Statistical optimization of floating-bioadhesive drug delivery system for risedronate sodium: In vitro, ex vivo and in vivo evaluation

AbstractThe objective of the present investigation was to apply statistical design for the development of risedronate sodium floating-bioadhesive tablets (RSFBT) employing response surface methodology (RSM). A central composite design (CCD) was developed using Design of Expert (DOE) software to study the effect of formulation variables on the drug delivery system. The RSFBT were prepared by direct compression using hydroxy propyl methyl cellulose (HPMC K100M) as release retardant; carbopol (CP 974P) as bioadhesive polymer and sodium bicarbonate (NaHCO3) as a gas-former. The quantities of HPMC K100M (X1), CP 974P (X2) and NaHCO3 (X3) were taken as independent variables and percentage drug release at 2 h (Q2), 6 h (Q6) and 12 h (Q12), floating lag time (FLT), total floating time (TFT) and bioadhesive strength (BS) were selected as responses. The BS was determined using porcine gastric mucosa. In all 15 formulations were prepared and studied. The results of the CCD indicated that high levels of both X1 and X3, and low level of X2 were required for the preparation of RSFBT. Further, a good correlation was observed between predicted and experimental values of the independent variables selected for this study. The drug release profiles of all the formulations were fitted into zero-order, first-order, Higuchi and Peppas models. The optimized formulation followed the Peppas model with a non-Fickian diffusion mechanism. The statistically optimized formulation (RSFBTsopt) was found to be physically stable when stored at 40 ± 2 oC/75 ± 5% RH for 3 months. In vivo evaluation of RSFBTsopt, BaSO4-loaded tablets revealed a mean gastric retention time of 5 ± 0.86 h (n=3) in healthy volunteers.

Development, intra-gastric performance and pharmacokinetic study of gastroretentive drug delivery system for cefdinir in human volunteers

The objective of this study was to develop sustained-release floating tablets of cefdinir (CFDN) using effervescent technique to prolong gastric residence time (GRT) and compare their pharmacokinetics with immediate release (IR) and conventional sustained release (SR) tablets. The tablets were designed using CaCO3 as gas-former and three grades of polyethylene oxide as release-retardants and further were evaluated for their physical characters, in vitro drug release and buoyancy studies. The optimized formulation (F3) was found to be physically stable when stored at 40 oC/75% RH for 3 months. In vivo radiographic imaging of F3 revealed a mean GRT of 4.83 ± 0.57 h (n=3). Comparative pharmacokinetic study was performed for F3, IR and SR tablets of CFDN in humans. Based on in vivo performance, the difference between tmax, AUC0-∞, t1/2 and MRT of F3, IR and SR tablets were found to be statistically significant (p < 0.05). The difference between Cmax of F3 and IR tablet was statistically significant, but the Cmax of F3 and SR tablet was not statistically significant. The relative bioavailability of F3 was 1.71 fold to IR and 1.24 fold to SR. This improved bioavailability is due to the combined effect of sustained release and increased GRT

Development, intra-gastric performance and pharmacokinetic study of gastroretentive drug delivery system for cefdinir in human volunteers

The objective of this study was to develop sustained-release floating tablets of cefdinir (CFDN) using effervescent technique to prolong gastric residence time (GRT) and compare their pharmacokinetics with immediate release (IR) and conventional sustained release (SR) tablets. The tablets were designed using CaCO3 as gas-former and three grades of polyethylene oxide as release-retardants and further were evaluated for their physical characters, in vitro drug release and buoyancy studies. The optimized formulation (F3) was found to be physically stable when stored at 40 oC/75% RH for 3 months. In vivo radiographic imaging of F3 revealed a mean GRT of 4.83 ± 0.57 h (n=3). Comparative pharmacokinetic study was performed for F3, IR and SR tablets of CFDN in humans. Based on in vivo performance, the difference between tmax, AUC0-∞, t1/2 and MRT of F3, IR and SR tablets were found to be statistically significant (p < 0.05). The difference between Cmax of F3 and IR tablet was statistically significant, but the Cmax of F3 and SR tablet was not statistically significant. The relative bioavailability of F3 was 1.71 fold to IR and 1.24 fold to SR. This improved bioavailability is due to the combined effect of sustained release and increased GRT

Preparation, Characterization And In Vitro Evaluation Of Stealth Docetaxel Lipid Nanoemulsions For Efficient Cytotoxicity

