Development and uniform evaluation of ropinirole osmotic pump tablets with REQUIP XL both in vitro and in beagle dogs

REQUIP XL, prolonged release formulation of ropinirole hydrochloride (RH) in market, could release ropinirole constantly and showed satisfactory therapeutic effect and good compliance. REQUIP XL was composed of more than 10 kinds of excipients and prepared by Geomatrix technology, which was complex and laborious. The purpose of this study was to obtain a dosage form of RH with similar in vitro release profile and bioequivalence in vivo compared to REQUIP XL. Osmotic pump tablet combined with fast release phase was selected as the delivery system of RH and similar release curves were obtained in different media. The tablets were also administered to beagle dogs and the pharmacokinetic parameters were calculated using a non-compartmental model. C_max, t_max, mean residence time (MRT), and area under the curve from 0 to 24?h (AUC_0–24) were 3.97?±?0.53?ng/mL, 3.58?±?0.49?h, 8.29?±?0.93?h, and 35.20?±?8.11?ng/mL???h for ropinirole osmotic pump tablets (ROPT) and 4.15?±?1.07?ng/mL, 2.92?±?0.49?h, 7.84?±?1.09?h, and 34.34?±?10.06?ng/mL???h for REQUIP XL. The log-transformed mean C_max and AUC_0–24 of ROPT were about 92.15% and 102.49% relative to that of REQUIP XL, respectively. The 90% confidence intervals of C_max and AUC_0–24 for ROPT were 75.69–115.31% and 88.89–122.30%, respectively. So it could be concluded that ROPT was uniform with REQUIP XL both in vitro and in beagles and the release profiles of Geomatrix technology may be obtained by osmotic pump combined with fast release technology.     

Sustained-release of Cyclosporin A pellets: preparation,in vitro release,pharmacokinetic studies and in vitro–in vivo correlation in beagle dogs

The aim of this study was to develop Cyclosporin A (CsA) sustained-release pellets which could maintain CsA blood concentration within the therapeutic window throughout dosing interval and to investigate the in vitro–in vivo correlation (IVIVC) in beagle dogs. The CsA sustained-release pellets (CsA pellets) were prepared by a double coating method and characterized in vitro as well as in vivo. Consequently, the CsA pellets obtained were spherical in shape, with a desirable drug loading (7.18?±?0.17?g/100?g), good stability and showed a sustained-release effect. The C_max, T_max and AUC_0–24 of CsA pellets from the in vivo pharmacokinetics evaluation was 268.22?±?15.99?ng/ml, 6?±?0?h and 3205.00?±?149.55?ng·h/ml, respectively. Compared with Neoral®, CsA pellets significantly prolonged the duration of action, reduced the peak blood concentration and could maintain a relatively high concentration level till 24?h. The relative bioavailability of CsA pellets was 125.68?±?5.37% that of Neoral®. Moreover, there was a good correlation between the in vitro dissolution and in vivo absorption of the pellets. In conclusion, CsA pellets which could ensure a constant systemic blood concentration within the therapeutic window for 24?h were prepared successfully. Meanwhile, this formulation possessed a good IVIVC.     

Development and pharmacokinetic evaluation of alginate-pectin polymeric rafts forming tablets using box behnken design

