Cytotoxic effect of transdermal invasomal anastrozole gel on MCF-7 breast cancer cell line

Introduction: Anastrozole is an anti-cancer drug, an effective aromatase inhibitor for the treatment of breast cancerin post-menopausal women. As it undergoes extensive first-pass metabolism and has many side effects related to oraluse, it has been envisaged to develop anastrozole invasomes in the form of transdermal gel.Objective: The objective of this work was to prepare, characterize, and evaluate invasomal gel of anastrozole.Materials and Methods: Invasomes were prepared by thin layer film hydration method using Phospholipon 80H,fenchone (terpene), and ethanol. The optimized invasomes were incorporated into sodium carboxy methyl cellulosegel. Prepared formulations were evaluated and cytotoxic study on Michigan cancer foundation (MCF)-7 cancer cellline was studied.Results and Discussion: The scanning electron microscope results of the optimized formulation showed sphericalshaped vesicles.The ex vivo permeation of invasomes and the skin deposition (73%) were studied on male Wistar ratskin. Cell line studies on MCF-7 cells showed cytotoxic effect of optimized formulation at 5 µl/ml.Conclusion: It was concluded that the developed anastrozole invasomes enhanced the transdermal flux and theresults obtained encouraged the use of the anastrozole invasomal gel for the potential treatment of breast cancer inpost-menopausal women.

Cytotoxic effect of transdermal invasomal anastrozole gel on MCF-7 breast cancer cell line

Introduction: Anastrozole is an anti-cancer drug, an effective aromatase inhibitor for the treatment of breast cancerin post-menopausal women. As it undergoes extensive first-pass metabolism and has many side effects related to oraluse, it has been envisaged to develop anastrozole invasomes in the form of transdermal gel.Objective: The objective of this work was to prepare, characterize, and evaluate invasomal gel of anastrozole.Materials and Methods: Invasomes were prepared by thin layer film hydration method using Phospholipon 80H,fenchone (terpene), and ethanol. The optimized invasomes were incorporated into sodium carboxy methyl cellulosegel. Prepared formulations were evaluated and cytotoxic study on Michigan cancer foundation (MCF)-7 cancer cellline was studied.Results and Discussion: The scanning electron microscope results of the optimized formulation showed sphericalshaped vesicles.The ex vivo permeation of invasomes and the skin deposition (73%) were studied on male Wistar ratskin. Cell line studies on MCF-7 cells showed cytotoxic effect of optimized formulation at 5 µl/ml.Conclusion: It was concluded that the developed anastrozole invasomes enhanced the transdermal flux and theresults obtained encouraged the use of the anastrozole invasomal gel for the potential treatment of breast cancer inpost-menopausal women

Novel core in cup (In-lay) tablets of lamotrigine for mucoadhesive drug delivery system.

Lamotrigine a BCS class II drug used in treatment of epilepsy has several disadvantages when taken orally (first pass metabolism and increased Cmax). The aim of the study is to design core in cup (In lay) buccoadhesive tablets which aims for controlled, unidirectional release, increased patient compliance and decreased side effects. The present study involves the preparation of core in cup tablets containing release retarding polymers like sodium alginate, xanthan gum and HPMC E 15LV in core and HPMC K 15M in cup for mucoadhesion. L9 orthogonal array Taguchi design was constructed for the study. The dependent variable studied for L9 orthogonal array Taguchi runs include % drug release from which the formulation with highest S/N ratio was optimized. All the runs were evaluated for physical parameters, drug release, mucoadhesive studies and assay. L1, L2, L4 and L8 formulations showed controlled release for up-to 8 hours with good assay values. The model dependent kinetics showed zero order kinetics with super case II transport and Hixson Crowell mechanism which indicates unidirectional drug release.

Design and Optimization of Hydrodynamically Balanced Oral In situ Gel of Glipizide.

