COMPARISON OF NASAL INSULIN POWDERS PREPARED BY SUPERCRITICAL FLUID AND FREEZE-DRYING TECHNIQUES

In this study, the effect of drug loading on the nasal absorption of insulin was determined. Human insulin was loaded into different drug carriers by two methods: supercritical fluid processing and freeze-drying. The powder formulations were characterized and then evaluated after nasal administration to alloxan induced diabetic rabbits at a dose of 5U/kg and 7.5U/kg. The blood glucose levels and serum insulin levels were monitored for five hours after administration of insulin formulations. The drug carriers evaluated were: ammonium glycyrrhizinate (AG), polyacrylic acid (PAA), cross-linked polyacrylic acid (CPAA), polyethylene oxide (PEO) and chitosan (CHTN).

Nasal administration of AG infused with insulin by carbon dioxide resulted in absolute bioavailability of 9.81% as compared to 2.86% observed with same powder loaded with insulin by freeze-drying. 8.05% bioavailability was obtained with PAA powder loaded with insulin by carbon dioxide as compared to much lower absorption seen with freeze-dried formulation. Similarly a two fold increase in absolute bioavailability was observed when carbon dioxide infused CPAA powder formulation was compared to the lyophilized powder. Nasal administration of PEO and CHTN loaded with insulin by carbon dioxide resulted in bioavailabilities of 1.55% and 1. 18% respectively.

The drug-loading process seems to have a significant effect on nasal absorption of insulin. The powders loaded with insulin by carbon dioxide infusion resulted in significantly higher absorption. The exact mechanism is still not known and a possible explanation for increased absorption may be due to improved stability of insulin in carbon dioxide infused formulations. Among the powders evaluated, polyacrylic acid and ammonium glycyrrhizinate prepared by carbon dioxide infusion as drug-loading method seem to offer good potential for development of nasal powder dosage forms for insulin.     

Nasal absorption of sulfobromophthalein and amaranth

Abstract

Nasal absorption of sulfobromophthalein (BSP) and amaranth (AM) was investigated and compared with oral absorption in the rat. Bioavailability of BSP and AM after nasal administration was about 26% and 30% respectively. Oral absorption of them was not detected. Nasal route was considered more effective than oral route for these anionic model drugs, but their nasal bioavailability was not so good as expected from the reports for other drugs. High nasal mucus binding of BSP and AM were implied by their high binding to plasma protein (97% and 94%) or to intestinal mucus (78% and 81%). They seemed to have very low lipophilicity since their apparent partition coefficient(APC) between phosphate buffer of various pH and n-octanol were almost zero. They have too large molecular size to pass through the pore (<0.4nm) of nasal mucus membrane. Therefore it was concluded that the low nasal bioavailability of these anionic model drugs might be due to either nonspecific binding to nasal mucus, or low lipophilicity to pass the nasal mucus membrane, or their large molecular size to pass through the pore route of the nasal mucus. Possibility of nasal metabolism in the mucus membrane was excluded since the reported enzymes in the nasal mucus may not affect the metabolism of them.     

Formulation and evaluation of insulin dry powder for inhalation

PURPOSE: Dry powder formulation of insulin for pulmonary administration was prepared to obtain increased drug deposition in the alveolar absorptive region. The deposition was studied by investigating the dispersion and deaggregation of insulin from the carrier lactose using an Andersen cascade impactor and twin stage impinger. The subsequent absorption following the deposition was studied by in vivo method. METHODS: Insulin in solution with absorption promoters was lyophilized. The powder was incorporated with lactose of different grades and their combinations as carriers to deliver using an inhaler device. Solid-state characteristics of the carrier as well as the drug powder were assessed by particle size and distribution measurement. The flow properties such as moisture content, powder density, angle of repose, and carr's compressibility index of the powder mixture were determined. The aerosol behavior of the powder was studied by dispersion using rotahaler(c) connected to a twin-stage impinger (TSI) and an eight-stage Andersen cascade impactor (ACI) operating at different flow rates of 30-90 l/min. The in vivo performance was studied by deliverance to the respiratory tract of guinea pigs. The intratracheal bioavailability with respective to intravenous route was calculated by measuring the blood glucose reduction. RESULTS: The coarser particles of lactose in fractions of carrier containing a wide particle size distribution impacted in the preseperator of cascade impactor, and only the particle less than 10 microm size entered stage 0-stage 7. Formulation containing 1:1 mixture of Respitose ML006 (62%<50 microm) and Respitose ML003 (37.8%<50 microm) as carrier imparts well deaggregation of insulin, and higher deposition leads to 52.3% of fine particle fraction at 60 Lit/min and in vivo bioavailability of 82%. CONCLUSIONS: Insulin formulations containing 1:1 mixture of Respitose ML006 and Respitose ML003 as carrier can impart deeper deposition of drug particles and cause higher bioavailability. This suggests that carrier used in the formulation influenced the amount of insulin deposition in the alveolar region of the lung. Hence, it was concluded that the availability of insulin for systemic absorption depends on the particle size of the drug as well as the carrier lactose.     