Docetaxel is currently used in treatment of breast and ovarian cancers, administered in the form of parenteral IV infusion. Lipid nanoemulsion (LNE) delivery system is biocompatible, biodegradable and easy to prepare. The aim of this study was to develop stable parenteral pegylated docetaxel lipid nanoemulsions (LNEs) for improving cytotoxicity. The O/W LNEs were prepared by homogenization and ultrasonication process. The globule sizes and zeta potentials were measured by using Malvern Zetasizer.  The sizes of oil globules varied from 70.2 to 243.3 nm and zeta potential from −25.5 to −40.2mV. During in vitro drug release studies, the cumulative percentage drug released within 15 h from pegylated lipid nanoemulsions, PLNE-3 and PLNE-6 was 84.02±4.79 and 88.51±4.5 respectively. The total drug content and entrapment efficiencies for the prepared LNEs were determined by HPLC. The in vitro cell line studies were performed on two cell lines (MCF-7 and Hela cell lines). When compared to drug solution, PLNE-6 was found to have 1.55 and 1.6 folds more cytotoxic activity on MCF-7 and Hela cell lines respectively. The IC 50 values of pegylated LNEs on both the cell lines was statistically significant when compared to DS, P<0.05. In conclusion, stealth LNEs were prepared, characterized and  found to be stable and superior in delivery of docetaxel  to cancer cell lines in comparison to plain LNE and drug solution

Development of a self-microemulsifying drug delivery system of domperidone: In vitro and in vivo characterization

The main objective of this work was to prepare a self-micro emulsifying drug delivery system (SMEDDS) for enhancement of oral bioavailability of domperidone, a poorly water soluble drug. The solubility of the drug was determined in various vehicles. A pseudo ternary phase diagram was constructed to identify the self-micro emulsification region. The in vitro self-micro emulsification properties and droplet size of SMEDDS were studied following their addition to water under mild agitation. Further, the resultant formulations were investigated for clarity, phase separation, globule size, effect of pH and dilutions (1:100, 1:500, 1:1000). The optimized formulation, SMEDDS-B used for in vitro dissolution and bioavailability assessment, contained oil (Labrafac CC, 25 %, m/m), surfactant (Tween 80, 55 %, m/m), and co-surfactant (Transcutol®, 20 %, m/m). The preliminary oral bioavailability of domperidone from SMEDDS was 1.92-fold higher compared to that of domperidone suspension in rats. The AUC0-24 and cmax values were 3.38 ± 0.81 µg h mL–1 and 0.44 ± 0.03 µg mL–1 for SMEDDS-B formulation in comparison with 1.74 ± 0.18 µg h mL–1 and 0.24 ± 0.02 µg mL-1 for domperidone suspension suggesting a significant increase (p < 0.05) in oral bioavailability of domperidone from SMEDDS

Razvoj i vrednovanje plutajućih tableta norfloksacina s produljenim zadržavanjem u želucu

Floating matrix tablets of norfloxacin were developed to prolong gastric residence time, leading to an increase in drug bioavailability. Tablets were prepared by the wet granulation technique, using polymers such as hydroxy propyl methylcellulose (HPMCK4M, HPMCK100M) and xanthan gum. Tablets were evaluated for their physical characteristics viz., hardness, thickness, friability, and mass variation, drug content and floating properties. Further, tablets were studied for in vitro drug release characteristics for 9 hours. The tablets exhibited controlled and prolonged drug release profiles while floating over the dissolution medium. Non-Fickian diffusion was confirmed as the drug release mechanism from these tablets, indicating that water diffusion and the polymer rearrangement played an essential role in drug release. The best formulation (F4) was selected based on in vitro characteristics and was used in vivo radiographic studies by incorporating BaSO4. These studies revealed that the tablets remained in the stomach for 180 ± 30 min in fasting human volunteers and indicated that gastric retention time was increased by the floating principle, which was considered desirable for absorption window drugs.Razvijene su plutajuće tablete norfloksacina koje se produljeno zadržavaju u želucu i time povećavaju bioraspoloživost. Tablete su pripravljene metodom vlažne granulacije, koristeći hidroksipropil metilcelulozu (HPMCK4M, HPMCK100M) i ksantan gumu. Tabletama su određena fizikalna svojstva (čvrstoća, debljina, lomljivost i varijacija mase) te sadržaj ljekovite tvari i plutajuća svojstva. Nadalje, praćeno je oslobađanje ljekovite tvari in vitro tijekom 9 h. Uočeno je da je oslobađanje kontrolirano i produljeno te da tablete plutaju u ispitivanom mediju. Mehanizam oslobađanja nije slijedio Fickov zakon, što ukazuje da difuzija vode i promjene u strukturi polimera imaju bitnu ulogu u oslobađanju ljekovite tvari. Najbolja formulacija (F4) in vitro uporabljena je s dodatkom barijevog sulfata za radiografska ispitivanja in vivo. Ispitivanja na volonterima koji su apstinirali od hrane pokazala su da primjena plutajućih tableta produljuje vrijeme zadržavanja u želucu na 180 ± 30 min

Studies on the Influence of Charge Inducer and it’s Combination with P-gp Inhibitor to Improve the Oral Bioavailability of Nimodipine via Submicron Lipid Emulsions