Objective: The purpose of the present investigation was to formulate hydrodynamically balanced oral In situ gel of glipizide inorder to increase the gastric residence time and to modulate the release behavior of the drug. Material and method: In situgel formulations were prepared by using different concentrations of sodium alginate, calcium carbonate, trisodium citrate and release retardant polymers. pH triggered ionic gelation is the mechanism involved in the present study. Taguchi L9 OA experimental design was employed for the optimization of formulations. All the formulations were subjected to various evaluation parameters. Results: Formulation F9 containing 3% of sodium alginate, 1.0 % of CaCO3, 0.2% of trisodium citrate and 0.5% of HPMC-K100M was selected as optimized batch based on Q12 58.26%, floating time 47.76 sec and drug content 98.2%. The release pattern of drug was found to follow first order. The value of ‘n’ from Korsemeyer equation was found to be 1.00 indicating the drug release by supercase II. The DSC study revealed that there was no incompatibility. Gastroretentive X-ray imaging study on Albino rabbit demonstrated that it was able to float in the stomach for more than 8hrs. Pharmacodynamic study on Wistar rats demonstrated significant hypoglycaemic activity of the optimized formulation. Conclusion: It was concluded that the hydrodynamically balanced oral In situ gel of glipizide could be an effective dosage form which remains buoyant and sustain the drug release for 24hrs.

Effect of synthetic super disintegrants and natural polymers in the preparation of donepezil hydrochloride fast disintegration films.

The main aim of the present research was to develop a fast dissolving oral polymeric film with good mechanical properties, faster disintegration and dissolution when placed on tongue. Donepezil hydrochloride (DPH) is prescribed in the treatment of mild to moderate Alzheimer’s disease (AD). The polymers selected for preparing films were sodium alginate (SA), poly vinyl alcohol (PVA) and guar gum (GG). Three batches of films were prepared by solvent casting method with sodium alginate, sodium alginate & PVA and with the combination of sodium alginate & guar gum. From these three batches, three optimized film formulations S3, SP7 and SG8 were selected based on disintegration time. To these three selected film formulations, superdisintegrants sodium starch glycolate (SSG), cross carmellose sodium (CCS) and cross povidone (CP) were added at a concentration of 4% w/w of polymer to improve the disintegration time. The films prepared with or without superdisintegrants were compared for fast releasing properties. Based on DT and in vitro dissolution data, S3CP was selected as the best formulation among the all formulations.

Effect of synthetic super disintegrants and natural polymers in the preparation of donepezil hydrochloride fast disintegration films.

The main aim of the present research was to develop a fast dissolving oral polymeric film with good mechanical properties, faster disintegration and dissolution when placed on tongue. Donepezil hydrochloride (DPH) is prescribed in the treatment of mild to moderate Alzheimer’s disease (AD). The polymers selected for preparing films were sodium alginate (SA), poly vinyl alcohol (PVA) and guar gum (GG). Three batches of films were prepared by solvent casting method with sodium alginate, sodium alginate & PVA and with the combination of sodium alginate & guar gum. From these three batches, three optimized film formulations S3, SP7 and SG8 were selected based on disintegration time. To these three selected film formulations, superdisintegrants sodium starch glycolate (SSG), cross carmellose sodium (CCS) and cross povidone (CP) were added at a concentration of 4% w/w of polymer to improve the disintegration time. The films prepared with or without superdisintegrants were compared for fast releasing properties. Based on DT and in vitro dissolution data, S3CP was selected as the best formulation among the all formulations.

