Development of ß-cyclodextrin/polyvinypyrrolidone-co-poly (2-acrylamide-2-methylpropane sulphonic acid) hybrid nanogels as nano-drug delivery carriers to enhance the solubility of Rosuvastatin: An in vitro and in vivo evaluation.

The present study is aimed at enhancing the solubility of rosuvastatin (RST) by designing betacyclodextrin/polyvinypyrrolidone-co-poly (2-acrylamide-2-methylpropane sulphonic acid) crosslinked hydrophilic nanogels in the presence of crosslinker methylene bisacrylamide through free-radical polymerization method. Various formulations were fabricated by blending different amounts of betacyclodextrin, polyvinylpyrrolidone, 2-acrylamide-2-methylpropane sulphonic acid, and methylene bisacrylamide. The developed chemically crosslinked nanogels were characterized by FTIR, SEM, PXRD, TGA, DSC, sol-gel analysis, zeta size, micromeritics properties, drug loading percentage, swelling, solubility, and release studies. The FTIR spectrum depicts the leading peaks of resultant functional groups of blended constituents while a fluffy and porous structure was observed through SEM images. Remarkable reduction in crystallinity of RST in developed nanogels revealed by PXRD. TGA and DSC demonstrate the good thermal stability of nanogels. The size analysis depicts the particle size of the developed nanogels in the range of 178.5 ±3.14 nm. Drug loading percentage, swelling, solubility, and release studies revealed high drug loading, solubilization, swelling, and drug release patterns at 6.8 pH paralleled to 1.2 pH. In vivo experiments on developed nanogels in comparison to marketed brands were examined and better results regarding pharmacokinetic parameters were observed. The compatibility and non-toxicity of fabricated nanogels to biological systems was supported by a toxicity study that was conducted on rabbits. Efficient fabrication, excellent physicochemical properties, improved dissolution, high solubilization, and nontoxic nanogels might be a capable approach for the oral administration of poorly water-soluble drugs.

Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression.

OBJECTIVE: Preclinical evidence indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes and may trigger postpartum depression (PPD) in some women. Considering the pathophysiology of PPD (i.e., triggered by reproductive steroids), the need for fast-acting, efficacious treatments and the negative consequences of untreated PPD, there is an increasing focus on developing PPD therapies. Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary injectable allopregnanolone formulation, was evaluated as a treatment for severe PPD in a proof-of-concept, open-label study. METHODS: Four women with severe PPD, defined as a baseline 17-item Hamilton Rating Scale for Depression (HAMD) score of ≥20, received brexanolone, titrated to a dose reflecting third-trimester allopregnanolone levels. After a 36-hour maintenance infusion, tapering occurred over 12 hours. Primary outcomes were measures of safety. Secondary outcomes were assessments of efficacy, including HAMD. RESULTS: All enrolled patients completed the study. Fourteen adverse events were reported, of which none was severe. Starting at the first measure after infusion initiation and continuing through Hour 84, mean HAMD total scores were reduced to levels consistent with remission of symptoms. All other efficacy assessments showed similar improvements. CONCLUSIONS: Brexanolone was well tolerated and demonstrated activity in severe PPD. Larger, double-blind trials are needed for further evaluation.

Sequel of MgO nanoparticles in PLACL nanofibers for anti-cancer therapy in synergy with curcumin/ß-cyclodextrin.

