Pharmacokinetic study of niosome encapsulated insulin

Pharmacokinetic profile and hypoglycemic effect, after intraperitoneal injection of insulin and insulin encapsulated in niosomes were determined in diabetic rats. Niosomes (non-ionic surfactant vesicles) of different doses and different lipid compositions were prepared by lipid layer hydration method. Plasma samples were collected at specified time intervals and plasma concentration of insulin was determined by HPLC. Blood glucose level was estimated spectrophotometrically using commercial glucose assay kit. In vitro release and pharmacokinetic profile of niosomal formulation and free insulin were evaluated. Though there was a slight delay in the in vitro drug release due to cholesterol content in the niosomes, there was no difference between the two preparations when plasma levels were compared in vivo. Niosomes significantly reduced the blood glucose level in diabetic rats. Fall in blood glucose level was almost 92% of initial value. In case of the niosomal form the half-life of insulin was prolonged by 4 -5 hr in contrast to 2 hr for free drug. Niosomes maintained the plasma insulin level up to 12 hr, but free drug was cleared quickly. The area under the plasma concentration-time curve for niosomal forms was, 26.07 degrees +/- 0.99 mIU. hr/ml and for free insulin was 11.722 +/- 1.00 mIU. hr/ml. More than 80% of the drug was successfully encapsulated to give a formulation with sustained release characteristics. Entrapment efficiency increased with increasing lipid concentration and decreased with increasing drug concentration. The results showed that insulin entrapped in niosomes prolongs the existence of drug in the body therefore increasing its therapeutic value.     

A novel injectable in situ forming poly-DL-lactide and DL-lactide/glycolide implant containing lipospheres for controlled drug delivery

One of the greatest challenges in in situ forming implant (ISFI) systems by polymer precipitation is the large burst release during the first 1-24 hours after implant injection. The aim of this study was to decrease the burst-release effect of a water-soluble model drug, donepezil HCl, with a molecular weight of 415.96?Da, from in situ forming implants using a novel in situ implant containing lipospheres (ISILs). In situ implant suspensions were prepared by dispersing cetyl alcohol and glyceryl stearate lipospheres in a solution of poly-DL-lactide (PDL) or DL-lactide/glycolide copolymer (PDLG). Also, in situ implant solutions were prepared using different concentrations of PDL or PDLG solutions in N-methyl-2-pyrrolidone (NMP). Triacetin and Pluronic L121 were used to modify the release pattern of donepezil from the in situ implant solutions. In vitro release, rheological measurement, and injectability measurement were used to evaluate the prepared in situ implant formulae. It was found that ISIL decreased the burst effect as well as the rate and extent of drug release, compared to lipospheres, PDL, and PDLG in situ implant. The amount of drug released in the first day was 37.75, 34.99, 48.57, 76.3, and 84.82% for ISIL in 20% PDL (IL-1), ISIL in 20% PDLG (IL-2), lipospheres (L), 20% PDL ISFI (I5), and 20% PDLG ISFI (I8), respectively. The prepared systems showed Newtonian flow behavior. ISIL (IL-1 and IL-2) had a flow rate of 1.94 and 1.40?mL/min, respectively. This study shows the potential of using in situ implants containing lipospheres in controlling the burst effect of ISFI.     

Controlled release of all-trans-retinoic acid from PEGylated gelatin nanopaticles by enzymatic degradation

A new targeting drug carrier for anticancer drug, all-trans-retinoic acid (atRA), was proposed by using angiogenesis which is one of the specific physiological properties of cancer cells. The proposed drug carrier was prepared as PEGylated gelatin nanoparticle (176 nm size). The gelatin molecules were aggregated by coupled deoxycholic acid and the surface of the nanoparticles was covered by polyethylene glycol to reduce reticuloendothelial system (RES) uptake. To prove the feasibility of the nanoparticles as a targeting drug carrier, the degradation of the nanoparicles by collagenase IV and the release pattern of atRA from the nanoparticles by enzymatic degradation were evaluated. The PEGylated gelatin nanoparticles were significantly degraded by collagenase IV within 10 seconds, with most of them degraded within 1 min. When atRA loaded in the PEGylated gelatin nanoparticles was released in phosphate buffered saline (PBS), only twelve percent of atRA were released for one hour. However, when the nanoparticles were put into PBS with collagenase IV of 0.1 μM, a burst effect of atRA was about 40% for the initial 10 min, followed by a continuous release of atRA upto 75% for 5 hr. Therefore, the PEGylated gelatin nanoparticles released anticancer drug very sensitively by collagenase IV, which is one of major matrix metalloproteases involved in angiogenesis. These results showed a feasibility that PEGylated gelatin nanoparticles could be used as a new targeting anticancer drug carrier using angiogenesis as a specific physiological property of cancer cells.     

