Spherical crystal agglomeration technique for improved flow properties and oral bioavailability of atazanavir sulphate.

Aim: The current research focused on formulation of spherical crystal agglomerates (SCA) of atazanavir sulphate for improving flow property and solubility. Materials & methods: SCA were formulated by quasi-emulsification solvent diffusion. Methanol, water and dichloromethane were employed as a good solvent, bad solvent and bridging liquid respectively. Results & conclusion: SCA with improved solubility and micromeritic properties were directly compressed into a tablet. The SCA tablets had higher dissolution rates compared with plain drug and marketed product. In vivo pharmacokinetic studies revealed higher Cmax and AUC0-t of the SCA than marketed product with relative bioavailability of 1.74. The formulation was stable for more than 3 months, with insignificant difference in % drug content and % drug dissolution.

Atazanavir sulphate is a drug used for treatment of AIDS in which the patients are infected with HIV. Presently, it is available as a capsule. The amount of the drug reaching the blood after oral delivery is less due to the poor solubility of the drug. Compared with capsules, tablets are more preferred dosage forms due to its ease of manufacturing and tamper proof nature. In the present research work, we have developed a tablet formulation of the drug, which has improved solubility. The higher solubility leads to greater absorption after oral delivery. Thus the formulation is beneficial to the patients as the dose can be reduced and the treatment can be made more economic.

Carboplatin-loaded ultradeformable vesicles for the management of endometrial cancer: in vitro and in vivo evaluation.

Aim: Present research work aimed to explore intravaginal route for the drug delivery for treatment of endometrial cancer (EC). Material & methods: Carboplatin (CBP)-loaded ultradeformable vesicle (CBP-UDV) was prepared and characterized for in vitro quality attributes and evaluated for its efficacy in rabbits using ultrasound imaging after intravaginal administration. Results & conclusion: The results showed that the formulation capable of carrying and localizing drug in uterus for prolonged period assisted by first uterine pass effect. Ultrasound imaging of the EC-induced rabbit model before and after treatment with CBP-UDV showed considerable regression in the EC tumor mass. The findings serve as the basis of successful utilization of the intravaginal route for management of EC by designing the formulation which can improve patient compliance.

Intranasal spray of cubosomal tizanidine hydrochloride for brain targeting: in vitro and in vivo characterisation.

Tizanidine HCl (TH) is used as first-line therapy for the treatment of muscular spasm. The intranasal cubosomal delivery system of TH for site-specific delivery, i.e. CNS was developed. Cubosomes of TH were prepared using glyceryl monooleate (GMO) as a lipid, poloxamer 407 as stabiliser, and ethanol and polyethylene glycol 200 as co-solvent. Optimised cubosomes of TH were characterised for vesicle size, zeta potential, % drug entrapment, and mucin binding efficiency, which were found to be 50.22 nm, -6.39 mV, 69.28%, and 42.12%. It is also evaluated for CRYO-FESEM, CRYO-TEM, SAXS, residual solvent content, and in vitro drug release. Ex vivo permeation was also conducted at 7.4 and it indicates that almost 93.66% drug was diffused from a formulation in 6 h. Histopathological study of the optimised TH cubosomes suggests that the prepared formulation is non-toxic to the nasal mucosa. Pharmacokinetic and brain distribution study indicates targeted action of the formulated TH cubosomes.

Formulation Development of Fast Dissolving Microneedles Loaded with Cubosomes of Febuxostat: In Vitro and In Vivo Evaluation.