Pharmaceutical industries spend more money in developing new and efficient methods for delivering successful drugs for anticancer therapy. Electrospun nanofibers and nanoparticles loaded with drugs have versatile biomedical applications ranging from wound healing to anticancer therapy. We aimed to attempt for fabricating elastomeric poly (l-lactic acid-co-ε-caprolactone) (PLACL) with Aloe Vera (AV), magnesium oxide (MgO) nanoparticles, curcumin (CUR) and ß-cyclodextrin (ß-CD) composite nanofibers to control the growth of MCF-7 cells for breast cancer therapy. The study focused on the interaction of MgO nanoparticle with CUR and ß-CD inhibiting the proliferation of Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. FESEM micrographs of fabricated electrospun PLACL, PLACL/AV, PLACL/AV/MgO, PLACL/AV/MgO/CUR and PLACL/AV/MgO/ß-CD nanofibrous scaffolds achieved bead free, random and uniform nanofibers with fiber diameter in the range of 786±286, 507±171, 334±95, 360±94 and 326±80nm respectively. Proliferation of MCF-7 cells was decreased by 65.92% in PLACL/AV/MgO/CUR with respect to PLACL/AV/MgO nanofibrous scaffolds on day 9. The obtained results proved that 1% CUR interacting with MgO nanoparticles showed higher inhibition of MCF-7 cells among all other nanofibrous scaffolds thus serving as a promising biocomposite material system for the breast cancer therapy.

A novel nasal powder formulation of glucagon: toxicology studies in animal models.

BACKGROUND: Glucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic glucagon (10% w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety of this formulation was evaluated in four studies in animal models. METHODS: The first study evaluated 28-day sub-chronic toxicology in rats treated intranasally with 1 and 2 mg of GNP/day (0.1 and 0.2 mg glucagon/rat/day). The second study evaluated 28-day sub-chronic toxicology in dogs administered 20 and 40 mg of formulation/dog/day (2 and 4 mg glucagon/dog/day) intranasally. A pulmonary insufflation study assessed acute toxicology following intra-tracheal administration of 0.5 mg of GNP (0.05 mg glucagon) to rats. Local tolerance to 30 mg of GNP (equivalent to 3 mg glucagon, the final dose for humans) was tested through direct administration into the eyes of rabbits. RESULTS: There were no test article-related adverse effects on body weight and/or food consumption, ophthalmology, electrocardiography, hematology, coagulation parameters, clinical chemistry, urinalysis, or organ weights, and no macroscopic findings at necropsy in any study. In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects. In dogs, the only adverse findings following sub-chronic use were transient (<30 s) salivation and sneezing immediately post-treatment and mild to moderate reversible histological changes to the nasal mucosa. Daily dosing over 28 days in rats resulted in mild to moderate, unilateral or bilateral erosion/ulceration of the olfactory epithelium, frequently with minimal to mild, acute to sub-acute inflammation of the lamina propria at the dorsal turbinates of the nasal cavity in 2/10 males and 3/10 females in the high-dose group (0.2 mg glucagon/day). These lesions resolved completely over 14 days. Histological examination of tissues from both sub-chronic studies in dogs and rats revealed no microscopic findings. In rabbits, clinical observations noted in the GNP-treated eye and/or surrounding areas included ≥1 of the following: clear discharge, red conjunctiva, partial closure, and swelling of the peri-orbital area, which correlated with erythema and edema noted during ocular observations and grading. DISCUSSION: The studies reported here revealed no safety concerns associated with GNP in animal models. Studies published earlier have highlighted the local safety profile of intranasally administered cyclodextrins (a component of GNP). The choline group, the phosphate group, and the saturated 12-carbon aliphatic chain that are present in the dodecylphosphocholine excipient used in GNP are all present in the phospholipids and lecithins seen ubiquitously in mammalian cell membranes and are unlikely to pose safety concerns; this notion is supported by several studies conducted by the authors that revealed no safety concerns. Taken together, these results suggest that intranasal delivery of GNP holds promise as a future rescue medication for use by caregivers to treat insulin-induced hypoglycemic episodes in patients with type 1 or type 2 diabetes. CONCLUSION: This novel drug product is well tolerated in animal models.

Inclusion complexes of bendamustine with ß-CD, HP-ß-CD and Epi-ß-CD: in-vitro and in-vivo evaluation.