Formulation and Evaluation of Insulin Dry Powder for Inhalation

Abstract

Purpose. Dry powder formulation of insulin for pulmonary administration was prepared to obtain increased drug deposition in the alveolar absorptive region. The deposition was studied by investigating the dispersion and deaggregation of insulin from the carrier lactose using an Andersen cascade impactor and twin stage impinger. The subsequent absorption following the deposition was studied by in vivo method. Methods. Insulin in solution with absorption promoters was lyophilized. The powder was incorporated with lactose of different grades and their combinations as carriers to deliver using an inhaler device. Solid-state characteristics of the carrier as well as the drug powder were assessed by particle size and distribution measurement. The flow properties such as moisture content, powder density, angle of repose, and carr's compressibility index of the powder mixture were determined. The aerosol behavior of the powder was studied by dispersion using rotahaler^© connected to a twin-stage impinger (TSI) and an eight-stage Andersen cascade impactor (ACI) operating at different flow rates of 30–90 l/min. The in vivo performance was studied by deliverance to the respiratory tract of guinea pigs. The intratracheal bioavailability with respective to intravenous route was calculated by measuring the blood glucose reduction. Results. The coarser particles of lactose in fractions of carrier containing a wide particle size distribution impacted in the preseperator of cascade impactor, and only the particle less than 10 µm size entered stage 0–stage 7. Formulation containing 1:1 mixture of Respitose ML006 (62%<50 µm) and Respitose ML003 (37.8%<50 µm) as carrier imparts well deaggregation of insulin, and higher deposition leads to 52.3% of fine particle fraction at 60 Lit/min and in vivo bioavailability of 82%. Conclusions. Insulin formulations containing 1:1 mixture of Respitose ML006 and Respitose ML003 as carrier can impart deeper deposition of drug particles and cause higher bioavailability. This suggests that carrier used in the formulation influenced the amount of insulin deposition in the alveolar region of the lung. Hence, it was concluded that the availability of insulin for systemic absorption depends on the particle size of the drug as well as the carrier lactose.     

Transport characteristics of wheat germ agglutinin-modified insulin-liposomes and solid lipid nanoparticles in a perfused rat intestinal model

Wheat germ agglutinin (WGA) modified liposomes and solid lipid nanoparticles (SLNs) were evaluated for improving intestinal absorption of insulin. In an in situ local intestinal perfusion experiment, formulations containing 100 IU/kg insulin were administered to the duodenum, jejunum, and ileum of fasted rats. As hypothesized, ileum was the best intestinal location for the absorption of insulin-containing liposomes. Serum insulin concentrations decreased for the various formulations in different absorption sites according to the following trends: Duodenum > ileum > jejunum for WGA-modified insulin-containing liposomes; duodenum > jejunum > ileum for WGA-modified insulin-containing SLNs; ileum > jejunum > duodenum for insulin-containing liposomes; ileum > duodenum > jejunum for insulin-containing SLNs; and duodenum > or = ileum > jejunum for aqueous solution of insulin. These results imply that the nanoparticle type and delivery site were important factors with respect to increasing the bioavailability of insulin following oral administration. The proteolytic degradation as well as the epithelial permeability were primary determinants influcing insulin mucosal absorption.     