A novel injectable in situ forming poly-DL-lactide and DL-lactide/glycolide implant containing lipospheres for controlled drug delivery

One of the greatest challenges in in situ forming implant (ISFI) systems by polymer precipitation is the large burst release during the first 1–24 hours after implant injection. The aim of this study was to decrease the burst-release effect of a water-soluble model drug, donepezil HCl, with a molecular weight of 415.96?Da, from in situ forming implants using a novel in situ implant containing lipospheres (ISILs). In situ implant suspensions were prepared by dispersing cetyl alcohol and glyceryl stearate lipospheres in a solution of poly-DL-lactide (PDL) or DL-lactide/glycolide copolymer (PDLG). Also, in situ implant solutions were prepared using different concentrations of PDL or PDLG solutions in N-methyl-2-pyrrolidone (NMP). Triacetin and Pluronic L121 were used to modify the release pattern of donepezil from the in situ implant solutions. In vitro release, rheological measurement, and injectability measurement were used to evaluate the prepared in situ implant formulae. It was found that ISIL decreased the burst effect as well as the rate and extent of drug release, compared to lipospheres, PDL, and PDLG in situ implant. The amount of drug released in the first day was 37.75, 34.99, 48.57, 76.3, and 84.82% for ISIL in 20% PDL (IL-1), ISIL in 20% PDLG (IL-2), lipospheres (L), 20% PDL ISFI (I5), and 20% PDLG ISFI (I8), respectively. The prepared systems showed Newtonian flow behavior. ISIL (IL-1 and IL-2) had a flow rate of 1.94 and 1.40?mL/min, respectively. This study shows the potential of using in situ implants containing lipospheres in controlling the burst effect of ISFI.     

Production of Electrospun Fast-Dissolving Drug Delivery Systems with Therapeutic Eutectic Systems Encapsulated in Gelatin

Fast-dissolving delivery systems (FDDS) have received increasing attention in the last years. Oral drug delivery is still the preferred route for the administration of pharmaceutical ingredients. Nevertheless, some patients, e.g. children or elderly people, have difficulties in swallowing solid tablets. In this work, gelatin membranes were produced by electrospinning, containing an encapsulated therapeutic deep-eutectic solvent (THEDES) composed by choline chloride/mandelic acid, in a 1:2 molar ratio. A gelatin solution (30% w/v) with 2% (v/v) of THEDES was used to produce electrospun fibers and the experimental parameters were optimized. Due to the high surface area of polymer fibers, this type of construct has wide applicability. With no cytotoxicity effect, and showing a fast-dissolving release profile in PBS, the gelatin fibers with encapsulated THEDES seem to have promising applications in the development of new drug delivery systems.     

The Biodegradation of Zein <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> and its Application in Implants

A unique polymer-based sustained-release implant drug delivery system was prepared by using biocompatible and biodegradable Zein as the skeleton meterial. After preparing Zein colloids, the Zein-loaded implant rods were formulated by injection molding followed by evaporating the solvent, and being coated with poly(lactic-co-glycolic) acid (PLGA) solution. Drug release kinetics was examined by using Fluorouracil (5-FU) as model drug. Nearly zero-order release was achieved for the model drugs for a period of 0–25 days when the implants were incubated in distilled water at 37°C. And then the degradation kinetics of the rods in vivo and in vitro were evaluated, which indicated that Zein could be absorbed by body and has good degradation property. The effects of different ratios of Zein/5-FU and the rods’ diameter on drug release were studied, respectively. The plasma concentration of 5-FU in the implants were determined by HPLC after implanting a single dose of the implants in rats. All data were subsequently processed by using the computer program 3P97, and the values were showed as follows: the area under the plasma concentration–time curve (AUC) value was 321.88 (μg/ml) × day, and the mean residence time (MRT) value was 23.05 days. The sustained-release implants of Zein/5-FU were successfully formulated. The uniqueness of the article is that Zein has been used as a skeleton material in implant delivery system for the first time and zero-order release kinetics has been obtained successfully.     