The objective of the present work was to investigate the inclusion behavior of bendamustine (BM) with ß-cyclodextrin and its hydrophilic derivatives (HP-ß-CD and Epi-ß-CD) for the enhancement of aqueous solubility, dissolution and bioavailability. The supramolecular binary complexes were prepared by three different methods, viz. physical mixture (PM), kneading (KND) and co-evaporation (COE). Phase-solubility study revealed the higher solubilizing and complexing ability of polymerized cyclodextrin (Ks = 645 M(-1)) than parent cyclodextrin (Ks = 43 M(-1)) and chemically derived cyclodextrin (Ks = 100 M(-1)). Meanwhile, the solubility of BM was significantly enhanced in phosphate buffer of pH 6.8, which was 24.5 folds greater compared with the phosphate buffer pH 4.5 and four times greater than aqueous medium. The dissolution efficiency was found to be highest for BM: Epi-ß-CD complex (87%) compared to BM: HP-ß-CD complex (84%), BM: ß-CD (79%) and pure drug (20%). In-vivo pharmacokinetic study revealed that the bioavailability of BM was enhanced 2.55 times on complexation with Epi-ß-CD using KND method. The t1/2 of BM was increased from 34.2 min to approximately 75.7 min, allowing the absorption for longer time. The order of increase in solubility, dissolution and bioavailability of BM was KND > COE > PM > pure drug. Thus, the strategy of host-guest inclusion was very effective and could be successfully used in the development of suitable pharmaceutical dosage form with enhanced therapeutic activity.

Immediate release three-layered chewing gum tablets of fenoprofen calcium: preparation, optimization and bioavailability studies in healthy human volunteers.

A three-layered gum tablet (1800 mg), containing 200 mg of Fenoprofen Calcium (Fn) with an inner core containing the drug, and two external layers containing antiadherent lubricant, has been prepared using direct compression. A 2(3) factorial plan has been designed to evaluate the effect of formulation variables namely, Pharmagum(®) M concentration, Maltodextrin type, and Co-adjuvant type on the release characteristics of Fn from the prepared tablets. The formula consisting of 65% Pharmagum(®) M, 75% Maltodextrin DE 39 and 5% Talc comparatively exhibited the highest release (66.59% ± 2.39) in the mouth after 5 min of chewing. Binary and ternary ß-cyclodextrin (ß-CD) complexation was adopted to enhance the release of Fn from the selected gum tablet. The highest significant release (p < 0.05) was achieved from the lyophilized ternary complex containing 100 mg of Fn in presence of polyvinylpyrrolidone (PVP K(25)), exhibiting a release of 88.25% ± 0.93 after 5 min of chewing. The relative bioavailability of the selected gum tablet was found to be 166.06% compared to Nalfon(®) 200 mg capsules. Reduction of the dose to 100 mg exhibited faster absorption rate than Nalfon(®) capsules. The obtained results suggest the possibility of reducing the dose of Fn in chewing gum.

Pharmacokinetic study of rhizoma Curcumae oil and rhizoma Curcumae oil-ß-cyclodextrin inclusion complex in pigs after oral administration.

Pharmacokinetics of rhizoma Curcumae oil-pure drug (RCO-PD) and its ß-cyclodextrin inclusion complex (RCO-ßCD) were studied in a randomized two-way crossover design following a single oral administration of the two formulations. Germacrone concentrations in plasma were determined by high-performance liquid chromatography with UV detector. The concentrations vs. time data were analyzed by a noncompartmental pharmacokinetic method. The result showed that germacrone in both groups was rapidly absorbed followed by a slow elimination. The main parameters in RCO-PD group were as follows: t(1/2λz) 6.63±1.08 h, C(max) 2.50±0.34 µg/mL, MRT 7.19±0.93 h, and AUC(0-∞) 13.92±2.75 mg/L·h, while in RCO-ßCD group, t(1/2λz) 6.77 ± 0.67 h, C(max) 2.98±0.24 µg/mL, MRT 8.87±0.76 h, and AUC(0-∞) 21.60 ± 1.95 mg/L·h, respectively. The above results indicated that C(max), T(max), AUC(0-t), AUC(0-∞), and MRT in RCO-ßCD group were significantly different from RCO-PD group, and the relative bioavailability of RCO-ßCD group is significantly higher while compared to RCO-PD group (F=156%, with its 90% confidence interval of 145-169%).