Preparation and evaluation of carfentanil nasal spray employing cyclodextrin inclusion technology

Carfentanil (CFTN), a derivative of fentanyl, is highly effective as an analgesic, but its relatively poor solubility in water has limited its nasal application. The objective of this study was to develop the new CFTN-CD inclusion technology to increase the solubility of CFTN. The inclusion compound CFTN–DM-β-CD was prepared by the ultrasonic method and characterized using X-ray powder diffraction and morphological shapes analysis (the scanning electron microscopy). The in vitro dissolution profiles of CFTN–DM-β-CD were assessed in hydrochloric acid and phosphate buffer. Nasal ciliotoxicity studies were carried out using isolated toad palate. Rats were treated with CFTN–DM-β-CD (250?µg/kg) by intravenous, intramuscular injection, oral, or nasal drops. The results showed that CFTN was successfully enveloped by DM-β-CD. The in vitro cumulative dissolution of CFTN–DM-β-CD was obviously enhanced compared to free CFTN in two buffers. Nasal ciliotoxicity studies have shown that the CFTN–DM-β-CD does not exhibit higher nasal ciliotoxicity than that of free CFTN. Pharmacokinetic studies demonstrated that CFTN–DM-β-CD by nasal administration was absorbed more rapidly and has higher C_max and bioavailability than that of either intramuscular injection or oral administration. In conclusion, the CFTN–DM-β-CD nasal spray was shown to be a relatively safe dosage form for the rapid and effective intranasal delivery of CFTN.     

Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery

Objective: The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus^® (BASF, Germany) using a freeze-drying technique, in order to improve dissolution and absorption through the nasal route.

Significance: The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray.

Methods: The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus–BUD formulation.

Results: The freeze-dried Soluplus–BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334?±?0.0178 m²/g. The calorimetric analysis confirmed an interaction between BUD and Soluplus and X-ray powder diffraction the amorphous status of the drug. The freeze-dried formulation (LYO) showed faster release compared to both water-based suspension and dry powder commercial products. Furthermore, a LYO formulation, bulked with calcium carbonate (LYO-Ca), showed suitable aerodynamic characteristics for nasal drug delivery. The permeation across RPMI 2650 nasal cell model was higher compared to a commercial water-based BUD suspension.

Conclusions: Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.     

Absorption removal of carbon dioxide in the presence of inert solid particles (flour powder)

Abstract

An experimental analysis of the absorption removal of carbon dioxide with the presence of inert solid particles on the surface of the absorbent liquid is presented. A batch absorber with quiescent absorbent liquid has been applied to study the absorption removal of carbon dioxide by water in the isothermal system. The flour powder is introduced as the inert solid particles in the carbon dioxide absorption system. Tests with the flour powder in water are examined. The mass fluxes of carbon dioxide for the cases with and without the flour powder are then compared to elucidate the effects of inert solid particles on isothermal gas absorption. The results indicate a significant difference between these two cases for the concentrations of the flour powder in the absorbent liquid (WF) being in the range of experimental conditions, namely 0.001 to 0.03 g flour in 10 ml liquid. In general, the inert solid particles of the flour powder as the impurities in water with WF in the range of this study tend to decrease the carbon dioxide absorption rates for the experimental absorption system under investigation. Thus, various concentrations of inert solid particles cause various levels of surface resistance and affect the gas absorption rates. This kind of information is very useful for the gaseous pollutants removal that the impurities of inert solid particles contaminate the isothermal gas absorption system, and for the absorption removal of carbon dioxide associated with the control of the green house effect.     

Novel instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of dapoxetine hydrochloride: in-vitro optimization,ex-vivo permeation studies,and in-vivo evaluation

Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive metabolism in the liver. The aim of this study was to enhance the bioavailability of D via preparing instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of D. IDNPs were prepared using the thin film hydration technique, followed by freeze-drying to obtain easily reconstituted powder providing rapid and ready method of administration. The produced nanocarrier systems were evaluated for drug content, entrapment efficiency percentage, particle size, polydispersity index, zeta potential, and drug payload. The optimized nanocarrier system was morphologically evaluated via transmission electron microscopy and the optimized freeze-dried IDNPs were evaluated for ex-vivo permeation and in-vivo pharmacokinetic studies in rabbits following intranasal and oral administration. The relative bioavailability of D after intranasal administration of freeze-dried IDNPs was about 235.41% compared to its corresponding oral nanocarrier formulation. The enhanced D permeation and improved bioavailability suggest that IDNPs could be a promising model for intranasal delivery of drugs suffering from hepatic first pass effect.     