Background: Nimodipine (NM), is a dihydropyridine calcium channel blocker with poor oral bioavailability (BA) of about 13% due to first-pass metabolism and P-gp efflux.&nbsp;Objective: The present work aimed to study the influence of the charge inducer and its combination with P-gp inhibitor to improve the oral bioavailability of NM by developing a suitable delivery system of Submicron Lipid Emulsion (SME).&nbsp;Methods: Five SME formulations of NM were prepared by homogenization followed by ultrasonication. Prepared SMEs were characterized for particle size, PDI, Zeta Potential (ZP), Entrapment Efficiency (EE), and drug content. In vitro, release studies were performed in 0.1N HCl and pH 6.8 phosphate buffer by open tube method. The physical stability of all NM&ndash;SMEs was tested by the individual effects of centrifugation, dilution (desorption stress), and storage. Bioavailability studies were conducted on male Wistar rats after oral administration of NM suspension and F1 to F5 SME formulations.&nbsp;Results and conclusion: Five NM- SMEs were developed with a mean size ranging from 93 - 137 nm, Zeta potential of &ndash; 26 &plusmn; 1 mV (negatively charged), +45.8 to +46.3 mV (positively charged), and PDI of 0.15 - 0.25. The in vitro release studies showed that relatively more cumulative percentage release of NM &ndash; SMEs in 0.1N HCl than in pH phosphate buffer during 24 hours. The physical stability of NM&ndash;SMEs indicated that they were stable to the effects of centrifugation, dilution, and storage. Pharmacokinetic (PK) studies showed that the oral bioavailability of NM in F4 SME was significantly higher than that of all other formulations. Taken together, the results indicated the development of a stable lipid-based carrier, F4 SME to improve the oral bioavailability of this drug by minimizing first-pass metabolism due to lymphatic transport, reducing the efflux by P-gp inhibition, and further, by increased uptake of the positively charged F4 SME globules by enterocytes. Future: The research study findings increase the possibility of developing NM F4 SME by the pharmaceutical industry for the patient&rsquo;s benefit

Tween 80 containing lipid nanoemulsions for delivery of indinavir to brain

Indinavir is a protease inhibitor used in the treatment of HIV infection. However, it has limited efficacy in eradicating the virus in the brain due to efflux by P-glycoprotein (P-gp) expressed at the blood–brain barrier (BBB). The objective of this work was to develop an o/w lipid nanoemulsion (LNE) of indinavir using Tween 80 as co-emulsifier to improve its brain specific delivery. LNEs were prepared with different compositions and were characterized for globule size, polydispersity index, zeta potential and in vitro drug release. Five formulations were then evaluated for drug content, entrapment efficiency and stability after which brain uptake studies were carried out using fluorescent labeled LNEs and pharmacokinetic (PK) and tissue distribution studies were conducted after intravenous administration in mice. Brain uptake of indinavir was shown to be improved for a 1% Tween 80 containing formulation (F5) compared to a formulation containing 0.3% cholesterol (F2). In PK studies, the brain level of indinavir subsequent to administration of F5 was significantly (P<0.05) higher than produced by administration of a drug solution (2.44-fold) or a control nanoemulsion (F1) (1.48-fold) or formulation F2 (1.6-fold). The increased brain specific accumulation of indinavir from F5 is probably due to enhanced low density lipoprotein-mediated endocytosis and P-gp inhibition by Tween 80 at the BBB. These results suggest Tween 80 containing LNEs could provide a simple but effective means of delivering indinavir to brain

Screening, isolation, taxonomy and fermentation of an antibiotic producer <i style="mso-bidi-font-style:normal">Streptomyces xinghaiensis</i> from soil capable of acting against linezolid resistant strains

718-728Linezolid resistant cultures are emerging in hospitals. In the present study 3 soil actinomycetes were isolated in a screening programme having potential to produce antibiotic against linezolid resistant cases. One culture was coded as RK-46 and further studied. The micromorphology, biochemical tests and 16S ribosomal DNA gene sequence analysis were conducted to know the identity of the culture and was found as a strain of Streptomyces xinghaiensis. The culture produced antibiotic active against five clinical resistant strains. The antibiotic production was tested by cultivating in eleven different media. The fermentation profile was studied in YEME medium supplemented with calcium carbonate. The maximum activity was noticed at 72 h. Antibiotic activity was extracted into ethyl acetate and was subjected to activity guided purification by column chromatography, TLC and HPLC methods. The pure compound was eluted with retention time of 6.8 min and subjected to 1H, 13C NMR and Mass spectral analysis. The acquired data was compared with that in natural products data base, and was found to be a known antibiotic, reductiomycin. The purified compound showed activity against 5 linezolid resistant cultures and on Mycobacterium tuberculosis. This compound is also showing mild anti cancer activity and is biologically permeable as per Lipinksi’s rule