Hepatic and renal toxicities of indomethacin acid, salt form and complexed forms with hydroxypropyl-ß-cyclodextrin on Wistar rats after oral administration.

Indomethacin (IM), a non-steroidal anti-inflammatory drug, has the capacity to induce hepatic and renal injuries when administrated systemically. The aim of this study is to assess the IM absorption from complexed forms when orally administered to rats, by means of a comparative evaluation of its capacity to induce hepatic and renal injury in different forms, namely IM acid, IM sodium salt or IM complexed with hydroxypropyl-ß-cyclodextrin (HP-ß-CD), using freeze- and spray-drying methods. A total of 135 Wistar rats weighing 224.4 ± 62.5 g were put into 10 groups. They were allowed free access to water but were maintained on fast for 18 h before the first administration until the end of the experiment. Water and HP-ß-CD (control groups) and IM acid form, IM trihydrated-sodium-salt and IM-HP-ß-CD spray- and freeze-dried, at normal and toxic doses (test groups), were orally administered once/day for 3 days. Seventy-two hours after the first administration, the animals were sacrificed and a fragment of the liver and one kidney were collected and prepared for histopathological evaluation. Lesion indexes (rated 0/4 for liver and 0/3 for kidney) were developed and the type of injury scored according to the severity of damage. A statistical analysis of the severity and incidence of lesions was carried out. Animals administered with IM complexed forms showed similar hepatic and renal lesions, both in toxic and therapeutic doses, when compared with those observed in animals administered with IM acid or salt forms. This suggests that under the present experimental conditions, IM is equally absorbed from the gastrointestinal tract, independently of the administered IM form.

Two novel ternary albendazole-cyclodextrin-polymer systems: dissolution, bioavailability and efficacy against Taenia crassiceps cysts.

The effect of two water-soluble polymers: pectin and polyvinylpyrrolidone in combination with beta-cyclodextrin, on the dissolution, bioavailability and cysticidal efficacy of albendazole was evaluated using a commercial suspension as reference product. The dissolution of the albendazole-beta-cyclodextrin-pectin formulation was slow and incomplete (44.7%). No statistical differences in C(max) and AUC were found between this formulation and the reference. Also its cysticidal efficacy (33%) was similar to the reference (38%). The albendazole-beta-cyclodextrin-polyvinylpyrrolidone formulation exhibited the highest dissolution rate (78.5%) and its bioavailability was also significantly increased (2.3-fold). In addition, the cysticidal activity of this formulation (83%) was greater than a commercial suspension. Our results suggest that the ternary system of albendazole-beta-cyclodextrin-polyvinylpyrrolidone could be a potential alternative for the treatment of systemic helmintic diseases and it is worth to continue its preclinical evaluation.

Pharmacokinetic characterization of hydroxylpropyl-beta-cyclodextrin-included complex of cryptotanshinone, an investigational cardiovascular drug purified from Danshen (Salvia miltiorrhiza).

1. The study aimed to investigate the pharmacokinetics of cryptotanshinone in a hydroxylpropyl-beta-cyclodextrin-included complex in dogs and rats. 2. Animals were administrated the inclusion complex of cryptotanshinone and the concentrations of cryptotanshinone and its major metabolite tanshinone IIA were determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. 3. Cryptotanshinone in inclusion complex was absorbed slowly after an oral dose, and the C(max) and AUC(0-)(t) were dose-proportional. The bioavailability of cryptotanshinone in rats was (6.9% +/- 1.9%) at 60 mg kg(-1) and (11.1% +/- 1.8%) in dogs at 53.4 mg kg(-1). The t(1/2) of the compound in rats and dogs was 5.3-7.4 and 6.0-10.0 h, respectively. Cryptotanshinone showed a high accumulation in the intestine, lung and liver after oral administration, while the lung, liver and heart had the highest level following intravenous dose. Excretion data in rats showed that cryptotanshinone and its metabolites were mainly eliminated from faeces and bile, and the dose recovery rate was 0.02, 2.2, and 14.9% in urine, bile, and faeces, respectively. 4. The disposition of cryptotanshinone in an inclusion complex was dose-independent and the bioavailability was increased compared with that without cyclodextrin used to formulate the drug. Cryptotanshinone was distributed extensively into different organs. Excretion of cryptotanshinone and its metabolites into urine was extremely low, and they were mainly excreted into faeces and bile.