Administration Route Dependent Bioavailability of Interferon-α and Effect of Bile Salts on the Nasal Absorption

Abstract

Administration route dependent bioavailability of recombinant human interferon alpha (IFN-α) and effect of seven bile salts and polyoxyethylene-9-lauryl ether (BL-9) on nasal absorption of IFN-a were studied in rats. IFN-a (1.5 × 10 ⁷ IU/kg) was administered through iv, pv, po and ip routes and AUC of the routes were compared. As a result, it was found that IFN-α is extracted almost completely during its passage through the GI lumen, and is not absorbed from the GI lumen. Moreover, IFN-α sparingly transported through the GI lumen suffers additional extraction by the GI mucosa (57%) and the liver (8%) consecutively and only about 40% of it can reach the systemic circulation. Therefore, a high bioavailability of IFN-a cannot be expected through the oral route even with the aid of absorption enhancers. On the other hand, significant absorption of IFN-α could be attained through the nasal route with some absorption enhancers (1% w/v). Among the enhancers examined, sodium cholate (CH), sodium glycocholate (GC), sodium taurocholate (TC), sodium glycodeoxycholate (GDC), sodium taurodeoxycholate (TDC) and BL-9 increased the nasal bioavailability of IFN-a. However, sodium dehydrocholate (DHC) and sodium deoxycholate (DOC) did not show such effect. Nasal bioavailability of IFN-a was increased up to 32.3 (± 15.5)% by 1% TC. The enhancing effect of TC was significantly (p<0.05) greater than those of CH, DOC, DHC and BL-9. TC and GC seemed to be potential candidates for the nasal absorption enhancers of IFN-α, considering that they are reportedly less toxic than GDC and TDC.     

Preparation of azithromycin nanosuspensions by high pressure homogenization and its physicochemical characteristics studies

The azalide azithromycin was proved to be clinically effective against Gram-positive and Gram-negative bacteria. But the low bioavailability caused by its poor solubility and gastrointestinal response limited its application in clinic. With the purpose of increasing its saturation solubility and dissolution velocity, azithromycin was produced as nanosuspensions by high pressure homogenization. Nanosuspensions could increase the drug-loading and reduce the administration dosage, thus the gastrointestinal response could be minimized. In order to enhance the stability of the nanosuspensions, we got the freeze-dried powder by lyophilization. After dispersed in distilled water, the nanoparticles had a bulk population of about 400 nm and a spherical figure (watched by transmission electron microscopy). The analysis of differential scanning calorimetry and powder X-ray diffraction demonstrated that the crystal state of azithromycin had changed. In vitro release studies showed that the dissolution rate of nanosuspension, compared with micronized powder, had been obviously increased.     

二氧化碳致裂器激发药剂爆炸性分类的研究

作为一种非炸药类爆破工具,二氧化碳致裂器在生产、运输和使用过程中的安全性一直是爆破行业和公安管理部门关注的焦点。以二氧化碳致裂器中发热管装的药剂为研究对象,通过隔板试验、克南试验和时间/压力试验等对含高氯酸钾、草酸铵、水杨酸配方的发热管药剂性质开展研究。研究结果表明:按照联合国关于危险货物分级程序,该种常见的二氧化碳致裂器发热管药剂可以定性为爆炸性物质;但该药剂足够钝感,可不划为爆炸品。     

Enhanced oral bioavailability of piroxicam in rats by hyaluronate microspheres

To enhance the dissolution and oral bioavailability of poorly water soluble piroxicam, the piroxicam-loaded hyaluronic microspheres were prepared with various ratios of piroxicam, sodium hyaluronate and polyethylene glycol 4000 (PEG) using a spray dryer, and their physicochemical properties such as shape, size, drug-loading efficiency and dissolution were investigated. The pharmacokinetic study of piroxicam-loaded hyaluronic micropheres in rats was then performed compared to piroxicam powder. The piroxicam-loaded hyaluronic microspheres, spherical in shape, had the geometric mean diameters of about 1.5 μm and drug loading efficiency of about 90%, irrespective of ratio of piroxicam/sodium hyaluronate/PEG. The hyaluronic microspheres containing PEG gave significantly higher dissolution rates of drug than did piroxicam powder, PEG-based solid dispersion system and hyaluronic microspheres without PEG, suggesting that the hyaluronic microsphere with sodium hyaluronate and PEG was more useful for improving the dissolution rate of poorly water soluble piroxicam. The piroxicam-loaded hyaluronic microcapsule composed of (piroxicam/sodium hyaluronate/PEG; 2: 20: 1) gave about threefold improved dissolution of drug in water for 4 h compared to piroxicam powder. It showed higher plasma concentrations of drug compared to piroxicam powder. It gave significantly higher AUC and faster T_max of piroxicam than did piroxicam powder. In particular, the AUC of piroxicam from hyaluronic microsphere was about twofold higher than that from piroxicam powder, suggesting that it could enhance the oral bioavailability of piroxicam. Thus, the hyaluronic microsphere developed using spray-drying technique with sodium hyaluronate and PEG was a more effective oral dosage form for poorly water soluble piroxicam.     

