Sridhar Duvvuri | University of Missouri Kansas City (original) (raw)

Papers by Sridhar Duvvuri

Alzheimer's & Dementia, 2012

Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics, 2007

The aim of this study was to develop a formulation for intravitreal delivery by dispersing gancic... more The aim of this study was to develop a formulation for intravitreal delivery by dispersing ganciclovir (GCV)-loaded Poly(d,L-lactide-co-glycolide (PLGA) microspheres in thermogelling PLGA-PEG-PLGA gel and to study the mechanism of drug-release characteristics both in vitro and in vivo. PLGA microspheres of GCV were prepared by the solvent evaporation method from Resomer RG 502H (D,L-lactide:glycolide::50:50; Mw, 8000 Da) and a 1:3 polymer blend of Resomer RG 502H and PLGA 6535 (D,L-lactide:glycolide::65:35; Mw, 45,000-75,000 Da). The prepared microspheres were dispersed uniformly and as a mixture (1:1) in 23% w/w of PLGA-PEG-PLGA aqueous gel solutions. GCV release in the aqueous medium was studied in vitro. A conscious rabbit microdialysis model with permanently implanted probes was selected as the method for investigating the vitreous GCV levels following an intravitreal administration of the formulation. The formulation prepared, by a physical mixture of microspheres, was prepared...

Advanced drug delivery reviews, Jan 13, 2005

Posterior segment drug delivery challenges inherent in the treatment of many sight-threatening di... more Posterior segment drug delivery challenges inherent in the treatment of many sight-threatening diseases have become increasingly apparent. Therapeutic interventions for ocular diseases such as neovascular retinopathies, inflammatory and/or infectious diseases may involve drug delivery to vitreoretinal targets. An important part of successful therapeutic strategies for such diseases involves verification that efficacious concentrations of the pharmacological agent are achieved within relevant intraocular regions. Microdialysis has been effectively employed for characterizing intraocular disposition in both anterior and posterior segments, providing important documentation of successful drug delivery to desired targets. Recent papers that showcase the maturation in the model development of microdialysis approaches for estimating posterior segment pharmacokinetics and further validation of the methodology are described in this review. Special problems examined include anterior and post...

Journal of controlled release : official journal of the Controlled Release Society, Jan 28, 2005

The purpose of this work is to develop empirical equations for describing the in vitro ganciclovi... more The purpose of this work is to develop empirical equations for describing the in vitro ganciclovir (GCV) release from PLGA microspheres and also to develop and characterize a formulation containing GCV loaded PLGA microspheres dispersed in thermogelling PLGA-PEG-PLGA polymer gel. Effect of polymer chain length and polymer blending on GCV entrapment and release from PLGA microspheres is also examined. PLGA microspheres of GCV were prepared from two polymers PLGA 6535 (d,l-lactide:glycolideColon, two colons65:35, Mw=45,000-75,000 Da) and Resomer RG 502H (d,l-lactide:glycolideColon, two colons50:50, Mw=8000 Da) and a 3:1 mixture. PLGA-PEG-PLGA polymer was synthesized and characterized. In vitro GCV release studies were conducted with microspheres and microspheres dispersed in 23% w/v PLGA-PEG-PLGA solution. Polymer blended microspheres entrap more GCV (72.67+/-2.49%) than both PLGA 6535 (51.37+/-2.7%) and Resomer RG 502H (47.13+/-1.13%) microspheres. In vitro drug release data was fit ...

Expert opinion on biological therapy, 2003

Retinal drug delivery is a challenging area in the field of ophthalmic drug delivery. An ideal dr... more Retinal drug delivery is a challenging area in the field of ophthalmic drug delivery. An ideal drug delivery system for the retina and vitreous humor has not yet been found, despite extensive research. Drug delivery to retinal tissue and vitreous via systemic administration is constrained due to the presence of a blood-retinal barrier (BRB) which regulates permeation of substances from blood to the retina. Although intravitreal administration overcomes this barrier, it is associated with several other problems. In recent years, transporter targeted drug delivery has become a clinically significant drug delivery approach for enhancing the bioavailabilities of drug molecules with poor membrane permeability characteristics. Various nutrient transporters, which include peptide, amino acid, folate, monocarboxylic acid transporters and so on, have been reported to be expressed on the retina and BRB. Prodrug derivatisation of drug molecules which target these transporters could result in e...