[Preparation of coated tablets of glycyrrhetic acid-HP-beta-cyclodextrin tablets for colon-specific release].

OBJECTIVE: To prepare coated tablets of glycyrrhetinic acid and hydroxypropyl-beta-cyclodextrin (GTA-HP-beta-CYD) inclusion complex tablets for colon-specific release. METHOD: In order to improve the solubility of GTA, the GTA-HP-beta-CYD inclusion complex was prepared by ultrasonic-lyophilization technique and its formation were characterized by X-ray powder diffraction profiles and infrared spectrometry. The effects of inclusion condition on the inclusion efficiency and stability coefficient of inclusion complex were investigated, respectively. After prepared GTA-HP-beta-CYD tablets by powder direct compression, the pH dependant polymer Eudragit III and/or mixed with Eudragit II were used for further coating materials in fluid-bed coater. The influences of coating weight on the GTA release in different pH conditions were evaluated to establish the method for prepering colon specific delivery tablets with pulsed release properties. RESULT: The formation of inclusion complexes were proved by X-ray powder diffraction profile and phase solubility curve. The effect of pH value of solvent was played critical role on the preparation of GTA- HP-beta-CYD inclusion complex. And the inclusion efficiency of GTA was 9. 3% and the solubility was increased to 54. 6 times at optimized method. The Eudragit III coated GTA- HP-beta-CYD tablets with coating weight 10% and 16% were showed pH dependant colon specific release profiles with slow release rate. The release profile of tablets coated with the mixture of Eudragit II and Eudragit III (1:2) were indicated typical pH dependant colon specific and pulsed release properties while the coating weight was 17%. CONCLUSION: The preliminary method for preparation of colon specific release tablets containing glycyrrhetinic acid with improved solubility was established for further in vivo therapeutic experiment.

Nasal absorption of metoclopramide from different Carbopol 981 based formulations: In vitro, ex vivo and in vivo evaluation.

There is a need for nasal drug delivery of metoclopramide HCI (MTC) in specific patient populations where the use of commercially available intravenous and oral dosage forms may be inconvenient and/or unfeasible. In this perspective, nasal dosage forms (solution, gel and lyophilized powder) of MTC were prepared by using a mucoadhesive polymer Carbopol 981 (CRB 981). The drug release studies of formulations were performed by using a modified horizontal diffusion chamber with cellulose membrane and excised cattle nasal mucosa as diffusion barriers. After the ex vivo experiments, the morphological appearances of the nasal mucosa were analyzed with the light microscopic studies. In vivo experiments were carried on sheep model. The release of MTC from solution and powder formulations was found higher than gel formulation (p < 0.05) and no severe damage was found on the integrity of nasal mucosa after ex vivo experiments. The penetration enhancing effect of dimethyl-beta-cyclodextrin (DM-beta-CD) used in powder formulations was observed in ex vivo and in vivo experiments. In contrast to in vitro and ex vivo experiments the nasal bioavailability of gel formulation was found higher than those of the solution and powder (p < 0.05) and might represent a promising novel tool for the systemic delivery of MTC.

Methyl-beta-cyclodextrin enhances the susceptibility of human breast cancer cells to carboplatin and 5-fluorouracil: involvement of Akt, NF-kappaB and Bcl-2.