Evaluation of Ionotropic Cross-Linked Chitosan/Gelatin B Microspheres of Tramadol Hydrochloride

Microspheres of tramadol hydrochloride (TM) for oral delivery were prepared by complex coacervation method without the use of chemical cross-linking agents such as glutaraldehyde to avoid the toxic reactions and other undesirable effects of the chemical cross-linking agents. Alternatively, ionotropic gelation was employed by using sodium-tripolyphosphate as cross-linking agent. Chitosan and gelatin B were used as polymer and copolymer, respectively. All the prepared microspheres were subjected to various physicochemical studies, such as drug–polymer compatibility by thin layer chromatography (TLC) and Fourier transform infrared (FTIR) spectroscopy, surface morphology by scanning electron microscopy, frequency distribution, drug entrapment efficiency, in vitro drug release characteristics and release kinetics. The physical state of drug in the microspheres was determined by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). TLC and FTIR studies indicated no drug–polymer incompatibility. All the microspheres showed initial burst release followed by a fickian diffusion mechanism. DSC and XRD analysis indicated that the TM trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. From the preliminary trials, it was observed that it may be possible to formulate TM microspheres by using biodegradable natural polymers such as chitosan and gelatin B to overcome the drawbacks of TM and to increase the patient compliance.     

In vitro and in vivo evaluation of oridonin-loaded long circulating nanostructured lipid carriers

The purpose of this study was to develop poly(ethylene glycol)-coated nanostructured lipid carriers (PEG-NLC) for parenteral delivery of oridonin (ORI) to prolong drug circulation time in blood. Oridonin-loaded PEG-NLC (ORI-PEG-NLC) consisting of PEG(2000)-stearate, glycerol monostearate and medium chain triglycerides were prepared by emulsion-evaporation and low temperature-solidification technique. Oridonin-loaded NLC (ORI-NLC) were also prepared as control. ORI-PEG-NLC were observed by transmission election microscope and the morphology was in rotiform shape. The mean particle size of ORI-PEG-NLC was 329.2 nm and entrapment efficacy was 71.18%. The results of differential scanning calorimetry and X-ray diffraction revealed a low-crystalline structure of ORI and verified the incorporation of ORI into the nanoparticles. In vitro drug release of ORI-PEG-NLC exhibited biphasic drug release patterns with burst release initially and prolonged release afterwards. Pharmacokinetic analysis showed that the mean residence time of ORI-PEG-NLC was prolonged and AUC (area under tissue concentration-time curve) value was also improved compared with ORI-NLC and ORI solution. In conclusion, ORI-PEG-NLC could be a potential carrier to get prolonged retention time of oridonin in blood.     

Sustained release of an antimalarial drug using a copolymer of glycolic/lactic acid

A copolymer of d1-lactic acid and glycolic acid (25% and 75% by weight, respectively) was evaluated as an implantable controlled release delivery system for the antimalarial drug 2, 4-diamino-6-(2-napthylsulfonyl)-quinazoline (WR-158122). Two preparations of drug/polymer (16.7% and 33.3% drug by weight) were spray dried from common solvent systems into finely divided particles of less than 125 microns size. Suspensions in carboxymethyl cellulose of each preparation were injected in the scapular region of mice and were evaluated for efficacy against the rodent malaria $\text{Plasmodium berghei}$ by repeated infective challenges and by the Rane antimalarial drug screening system. Duration of release was studied by measurement of trace radioactivity from the drug excreted into urine and feces. In the challenge test, several dosages of the implanted drug/polymer material and antimalarial activity over a prolonged period of time; parasitemia was not detected for several weeks and some animals survived through 14 weeks of weekly challenges, whereas all mice in control groups became malarious and survived only an average of 12 days after infection. Both preparations were effective in the Rane drug screening system; the curative dose as drug was calculated to be approximately 50 mg/kg body weight for each preparation. Recovery of excreted radioactivity indicated a sustained release through 14 weeks and residual activities at the implant sites were 2% and 13% for the 16.7% and 33.3% drug/polymer preparations, respectively. Based on these results, it is anticipated that delivery systems of this type can be developed for eventual testing against human malaria.     