Abstract

Raft is an emerging drug delivery system, which is suitable for controlled release drug delivery and targeting. The present study aimed to evaluate the physico-chemical properties of raft, in vitro release of pantoprazole sodium sesquihydrate and conduct bioavailability studies. Box behnken design was used with three independent and dependent variables. Independent variables were sodium alginate (X₁), pectin (X₂) and hydroxypropyl methyl cellulose K100M (X₃) while dependent variables were percentage drug release at 2 (Y₂), 4 (Y₄) and 8?h (Y₈). The developed rafts were evaluated by their physical and chemical properties. Fourier transform infrared spectroscopy and differential scanning calorimetry were used to study the chemical interaction and thermal behaviour of drug with polymers. Alginate and pectin contents of R9 formulation were 99.28% and 97.29%, respectively, and acid neutralization capacity was 8.0. R9 formulation showed longer duration of neutralization and nature of raft was absorbent. The raft of R9 formulation showed 98.94% release of PSS at 8?h in simulated gastric fluid. Fourier transform infrared spectroscopy showed no chemical interaction and differential scanning calorimetry indicated endothermic peaks at 250?°C for pantoprazole sodium sesquihydrate. t_max for the test and reference formulations were 8?±?2.345?h and 8?±?2.305?h, respectively. C_max of test and reference formulations were 46.026?±?0.567?µg/mL and 43.026?±?0.567?µg/mL, respectively. AUC_(0-t) of the test and reference formulations were 472.115?±?3.467?µg?×?h/mL and 456.105?±?2.017?µg?×?h/mL, respectively. Raft forming system successfully delivered the drug in controlled manner and improved the bioavailability of drugs.     

Sildenafil vaginal suppositories: preparation,characterization, in vitro and in vivo evaluation

Aim: The main objective was to investigate the in vitro release profile/kinetics, and in vivo plasma pharmacokinetics (PK) and organ biodistribution (BD) of the prepared sildenafil vaginal suppositories (SVS).

Methods: Suppositories containing 25?mg of sildenafil were prepared by the cream melting technique using Witepsol H-15 as a suppository base. The suppositories were characterized for weight variation, content uniformity, hardness, disintegration time and crystallinity change. The in vitro dissolution in pH 4.5, and in vivo plasma PK and organ BD of sildenafil from SVS in female Sprague Dawley rats, were also investigated.

Results: The mean weight variation, content uniformity, hardness and disintegration time of the prepared SVS were 1.127?±?0.020?g, 98.25?±?2.50%, 2.5?±?0.08?kg and 9?±?1.0?min, respectively. The release of sildenafil from the SVS was more than 90% at 30?min, with a release kinetic of Hixson--Crowell model and non-Fickian diffusion (n?=?0.464). The plasma PK study demonstrated a significantly lower C_max (～10 times) and AUC_0–24?h (～13 times) of sildenafil in plasma following intravaginal (IVG) administration of suppositories compared to oral (PO) administration of sildenafil solution. Nevertheless, the organ BD study showed a phenomenally higher C_max (～40 times) and AUC_0–24?h (～20 times) of sildenafil in uterus following IVG administration of suppositories than PO administration of sildenafil solution.

Conclusion: This study demonstrated enhanced sildenafil exposure in the uterus following IVG administration of SVS, which could be used to target the uterus for therapeutic benefits.     

Iontophoresis for drug delivery into the nail apparatus: exploring hyponychium as the site of delivery

In present studies, a hyponychium pathway (from ventral side of the nail plate) was investigated as a potential route of drug delivery into the nail apparatus using iontophoresis as an active physical method. In vitro transport studies were performed across the human nail plate using sodium fluorescein as a marker substrate for 24?h. After transport studies, the amount of sodium fluorescein extracted from an active diffusion area of the nail plate in case of iontophoresis was found to be ～54-folds more to that of passive. The amount of sodium fluorescein retained in the peripheral area of the nail plate after application of iontophoresis was found to be ～30-folds more relative to passive. Ex vivo transport studies were performed on excised human cadaver toe using terbinafine hydrochloride as a model drug for three days (8?h/day). The amount of terbinafine retained in the nail plate after application of iontophoresis (3.43?±?1.34?µg/mg) was ～20-folds more when compared with passive (0.17?±?0.10?µg/mg). The amount of drug extracted from the nail bed and nail matrix was 1.73?±?0.12?µg/mg and 0.55?±?0.22?µg/mg, respectively. On the other hand, there was no detectable amount of terbinafine found in the nail bed and nail matrix in case of control (passive delivery). These studies show that the iontophoretic drug delivery through hyponychium region to other parts of the nail apparatus could be a potential way of onychomycosis treatment.     