The response rates of extensively used chemotherapeutic drugs, carboplatin (Carb) or 5-fluorouracil (5-FU) are relatively disappointing because of considerable side effects associated with their high-dose regimen. In the present study, we determined whether treatment with a cholesterol depleting agent, methyl-beta-cyclodextrin (MCD), enhances the weak efficacy of low doses of Carb or 5-FU in human breast cancer cells. Data demonstrate that pretreatment with MCD significantly potentiates the cytotoxic activity of Carb and 5-FU in both MCF-7 and MDA-MB-231. Furthermore, we explored the molecular basis of enhanced cytotoxicity, and our data revealed that low-dose treatment with these drugs in MCD pretreated cells exhibited significantly decreased Akt phosphorylation, NF-kappaB activity and down-regulation in expression of anti-apoptotic protein Bcl-2. In addition, MCD pretreated cells demonstrated an increased intracellular drug accumulation as compared to cells treated with drugs alone. Taken together, our data provide the basis for potential therapeutic application of MCD in combination with other conventional cytotoxic drugs to facilitate reduction of drug dosage that offers a better chemotherapeutic approach with low toxicity.

[Pharmacokinetics of breviscapine and its beta-cyclodextrin complex in rats].

AIM: To establish RP-HPLC method for determination of plasma scutellarin concentration and study of the pharmacokinetic behavior of scutellarin in rat after ig administration of breviscapine and its beta-cyclodextrin complex (breviscapine-beta-CD). METHODS: Mobile phase composed of methanol and acetate buffer. The column was Shim-pack C18. Twelve rats randomized into 2 groups were separately given breviscapine and breviscapine-beta-CD at single dose of 10.8 mg.kg(-1). Drug in plasma was extracted and determined by HPLC. The pharmacokinetic parameters were calculated by 3P97 software. RESULTS: Linearity was obtained over the range of 10-400 ng.mL(-1). The recovery was 95.32%-98.81%. C(max) and AUC(0-12 h) of breviscapine were (154 +/- 18) ng.mL(-1) and (710 +/- 126) ng.h.mL(-1). For breviscapine-beta-CD, C(max) and AUC(0-12 h) were (328 +/- 31) ng.mL(-1) and (1,093 +/- 200) ng.h.mL(-1), respectively. There were significant differences of AUC(0-12 h) between breviscapine and breviscapine-beta-CD (P < 0.01). CONCLUSION: The assay method was suitable for the determination of scutellarin plasma concentration in rat. Brevescapine-beta-CD showed greater absorption compared with that of brevescapine.

[Pharmacokinetic studies of quercetin-hydroxypropyl-beta-cyclodextrin inclusion compound in rats].

To estabilish a HPLC method for determination of quercetin-hydroxypropyl-beta-cyclodextrin in rats plasma and investigate the pharmacokinetics characteristics of it in rats. The plasma was extracted with methanol-aceitc acid (9:1). The mobile phase was acetonitrilewater. Absorbance of the effluence was monitored at 360 nm. The linear limit of quercetin was within the range of 1 to 150 microg/ml. The lowest limit of quercetin was 0.5 microg/ml. The concentration-time curve of quercetin in rats was considered of a two-compartment open model, and the t1/2 (beta) of the inclusion compound when ig is 2.220 h, the t1/2 (beta) of the inclusion compound when iv is 90.871 min.

Formulation studies and in vivo evaluation of a flurbiprofen-hydroxypropyl beta-cyclodextrin system.

The purpose of this study was 1) to investigate in vivo advantages of a flurbiprofen (FPN)-hydroxypropyl beta-cyclodextrin (HPbetaCD) solid dispersion (SD) in rats, 2) to study factors affecting the drug release from SD formulations, and 3) to evaluate the pharmacokinetic profile of the drug when administered as SD, in humans. The solubility of FPN in water and dissolution media was evaluated as a function of HPbetaCD concentration. The SD was prepared by coevaporation from dilute aqueous NH3 and evaluated in rats. The release of the drug from tablet formulations and capsules of SD was studied in simulated gastric fluid and phosphate buffer, pH 7.2. The bioavailability of drug when administered as SD was evaluated in humans. HPbetaCD enhanced the solubility of the drug, and SD improved bioavailability and reduced ulcerogenicity of the drug in rats. The type of excipient used affected drug release from tablets. Presence of microcrystalline cellulose, a hydrophilic polymeric excipient, resulted in uptake of water and stabilization of the resulting gels-like structure of HPbetaCD-containing tablets. This adversely affected drug release. The release from capsules filled with SD was comparable to that obtained from plain SD powder. The drug-HPbetaCD association constant in water was much lower than the values reported in literature. The bioavailability (which could suffer in case of higher association constant) was enhanced on administration of SD-filled capsules to humans.