Advanced Drug Delivery Reviews, 2004

The bioavailability of drugs is often severely limited due to the presence of biological barriers... more The bioavailability of drugs is often severely limited due to the presence of biological barriers in the form of epithelial tight junctions, efflux proteins and enzymatic degradation. Physicochemical properties, such as lipophilicity, molecular weight, charge, etc., also play key roles in determining the permeation properties of drug candidates. As a result, many potential drug candidates may be dropped from the

Pharmaceutical Research, 2006

The aim of the study is to investigate the effect of polymer blending on entrapment and release o... more The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(D,L-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations. Two grades of PLGA, PLGA 7525 [D,L-lactide:glycolide(75:25), MW 90,000-126,000 Da] and Resomer RG 502H [D,L-lactide:glycolide(50:50), MW 8000 Da], were employed in the preparation of PLGA microspheres. Five sets of microsphere batches were prepared with two pure polymers and their 1:3, 1:1, and 3:1 blends. Drug entrapment, surface morphology, particle size analysis, drug release, and differential scanning calorimetric studies were performed. In vitro drug-release data were fitted to a set of empirical sigmoidal equations by nonlinear regression analysis that could effectively predict various parameters that characterize both diffusion and degradation cum diffusion-controlled release phases of GCV. Entrapment efficiencies of GCV ranged from 47 to 73%. Higher amounts of GCV were entrapped in polymer blend microspheres relative to individual polymers. Triphasic GCV release profiles were observed, which consisted of both diffusion and degradation cum diffusion-controlled phases. In vitro GCV release was shortest for Resomer RG 502H microsphere (10 days) and longest for PLGA 7525 microspheres (90 days). Upon blending, the duration of release gradually decreased as the content of Resomer RG 502H in the matrix was raised. Equations effectively estimated the drug-release rate constants during both the phases with high R2 values (>0.990). GCV release was slower from the blend microsphere during the initial diffusion phase. Majority of entrapped drug (70-95%) was released during the matrix degradation cum diffusion phase. Drug entrapment and release parameters estimated by the equations indicate more efficient matrix packing between PLGA 7525 and Resomer RG 502H in polymer-blended microspheres. The overall duration of drug release diminishes with rising content of Resomer RG 502H in the matrix. Differential scanning calorimetry studies indicate stronger binding between the polymers in the PLGA 7525/Resomer RG 502HColon, two colons 3:1 blend. Polymer blending can effectively alter drug-release rates of controlled delivery systems in the absence of any additives.

Journal of Ocular Pharmacology and Therapeutics, 2010

The purpose of this study was to evaluate partitioning into and transport across posterior segmen... more The purpose of this study was to evaluate partitioning into and transport across posterior segment tissues (sclera, retinal pigment epithelium (RPE)-choroid) of AL-4940, the active metabolite of angiostatic cortisene anecortave acetate (AL-3789). Transport of [(14)C]-AL-4940 was measured through RPE-choroid-sclera (RCS) and sclera, excised from Dutch Belted pigmented rabbits' eyes, in the directions of scleral to vitreal (S-->V) and vitreal to scleral (V-->S) for 3 h at 37 degrees C using Ussing chambers. Tissue integrity was monitored by transepithelial electrical resistance (TEER), potential difference (PD), and biochemical assay (LDH). Partitioning in RPE-choroid and sclera was determined separately for both [(14)C]-AL-4940 and [(14)C]-AL-3789. Mathematical analysis for bilaminate membranes used partitioning and transport data to derive diffusion coefficients for 2 tissue layers sclera and RPE-choroid. Partitioning of drug in tissue was comparable for both [(14)C]-AL-4940 and [(14)C]-AL-3789. Partition coefficients of drug in tissue were 2.2 for sclera and about 4 for RPE-choroid. Permeability through sclera alone was about 3 x 10(-5) cm/s and about 1 x 10(-5) cm/s through the RCS tissue, irrespective of the direction of transport (S-->V) or (V-->S). Results from bioelectrical and biochemical evaluation of tissue with modified LDH assay provided evidence that the RCS tissue preparation remained viable during the period of transport study. The thin RPE-choroid layer contributes significantly to resistance to drug transport, and diffusivity in this layer is 10 times less than in sclera. This experimental scheme is proposed as an important component for the development of a general ocular physiologically based pharmacokinetic model.