Preparation,characterization and in vitro and in vivo evaluation of a solid dispersion of Naringin

Naringin (NA) is one of typical flavanone glycosides widely distributed in nature and possesses several biological activities including antioxidant, anti-inflammatory, and antiapoptotic. The aim of this study was to develop solid dispersion (SD) and to improve the dissolution rate and oral bioavailability of NA. NA–SD was prepared by the traditional preparation methods using PEG6000, F68, or PVP K30 as carrier at different drug to carrier ratios. According to the results of solubility and in vitro dissolution test, the NA–PEG6000 (1:3) SD was considered as an optimal formulation to characterize by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry and powder X-ray diffraction. Furthermore, oral bioavailabilities of NA–PEG6000 (1:3) SD and NA–suspension with the same dosage were investigated in SD rats. The results confirmed the formation of SD and the pharmacokinetic parameters of NA–PEG6000 (1:3) SD (C_max?=?0.645?±?0.262?µg/ml, AUC_0–t?=?0.471?±?0.084?µg/ml?h) were higher than that of NA–suspension (C_max?=?0.328?±?0.183?µg/ml, AUC_0–t =?0.361?±?0.093?µg/ml?h). Based on the results, the SD is considered as a promising approach to enhance the dissolution rate and oral bioavailability of NA.     

Two-layered dissolving microneedles for percutaneous delivery of sumatriptan in rats

A novel transdermal delivery of sumatriptan (ST) was attempted by application of dissolving microneedle (DM) technology. Dextran DM (d-DM) and hyaluronate DM (h-DM) were prepared by adding ST solution to dextran solution or hyaluronic acid solution. One DM chip, 1.0?×?1.0?cm, contains 100 microneedle arrays in a 10?×?10 matrix. The mean lengths of DMs were 496.6?±?2.9 μm for h-DM and 494.5?±?1.3 μm for d-DM. The diameters of the array basement were 295.9?±?3.9 μm (d-DM) and 291.7?±?3.0 μm (h-DM), where ST contents were 31.6?±?4.5?μg and 24.1?±?0.9?μg. These results suggest that ST was stable in h-DM. Each DM was administered to rat abdominal skin. The maximum plasma ST concentrations, C_max, and the areas under the plasma ST concentration versus time curves (AUC) were 44.6?±?4.9?ng/ml and 24.6?±?3.9?ng · h/ml for h-DM and 38.4?±?2.7?ng/ml and 14.1?±?1.5?ng · h/ml for d-DM. The bioavailabilities of ST from DMs were calculated as 100.7?±?18.8% for h-DM and 93.6?±?10.2% for d-DM. Good dose dependency was observed on C_max and AUC. The stability study of ST in DM was performed for 3 months under four different conditions, ?80, 4, 23, and 50°C. At the end of incubation period, they were, respectively, 100.0?±?0.3%, 97.8?±?0.2%, 98.8?±?0.2%, and 100.7?±?0.1%. These suggest the usefulness of DM as a noninvaisive transdermal delivery system of ST to migraine therapy.     

Process and formulation variables of pregabalin microspheres prepared by w/o/o double emulsion solvent diffusion method and their clinical application by animal modeling studies

Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. In conventional therapy recommended dose for pregabalin is 75?mg twice daily or 50?mg three times a day, with maximum dosage of 600?mg/d. To achieve maximum therapeutic effect with a low risk of adverse effects and to reduce often drug dosing, modified release preparations; such as microspheres might be helpful. However, most of the microencapsulation techniques have been used for lipophilic drugs, since hydrophilic drugs like pregabalin, showed low-loading efficiency and rapid dissolution of compounds into the aqueous continous phase. The purpose of this study was to improve loading efficiency of a water-soluble drug and modulate release profiles, and to test the efficiency of the prepared microspheres with the help of animal modeling studies. Pregabalin is a water soluble drug, and it was encapsulated within anionic acrylic resin (Eudragit S 100) microspheres by water in oil in oil (w/o/o) double emulsion solvent diffusion method. Dichloromethane and corn oil were chosen primary and secondary oil phases, respectively. The presence of internal water phase was necessary to form stable emulsion droplets and it accelerated the hardening of microspheres. Tween 80 and Span 80 were used as surfactants to stabilize the water and corn oil phases, respectively. The optimum concentration of Tween 80 was 0.25% (v/v) and Span 80 was 0.02% (v/v). The volume of the continous phase was affected the size of the microspheres. As the volume of the continous phase increased, the size of microspheres decreased. All microsphere formulations were evaluated with the help of in vitro characterization parameters. Microsphere formulations (P1–P5) exhibited entrapment efficiency ranged between 57.00?±?0.72 and 69.70?±?0.49%; yield ranged between 80.95?±?1.21 and 93.05?±?1.42%; and mean particle size were between 136.09?±?2.57 and 279.09?±?1.97?µm. Pregabalin microspheres having better results among all formulations (Table 3) were chosen for further studies such as differential scanning calorimetry, Fourier transform infrared analysis and dissolution studies. In the last step, the best pregabalin microsphere formulation (P3) was chosen for in vivo animal studies. The pregabalin-loaded microspheres (P3) and conventional pregabalin capsules were applied orally in rats for three days, resulted in clinical improvement of cold allodynia, an indicator of peripheral neuropathy. This result when evaluated together with the serum pregabalin levels and in vitro release studies suggests that the pregabalin microspheres prepared with w/o/o double emulsion solvent diffusion method can be an alternative form for neuropathic pain therapy. Conclusively, a drug delivery system successfully developed that showed modified release up to 10?h and could be potentially useful to overcome the frequent dosing problems associated with pregabalin conventional dosage form.     

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.     

Dual-purpose vardenafil hydrochloride/dapoxetine hydrochloride orodispersible tablets: in vitro formulation/evaluation,stability study and in vivo comparative pharmacokinetic study in healthy human subjects

Erectile dysfunction (ED) is the most important disorder after premature ejaculation for sexual activity in men. Vardenafil hydrochloride (VH) is an oral therapy for the treatment of erectile dysfunction. VH oral disintegrating tablets (ODTs) have been prepared by freeze drying technique to improve its dissolution profile and the overall clinical performance. Dapoxetine hydrochloride (DH) was added to the best three formulae of the prepared VH ODTs to treat premature ejaculation. All the ODTs formulae were evaluated for weight variation, friability, drug content, in vitro disintegration time, wetting time, and the dissolution study. Gelatin as a matrix former with N-methylpyrrolidone as a solubilizer in VH/DH ODTs improved the dissolution rate and extent of release of VH and DH with 100% of drug being dissolved after 15?min. In vivo study results from six healthy male volunteers showed shorter T_max of VH from VH/DH ODT of 0.583?±?0.129?h and shorter T_max of DH from VH/DH ODT of 0.625?±?0.137?h and showed AUC_0–12 of VH from VH/DH ODT of 39.234?±?10.932?ng/ml^?h¹ and AUC_0–12 of DH from VH/DH ODT of 531.681?±?129.544?ng/ml^?h¹, with relative bioavailability values of 100.9 and 85%, respectively, compared to (Levitra^®) and (Priligy^®).     

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization,in vitro and in vivo pharmacokinetic studies

Objectives: The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS).

Methods: Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3² factorial design was done using Polyox WSR 303 (X₁) and HPMC K₄M (X₂) as independent variables and cumulative percentage drug released at 6?h (Q6h) as dependent variable.

Results: Optimized formulation showed floating lag time of 4–5 s, floated for more than 12?h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6?h. In vivo pharmacokinetic studies in rabbits showed C_max of 189.96?±?13.04?ng/mL and T_max of 4?±?0.35?h for GFDDS. The difference for AUC_(0–T) and AUC_(0–∞) between the test and reference formulation was statistically significant (p > 0.05). AUC_(0–T) and AUC_(0–∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively.

Conclusion: GFDDS provided prolonged gastric residence and showed significant increase in bi oavailability of baclofen.     