Brain-targeted intranasal zaleplon solid dispersion in hydrophilic carrier system; 23 full-factorial design and in vivo determination of GABA neurotransmitter

Intranasal zaleplon solid dispersion was formulated to enhance the solubility, bioavailability and deliver an effective therapy. Zaleplon belongs to Class II drugs, and undergoes extensive first-pass metabolism after oral absorption exhibiting 30% bioavailability. A 2³ full-factorial design was chosen for the investigation of solid dispersion formulations. The effects of different variables include drug to carrier ratio (1:1 and 1:2), carrier type (polyethylene glycol 4000 and poloxamer 407), and preparation method (solvent evaporation and freeze drying) on different dissolution parameters were studied. The dependent variables determined from the in vitro characterization and their constraints were set as follows: minimum mean dissolution time, maximum dissolution efficiency and maximum percentage release. Numerical optimization was performed according to the constraints set based on the utilization of desirability functions. Differential scanning calorimetry, infrared spectroscopy, X-ray diffraction and scanning electron microscopy were performed. Ex vivo estimation of nasal cytotoxicity and assessment of the γ-aminobutyric acid level in plasma and brain 1?h after nasal SD administration in rabbits compared to the oral market product were conducted. The selected ZP-SD, with a desirability 0.9, composed of poloxamer 407 at drug to carrier ratio 1:2 successfully enhanced the bioavailability showing 44% increase in GABA concentration than the marketed tablets.     

Development of thiolated poly(acrylic acid) microparticles for the nasal administration of exenatide

The purpose of this study was to develop a microparticulate formulation for nasal delivery of exenatide utilizing a thiolated polymer. Poly(acrylic acid)-cysteine (PAA-cys) and unmodified PAA microparticles loaded with exenatide were prepared via coprecipitation of the drug and the polymer followed by micronization. Particle size, drug load and release of incorporated exenatide were evaluated. Permeation enhancing properties of the formulations were investigated on excised porcine respiratory mucosa. The viability of the mucosa was investigated by histological studies. Furthermore, ciliary beat frequency (CBF) studies were performed. Microparticles displayed a mean size of 70–80?µm. Drug encapsulation was ～80% for both thiolated and non-thiolated microparticles. Exenatide was released from both thiolated and non-thiolated particles in comparison to exenatide in buffer only within 40?min. As compared to exenatide dissolved in buffer only, non-thiolated and thiolated microparticles resulted in a 2.6- and 4.7-fold uptake, respectively. Histological studies performed before and after permeation studies showed that the mucosa is not damaged during permeation studies. CBF studies showed that the formulations were cilio-friendly. Based on these results, poly(acrylic acid)-cysteine-based microparticles seem to be a promising approach starting point for the nasal delivery of exenatide.     

Effect of bioadhesive polymers,sodium salicylate,polyoxyethylene-9-lauryl ether,and method of preparation on the relative hypoglycemia produced by insulin enteric-coated capsules in diabetic beagle dogs