Febuxostat is a widely prescribed drug for the treatment of gout, which is a highly prevalent disease worldwide and is a major cause of disability in mankind. Febuxostat suffers from several limitations such as gastrointestinal disturbances and low oral bioavailability. Thus, to improve patient compliance and bioavailability, transdermal drug delivery systems of Febuxostat were developed for obtaining enhanced permeation. Cubosomes of Febuxostat were prepared using a bottom-up approach and loaded into a microneedle using a micromolding technique to achieve better permeation through the skin. Optimization of the process and formulation parameters were achieved using our design of experiments. The optimized cubosomes of Febuxostat were characterized for various parameters such as % entrapment efficiency, vesicle size, Polydispersity index, Transmission electron microscopy, in vitro drug release, Small angle X-ray scattering, etc. After loading it in the microneedle it was characterized for dissolution time, axial fracture force, scanning electron microscopy, in vitro drug release, pore closure kinetics, etc. It was also evaluated for various ex vivo characterizations such as in vitro cell viability, ex vivo permeation, ex vivo fluorescence microscopy and histopathology which indicates its safety and better permeation. In vivo pharmacokinetic studies proved enhanced bioavailability compared with the marketed formulation. Pharmacodynamic study indicated its effectiveness in a disease-induced rat model. The developed formulations were then subjected to the stability study, which proved its stability.

Formulation considerations for improving intranasal delivery of CNS acting therapeutics.

One of the principal impediments for the treatment of neurological conditions is the lack of ability of most of the medicinal agents to evade the blood-brain barrier. Among all the novel approaches to bypass the blood-brain barrier, nose to brain transport is the most patient compliant, non-invasive and effective approach. It directly transports drugs to the CNS via the trigeminal and olfactory nerves present in the nasal cavity. This review article focuses on anatomy and physiology of nasal cavity, potential of intranasal drug delivery, mechanisms of drug transport to brain, its advantages and limitations, novel intranasal formulations, marketed products, factors affecting nose to brain transport, formulation consideration of intranasal products and the future perspectives of CNS targeting via intranasal drug administration.

Design and pharmacodynamic evaluation of DPK-060 loaded Nanostructured lipid carrier embedded gel for dermal delivery: A novel approach in the treatment of atopic dermatitis.

DPK-060 is a synthetic, 17 amino acid peptide, structurally derived from the human protein kininogen. DPK-060 mainly acts by membrane disruption mechanism, thus demonstrating strong broad-spectrum antimicrobial activity against both gram-positive and gram-negative microbes, including methicillin-resistant S. aureus (MRSA) in-vitro and in-vivo. Apart from its antimicrobial effect, DPK-060 also possesses anti-inflammatory activity. In addition, DPK-060 has demonstrated positive results in phase II clinical trials in atopic dermatitis (AD) patients; but was not statistically conclusive due to the instability of DPK-060 as a drug substance in the formulation. Thus, the present investigation was aimed to assess and compare the efficacy of DPK-060 nanostructured lipid (NLC) based gel with conventional formulations (free DPK-060 gel and lotion) in AD mice animal models. DPK-060 loaded NLCs were formulated by meltemulsification technique and loaded into Carbopol 934 P gel and characterized for various physicochemical parameters such as particle size, zeta-potential, shape and surface morphology, rheological parameters, in-vitro drug release, cytotoxicity, cellular uptake, ex-vivo skin permeation/deposition, in-vitro antimicrobial activity, and proteolytic stability studies. NLCs exhibited 85 % encapsulation with 6.7 % loading efficacy, a size, and zeta potential of 128.6 nm and -22.5 mv, respectively. Additionally, DPK-060 NLC gel demonstrated controlled release and a better permeation profile in comparison to free DPK-060 gel and lotion. A substantial reduction in pro-inflammatory cytokines levels and improvement in AD lesions was achieved by DPK-060 NLC gel compared to free DPK-060 gel and lotion-based formulations. The present study confirms that DPK-060 NLC gel-based formulation can be an effective, safe, and novel alternative for the treatment of AD.

Liposomes encapsulating novel antimicrobial peptide Omiganan: Characterization and its pharmacodynamic evaluation in atopic dermatitis and psoriasis mice model.

