquid chromatographic determination, pharmacokinetic and comparative bioavailability studies of cisapride.

A sensitive and specific reversed phase HPLC method was developed to quantitate plasma levels of cisapride in order to conduct comparative bioavailability studies. The drug and internal standard was extracted from plasma with heptane-isoamyl alcohol (95:5 v/v) and back extracted with sulfuric acid. The acidic layer was then re-extracted with the same extracting solvent. The separated organic layer was evaporated to dryness under nitrogen and the residue reconstituted with acetonitrile. Analysis was performed on a C-8 Sil-X-10 HPLC column, with a mobile phase of acetonitrile, water, and triethylamine (75:25:0.01) and UV detection at 215 nm. The standard curve covering the concentration range 5-160 ng/ml was linear (r(2)=0.9992), relative errors were within +/-10% and the CV% ranged from 1.34 to 11.82. The in vivo study was carried out in 12 healthy volunteers according to a single dose, two-sequence, cross over randomized design. The bioavailability was compared using the total area under the plasma level versus time curve (AUC(0-34,) AUC(0- infinity )), peak plasma concentration (C(max)) and time to C(max) (T(max)). No statistically significant difference was found between the AUC(0- infinity ) or C(max) values of the test (cisapride) and reference (Propulsid). It was, therefore, concluded that the generic cisapride was bioequivalent with the innovator formulation.

Development and characterization of buccoadhesive nifedipine tablets.

The buccoadhesive controlled-release tablets for delivery of nifedipine were prepared by direct compression of carboxymethyl cellulose (CMC) with carbomer (CP), which showed superior bioadhesion properties compared to polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropylmethyl cellulose (HPMC), and acacia in a modified tensiometry method in vitro. The tablets containing 30mg of nifedipine and various amounts of CMC and CP showed a zero-order drug release kinetic. The adhesion force was significantly affected by the mixing ratio of CP:CMC in the tablets. The weakest and highest adhesion force was observed at the mixing ratios of 1:0 and 8:2 of CP:CMC, respectively. The tablets containing 15% CMC and 35% CP adhered for over 8h to the upper gums of six healthy human volunteers. These tablets released about 56% of the loaded drug after 8h in vivo with a rate of 2.17h(-1) and were perfectly tolerated, while they released about 100% of their content after the same time with a rate of 3.49h(-1) in vitro. A good correlation (r(2)=0.989) was observed between drug-released in vitro and in vivo.