The hypoglycemic effect of oral insulin capsules coated with pH-dependent Eudragit® S100 and containing various absorption promoters was studied in hyperglycemic beagle dogs. The absorption enhancers used were bioadhesive polymers, sodium salicylate, and non-ionic surfactants. A comparative study of the bioadhesive polymers, polycarbophil (PC), hydroxypropyl methylcellulose (HPMC), and carbopol 934 in insulin-coated capsules revealed no significant difference between the insulin capsules containing these polymers, giving relative hypoglycemia (RH) values ranging from 4.3±2.3% to 6.5±5.1%. It was also found that the method of preparation of the mixture of the bioadhesive polymer with insulin either by physical mixing or freeze-drying did not affect the RH values obtained. Sodium salicylate, when used in insulin enteric-coated capsules (50 mg) mixed with insulin as a physical mixture, or prepared by wet granulation using 10% polyvinyl pyrollidone (PVP), or by freeze-drying, produced RH values ranging from 7.3±2.9% to 9.4±3.7%. When sodium salicylate (100 mg) was used with insulin in freeze-dried granules an RH value of 10±2.6% was produced. As the dose of insulin increased from 6 to 9 U/kg, the area under curve (AUC) of the enteric-coated capsules containing 50 mg sodium salicylate increased from 73.2±27.8% to 121.4±102.7% reduction, but the RH did not change significantly. Insulin capsules containing polyoxyethylene-9-lauryl ether (POELE) used in its optimum concentration (2%), found in these experiments, produced RH of 9.5±6.8% when prepared as granules by wetting with a few drops of absolute alcohol in the presence of PC (50 mg). Insulin capsules containing lower (1%) or higher (3%) concentrations of POELE and prepared with PC, 50 mg by wet granulation produced lower RH of about 6%. The enteric-coated oral insulin capsules containing insulin (6 or 9 U/kg) and sodium salicylate (50 mg) as an absorption promoter, together with the bioadhesive polymer polycarbophil (50 mg), and prepared either by wet granulation using ethanol or by freeze-drying, are the best formulations to be used. They achieved a reduction in plasma glucose levels of about 25-30% and RH of about 10%. Also insulin (9 U/kg) capsules containing 2% POELE produced a 28% reduction in plasma glucose levels and RH of 9.6±6.8%.     

Enhanced Oral Bioavailability of Piroxicam in Rats by Hyaluronate Microspheres

ABSTRACT

To enhance the dissolution and oral bioavailability of poorly water soluble piroxicam, the piroxicam-loaded hyaluronic microspheres were prepared with various ratios of piroxicam, sodium hyaluronate and polyethylene glycol 4000 (PEG) using a spray dryer, and their physicochemical properties such as shape, size, drug-loading efficiency and dissolution were investigated. The pharmacokinetic study of piroxicam-loaded hyaluronic micropheres in rats was then performed compared to piroxicam powder. The piroxicam-loaded hyaluronic microspheres, spherical in shape, had the geometric mean diameters of about 1.5 μm and drug loading efficiency of about 90%, irrespective of ratio of piroxicam/sodium hyaluronate/PEG. The hyaluronic microspheres containing PEG gave significantly higher dissolution rates of drug than did piroxicam powder, PEG-based solid dispersion system and hyaluronic microspheres without PEG, suggesting that the hyaluronic microsphere with sodium hyaluronate and PEG was more useful for improving the dissolution rate of poorly water soluble piroxicam. The piroxicam-loaded hyaluronic microcapsule composed of (piroxicam/sodium hyaluronate/PEG; 2: 20: 1) gave about threefold improved dissolution of drug in water for 4 h compared to piroxicam powder. It showed higher plasma concentrations of drug compared to piroxicam powder. It gave significantly higher AUC and faster T_max of piroxicam than did piroxicam powder. In particular, the AUC of piroxicam from hyaluronic microsphere was about twofold higher than that from piroxicam powder, suggesting that it could enhance the oral bioavailability of piroxicam. Thus, the hyaluronic microsphere developed using spray-drying technique with sodium hyaluronate and PEG was a more effective oral dosage form for poorly water soluble piroxicam.     

Thermoreversible mucoadhesive in situ nasal gel for treatment of Parkinson’s disease