Omiganan is a novel 12 amino acid synthetic cationic peptide from the cathelicidin family. Omiganan possesses antimicrobial action against a wide range of microbes, including gram-positive and gram-negative bacteria and fungi. Omiganan mainly acts by depolarizing the cytoplasmic membrane, resulting in cellular disruption and death. Apart from its antimicrobial effect, Omiganan also has anti-inflammatory activity. The present investigation aimed to evaluate and compare the efficacy of Omiganan liposomal gel with conventional formulations (Omiganan gel and lotion) in atopic dermatitis (AD) and psoriasis mice animal models. Liposomes encapsulating Omiganan were prepared using the reverse-phase evaporation technique and incorporated into Carbopol 934P gel. The optimized Omiganan liposomes were then characterized for various physicochemical parameters such as vesicle size, shape and surface morphology, zeta-potential, rheological parameters, in-vitro drug release, ex-vivo skin permeation/deposition, in-vitro antimicrobial activity, proteolytic stability, and cellular toxicity and uptake studies. Liposomes exhibited 72 % encapsulation with 7.8 % loading efficacy, a vesicle size, and zeta potential of 120 nm and - 17.2 mv, respectively. Moreover, Omiganan liposomal gel demonstrated controlled release and a better permeation profile than conventional formulations. A substantial reduction in levels of pro-inflammatory cytokines and improvement in AD and psoriatic lesions were achieved by Omiganan liposomal gel compared to Omiganan gel and lotion-based formulations. The present study confirms that Omiganan liposomal formulation can be an effective, safe, and novel alternative treatment approach in atopic dermatitis and psoriasis.

Polymer-drug conjugates: Design principles, emerging synthetic strategies and clinical overview.

Adagen, an enzyme replacement treatment for adenosine deaminase deficiency, was the first protein-polymer conjugate to be approved in early 1990 s. Post this regulatory approval, numerous polymeric drugs and polymeric nanoparticles have entered the market as advanced or next-generation polymer-based therapeutics, while many others have currently been tested clinically. The polymer conjugation to therapeutic moiety offers several advantages, like enhanced solubilization of drug, controlled release, reduced immunogenicity, and prolonged circulation. The present review intends to highlight considerations in the design of therapeutically effective polymer-drug conjugates (PDCs), including the choice of linker chemistry. The potential synthetic strategies to formulate PDCs have been discussed along with recent advancements in the different types of PDCs, i.e., polymer-small molecular weight drug conjugates, polymer-protein conjugates, and stimuli-responsive PDCs, which are under clinical/preclinical investigation. Current impediments and regulatory hurdles hindering the clinical translation of PDC into effective therapeutic regimens for the amelioration of disease conditions have been addressed.

Investigation on Potential of Chitosan Nanoparticles for Oral Bioavailability Enhancement of Risedronate Sodium.

Risedronate sodium (RS) is used in osteoporosis for bone reabsorption. It is a BCS class III drug having poor oral bioavailability (<0.63%) due to low permeability. In the present study, RS-loaded chitosan nanoparticles were developed to increase oral bioavailability and evaluated for various parameters. The DSC study indicated compatibility of RS with excipients in their physical mixture. The nanoparticles were prepared by ionotropic gelation technique and lyophilized. The optimized batch (RS-CNs) was found to have particles of size 268.7 nm and zeta potential of 24.9 mV. The TEM image of RS-CNs revealed discrete spherical particles. Angle of repose of 27.02 indicates good flow property of nanoparticles. FT-IR spectra of RS-CNs showed characteristic peaks of RS indicating compatibility of RS with the excipients. The mucin binding efficiency of RS-CNs was obtained as 63.42%. The in vitro release study of RS indicated controlled delivery from RS-CNs over 22 h. The release mechanism was found to be diffusion- and erosion-controlled release. Ex vivo study using rat intestine revealed faster permeation of 32.78% in 6 h from RS-CNs compared to plain drug solution. In vivo pharmacokinetic study in rats showed increased Cmax (1.8 fold) from RS-CNs compared to marketed formulation. The relative bioavailability of 193% from RS-CNs indicated significant enhancement in bioavailability upon nanoparticle formulation. The RS-CNs were found to be stable at room and refrigerated conditions. In conclusion, developed RS-loaded chitosan nanoparticles seem to be a promising approach to increase oral bioavailability and can avoid upper GI tract side effects.