Synthesis and characterization of hydrogels based on grafted chitosan for the controlled drug release

Temperature and pH-responsive hydrogels based on chitosan grafted with poly acrylic acid (PAAc), poly hydroxy propyl methacrylate (PHPMA), poly (vinyl alcohol) (PVA) and gelatin were prepared for controlled drug delivery. These stimuli-responsive hydrogels were synthesized by gamma irradiation technique. The degree of gelation was over 90% and increased as chitosan, AAc and PVA content increased, while the degree of gelation decrease with the increase of gelatin content. The equilibrium swelling studies of hydrogels prepared in various conditions were carried out in an aqueous solution, and the pH sensitivity in the range of 2–9 was investigated. An increase of swelling degree with an increase in the pH was noticed and showed the highest value at pH 9. Also antibiotic drug Oxttetracycline was loaded into the hydrogels and the release studies were carried out at different pH and temperature. The in vitro release profiles of the drug showed that, the release of the drug increased as the time, temperature and pH increased and reached to maximum after 48 h at pH 9. The prepared hydrogels were characterized by using SEM, FTIR, and DSC.     

Sustained activity and release of leuprolide acetate from an in situ forming polymeric implant

The primary objective of this study was to evaluate the effect of drug loading on the release of leuprolide acetate from an injectable polymeric implant, formed in situ, and efficacy of the released drug in suppressing serum testosterone levels in dogs for at least 90 days. An additional objective was to compare the optimum implant formulation with a commercial microsphere product. Evaluated implant formulations contained 45% w/w 75/25 poly (DL-lactide-co-glycolide) polymer having an intrinsic viscosity of 0.20 dL/g, dissolved in N-methyl-2-pyrrolidone. Irradiated polymer solution was mixed with leuprolide at different drug loads (3%, 4.5%, and 6% w/w) prior to subcutaneous administration to dogs. Dog serum was analyzed for testosterone (RIA) and leuprolide (LC/MS/MS) levels and comparisons within the three implant formulation groups were made. Varying the drug load did not significantly affect the release of leuprolide or efficacy of the implant formulation. Thus, the 6% w/w formulation with the smaller injection volume was selected for comparison with the commercial LUPRON Depot product, which was administered intramuscularly at a similar dosage. These comparisons of serum testosterone and leuprolide levels showed no significant difference in the pharmacologic efficacy even though drug levels were different at a number of points. This was mainly due to associated high standard deviations. Based on these studies, the 6% w/w leuprolide implant formulation was considered to be a suitable candidate for further development. Additional benefits of this system include its simple manufacturing and lower costs.     

Intragastric floating drug delivery system of cefuroxime axetil: In vitro evaluation

This investigation describes the development of an intragastric drug-delivery system for cefuroxime axetil. The 3² full factorial design was employed to evaluate contribution of hydroxypropyl methyl cellulose (HPMC) K4M/HPMC K100 LV ratio (polymer blend) and sodium lauryl sulfate (SLS) on drug release from HPMC matrices. Tablets were prepared using direct compression technique. Formulations were evaluated for in vitro buoyancy and drug release study using United States Pharmacopeia (USP) 24 paddletype dissolution apparatus using 0.1N HCl as a dissolution medium. Multiple regression analysis was performed for factorial design batches to evaluate the response. All formulations had floating lag times below 2 minutes and constantly floated on dissolution medium for more than 8 hours. It was found that polymer blend and SLS significantly affect the time required for 50% of drug release, percentage drug release at 12 hours, release rate constant, and diffusion exponent (P<.05). Also linear relationships were obtained between the amount of HPMC K100 LV and diffusion exponent as well as release rate constant. Kinetic treatment to dissolution profiles revealed drug release ranges from anomalous transport to case 1 transport, which was mainly dependent on both the independent variables. Published: February 24, 2006     