Journal of Ocular Pharmacology and Therapeutics, 2007

The aim of this study was to develop a formulation for intravitreal delivery by dispersing gancic... more The aim of this study was to develop a formulation for intravitreal delivery by dispersing ganciclovir (GCV)-loaded Poly(d,L-lactide-co-glycolide (PLGA) microspheres in thermogelling PLGA-PEG-PLGA gel and to study the mechanism of drug-release characteristics both in vitro and in vivo. PLGA microspheres of GCV were prepared by the solvent evaporation method from Resomer RG 502H (D,L-lactide:glycolide::50:50; Mw, 8000 Da) and a 1:3 polymer blend of Resomer RG 502H and PLGA 6535 (D,L-lactide:glycolide::65:35; Mw, 45,000-75,000 Da). The prepared microspheres were dispersed uniformly and as a mixture (1:1) in 23% w/w of PLGA-PEG-PLGA aqueous gel solutions. GCV release in the aqueous medium was studied in vitro. A conscious rabbit microdialysis model with permanently implanted probes was selected as the method for investigating the vitreous GCV levels following an intravitreal administration of the formulation. The formulation prepared, by a physical mixture of microspheres, was prepared from Resomer RG 502H, and the polymer blend exhibited fairly constant in vitro GCV release profiles. The amounts of GCV entrapped in the microspheres were sufficient to administer therapeutically relevant doses in 60 microL of the formulation. The vitreal elimination half-life of GCV in the conscious rabbit microdialysis model was 6.45 +/- 0.83 h, with an apparent volume of distribution (V(z)) of 1.18 +/- 0.61 mL. A direct vitreous injection of GCV resulted in the maintenance of concentrations in the vitreous for only 54 h, whereas the gel formulation produced steady-state GCV levels in the vitreous for at least 14 days. PLGA microspheres containing GCV were prepared by two kinds of PLGA polymers and their blend (1:3). A formulation suitable for in vivo administration was prepared by dispersing GCV-loaded microspheres in a thermogelling PLGA-PEG-PLGA solution. An ideal in vitro release of encapsulated GCV was obtained by physically mixing microspheres prepared from different polymer blends prior to its dispersion in the thermogelling polymer. The formulation maintained mean vitreal concentrations of GCV at approximately 0.8 microg/mL for 14 days, whereas direct injections could maintain drug levels above 0.8 microg/mL for 54 h only.

Journal of Controlled Release, 2005

The purpose of this work is to develop empirical equations for describing the in vitro ganciclovi... more The purpose of this work is to develop empirical equations for describing the in vitro ganciclovir (GCV) release from PLGA microspheres and also to develop and characterize a formulation containing GCV loaded PLGA microspheres dispersed in thermogelling PLGA-PEG-PLGA polymer gel. Effect of polymer chain length and polymer blending on GCV entrapment and release from PLGA microspheres is also examined. PLGA microspheres of GCV were prepared from two polymers PLGA 6535 (d,l-lactide : glycolide D 65 : 35, Mw = 45,000-75,000 Da) and Resomer RG 502H (d,l-lactide : glycolide D 50 : 50, Mw = 8000 Da) and a 3 : 1 mixture. PLGA-PEG-PLGA polymer was synthesized and characterized. In vitro GCV release studies were conducted with microspheres and microspheres dispersed in 23% w/v PLGA-PEG-PLGA solution. Polymer blended microspheres entrap more GCV (72.67 F 2.49%) than both PLGA 6535 (51.37 F 2.7%) and Resomer RG 502H (47.13 F 1.13%) microspheres. In vitro drug release data was fit to sigmoid equations and release parameters were estimated by nonlinear regression analysis. These equations effectively describe three different phases in GCV release from PLGA microspheres, initial diffusion, matrix hydration and degradation. The amount of drug release during the initial phase decreased for the blend microspheres indicating efficient packing between the PLGA 6535 and Resomer RG 502H in the microsphere matrix. Moreover, upon dispersion into the polymer gel, the rate of drug release during initial diffusion phases slowed relative to microspheres alone. In conclusion, this study reports the development of PLGA microspheres with high payloads and their PLGA-PEG-PLGA gel based formulations. Drug release equations have been developed that effectively describe the triphasic GCV release. D