Formulation and evaluation of raloxifene hydrochloride dry emulsion tablet using solid carrier adsorption technique.

Aim: The present study focused on the development of a dry emulsion tablet of raloxifene hydrochloride (RXF) using a solid carrier adsorption technique to enhance oral bioavailability. Methods: An oil-in-water emulsion was formulated and converted into dry powder using HPMC K4M plus Aerosil 200, then compressed into tablets. Results: The prepared emulsion was evaluated for globule size, drug content and zeta potential. In vitro release study revealed significantly higher release from emulsion. The prepared tablets possessed acceptable hardness, friability, weight variation, disintegration time, thickness, etc. In vivo pharmacokinetic studies indicated a more than sevenfold increase in oral bioavailability. Stability studies indicated good physical and chemical stability of the developed formulation. Conclusion: The authors successfully formulated dry emulsion tablets with enhanced oral bioavailability.

QbD-driven development of dissolving microneedle patch loaded with ultradeformable liposomes encapsulated Noopept: Exploring a patient friendly, once-daily option to manage dementia.

Noopept (NPT), a potent neuroprotective agent, suffers the problem of poor oral bioavailability (~10%) and thus demands exploration of ways of bioavailability improvement. Present work focuses on confronting this issue via development of NPT loaded ultradeformable liposomes (UDL) and its further incorporation in fast dissolving microneedle patch (MNP) for transdermal route. A combination of Phospholipon 90 G and Phospholipon 90H was used as bilayer forming lipids while sodium deoxycholate was used as edge activator to formulate NPT UDL by ethanol injection method. QbD approach was adapted to optimize NPT UDL considering vesicle size and entrapment efficiency as critical quality attributes (CQA). Fractional factorial design established amount of lipids, surfactant and NPT as critical material attributes and their optimum levels were statistically derived using combined D-optimal design. These optimized NPT UDL were fabricated as fast dissolving MNP and exhaustively evaluated to establish their safety, efficacy and stability. NPT UDL MNP possessed axial needle fracture force of 0.688 N which was sufficient enough to breach stratum corneum. Physical stability evaluation revealed that NPT UDL re-dispersion obtained from MNP matrix dissolution possessed identical vesicle shape and size while retaining > 99% NPT when compared to optimized NPT UDL. In vitro viability of HaCaT cells after exposure to NPT UDL MNP matrix was found to be 89.74% supporting the formulation as safe for transdermal application. NPT UDL MNP showed a 6.5-fold increase in steady state flux across full thickness pig ear skin as compared to NPT suspension. A 3-fold increase in relative bioavailability with similar pharmacological response as compared to oral NPT suspension was also observed during PK-PD studies in Sprague Dawley rats. Results were found fairly encouraging and created a scope of reducing both dose and dosing frequency to eventually improve the associated patient compliance.

Development of intravaginal rod insert bearing liposomal raloxifene hydrochloride and Leuprolide acetate as a potential carrier for uterine targeting.

OBJECTIVES: This project aimed at the formulation of dual drug entrapped liposomes held as freeze-dried intravaginal rod insert (IVR), to be administered by vaginal route for uterine targeting. METHODS: Liposomes were formulated by dehydration-rehydration method using 3 : 1 molar ratio of1,2-distearoyl-sn-glycero-3-phosphocholine : Cholesterol. Characterization was done for vesicle size, zeta potential, entrapment efficiency, surface morphology and % loading. KEY FINDINGS: Spherical and discrete vesicles of size 354 nm were observed in transmission electron microscopy (TEM) image. The entrapment efficiency of 90.91% and 74.3% w/w was obtained for Raloxifene Hydrochloride (RLX) and Leuprolide acetate (LA) respectively. Drug release was sustained for 6 days. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results showed that dual drug entrapped liposomal formulation show significant cytotoxicity, as also confirmed by higher apoptosis in cell cycle analysis and apoptosis studies (FACS) analysis. Pharmacodynamic studies in New Zealand white female rabbits revealed that intravaginal administration of RLX-LA entrapped liposomal formulation shows considerable fibroid regression. CONCLUSIONS: Uterine targeting of liposomal RLX-LA suggests its potential to solve the limitations of the presently available therapeutic options.