Investigations on the Physical Structure and the Mechanism of Drug Release from an Enteric Matrix Microspheres with a Near-Zero-Order Release Kinetics Using SEM and Quantitative FTIR

The objectives of this study were to evaluate the physical structure and the release mechanisms of theophylline microspheres made of Eudragit S 100 polymer as an enteric polymer, combined with a nonerodible polymer, Eudragit RL 100. In the preparation process, polymer combinations (1:1) were dissolved in an organic solvent mixture composed of acetone and methanol at a specific ratio containing a theoretical drug loading of approximately 15%. Two microsphere formulations (LS1 and LS2) were prepared at two different total polymer concentrations (10% in LS1 and 12.7% in LS2). Dissolution studies were carried out using US Pharmacopeia Dissolution Apparatus II in an acidic medium for 8 h and in an acidic medium (2 h) followed by a slightly basic-buffered medium for 10 h. Both LS1 and LS2 microsphere formulations produced particles that were spherical in shape and had very narrow size distributions with one size fraction comprising 70–80% of the yield. Scanning electron microscopy and quantitative Fourier transform infrared were used for microsphere physical structure evaluation. Except for the absence of drug crystals, photomicrographs of both LS microspheres after dissolution in pH 1.2 and 7.2 buffer solutions were similar to those before dissolution. Dissolution results indicated the ability of LS microspheres to minimize drug release during the acid stage. However, in the slightly basic medium that followed the acidic stage, the drug release was sustained and controlled in its kinetics and data fitted to Peppas equation indicated a case II transport suggesting that the drug release is mainly through swelling/erosion mechanism.     

Ethylcellulose-Based Matrix-Type Microspheres: Influence of Plasticizer RATIO as Pore-Forming Agent

In this study, ethylcellulose (EC)-based microsphere formulations were prepared without and with triethyl citrate (TEC) content of 10% and 30% by water-in-oil emulsion-solvent evaporation technique. Diltiazem hydrochloride (DH) was chosen as a hydrophilic model drug and used at different drug/polymer ratios in the microspheres. The aim of the work was to evaluate the influence of plasticizer ratio on the drug release rate and physicochemical characteristics of EC-based matrix-type microspheres. The resulting microspheres were evaluated for encapsulation efficiency, particle size and size distribution, surface morphology, total pore volume, thermal characteristics, drug release rates, and release mechanism. Results indicated that the physicochemical properties of microspheres were strongly affected by the drug/polymer ratio investigated and the concentration of TEC used in the production technique. The surface morphology and pore volume of microspheres significantly varied based on the plasticizer content in the formulation. DH release rate from EC-based matrix-type microspheres can be controlled by varying the DH to polymer and plasticizer ratios. Glass transition temperature values tended to decrease in conjunction with increasing amounts of TEC. Consequently, the various characteristics of the EC microspheres could be modified based on the plasticized ratio of TEC.     

In vitro and in vivo evaluations of biodegradable implants for hormone replacement therapy: Effect of system design and PK-PD relationship