Nasal insulin delivery in the chitosan solution: in vitro and in vivo studies.

The effects of chitosan concentrations, osmolarity, medium and absorption enhancers in the chitosan solution on nasal insulin delivery were studied in vitro and in vivo. The penetration of insulin through the mucosa of rabbit nasal septum was investigated by measuring the transmucosal flux in vitro, while the nasal absorption of insulin in vivo was assessed by the efficiency in lowering the blood glucose levels in normal rats. It was demonstrated that increasing concentrations of chitosan up to 1.5% (w/v) caused an increase in the permeability of insulin across the nasal mucosa. Insulin given intranasally in hypo- or hyperosmotic formulation showed a higher hypoglycemic effect than insulin delivered in isoosmotic formulation. Insulin formulation in chitosan solution prepared with deionized water brought to a higher relative pharmacological bioavailability (Fr) value than that prepared with 50 mM pH 7.4 phosphate buffer. A formulation containing both 1% chitosan and 0.1% ethylenediaminetetraacetic acid (EDTA), 5% polysorbate 80 (Tween 80) or 1.2% beta-cyclodextrin (beta-CD) did not lead to a higher Fr than insulin formulated with 1% chitosan alone. The formulation containing both 5% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and 1% chitosan was more effective at reducing blood glucose levels than the formulation containing 5% HP-beta-CD or 1% chitosan alone. The studies indicated that chitosan concentrations, osmolarity, medium and absorption enhancers in chitosan solution have significant effect on the insulin nasal delivery. The results of in vitro experiments were in good agreement with that of in vivo studies.

Mathematical evaluation of in vitro release profiles of hydroxypropylmethylcellulose matrix tablets containing carbamazepine associated to beta-cyclodextrin.

The release kinetics of carbamazepine (CBZ) either complexed or physically mixed with beta-cyclodextrin (betaCD) from hydroxypropylmethylcellulose (HPMC) matrix tablets was investigated using different mathematical equations. The model-dependent approach was compared to the utilization of fit factors. Notwithstanding difference (f1) and similarity (f2) factors allowed the differentiation of the formulations containing CBZ complexed with betaCD from the one containing a simple physical mixture of CBZ and betaCD. The Weibull model was more useful for comparing the release profiles. Weibull parameters were more sensitive to the differences between the two release kinetic data.

Bioavailability of carbamazepine:beta-cyclodextrin complex in beagle dogs from hydroxypropylmethylcellulose matrix tablets.

The bioavailability of a carbamazepine:beta-cyclodextrin (CBZ:betaCD) complex from hydroxypropylmethylcellulose (HPMC) matrix tablets was evaluated in beagle dogs. A solubility study demonstrated the improvement of CBZ aqueous solubility by adding increasing amounts of betaCD. The 1:1 CBZ:betaCD molar ratio was chosen to produce the complex, which was obtained by spray-drying. Matrix tablets were prepared by direct compressing either a CBZ:betaCD complex or a physical mixture of both substances with HPMC. Both matrix formulations displayed a controlled-release profile when compared to the reference formulation (Tegretol CR 200). CBZ presented a significantly higher bioavailability from matrix tablets containing the CBZ:betaCD complex than that obtained from Tegretol CR 200). Although a high inter-subject variability was observed, the results pointed to the feasibility of using betaCD in order to modulate CBZ release and absorption, as well as to reduce the drug dosage maintaining the same plasma levels.