Vinpocetine loaded ultradeformable liposomes as fast dissolving microneedle patch: Tackling treatment challenges of dementia.

Vinpocetine (VPN) displays poor bioavailability (~7%) and short half-life (2-3 h) justifying the frequent dosing requirement of currently marketed oral tablets (thrice daily) and thus, posing a great challenge to patient compliance. Present work envisaged to achieve an infusion like delivery through transdermal route so as to tackle aforesaid challenges. With this aim, ultradeformable liposomes (UDL) incorporated fast dissolving microneedle patch (MNP) of VPN was developed and optimized for vesicle size and percent drug entrapment (critical quality attributes, CQA) utilizing the quality by design tool. Fractional factorial design followed by combined D-optimal design were applied to identify critical material attributes and obtain their statistically verified optimum levels (Phospholipon 90G, 15.17 mM; Phospholipon 90H, 4.83 mM; sodium deoxycholate, 15 mol% and Vinpocetine, 5 mol%) showing mean vesicle size of 75.65 nm and mean drug entrapment of 87.44%. An insignificant change in CQA of optimized UDL after incorporation in MNP further represented their physical compatibility with MNP components. In vitro characterization of these microneedles revealed rapid dissolution (~2 min) and good skin penetrability with around 0.684 N axial needle fracture force (ANFF). The safety was ascertained in vitro by exposing HaCaT cells to VPN UDL MNP components. A 94.27% cell viability advocated the safe nature of excipients used in formulation. Ex vivo permeation across full thickness pig ear skin revealed a steady state flux of 11.091 µg/cm2/h via VPN UDL MNP with around 9-fold enhancement when compared to flux value achieved through VPN suspension. In vivo pharmacokinetic and pharmacodynamic study in Sprague Dawley rats showed a 3-fold rise in relative bioavailability and a comparable mean escape latency via UDL MNP as compared to its oral suspension. In addition, half-life of 14 h and MRT of 21 h further confirmed the controlled release behavior of UDL MNP for prolonged period of time. In nutshell, the developed fast dissolving microneedle patch of VPN showed promising results with the prospect of lowering dose as well as dosing frequency for improved patient compliance.

Development of Solid Self-Microemulsifying System of Tizanidine Hydrochloride for Oral Bioavailability Enhancement: In Vitro and In Vivo Evaluation.

The aim of the present investigation was to formulate self-microemulsifying drug delivery system (SMEDDS) tablets to enhance the oral bioavailability of tizanidine hydrochloride. SMEDDS was prepared by using Capmul G as the oil phase, Tween 20 as the surfactant, and propylene glycol as the co-surfactant. The optimized formulation was characterized by dilution test, % transmittance, thermodynamic stability, dye solubility, assay, globule size, zeta potential, and TEM. A dye solubility test confirmed the formation of o/w microemulsion. Optimized formulation of SMEDDS had a drug content of 98 ± 0.75% (3.2± 0.3 mg) and droplet size of 96.61 ± 2.3 nm. Dilution and centrifugation tests indicated the physical stability of the formulation. The optimized SMEDDS was mixed with Neusilin as adsorbent, microcrystalline cellulose as diluent, and magnesium stearate as flow promoter, and compressed into tablets. The prepared tablets passed the tests of weight variation, hardness, friability, and assay. In vitro dissolution test indicated sustained release of tizanidine hydrochloride from the SMEDDS tablet for a period of 4 h. In vivo pharmacokinetic studies performed on male New Zealand rabbits showed a 4.61-fold increase in bioavailability compared with the marketed formulation. Thus, the developed SMEDDS tablet proved to be capable of enhancing oral bioavailability of tizanidine hydrochloride. Graphical abstract.

Formulation and evaluation of liquisolid compacts of itraconazole to enhance its oral bioavailability.