This investigation evaluated the feasibility of using subdermally implantable devices fabricated by nonconventional 3-dimensional printing technology for controlled delivery of ethinyl estradiol (EE₂). In vitro release kinetics of EE₂ and in vivo pharmacokinetics pharmacodynamics in ovariectomized New Zealand White rabbits were carried out to study 3 implant prototypes: implant I (single-channel EE₂ distribution in polycaprolactone polymer core), implant II (homogeneous EE₂ distribution in polycaprolactone polymer matrix), and implant III (concentration-gradient EE₂ distribution in polycaprolactone and poly(dl-lactide-co-glycolide) (50∶50 matrix). EE₂ was found to be released from all the implants in a nonlinear pattern with an order of implant III>implant II>implant I. The noncompartmental pharmacokinetic analysis of plasma EE₂ profiles in rabbits indicated a significant difference (p>.05) in C_max, t_max, and mean residence time between implant I and implants II and III, but no difference in the area under the plasma concentration time curves calculated by trapezoidal rule (AUC) among the implants. For pharmacodynamic studies, endogenous follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were observed to be suppressed following implantation of all implants, which demonstrated that a therapeutically effective dose of EE₂ had been delivered. Furthermore, the noncompartmental analysis of plasma FSH and LH profiles in rabbits showed a significant difference (p<.05) in AUC and the mean residence time between implant III and implants I and II. A good in vivo/in vitro relationship was observed between daily amounts of EE₂ released and plasma profiles of EE₂ for all implants. This relationship suggests that plasma profiles of EE₂ could be predicted from in vitro measurement of daily amount of EE₂ released Therefore, performing in vitro drug release studies may aid in the development of an EE₂ implant with the desired in vivo release rate. Published: September 21, 2001     

Preparation and characterization of biopolymeric nanoparticles used in drug delivery

Nanotechnology plays an important role in advanced biology and medicine research particularly in the development of potential site-specific delivery systems with lower drug toxicity and greater efficiency. These include microcapsules, liposomes, polymeric microspheres, microemulsions, polymer micelles, hydrogels, solid nanoparticles etc. In the present study, preparation and characterization of biopolymeric gelatin nanoparticles for encapsulating the antimicrobial drug sulfadiazine and its in vivo drug release in phosphate buffer saline (PBS) have been investigated. The nanoparticles prepared by second desolvation process varied in a size range 200 nm and 600 nm with a drug entrapment efficiency of 50% characterized by atomic force microscopy and dynamic light scattering. The drug release from the nanoparticles occurred up to 30% in a controlled manner.     

Paclitaxel delivery to brain tumors from hydrogels: a computational study

Malignant gliomas are aggressive forms of primary brain tumors characterized by a poor prognosis. The most successful treatment so far is the local implantation of polymer carriers (Gliadel® wafers) for the sustained release of carmustine. To improve the effectiveness of local drug treatment, new polymer carriers and pharmacological agents are currently being investigated. Of particular interest is a set of novel thermo‐gelling polymers for the controlled release of hydrophobic drugs such as paclitaxel (e.g., OncoGel?). Herein, we use computational mass transport simulations to investigate the effectiveness of paclitaxel delivery from hydrogel‐forming polymer carriers. We found similar (within 1–2 mm) therapeutic penetration distances of paclitaxel when released from these hydrogels as compared with carmustine released from Gliadel® wafers. Effective therapeutic concentrations were maintained for >30 days for paclitaxel when released from the hydrogel as compared with 4 days for carmustine released from Gliadel® wafers. Convection in brain tissue prevented the formation of a uniform drug concentration gradient around the implant. In addition, the surface area to volume ratio of the gel is an important factor that should be considered to maintain a controlled release of paclitaxel within the degradation lifetime of the polymer matrix. © 2011 American Institute of Chemical Engineers Biotechnol. Prog., 2011     

Synchronization of estrus in beef heifers with a norgestomet implant and prostaglandin F2alpha

In a 5-year study (1973-1977), 281 cycling beef heifers were treated with a 7-day norgestomet (SC21009) ear implant and an intramuscular injection of prostaglandin F(2alpha) (PGF(2alpha)) at the time of implant removal or 24 hr before implant removal. Percentages of heifers in estrus by 36, 48, 60, 72, and 120 hr after implant removal were 32.4, 52.7, 71.6, 80.1, and 93.2, respectively. Onset of estrus occurred an average of 49.8 +/- 4.7 hr after treatment. Percentages of heifers in estrus 36 hr after treatment were 5.7 and 51.7 for those with a corpus luteum and those without a corpus luteum (or determined regressing by palpation) at implant removal, respectively. When PGF(2alpha) was injected 24 hr before implant removal, 55% of the heifers were in estrus by 36 hr after implant removal compared to 30% when PGF(2alpha) was injected at the time of implant removal; however, by 60 hr after implant removal the difference was 76% vs. 71%. First-service conception rates for synchronized and nonsynchronized heifers were 62.2% and 59.6%, respectively. During 1976 and 1977 heifers were checked for estrus every 4 hr and inseminated 2, 6, 10, 14, 18, 22, 26, or 30 hr after first detected to be in standing estrus. Conception rate was not significantly affected by time of insemination but tended to be higher for heifers bred 26 and 30 hr after first being detected in standing estrus (78.9% and 70.0% vs. average 59.2%). Treatment with a 7-day norgestomet implant plus a single injection of PGF(2alpha) 24 hr before or at implant removal appears to be a practical technique for synchronizing estrus in cycling heifers without affecting conception.     