Abstract

Parkinson’s disease is a degenerative disorder of the central nervous system (CNS). The most obvious symptoms are movement-related such as shaking, rigidity, slowness of movement and difficulty with walking, rigid muscular movements and difficulty in chewing and swallowing especially solid dosage forms. Ropinirole is an anti-Parkinson drug that has low oral bioavailability which is primarily due to first-pass metabolism. The objective of proposed work was to increase bioavailability of ropinirole and avoid patient discomfort by formulating thermoreversible in situ nasal gel. Thermoreversible nasal gels were prepared by cold method using Pluronic F-127 and hydroxy methyl propyl cellulose (HPMC K4M) as gelling agents. Formulations were evaluated for various parameters such as drug content, pH, gelling time, gelling temperature, gel strength, mucoadhesive force, ex vivo diffusion, histological studies and in vivo bioavailability. Formulations displayed gelation at nasal temperature and the gelation time was found to be less than mucociliary clearance time. The nasal residence time was seen to be increased due to mucoadhesion and increased gel strength. The nasal gel formulations showed ex vivo drug release between 56–100% in 5?h. Histological study of sheep nasal mucosa revealed that the gel had a protective effect on the mucosa unlike plain ropinirole which showed evidence of moderate cellular damage. A fivefold increase in bioavailability in brain was observed on nasal administration as compared to IV route. Thermoreversible in situ nasal gel was found to a promising drug delivery for Parkinsonian patients.     

Tailor-made pH-sensitive polyacrylic acid functionalized mesoporous silica nanoparticles for efficient and controlled delivery of anti-cancer drug Etoposide

A multifaceted therapeutic platform has been proposed for controlled delivery of Etoposide (ETS) leading to a synergistic advantage of maximum therapeutic efficacy and diminished toxicity. A state of the art pH responsive nanoparticles (NPs) MSNs-PAA consisting of mesoporous silica nanoparticles core and polymeric shell layers, were developed for controlled release of model anti-cancer drug ETS. Graft onto strategy was employed and amination served as an interim step, laying a vital foundation for functionalization of the MSN core with hydrophilic and pH responsive polyacrylic acid (PAA). MCM-41-PAA were investigated as carriers for loading and regulated release of ETS at different pH for the first time. The PAA-MSNs contained 20.19% grafted PAA as exhibited by thermogravimetric analysis (TGA), which enormously improved the solubility of ETS in aqueous media. The synthesized PAA-MSNs were characterized by various techniques viz, SEM-EDS, TEM, BET, FT-IR and powder XRD. ETS was effectively loaded into the channels of PAA-MSN via electrostatic interactions. The cumulative release was much rapid at extracellular tumor (6.8) and endosomal pH (5.5) than that of blood pH (7.4). Hemolysis study was done for the prepared NPs. MTT assay results showed that the drug-loaded ETS-MCM-41-PAA NPs were more cytotoxic to both prostate cancer cells namely PC-3 and LNCaP than free ETS, which was attributed to their slow and sustained release behavior. The above results confirmed that PAA-MSN hold a great potential as pH responsive carriers with promising future in the field of cancer therapy.     

Preparation and bioavailability of sustained-release doxofylline pellets in beagle dogs

The objective of this study was to develop doxofylline-loaded sustained-release pellets coated with Eudragit NE30D alone (F1) or blend of Eudragit RL30D/RS30D (F2) and further evaluate their in vitro release and in vivo absorption in beagle dogs. Doxofylline-loaded cores with a drug loading of 70% (w/w) were prepared by layering drug-MCC powder onto seed cores in a centrifugal granulator and then coating them with different kinds of polymethacrylates in a bottom-spray fluidized bed coater. Dissolution behaviour of these formulations was studied in vitro under various pH conditions (from pH 1.2 to pH 7.4) to evaluate the effect of pH on drug release profiles. It was found that F2 produced a better release profile than F1 did and two different release mechanisms were assumed for F1 and F2, respectively. The relative bioavailability of the sustained-release pellets was studied in six beagle dogs after oral administration in a fast state using a commercially available immediate release tablet as a reference. Coated with Eudragit NE30D and a blend of Eudragit RL30D/RS30D (1:12), at 5% and 8% coating level, respectively, the pellets acquired perfect sustained-release properties and good relative bioavailability, with small fluctuation of drug concentration in plasma. But combined use of mixed Eudragit RL30D/RS30D polymers with proper features as coating materials produced a longer T(max), a lower C(max) and a little higher bioavailability compared to F1 (coated with Eudragit NE30D alone). The C(max), T(max) and relative bioavailability of F1 and F2 coated pellets were 15.16 microg/ml, 4.17 h, 97.69% and 11.41 microg/ml, 5 h, 101.59%, respectively. Also a good linear correlation between in vivo absorption and in vitro release was established for F1 and F2, so from the dissolution test, formulations in vivo absorption can be properly predicted.