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1.
The polyethylene glycol (PEG) treatment of ciprofloxacin-Indion 234 complex was aimed to retard rapid ion exchange drug release
at gastric pH. Ciprofloxacin loading on Indion 234 was performed in a batch process, and the amount of K+ in Indion 234 displaced by drug with time was studied as equilibrium constant KDM. Drug-resin complex (DRC) was treated with aqueous PEG solution (0.5%–2% wt/vol) of different molecular weights (MWs) for
2 to 30 minutes. The PEG-treated ciprofloxacin-Indion 234 complex was evaluated for particle size, water absorption time,
and drug release at gastric pH. During drug loading on Indion 234, the equilibrium constant (KDM) increased rapidly up to 20 minutes with efficient drug loading. Increased time of immersion of the drug resinate in PEG
solutions significantly retained higher size particles upon dehydration. The larger DRC particles showed longer water absorption
times owing to compromised hydrating power. The untreated DRC showed insignificant drug release in deionized water; while
at gastric pH, ciprofloxacin release was complete in 90 minutes. A trend of increased residual particle size, proportionate
increase in water absorption time, and hence the retardation of release with time of immersion was evident in PEG-treated
DRC. The time of immersion of DRC in PEG-treated DRC. The time of immersion of DRC in PEG solution had predominant release
retardant effect, while the effect of molecular weight of PEG was insignificant. Thus, PEG treatment of DRC successfully retards
ciprofloxacin ion exchange release in acidic pH. 相似文献
2.
3.
The purpose of this research was to apply vacuum foam drying (VFD) for processing of LaSota virus and to screen formulation
additives for its stability. The aqueous dispersion of harvest containing sucrose or trehalose in combination with additive
(monosaccharides, polymers, N-Z-amine) was prepared. The diluted dispersions in vials were vacuum concentrated, foamed to
form a continuous structure, and vacuum dried. The products were evaluated for foam characteristics, residual moisture, virus
titer, x-ray diffraction pattern, and stability profile. The foamability increased with solid content in solutions. The foamability
of sucrose was enhanced with incorporation of N-Z-amine (10% and 15% wt/vol) and polyvinyl pyrrolidone (PVP K30, 3% wt/vol).
The fructose- or galactose-containing mixtures were deposited irregularly on the vial surface. The virus titer increased with
disaccharides in the formulation. Sucrose provided better protection than trehalose. Unlike lyophilization, N-Z-amine with
sucrose protected the virus from Millard’s Browning. Amino acids do not have a catalytic effect on hydrolysis of sucrose during
VFD. Monosaccharides were ineffective. A synergistic effect of PVP K30 or polyethylene glycol 6000 (3% wt/vol) with N-Z-amine
provided the maximum virus titer (6.97 and 7.15, respectively). This formulation retained the desired virus potency at 5°,
25°, and 40°C. The diffraction pattern revealed that a threshold concentration of N-Z-amine was required for inhibiting crystallization
of sucrose during VFD. VFD was successfully applied to produce a solid LaSota formulation. The products were amorphous and
did not devitrify on storage.
Published: July 21, 2006 相似文献
4.
Nagarajan Muthukaman Macchindra Tambe Mahamadhanif Shaikh Dnyandeo Pisal Sanjay Deshmukh Shital Tondlekar Neelam Sarode Lakshminarayana Narayana Jitendra M. Gajera Vidya G. Kattige Srinivasa Honnegowda Vikas Karande Abhay Kulkarni Dayanidhi Behera Satyawan B. Jadhav Girish S. Gudi Neelima Khairatkar-Joshi Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2017,27(11):2594-2601
A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F = 33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model. 相似文献
5.