Eudragit-Based Nanosuspension of Poorly Water-Soluble Drug: Formulation and In Vitro–In Vivo Evaluation

The present study was performed to investigate potential of Eudragit RLPO-based nanosuspension of glimepiride (Biopharmaceutical Classification System class II drug), for the improvement of its solubility and overall therapeutic efficacy, suitable for peroral administration. Nanoprecipitation method being simple and less sophisticated was optimized for the preparation of nanosuspension. Physicochemical characteristics of nanosuspension in terms of size, zeta potential, polydispersity index, entrapment efficiency (% EE) and in vitro drug release were found within their acceptable ranges. The size of the nanoparticles was most strongly affected by agitation time while % EE was more influenced by the drug/polymer ratio. Differential scanning calorimetry and X-ray diffraction studies provided evidence that enhancement in solubility of drug resulted due to change in crystallinity of drug within the formulation. Stability study revealed that nanosuspension was more stable at refrigerated condition with no significant changes in particle size distribution, % EE, and release characteristics for 3 months. In vivo studies were performed on nicotinamide–streptozotocin-induced diabetic rat models for pharmacokinetic and antihyperglycaemic activity. Nanosuspension increased maximum plasma concentration, area under the curve, and mean residence time values significantly as compared to aqueous suspension. Oral glucose tolerance test and antihyperglycaemic studies demonstrated plasma glucose levels were efficiently controlled in case of nanosuspension than glimepiride suspension. Briefly, sustained and prolonged activity of nanosuspensions could reduce dose frequency, decrease drug side effects, and improve patient compliance. Therefore, glimepiride nanosuspensions can be expected to gain considerable attention in the treatment of type 2 diabetes mellitus due to its improved therapeutic activity.KEY WORDS: diabetes mellitus, glimepiride, nanoprecipitation, poloxamer, sustained release     

Mucoadhesive vaginal tablets as veterinary delivery system for the controlled release of an antimicrobial drug,acriflavine

The aim of the study was the development of mucoadhesive vaginal tablets designed for the local controlled release of acriflavine, an antimicrobial drug used as a model. The tablets were prepared using drug-loaded chitosan microspheres and additional excipients (methylcellulose, sodium alginate, sodium carboxymethylcellulose, or Carbopol 974). The microspheres were prepared by a spray-drying method, using the drug to polymer weight ratios 1:1 and 1:2 and were characterized in terms of morphology, encapsulation efficiency, and in vitro release behavior, as MIC (Minimum Inhibitory Concentration), MBC (Minimum Bacterial Concentration), and killing time (KT). The tablets were prepared by direct compression, characterized by in vitro drug release and in vitro mucoadhesive tests. The microparticles have sizes of 4 to 12 microm; the mean encapsulation yields are about 90%. Acriflavine, encapsulated into the polymer, maintains its antibacterial activity; killing time of the encapsulated drug is similar to that of the free drug. In vitro release profiles of tablets show differences depending on the excipient used. In particular Carbopol 974, which is highly cross-linked, is able to determine a drug-controlled release from the matrix tablets for more than 8 hours. The in vitro adhesion tests, carried out on the same formulation, show a good adhesive behavior. The formulation containing microspheres with drug to polymer weight ratios of 1:1 and Carbopol 974 is characterized by the best release behavior and shows good mucoadhesive properties. These preliminary data indicate that this formulation can be proposed as a mucoadhesive vaginal delivery system for the controlled release of acriflavine.