Preparation, evaluation and bioavailability studies of indomethacin-bees wax microspheres

The present study envisages the preparation of microspheres containing indomethacin (IM) as model drug and bees wax as carrier, and to compare the in vitro release and pharmacokinetics of prepared IM formulation with commercially available oral formulation Microcid^®SR. The microsphere formulations were prepared by meltable emulsified dispersion and cooling induced solidification. Surface morphology of microspheres has been evaluated using scanning electron microscopy (SEM). The SEM images revealed the spherical shape of microspheres and more than 98.0% of the isolated microspheres were in the size range 115–855 μm. Differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy studies indicated that the drug after encapsulation with bees wax was stable and compatible. A single dose randomized complete cross over study of IM (75 mg) microspheres was carried out on 8 healthy Albino sheeps. Plasma IM concentrations and other pharmacokinetic parameters obtained were statistically analyzed. The T _max, C _max, AUC_O-24 and T _1/2 values of Microcid^®SR and optimized formulation were 3.0 h, 2038 ± 51.31 ng/ml, 9528 ± 129.65 ng/ml h^?1, and 2.59 ± 0.02 h^?1; and 3.2 h, 1940 ± 22.61 ng/ml, 8751 ± 41.32 ng/ml h^?1, and 2.68 ± 0.02 h^?1, respectively. Beeswax microspheres showed controlled release and it can be concluded that both the prepared formulation and Microcid^®SR are bioequivalent.     

Dual effect biodegradable ciprofloxacin loaded implantable matrices for osteomyelitis: controlled release and osteointegration

Ciprofloxacin biodegradable implantable matrices (CPX-IMs) of tailored porous surfaces were fabricated by hot melt injection molding of poly-l-lactic acid (PLLA) followed by coating with PLLA/sodium chloride. CPX-IDs were designed to have a non-porous coat (NPC) or a porous coat of small pore size (SPC; 150–250?µm) or a large pore size (LPC; 250–350?µm). CPX-IMs surface pore size was confirmed by scanning electron microscope. The hardness of NPC, LPC, and SPC CPX-IMs were 58?±?2.8, 53?±?1.9, and 50?±?2.1?N, respectively. The measured porosity values were 41.2?±?1.53, 65.2?±?1.1, and 60.7?±?1.2%, respectively. Differential scanning calorimetry was employed to study the compatibility of ingredients, the effect of injection molding on polymer properties, and implants degradation. Coating of CPX-IMs prolonged drug release to reach a value of 90% release in 40?days. Antibacterial activity tests showed sufficiency of CPX to inhibit pathogens known to cause osteomyelitis. The in vivo study showed tissue compatibilities of the inserted matrices in tested rats with no sign of infection throughout the experiment period. SPC and LPC CPX-IMs demonstrated a better osteointegration, cell adhesion, and infiltration of different types of bone cells within implants structure compared to the non-porous matrix. Furthermore, LPC CPX-IMs showed a superior bone cell attachment and osteointegration relative to SPC CPX-IMs. Findings of this study confirmed the impact of porosity and pore sizes on cell proliferation and fracture healing concurrently with the sustained local antibiotic therapy for treatment or prevention of osteomyelitis.     

In vitro and in vivo evaluation of folate-mediated PEGylated nanostructured lipid carriers for the efficient delivery of furanodiene

Furanodiene (FN) loaded FA-PEG₂₀₀₀-DSPE modified nanostructured lipid carriers (FA-FN-NLCs) were developed to increase the solubility and bioavailability of FN, prolong the circulation time in blood and improve the targeting ability. FA-FN-NLCs were prepared using emulsification-ultrasonic and low temperature-solidification method and optimized by central composition design (CCD). In vitro and in vivo characteristics of FA-FN-NLCs were investigated in detail. The optimized formulations exhibited a spherical shape with particle size of 127.4?±?2.62?nm, PDI of 0.268?±?0.04, zeta potential of –14.7?±?1.08?mV, high encapsulation efficiency of 89.04?±?2.26% and loading capacity of 8.46?±?0.20%. Differential scanning calorimetry (DSC) indicated that FN was not in crystalline state in FA-FN-NLCs. In vitro drug release exhibited a biphasic release pattern which showed a relative burst drug release at the initial time and followed by a prolonged drug release. In vivo, compared with FN solution (FN-SOL) and FN loaded traditional NLCs (FN-NLCs), FA-FN-NLCs had a longer blood circulating time (t_1/2) and higher area under the curve (AUC). NiR fluorescence imaging study demonstrated that FA-FN-NLCs specially accumulated in tumor site by the receptor-mediated endocytosis. This study showed that FA-FN-NLCs was a promising drug delivery system for FN in the treatment of cancer.     