Current Eye Research, 2003

The objective of this study was to determine the effect of the multi-drug efflux transport protei... more The objective of this study was to determine the effect of the multi-drug efflux transport protein, P-glycoprotein (P-gp), on the ocular distribution of a model substrate, quinidine. Male New Zealand albino rabbits (2-2.5 kg) were employed in these studies. Animals were kept under anesthesia and a concentric microdialysis probe was implanted in the vitreous humor and a linear probe in the anterior chamber. Isotonic phosphate buffered saline was perfused through the probes, and samples were collected every 20 minutes over a period of 10 hours. Quinidine was administered both systemically (5 mg/kg bodyweight) and intravitreally (5.68 microg and 0.568 microg). Inhibition experiments were performed in vivo in the presence of verapamil, which is a known P-gp inhibitor. Vitreal pharmacokinetic parameters of quinidine in the presence of verapamil, i.e., Area under the curve (AUC) (39.27 +/- 6.47 min. microg/ml), maximum concentration achieved (Cmax) (0.095 +/- 0.011 microg/ml), vitreal elimination half-life (231.96 +/- 10.77 min), vitreal permeation half-life (16.57 +/- 6.96 min) were significantly different from the control values (19.21 +/- 3.73 min. microg/ml, 0.05 +/- 0.008 microg/ml, 165.08 +/- 31.5 min, 43.29 +/- 12.5 min respectively). A significant elevation in anterior chamber Cmax and AUC was also observed in the presence of verapamil. Verapamil had no significant effect on vitreal kinetics of quinidine following intravitreal dose of 5.68 micro g, but a significant difference was observed at a lower dose of quinidine (0.568 microg). A decrease in vitreal elimination half-life and AUC was observed in the presence of verapamil relative to control. Ocular kinetics of fluorescein was studied to ascertain ocular barrier integrity in the presence of verapamil. Western-blot analysis of retina-choroid sections indicates expression of P-gp on rabbit retina-choroid. Results suggest the involvement of a multi drug efflux transporter on the retinal pigment epithelium and neural retina affecting the intraocular kinetics of its substrates following systemic and intravitreal administrations.

Current Drug Metabolism, 2004

Metabolism is one of the primary routes of drug elimination from the body. This process comprises... more Metabolism is one of the primary routes of drug elimination from the body. This process comprises of mechanisms, such as oxidation and conjugation, which lead to inactivation and/or elimination from hepatic, biliary, pulmonary, renal and ocular tissues. Enzymes involved in metabolism are expressed in various tissues of the body, liver being the primary site. Studies involving ocular tissues have demonstrated the expression of several metabolic enzymes such as esterases, peptidases, ketone reductases, and CYP-450's in these tissues. These enzymes play an important role in ocular homeostasis by preventing entry and/or eliminating xenobiotics from the ocular tissues. Scientists have targeted these enzymes in drug design and delivery through prodrug derivatization. The prodrugs undergo biotransformation to the parent drug by ocular enzymatic degradation. This review examines the distribution pattern of various metabolic enzymes in the ocular tissues, their physiological role and utility in targeted prodrug delivery.

Journal of Oral and Maxillofacial Surgery, 2014

Alzheimer's & Dementia, 2012

Background: 5-HT 4 receptors in cortex and hippocampus area are considered as a possible target f... more Background: 5-HT 4 receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer's disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT 4 modulation in providing beneficial effects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and 5-HT 4 activity as output. The serotonergic model was calibrated using both in vivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated using data reported for working memory tasks in healthy humans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer's disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT 4 activation on working memory and to prospectively simulate the response of PF-04995274, a 5-HT 4 partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT 4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low intrinsic activity 5-HT 4 agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT 4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD patients.

Alzheimer's & Dementia, 2012

Alzheimer's & Dementia, 2012

Alzheimer's & Dementia, 2011

Alzheimer's & Dementia, 2011

Background: As of 2010, rivastigmine patch was licensed for the treatment of Alzheimer's disease ... more Background: As of 2010, rivastigmine patch was licensed for the treatment of Alzheimer's disease (AD) in 64 countries, including those in the EU and the USA. The current study was designed to evaluate the efficacy, safety and tolerability of the 5 cm 2 and 10 cm 2 rivastigmine patch in Japanese patients with AD. > Methods: This was a 24-week, multicenter, randomized, double-blind, placebo-controlled study of the 5 cm 2 (4.6 mg/24 h delivery rate) and 10 cm 2 (9.5 mg/24 h delivery rate) rivastigmine patch in Japanese patients with AD. Eligible participants were outpatients aged 50-85 years, with a diagnosis of dementia of the Alzheimer's type and a Mini-Mental State Examination score of 10-20. Participants were randomized to treatment and titrated to their target patch dose in 2.5 cm 2 increments every 4 weeks, from a starting size of 2.5 cm 2 . Primary efficacy assessments were the Japanese versions of the AD Assessment Scale-cognitive subscale (ADAS-J cog) and the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC plus-J).