Aim: Formulate and evaluate liquisolid compacts of Itraconazole, a biopharmaceutical classification system class II drug, which has poor bioavailability. Materials & methods: PEG 600 was used as a nonvolatile solvent, Alfacel PH 200 as a carrier and Aerosil 200 as a coating material. The Itraconazole solution upon mixing with a carrier and coating material resulted in a dry powder, which was compressed into tablets. Results & conclusion: The optimized formulation exhibited a significantly higher drug dissolution (90.73% in 90 min) compared with conventional tablets and marketed capsules. The antifungal activity was retained in the formulation. Higher values of Cmax and AUC0-24 of the formulation compared with the plain drug indicated enhancement in oral bioavailability. The formulation was stable at room temperature as well as in accelerated conditions.

Microneedle-Mediated Transdermal Delivery of Tizanidine Hydrochloride.

Tizanidine hydrochloride is a skeletal muscle relaxant used for the treatment of spasm, a sudden involuntary muscle contraction leading to pain. The presently available oral dosage form has limitations such as high first pass metabolism resulting in low oral bioavailability. The short half-life necessitates its frequent administration to maintain the required plasma concentration. Transdermal delivery of drug avoids its first pass hepatic metabolism and gives controlled release, making it possible for reduction in dosing frequency. Drug delivery through transdermal route is severely limited by the presence of a tough stratum corneum barrier. A penetration enhancement approach is often necessary to achieve desired plasma concentrations. Microneedles are very short and sharp needles which do not cause pain. Thus, in the present investigation, preparation and evaluation of a transdermal delivery system for tizanidine hydrochloride based on microneedles are described.

Enhanced oral bioavailability and brain uptake of Darunavir using lipid nanoemulsion formulation.

The present work aimed to formulate Darunavir loaded lipid nanoemulsion to increase its oral bioavailability and enhance brain uptake. Various batches of lipid nanoemulsion of Darunavir were prepared by high pressure homogenization using soya bean oil, egg lecithin and Tween 80. The optimized batch DNE-3 had globule size of 109.5 nm, zeta potential of -41.1 mV, entrapment efficiency 93% and creaming volume 98%. The batch remained stable at 4 °C for 1 month with an insignificant change in globule size and zeta potential (P > 0.05). In-vivo pharmacokinetics male wistar rats indicated 223% bioavailability of Darunavir relative to drug suspension. Cmax of DNE-3 was twofold higher than suspension form. The organ biodistribution study indicated 2.65 fold higher brain uptake for DNE-3 than that for suspension. The higher bioavailability of Darunavir from nanoemulsion could lessen the dose related side effects. Moreover, high organ distribution results in passive uptake of Darunavir to HIV reservoir organs.

99mTc-vinorelbine tartrate loaded spherulites: Lung disposition study in Sprague-Dawley rats by gamma scintigraphy.

Vinorelbine Tartrate (VLB) is the first line chemotherapeutic agent for treatment of Non-Small Cell Lung Cancer, whose non-specific distribution causes unwanted side effects. The aim of the present investigation was to formulate VLB loaded spherulites intended for targeting the lung. Spherulites were composed of Soyabean Phosphatidylcholine (SPC), Cholesterol (Chol), Potassium oleate and Mannitol. Lipid film prepared using SPC, Chol and Potassium oleate, was dispersed in aqueous phase comprising Mannitol and VLB, followed by controlled shearing and extrusion. PEGylated Spherulites were prepared by incorporating 1,2-distearoyl-sn-glycero-3 phosphatidylethanolamine-N-[methoxy poly (ethylene glycol)] (DSPE-PEG 2000) in the lipid phase. Vesicles were characterized for size, entrapment efficiency and drug release. In vitro cell cytotoxicity and apoptosis study were performed on A549 cell line. Radiolabeling of VLB was performed by direct labeling with reduced technetium-99m. Binding affinity of 99mTc- labelled complexes was assessed by diethylenetriaminepenta acetic acid (DTPA) challenge test. Biodistribution study was done in Sprague Dawley rats. Dynamic light scattering and Transmission electron micrographs confirmed that PEGylated and non-PEGylated Spherulites were discrete, spherical and exhibited the size range of 120-130 nm. Non-PEGylated and PEGylated Spherulites had an entrapment efficiency of 95.65% and 94.2% respectively. In vitro drug release study indicated VLB plain drug solution diffused completely within 24 h, however, Non-PEGylated and PEGylated Spherulites showed similar release pattern till 48 h. Results of cell line study showed that cells treated with VLB loaded Spherulites showed more cytotoxicity and underwent high degree of apoptosis at lower concentration compared to the VLB solution. Radiolabeled complex was stable in saline and serum, further, DTPA challenge study ensured the high binding strength. Gamma Scintigraphy displayed that PEGylated Spherulites were localized within lungs at higher concentration than non-PEGylated followed by plain drug.