Dual cross-linked chitosan microspheres formulated with spray-drying technique for the sustained release of levofloxacin

Objective: This study was aimed to develop sustained drug release from levofloxacin (LF)-loaded chitosan (CS) microspheres for treating ophthalmic infections.

Significance: Dual cross-linked CS microspheres developed by the spray-drying technique displays significantly higher level of sustained drug release compared with non-cross-linked CS microspheres.

Methods: LF-loaded CS microspheres were prepared using the spray-drying technique, and then solidified with tripolyphosphate and glutaraldehyde as dual cross-linking agents. The microspheres were characterized by surface morphology, size distribution, zeta potential, encapsulation efficiency, and drug release profiles in vitro. The drug quantification was verified and analyzed by high-performance liquid chromatography (HPLC). The structural interactions of the CS with LF were studied with Fourier transform infrared spectroscopy. The effect of various influencing excipients in the formulation of the dual cross-linked CS microspheres on drug encapsulation efficiency and the drug release profiles were extensively investigated.

Result: The microspheres demonstrated high encapsulation efficiency (72.4?～?98.55%) and were uniformly spherical with wrinkled surface. The mean particle size was between 1020.7?±?101.9 and 2381.2?±?101.6?nm. All microspheres were positively charged (zeta potential ranged from 31.1?±?1.32 to 42.81?±?1.55?mV). The in vitro release profiles showed a sustained release of the drug and it was remarkably influenced by the cross-linking process.

Conclusion: This novel spray-drying technique we have developed is suitable for manufacturing LF-loaded CS microspheres, and thus could serve as a potential platform for sustained drug release for effective therapeutic application in ocular infections.     

Thiolation of arabinoxylan and its application in the fabrication of pH-sensitive thiolated arabinoxylan grafted acrylic acid copolymer

Current research work was conducted to synthesize Thiol modified arabinoxylan and its application in fabrication of hydrogel. Thioglycolic acid was esterified with arabinoxylan to prepare Thiolatedarabinoxylan. Appearance of peak at 2533.34?cm^?1 in FTIR and thiol content showed successful thiolation. The pH-dependent Thiolatedarabinoxylan/acrylic acid (TAX/AA) hydrogels of perindopril erbumine were prepared via free-radical co-polymerization. Perindopril erbumine (PE) was employed as model drug. Different batches with different feed ratio of TAX, AA, and MBA were prepared and their influence on swelling, solvent penetration, and consequent drug release was investigated. Swelling coefficients increased with increase in pH. TAX/AA hydrogels were characterized by Fourier-transform infrared spectroscopy (FT-IR), Thermal Analysis (TA), X-Ray diffraction (XRD), and scanning electron microscope (SEM). Dissolution studies were performed at pH 1.2 and 7.4 in which drug release showed direct correlation with TAX and AA ratio. In vivo studies showed that C_max of TAX-co-AA based hydrogel was 81.57?±?0.35?ng/ml which was maintained for a longer time after its administration. All the results of in vivo studies were significant and TAX-co-AA based hydrogel enhances the bioavailability of perindopril erbumine.     