Alzheimer's & Dementia, 2013

Alzheimer's & Dementia, 2012

Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics, 2007

The aim of this study was to develop a formulation for intravitreal delivery by dispersing gancic... more The aim of this study was to develop a formulation for intravitreal delivery by dispersing ganciclovir (GCV)-loaded Poly(d,L-lactide-co-glycolide (PLGA) microspheres in thermogelling PLGA-PEG-PLGA gel and to study the mechanism of drug-release characteristics both in vitro and in vivo. PLGA microspheres of GCV were prepared by the solvent evaporation method from Resomer RG 502H (D,L-lactide:glycolide::50:50; Mw, 8000 Da) and a 1:3 polymer blend of Resomer RG 502H and PLGA 6535 (D,L-lactide:glycolide::65:35; Mw, 45,000-75,000 Da). The prepared microspheres were dispersed uniformly and as a mixture (1:1) in 23% w/w of PLGA-PEG-PLGA aqueous gel solutions. GCV release in the aqueous medium was studied in vitro. A conscious rabbit microdialysis model with permanently implanted probes was selected as the method for investigating the vitreous GCV levels following an intravitreal administration of the formulation. The formulation prepared, by a physical mixture of microspheres, was prepared...

Advanced drug delivery reviews, Jan 13, 2005

Posterior segment drug delivery challenges inherent in the treatment of many sight-threatening di... more Posterior segment drug delivery challenges inherent in the treatment of many sight-threatening diseases have become increasingly apparent. Therapeutic interventions for ocular diseases such as neovascular retinopathies, inflammatory and/or infectious diseases may involve drug delivery to vitreoretinal targets. An important part of successful therapeutic strategies for such diseases involves verification that efficacious concentrations of the pharmacological agent are achieved within relevant intraocular regions. Microdialysis has been effectively employed for characterizing intraocular disposition in both anterior and posterior segments, providing important documentation of successful drug delivery to desired targets. Recent papers that showcase the maturation in the model development of microdialysis approaches for estimating posterior segment pharmacokinetics and further validation of the methodology are described in this review. Special problems examined include anterior and post...

Journal of controlled release : official journal of the Controlled Release Society, Jan 28, 2005

The purpose of this work is to develop empirical equations for describing the in vitro ganciclovi... more The purpose of this work is to develop empirical equations for describing the in vitro ganciclovir (GCV) release from PLGA microspheres and also to develop and characterize a formulation containing GCV loaded PLGA microspheres dispersed in thermogelling PLGA-PEG-PLGA polymer gel. Effect of polymer chain length and polymer blending on GCV entrapment and release from PLGA microspheres is also examined. PLGA microspheres of GCV were prepared from two polymers PLGA 6535 (d,l-lactide:glycolideColon, two colons65:35, Mw=45,000-75,000 Da) and Resomer RG 502H (d,l-lactide:glycolideColon, two colons50:50, Mw=8000 Da) and a 3:1 mixture. PLGA-PEG-PLGA polymer was synthesized and characterized. In vitro GCV release studies were conducted with microspheres and microspheres dispersed in 23% w/v PLGA-PEG-PLGA solution. Polymer blended microspheres entrap more GCV (72.67+/-2.49%) than both PLGA 6535 (51.37+/-2.7%) and Resomer RG 502H (47.13+/-1.13%) microspheres. In vitro drug release data was fit ...

Expert opinion on biological therapy, 2003

Retinal drug delivery is a challenging area in the field of ophthalmic drug delivery. An ideal dr... more Retinal drug delivery is a challenging area in the field of ophthalmic drug delivery. An ideal drug delivery system for the retina and vitreous humor has not yet been found, despite extensive research. Drug delivery to retinal tissue and vitreous via systemic administration is constrained due to the presence of a blood-retinal barrier (BRB) which regulates permeation of substances from blood to the retina. Although intravitreal administration overcomes this barrier, it is associated with several other problems. In recent years, transporter targeted drug delivery has become a clinically significant drug delivery approach for enhancing the bioavailabilities of drug molecules with poor membrane permeability characteristics. Various nutrient transporters, which include peptide, amino acid, folate, monocarboxylic acid transporters and so on, have been reported to be expressed on the retina and BRB. Prodrug derivatisation of drug molecules which target these transporters could result in e...