Synergistic effect of iontophoresis and chemical enhancers on transdermal permeation of tolterodine tartrate for the treatment of overactive bladder

Purpose The objective of the study was to evaluate the synergistic transdermal permeation effect of chemical enhancers and iontophoresis technique on tolterodine tartrate (TT) transdermal gel and to evaluate its pharmacokinetic properties. Materials and Methods Taguchi robust design was used for optimization of formulations. Skin permeation rates were evaluated using the Keshary-chein type diffusion cells in order to optimize the gel formulation. In-vivo studies of the optimized formulation were performed in a rabbit model and histopathology studies of optimized formulation were performed on rats. Results Transdermal gels were formulated successfully using Taguchi robust design method. The type of penetration enhancer, concentration of penetration enhancer, current density and pulse on/off ratio were chosen as independent variables. Type of penetration enhancer was found to be the significant factor for all the responses. Permeation parameters were evaluated when maximum cumulative amount permeated in 24 hours (Q24) was 145.71 ± 2.00µg/cm2 by CIT4 formulation over control (91.89 ± 2.30µg/cm2). Permeation was enhanced by 1.75 fold by CIT4 formulation. Formulation CIT4 containing nerolidol (5%) and iontophoretic variables applied (0.5mA/cm2 and pulse on/off ratio 3:1) was optimized. In vivo studies with optimized formulation CIT4 showed increase in AUC and T1/2 when compared to oral suspension in rabbits. The histological studies showed changes in dermis indicating the effect of penetration enhancers and as iontophoresis was continued only for two cycles in periodic fashion so it did not cause any skin damage observed in the slides. Conclusion Results indicated that iontophoresis in combination with chemical enhancers is an effective method for transdermal administration of TT in the treatment of overactive bladder. .

Development of ethosomes with taguchi robust design-based studies for transdermal delivery of alfuzosin hydrochloride.

In the present investigation efficiency of ethosomes as novel lipid carriers for transdermal delivery of Alfuzosin Hydrochloride (AH) has been evaluated. Taguchi robust design method was used for optimization of ethosomal formulations. Phospholipid type, concentration of phospholipid and concentration of ethanol was selected as independent variables and their effect on the dependent variables (entrapment efficiency and flux) was studied. Ethosomal formulation (EA8) with soya phosphatidylcholine (3%) and ethanol 20% were optimized. Vesicles were spherical, unilamellar with smooth surface. The optimized formulation exhibited vesicle size (6.85 ± 1.35μm), zeta potential (-8.14 ± 0.62mv), entrapment efficiency (91.86 ± 3.25%), flux (27.42 ± 0.04μg/cm2/hr), lag time (0.26±0.20hr) and skin deposition (298.01 ± 15.4μg/g). Transdermal flux was enhanced by 6.92 times over drug solution. Vesicle skin interaction studies showed fatty change in the dermis. The formulations were stable at 4°C for 120 days. Results suggested ethosomes as efficient carriers for AH transdermal delivery.

Preparation and Evaluation of Modified Proniosomal Gel for Localised Urticaria and Optimisation by Statistical Method.

The objective of the study was to formulate a modified proniosomal gel (HMPG) of hydroxyzine hydrochloride. HMPG formulations were prepared by coacervation phase separation technique with different combination of non-ionic surfactants (Tweens and Spans) with phospholipids such as phospholipon 80H and 90H. Taguchi design of experiments was used to optimize the various formulation variables. The optimized HMPG formulations were evaluated for entrapment efficiency, vesicle size, SEM, FTIR, in vitro diffusion study, exvivo permeation, skin deposition, skin irritation and stability studies. Tween 60: Span 40 with Phospholipon 90 H formulation (H90-5) showed the highest entrapment efficiency of 94.8%. In vitro drug release was found to be as low as 1.33%, exvivo drug permeation into the skin showed only 1.18 % and drug deposition in the SC was found to be 88.24% at the end of 24 hr. The H90-5 formulation was found to be stable for three months at refrigeration temperature. The results revealed that modified proniosomal formulations of hydroxyzine hydrochloride were suitable for topical drug delivery system for the treatment of localized urticaria.