Study of a novel disintegrable oleanolic acid-polyvinylpolypyrrolidone solid dispersion

Novel solid dispersions of oleanolic acid-polyvinylpolypyrrolidone (OLA-PVPP SDs) were designed and prepared to improve the apparent solubility of drug, as well as to improve the stability, fluidity and compressibility of SDs. Disintegrable OLA-PVPP SDs were then evaluated both in vitro and in vivo. DSC, XRD, IR and SEM analysis proved the formation of OLA-PVPP SD and its amorphous state. The results of fluidity study, moisture absorption test and stability test showed that OLA-PVPP SD with good fluidity and qualified stability was successfully obtained. Meanwhile excellent dissolution rate was achieved for in vitro studies; dissolution test showed that ～50–75% of OLA was dissolved from SDs within the first 10?min, which is about 10–15 times of free OLA. In vivo study indicated that the formation of solid dispersion could largely improve the absorption of OLA, resulting in a much shorter T_max (p?C_max (p?0→∞ of OLA-PVPP SDs (1:6) were 155.4?±?37.24?h·ng/mL compared to the 103.11?±?26.69?h·ng/mL and 94.92?±?13.05?h·ng/mL of OLA-PVPP physical mixture (1:6) and free OLA, respectively. These proved PVPP could be a promising carrier of solid dispersions and was industrially feasible alternative carrier in the manufacture of solid dispersions.     

Microspheres for the oral delivery of insulin: preparation,evaluation and hypoglycaemic effect in streptozotocin-induced diabetic rats

Insulin-loaded microspheres were prepared by alternating deposition film layers that were composed of insulin and poly(vinyl sulfate) potassium on the surface of poly(lactic acid) (PLA) microspheres. The preparation of the insulin-loaded microspheres was optimized by an orthogonal test design, and the relationship between drug loading (DL) and film layers was studied. The particle size, DL and encapsulation efficiency of the obtained insulin-loaded microspheres with 10 films were 5.25?±?0.15?µm, 111.33?±?1.15?mg/g and 33.7?±?0.19%, respectively. Following this, the physical characteristics of the insulin-loaded microspheres were investigated. The results from scanning electron microscopy and a laser particle size analyzer (LPSA) indicated the spherical morphology, rough surface and increasing particle sizes of the insulin-loaded microspheres, which were compared to those of PLA microspheres. An in vitro release study showed that the insulin-loaded microspheres were stable in HCl solution (pH 1.0) and released insulin slowly in phosphate-buffered solution (pH 6.8). Finally, the drug efficacy of the prepared insulin-loaded microspheres via oral administration was evaluated in rats with diabetes induced by streptozotocin, and an obvious dose-dependent hypoglycemic effect was observed. This preliminary data could illustrate the prospect of using microspheres for the oral delivery of insulin.     

Pharmacodynamic and pharmacokinetic investigation of cyclodextrin-mediated asenapine maleate in situ nasal gel for improved bioavailability

Asenapine maleate (AM) is used in the treatment of schizophrenia. Its oral and sublingual bioavailability is <2% and 35%, respectively, due to first pass metabolism and poor solubility. To avoid first pass metabolism and to enhance solubility at all nasal pH conditions, thermo-responsive in situ nasal gel containing asenapine maleate-hydroxyl propyl β cyclodextrin inclusion complex (AM-HPβCD) was prepared in the present study. Inclusion complex (1:1 molar ratio) was characterized using UV spectroscopy, FITR and XRD techniques. Selected formulation (F8b) contained a thermo-sensitive polymer poloxamer 407 which formed gel at 23%w/v concentration and a mucoadhesive polymer PVP K 30 (0.3%w/v) in temperature range of 29–34?°c. It was analyzed for pH, clarity, gelation temperature, mucoadhesive strength, gel strength and rheological parameters using Anton paar compact rheometer. This formulation was subjected to in vitro drug diffusion study using the Franz diffusion cell. Maximum % drug diffusion was obtained at the end of 120?min (99.1?±?0.44%w/v). Dissolution in simulated nasal fluid was 92.33?±?0.15%w/v at the end of 120?min. Locomotor activity was improved with nasal gel containing AM-HPβCD as compared to AM and AM-HPβCD oral solution in rats. C_max for nasal gel was found to be more (9?ng/ml) as compared to AM-HPβCD (5.5?ng/mL) and oral standard solution (2?ng/ml). T_max was found to be 1.5?h. AUC and thus bioavailability in rats by nasal route was increased by 2.5 fold.