Advanced Drug Delivery Reviews, 2004

The bioavailability of drugs is often severely limited due to the presence of biological barriers... more The bioavailability of drugs is often severely limited due to the presence of biological barriers in the form of epithelial tight junctions, efflux proteins and enzymatic degradation. Physicochemical properties, such as lipophilicity, molecular weight, charge, etc., also play key roles in determining the permeation properties of drug candidates. As a result, many potential drug candidates may be dropped from the

Pharmaceutical Research, 2006

The aim of the study is to investigate the effect of polymer blending on entrapment and release o... more The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(D,L-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations. Two grades of PLGA, PLGA 7525 [D,L-lactide:glycolide(75:25), MW 90,000-126,000 Da] and Resomer RG 502H [D,L-lactide:glycolide(50:50), MW 8000 Da], were employed in the preparation of PLGA microspheres. Five sets of microsphere batches were prepared with two pure polymers and their 1:3, 1:1, and 3:1 blends. Drug entrapment, surface morphology, particle size analysis, drug release, and differential scanning calorimetric studies were performed. In vitro drug-release data were fitted to a set of empirical sigmoidal equations by nonlinear regression analysis that could effectively predict various parameters that characterize both diffusion and degradation cum diffusion-controlled release phases of GCV. Entrapment efficiencies of GCV ranged from 47 to 73%. Higher amounts of GCV were entrapped in polymer blend microspheres relative to individual polymers. Triphasic GCV release profiles were observed, which consisted of both diffusion and degradation cum diffusion-controlled phases. In vitro GCV release was shortest for Resomer RG 502H microsphere (10 days) and longest for PLGA 7525 microspheres (90 days). Upon blending, the duration of release gradually decreased as the content of Resomer RG 502H in the matrix was raised. Equations effectively estimated the drug-release rate constants during both the phases with high R2 values (>0.990). GCV release was slower from the blend microsphere during the initial diffusion phase. Majority of entrapped drug (70-95%) was released during the matrix degradation cum diffusion phase. Drug entrapment and release parameters estimated by the equations indicate more efficient matrix packing between PLGA 7525 and Resomer RG 502H in polymer-blended microspheres. The overall duration of drug release diminishes with rising content of Resomer RG 502H in the matrix. Differential scanning calorimetry studies indicate stronger binding between the polymers in the PLGA 7525/Resomer RG 502HColon, two colons 3:1 blend. Polymer blending can effectively alter drug-release rates of controlled delivery systems in the absence of any additives.

Journal of Ocular Pharmacology and Therapeutics, 2010

The purpose of this study was to evaluate partitioning into and transport across posterior segmen... more The purpose of this study was to evaluate partitioning into and transport across posterior segment tissues (sclera, retinal pigment epithelium (RPE)-choroid) of AL-4940, the active metabolite of angiostatic cortisene anecortave acetate (AL-3789). Transport of [(14)C]-AL-4940 was measured through RPE-choroid-sclera (RCS) and sclera, excised from Dutch Belted pigmented rabbits' eyes, in the directions of scleral to vitreal (S-->V) and vitreal to scleral (V-->S) for 3 h at 37 degrees C using Ussing chambers. Tissue integrity was monitored by transepithelial electrical resistance (TEER), potential difference (PD), and biochemical assay (LDH). Partitioning in RPE-choroid and sclera was determined separately for both [(14)C]-AL-4940 and [(14)C]-AL-3789. Mathematical analysis for bilaminate membranes used partitioning and transport data to derive diffusion coefficients for 2 tissue layers sclera and RPE-choroid. Partitioning of drug in tissue was comparable for both [(14)C]-AL-4940 and [(14)C]-AL-3789. Partition coefficients of drug in tissue were 2.2 for sclera and about 4 for RPE-choroid. Permeability through sclera alone was about 3 x 10(-5) cm/s and about 1 x 10(-5) cm/s through the RCS tissue, irrespective of the direction of transport (S-->V) or (V-->S). Results from bioelectrical and biochemical evaluation of tissue with modified LDH assay provided evidence that the RCS tissue preparation remained viable during the period of transport study. The thin RPE-choroid layer contributes significantly to resistance to drug transport, and diffusivity in this layer is 10 times less than in sclera. This experimental scheme is proposed as an important component for the development of a general ocular physiologically based pharmacokinetic model.