Overview of P-glycoprotein inhibitors: a rational outlook

P-glycoprotein (P-gp), a transmembrane permeability glycoprotein, is a member of ATP binding cassette (ABC) super family that functions specifically as a carrier mediated primary active efflux transporter. It is widely distributed throughout the body and has a diverse range of substrates. Several vital therapeutic agents are substrates to P-gp and their bioavailability is lowered or a resistance is induced because of the protein efflux. Hence P-gp inhibitors were explored for overcoming multidrug resistance and poor bioavailability problems of the therapeutic P-gp substrates. The sensitivity of drug moieties to P-gp and vice versa can be established by various experimental models in silico, in vitro and in vivo. Ever since the discovery of P-gp, the research plethora identified several chemical structures as P-gp inhibitors. The aim of this review was to emphasize on the discovery and development of newer, inert, non-toxic, and more efficient, specifically targeting P-gp inhibitors, like those among the natural herb extracts, pharmaceutical excipients and formulations, and other rational drug moieties. The applications of cellular and molecular biology knowledge, in silico designed structural databases, molecular modeling studies and quantitative structure-activity relationship (QSAR) analyses in the development of novel rational P-gp inhibitors have also been mentioned.

Glicoproteína-p (P-gp), uma glicoproteína de transmembrana permeável, é um membro da superfamília (ABC) de cassete de gene de ligação de ATP que funciona especificamente como um carreador mediado pelo transportador de efluxo ativo primário. É amplamente distribuído por todo o corpo e apresenta uma gama diversificada de substratos. Diversos agentes terapêuticos vitais são substratos para P-gp e sua biodisponibilidade é reduzida ou a resistência é induzida devido ao efluxo de proteínas. Portanto, os inibidores da P-gp foram explorados para a superação da resistência a múltiplas drogas e problemas de biodisponibilidade deficiente dos substratos terapêuticos da P-gp. A sensibilidade das moléculas da droga à P-gp e vice-versa, pode ser estabelecida por vários modelos experimentais in silico, in vitro e in vivo. Desde a descoberta da P-gp, diversas pesquisas identificaram várias estruturas químicas como inibidores da P-gp. O objetivo deste presente estudo foi o de enfatizar a descoberta e desenvolvimento de inibidores mais novos, inertes, atóxicos e mais eficazes, visando especificamente os da P-gp, como aqueles entre os extratos vegetais, excipientes e formulações farmacêuticas, e outras moléculas racionais de droga. As aplicações do conhecimento de biologia celular e molecular, bancos de dados estruturais in silico, estudos de modelagem molecular e análises da relação quantitativa estrutura-atividade (QSAR) no desenvolvimento de novos inibidores racionais da P-gp também foram mencionados.

Development of ethosomes with taguchi robust design-based studies for transdermal delivery of alfuzosin hydrochloride.

In the present investigation efficiency of ethosomes as novel lipid carriers for transdermal delivery of Alfuzosin Hydrochloride (AH) has been evaluated. Taguchi robust design method was used for optimization of ethosomal formulations. Phospholipid type, concentration of phospholipid and concentration of ethanol was selected as independent variables and their effect on the dependent variables (entrapment efficiency and flux) was studied. Ethosomal formulation (EA8) with soya phosphatidylcholine (3%) and ethanol 20% were optimized. Vesicles were spherical, unilamellar with smooth surface. The optimized formulation exhibited vesicle size (6.85 ± 1.35μm), zeta potential (-8.14 ± 0.62mv), entrapment efficiency (91.86 ± 3.25%), flux (27.42 ± 0.04μg/cm2/hr), lag time (0.26±0.20hr) and skin deposition (298.01 ± 15.4μg/g). Transdermal flux was enhanced by 6.92 times over drug solution. Vesicle skin interaction studies showed fatty change in the dermis. The formulations were stable at 4°C for 120 days. Results suggested ethosomes as efficient carriers for AH transdermal delivery.

Formulation and evaluation of Diphenhydramine hydrochloride and Ibuprofen soft gelatin capsules.