Darunavir-Loaded Lipid Nanoparticles for Targeting to HIV Reservoirs.

Darunavir has a low oral bioavailability (37%) due to its lipophilic nature, metabolism by cytochrome P450 enzymes and P-gp efflux. Lipid nanoparticles were prepared in order to overcome its low bioavailability and to increase the binding efficacy of delivery system to the lymphoid system. Darunavir-loaded lipid nanoparticles were prepared using high-pressure homogenization technique. Hydrogenated castor oil was used as lipid. Peptide, having affinity for CD4 receptors, was grafted onto the surface of nanoparticles. The nanoparticles were evaluated for various parameters. The nanoparticles showed size of less than 200 nm, zeta potential of - 35.45 mV, and a high drug entrapment efficiency (90%). 73.12% peptide was found conjugated to nanoparticles as studied using standard BSA calibration plot. Permeability of nanoparticles in Caco-2 cells was increased by 4-fold in comparison to plain drug suspension. Confocal microscopic study revealed that the nanoparticles showed higher uptake in HIV host cells (Molt-4 cells were taken as model containing CD4 receptors) as compared to non-CD4 receptor bearing Caco-2 cells. In vivo pharmacokinetic in rats showed 569% relative increase in bioavailability of darunavir as compared to plain drug suspension. The biodistribution study revealed that peptide-grafted nanoparticles showed higher uptake in various organs (also in HIV reservoir organs namely the spleen and brain) except the liver compared to non-peptide-grafted nanoparticles. The prepared nanoparticles resulted in increased binding with the HIV host cells and thus could be promising carrier in active targeting of the drugs to the HIV reservoir.

Formulation of 99mTechnetium-labeled leuprolide loaded liposomes and its biodistribution study in New Zealand white female rabbits for assessment of its uterine targeting efficiency.

Leuprolide acetate (LPA), a GnRH analogue, is drug of choice for treatment of uterine fibroids and endometriosis. The current marketed formulations of LPA show severe systemic side effects. This project aims to formulate LPA loaded liposomes to be administered by vaginal route for uterine targeting. Liposomes were prepared by thin film hydration method using 1:1 M ratio of DSPC: Cholesterol and characterized for vesicle size, zeta potential, entrapment efficiency, and loading. Radiolabeling of LPA was performed by direct labeling with reduced technetium-99m. Binding affinity of 99mTc-labeled complexes was assessed by diethylenetriaminepentaacetic acid (DTPA) challenge test. Biodistribution study was done in New Zealand white female rabbits by administering the formulation via vaginal route. Spherical and discrete vesicles of size 189 nm were seen in TEM results with entrapment efficiency and loading of 74.36% and 9.29%w/w, respectively. Liposomes were able to sustain the drug release for 5 days. 99mTc-labeled complexes showed high labeling efficiency and stability both in saline and serum. DTPA challenge test confirmed low transchelation of 99mTc-labeled complexes. Biodistribution study by gamma scintigraphy revealed the preferential uptake of the formulation by uterus when administered vaginally. Compared to plain drug, liposomes concentrated and were retained within the uterus for a longer period of time. Uterine targeting of liposomal LPA indicates its potential to overcome the limitations of presently available formulations. Hence, this seems to be a promising approach for targeting the drugs, whose site of action is uterus.