Journal of Ocular Pharmacology and Therapeutics, 2007

The aim of this study was to develop a formulation for intravitreal delivery by dispersing gancic... more The aim of this study was to develop a formulation for intravitreal delivery by dispersing ganciclovir (GCV)-loaded Poly(d,L-lactide-co-glycolide (PLGA) microspheres in thermogelling PLGA-PEG-PLGA gel and to study the mechanism of drug-release characteristics both in vitro and in vivo. PLGA microspheres of GCV were prepared by the solvent evaporation method from Resomer RG 502H (D,L-lactide:glycolide::50:50; Mw, 8000 Da) and a 1:3 polymer blend of Resomer RG 502H and PLGA 6535 (D,L-lactide:glycolide::65:35; Mw, 45,000-75,000 Da). The prepared microspheres were dispersed uniformly and as a mixture (1:1) in 23% w/w of PLGA-PEG-PLGA aqueous gel solutions. GCV release in the aqueous medium was studied in vitro. A conscious rabbit microdialysis model with permanently implanted probes was selected as the method for investigating the vitreous GCV levels following an intravitreal administration of the formulation. The formulation prepared, by a physical mixture of microspheres, was prepared from Resomer RG 502H, and the polymer blend exhibited fairly constant in vitro GCV release profiles. The amounts of GCV entrapped in the microspheres were sufficient to administer therapeutically relevant doses in 60 microL of the formulation. The vitreal elimination half-life of GCV in the conscious rabbit microdialysis model was 6.45 +/- 0.83 h, with an apparent volume of distribution (V(z)) of 1.18 +/- 0.61 mL. A direct vitreous injection of GCV resulted in the maintenance of concentrations in the vitreous for only 54 h, whereas the gel formulation produced steady-state GCV levels in the vitreous for at least 14 days. PLGA microspheres containing GCV were prepared by two kinds of PLGA polymers and their blend (1:3). A formulation suitable for in vivo administration was prepared by dispersing GCV-loaded microspheres in a thermogelling PLGA-PEG-PLGA solution. An ideal in vitro release of encapsulated GCV was obtained by physically mixing microspheres prepared from different polymer blends prior to its dispersion in the thermogelling polymer. The formulation maintained mean vitreal concentrations of GCV at approximately 0.8 microg/mL for 14 days, whereas direct injections could maintain drug levels above 0.8 microg/mL for 54 h only.

Journal of Controlled Release, 2005

The purpose of this work is to develop empirical equations for describing the in vitro ganciclovi... more The purpose of this work is to develop empirical equations for describing the in vitro ganciclovir (GCV) release from PLGA microspheres and also to develop and characterize a formulation containing GCV loaded PLGA microspheres dispersed in thermogelling PLGA-PEG-PLGA polymer gel. Effect of polymer chain length and polymer blending on GCV entrapment and release from PLGA microspheres is also examined. PLGA microspheres of GCV were prepared from two polymers PLGA 6535 (d,l-lactide : glycolide D 65 : 35, Mw = 45,000-75,000 Da) and Resomer RG 502H (d,l-lactide : glycolide D 50 : 50, Mw = 8000 Da) and a 3 : 1 mixture. PLGA-PEG-PLGA polymer was synthesized and characterized. In vitro GCV release studies were conducted with microspheres and microspheres dispersed in 23% w/v PLGA-PEG-PLGA solution. Polymer blended microspheres entrap more GCV (72.67 F 2.49%) than both PLGA 6535 (51.37 F 2.7%) and Resomer RG 502H (47.13 F 1.13%) microspheres. In vitro drug release data was fit to sigmoid equations and release parameters were estimated by nonlinear regression analysis. These equations effectively describe three different phases in GCV release from PLGA microspheres, initial diffusion, matrix hydration and degradation. The amount of drug release during the initial phase decreased for the blend microspheres indicating efficient packing between the PLGA 6535 and Resomer RG 502H in the microsphere matrix. Moreover, upon dispersion into the polymer gel, the rate of drug release during initial diffusion phases slowed relative to microspheres alone. In conclusion, this study reports the development of PLGA microspheres with high payloads and their PLGA-PEG-PLGA gel based formulations. Drug release equations have been developed that effectively describe the triphasic GCV release. D