The present invention provides a new composition for treating pain-associated sleep disturbances, especially shortened sleep duration, comprising ibuprofen and diphenhydramine hydrochloride. In the present work the soft gelatin capsules were formulated comprising 25 mg diphenhydramine hydrochloride and 200 mg ibuprofen using polyethylene glycol 400, propylene glycol, potassium hydroxide and purified water. The prepared soft gelatin capsules were evaluated for weight variation test, assay, dissolution and disintegration. The capsules had a fill weight of 550 ± 5%, Disintegration time of 5-6 minutes and showed 97.00% to 99.50% of labeled amount of ibuprofen and diphenhydramine hydrochloride indicating uniformity in drug contents. The capsules containing 75 mg/capsule of propylene glycol released 99.40% of diphenhydramine hydrochloride and 99.70% of ibuprofen at the end of 60 minutes. Thus, it may be concluded that soft gelatin capsules of diphenhydramine hydrochloride and ibuprofen could be successfully prepared with existing technology and machinery which have a commercial viability and enhance patient compliance with improved bioavailability.

Niosomal methotrexate gel in the treatment of localized psoriasis: phase I and phase II studies.

BACKGROUND: Efficacy of topical methotrexate in psoriasis is limited by its penetration. AIMS: The study involved the preparation of niosomal methotrexate in chitosan gel and to test the same for irritation and sensitization on healthy human volunteers followed by assessing the efficacy of the gel through double-blind placebo-controlled study on psoriasis patients and also comparing its efficacy with a marketed methotrexate gel. METHODS: The methotrexate niosomes were prepared by lipid layer hydration method. The characterized niosomes were incorporated in chitosan gel. The gels were tested on 10 human volunteers to check for irritation and skin sensitivity by human repeated insult patch test (HRIPT). The formulations were assessed for efficacy by double-blind placebo-controlled study in 10 psoriasis patients for each formulation. The efficacy was calculated by psoriasis area and severity index scoring method. The global score was used to assess the progress of the disease. RESULTS: The HRIPT test did not produce any significant irritation or sensitization on healthy human volunteers. The placebo and marketed gels were compared with niosomal methotrexate gel. At Week 12, with niosomal methotrexate gel, there was reduction in total score from 6.2378+/-1.4857 to 2.0023+/-0.1371. CONCLUSION: These results suggest that niosomal methotrexate gel is more efficacious than placebo and marketed methotrexate gel.

Prices & availability of common medicines at six sites in India using a standard methodology.

BACKGROUND & OBJECTIVE: The price and availability of medicines are key components in determining access to effective treatment. Data on prices and availability of common medicines in public and private sector in different States of India are scarce. Hence, surveys were undertaken in different States of India to evaluate these metrics. METHODS: During October 2004 to January 2005, six surveys were undertaken simultaneously in five States of India to assess medicine prices and availability of essential medicines (n = 21-28) using the World Health Organization and Health Action International methodology. Surveys were conducted at Chennai, Haryana, Karnataka, West Bengal, and at two sites in Maharashtra. For each medicine, data were collected for the Innovator Brand (IB), Most Sold Generic (MSG), and Lowest Priced Generic (LPG) at randomly selected public and private facilities in each site surveyed. Prices were compared to an international reference benchmark (expressed as median price ratio - MPR). RESULTS: The procurement price of medicines in the public sector was 0.27 to 0.48 times the international reference price. However, these medicines were inadequately available and the median availability in the public sector ranged from 0 to 30 per cent. The median prices of medicines in the private sector were less than twice the IRP, although a few innovator brands were more expensive. No difference was observed between the prices of the most sold generic (MSG) and the lowest priced generic (LPG) available at the facilities. Interestingly, price variation was observed among different generic equivalents of ciprofloxacin in each region. The price of LPG diazepam in the private sector was thirty three times its procurement price in the public sector. INTERPRETATION & CONCLUSION: The survey revealed low procurement prices and poor availability in the public sector. Thus, the majority of the population purchased medicines from private pharmacies, where generics were usually available although prices of certain medicines were high. Various policy measures could increase the availability and accessibility of medicines for the population.