Liposomes consisted of phosphatidylinositol (PI) and phosphatidylcholine (PC) have been utilized as delivery vehicle for drugs and proteins. In the present work, we studied the effect of soy PI on physical properties of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes such as phase state of lipid bilayer, lipid packing and phase properties using multiple orthogonal biophysical techniques. The 6-dodecanoyl-2-dimethylamino naphthalene (Laurdan) fluorescence studies showed that presence of PI induces the formation of fluid phases in DMPC. Differential scanning calorimetry (DSC), temperature dependent fluorescence anisotropy measurements, and generalized polarization values for Laurdan showed that the presence of as low as 10mol% of PI induces substantial broadening and shift to lower temperature of phase transition of DMPC. The fluorescence emission intensity of DPH labeled, PI containing DMPC lipid bilayer decreased possibly due to deeper penetration of water molecules in lipid bilayer. In order to further delineate the effect of PI on the physico chemical properties of DMPC is due to either significant hydrophobic mismatch between the acyl chains of the DMPC and that of soy PI or due to the inositol head group, we systematically replaced soy PI with PC species of similar acyl chain composition (DPPC and 18:2 (Cis) PC) or with diacylglycerol (DAG), respectively. The anisotropy of PC membrane containing soy PI showed largest fluidity change compared to other compositions. The data suggests that addition of PI alters structure and dynamics of DMPC bilayer in that it promotes deeper water penetration in the bilayer, induces fluid phase characteristics and causes lipid packing defects that involve its inositol head group. 相似文献
6.
Nagarajan Muthukaman Sanjay Deshmukh Macchindra Tambe Dnyandeo Pisal Shital Tondlekar Mahamadhanif Shaikh Neelam Sarode Vidya G. Kattige Pooja Sawant Monali Pisat Vikas Karande Srinivasa Honnegowda Abhay Kulkarni Dayanidhi Behera Satyawan B. Jadhav Ramchandra R. Sangana Girish S. Gudi Neelima Khairatkar-Joshi Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2018,28(7):1211-1218
In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160–950?nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6?mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106?mg/kg). 相似文献
7.
Abhisek Banerjee Lakshminarayana Narayana Firoj A. Raje Dnyandeo V. Pisal Pradip A. Kadam Srinivas Gullapalli Hemant Kumar Sandeep V. More Malini Bajpai Ramachandra Rao Sangana Satyawan Jadhav Girish S. Gudi Neelima Khairatkar-Joshi Ravi R.T. Merugu Sreedhara R. Voleti Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2013,23(24):6747-6754
The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a–d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis. 相似文献
8.
Nagarajan Muthukaman Macchindra Tambe Sanjay Deshmukh Dnyandeo Pisal Shital Tondlekar Mahamadhanif Shaikh Neelam Sarode Vidya G. Kattige Monali Pisat Pooja Sawant Srinivasa Honnegowda Vikas Karande Abhay Kulkarni Dayanidhi Behera Satyawan B. Jadhav Ramchandra R. Sangana Girish S. Gudi Neelima Khairatkar-Joshi Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2017,27(23):5131-5138
This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50?nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3?mg/kg in guinea pig. 相似文献
9.
The purpose of this research was to evaluate in vitro transnasal sustained-release ability of sorbitan monostearate (SMS)
organogels in isopropyl myristate (IM). Organogels were prepared containing SMS (2.5%–20%) and water (5%–25%) in IM and analyzed
microscopically for phase behavior. The effect of Tween surfactants on gel strength and in vitro nasal diffusion of propranolol
is reported. The in vitro nasal release retardant effect of SMS and Tween 20 was investigated using factorial design. The
microscopic changes in structure of organogel during in vitro nasal diffusion were studied. The water-holding capacity of
SMS organogels in IM increased with SMS concentration. The release retardant effect with incorportation of cosurfactant was
of the order of Tween 80> Tween 60> Tween 20. Gel strengthening and increased viscosity were evident with increased concentration
of SMS and Tween 20. The 3-dimensional network of SMS molecules controls the diffusional drug release. The organogel system
on nasal mucosa during diffusion is dynamic in nature and changes continuously with the time of diffusion. The water penetration
in the organogel network results in percolation and emulsification of organogel, thus affecting the release. Organogels provided
an effective barrier for diffusion of propranolol. The surface epithelium lining and the granular cellular structure of treated
nasal mucosa were intact. 相似文献
10.
Deepali Sundrani Vinita Khot Hemlata Pisal Savita Mehendale Girija Wagh Asmita Joshi Sadhana Joshi 《PloS one》2013,8(1)