Current Eye Research, 2003

The objective of this study was to determine the effect of the multi-drug efflux transport protei... more The objective of this study was to determine the effect of the multi-drug efflux transport protein, P-glycoprotein (P-gp), on the ocular distribution of a model substrate, quinidine. Male New Zealand albino rabbits (2-2.5 kg) were employed in these studies. Animals were kept under anesthesia and a concentric microdialysis probe was implanted in the vitreous humor and a linear probe in the anterior chamber. Isotonic phosphate buffered saline was perfused through the probes, and samples were collected every 20 minutes over a period of 10 hours. Quinidine was administered both systemically (5 mg/kg bodyweight) and intravitreally (5.68 microg and 0.568 microg). Inhibition experiments were performed in vivo in the presence of verapamil, which is a known P-gp inhibitor. Vitreal pharmacokinetic parameters of quinidine in the presence of verapamil, i.e., Area under the curve (AUC) (39.27 +/- 6.47 min. microg/ml), maximum concentration achieved (Cmax) (0.095 +/- 0.011 microg/ml), vitreal elimination half-life (231.96 +/- 10.77 min), vitreal permeation half-life (16.57 +/- 6.96 min) were significantly different from the control values (19.21 +/- 3.73 min. microg/ml, 0.05 +/- 0.008 microg/ml, 165.08 +/- 31.5 min, 43.29 +/- 12.5 min respectively). A significant elevation in anterior chamber Cmax and AUC was also observed in the presence of verapamil. Verapamil had no significant effect on vitreal kinetics of quinidine following intravitreal dose of 5.68 micro g, but a significant difference was observed at a lower dose of quinidine (0.568 microg). A decrease in vitreal elimination half-life and AUC was observed in the presence of verapamil relative to control. Ocular kinetics of fluorescein was studied to ascertain ocular barrier integrity in the presence of verapamil. Western-blot analysis of retina-choroid sections indicates expression of P-gp on rabbit retina-choroid. Results suggest the involvement of a multi drug efflux transporter on the retinal pigment epithelium and neural retina affecting the intraocular kinetics of its substrates following systemic and intravitreal administrations.

Current Drug Metabolism, 2004

Metabolism is one of the primary routes of drug elimination from the body. This process comprises... more Metabolism is one of the primary routes of drug elimination from the body. This process comprises of mechanisms, such as oxidation and conjugation, which lead to inactivation and/or elimination from hepatic, biliary, pulmonary, renal and ocular tissues. Enzymes involved in metabolism are expressed in various tissues of the body, liver being the primary site. Studies involving ocular tissues have demonstrated the expression of several metabolic enzymes such as esterases, peptidases, ketone reductases, and CYP-450's in these tissues. These enzymes play an important role in ocular homeostasis by preventing entry and/or eliminating xenobiotics from the ocular tissues. Scientists have targeted these enzymes in drug design and delivery through prodrug derivatization. The prodrugs undergo biotransformation to the parent drug by ocular enzymatic degradation. This review examines the distribution pattern of various metabolic enzymes in the ocular tissues, their physiological role and utility in targeted prodrug delivery.

Journal of Oral and Maxillofacial Surgery, 2014

Alzheimer's & Dementia, 2012

Background: 5-HT 4 receptors in cortex and hippocampus area are considered as a possible target f... more Background: 5-HT 4 receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer's disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT 4 modulation in providing beneficial effects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and 5-HT 4 activity as output. The serotonergic model was calibrated using both in vivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated using data reported for working memory tasks in healthy humans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer's disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT 4 activation on working memory and to prospectively simulate the response of PF-04995274, a 5-HT 4 partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT 4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low intrinsic activity 5-HT 4 agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT 4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD patients.

Alzheimer's & Dementia, 2012

Alzheimer's & Dementia, 2012

Alzheimer's & Dementia, 2011

Alzheimer's & Dementia, 2011

Background: As of 2010, rivastigmine patch was licensed for the treatment of Alzheimer's disease ... more Background: As of 2010, rivastigmine patch was licensed for the treatment of Alzheimer's disease (AD) in 64 countries, including those in the EU and the USA. The current study was designed to evaluate the efficacy, safety and tolerability of the 5 cm 2 and 10 cm 2 rivastigmine patch in Japanese patients with AD. > Methods: This was a 24-week, multicenter, randomized, double-blind, placebo-controlled study of the 5 cm 2 (4.6 mg/24 h delivery rate) and 10 cm 2 (9.5 mg/24 h delivery rate) rivastigmine patch in Japanese patients with AD. Eligible participants were outpatients aged 50-85 years, with a diagnosis of dementia of the Alzheimer's type and a Mini-Mental State Examination score of 10-20. Participants were randomized to treatment and titrated to their target patch dose in 2.5 cm 2 increments every 4 weeks, from a starting size of 2.5 cm 2 . Primary efficacy assessments were the Japanese versions of the AD Assessment Scale-cognitive subscale (ADAS-J cog) and the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC plus-J).

Alzheimer's & Dementia, 2013