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1.
Int J Pharm ; 611: 121302, 2022 Jan 05.
Article in English | MEDLINE | ID: mdl-34793935

ABSTRACT

The ß-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but systemic drug administration may cause unwanted cadiovascular effects. To overcome this limitation, a topical delivery system based on transfersome (T-CAR) was characterized ex vivo and in vivo. T-CAR was visualized by Transmission Electron Microscopy as nanoparticles of spherical and unilamellar structure. T-CAR incorporated into carbopol gel and in suspension showed similar drug permeation and deposition profiles in Franz diffusion cells loaded with porcine ear skin. In mice exposed to a single dose UV, topical T-CAR gel (10 µM) significantly reduced UV-induced skin edema and cyclobutane pyrimidine dimer formation. In mice exposed to chronic UV radiation for 25 weeks, topical T-CAR gel (10 µM) significantly delayed the incidence of tumors, reduced tumor number and burden, and attenuated Ki-67 and COX-2 expression. The T-CAR gel was subsequently examined for skin deposition, systemic absorption and cardiovascular effects in mice. In mice treated with repeated doses of T-CAR gel (100 µM), the drug was undetectable in plasma, the heart rate was unaffected, but skin deposition was significantly higher than mice treated with oral carvedilol (32 mg/kg/day). These data indicate that the carbopol-based T-CAR gel holds great promise for skin cancer prevention with negligible systemic effects.


Subject(s)
Pharmaceutical Preparations , Skin Neoplasms , Absorption, Physiological , Animals , Carvedilol , Mice , Skin Neoplasms/prevention & control , Swine , Ultraviolet Rays
2.
Front Pharmacol ; 12: 673209, 2021.
Article in English | MEDLINE | ID: mdl-34177584

ABSTRACT

Celastrol (also called tripterine) is a quinone methide triterpene isolated from the root extract of Tripterygium wilfordii (thunder god vine in traditional Chinese medicine). Over the past two decades, celastrol has gained wide attention as a potent anti-inflammatory, anti-autoimmune, anti-cancer, anti-oxidant, and neuroprotective agent. However, its clinical translation is very challenging due to its lower aqueous solubility, poor oral bioavailability, and high organ toxicity. To deal with these issues, various formulation strategies have been investigated to augment the overall celastrol efficacy in vivo by attempting to increase the bioavailability and/or reduce the toxicity. Among these, nanotechnology-based celastrol formulations are most widely explored by pharmaceutical scientists worldwide. Based on the survey of literature over the past 15 years, this mini-review is aimed at summarizing a multitude of celastrol nanoformulations that have been developed and tested for various therapeutic applications. In addition, the review highlights the unmet need in the clinical translation of celastrol nanoformulations and the path forward.

3.
Front Pharmacol ; 11: 323, 2020.
Article in English | MEDLINE | ID: mdl-32317961

ABSTRACT

Cancer research in pursuit of better diagnostic and treatment modalities has seen great advances in recent years. However, the incidence rate of cancer is still very high. Almost 40% of women and men are diagnosed with cancer during their lifetime. Such high incidence has not only resulted in high mortality but also severely compromised patient lifestyles, and added a great socioeconomic burden. In view of this, chemoprevention has gained wide attention as a method to reduce cancer incidence and its relapse after treatment. Among various stems of chemoprevention research, nanotechnology-based chemoprevention approaches have established their potential to offer better efficacy and safety. This review summarizes recent advances in nanotechnology-based chemoprevention strategies for various cancers with emphasis on lung and bronchial cancer, colorectal, pancreatic, and breast cancer and highlights the unmet needs in this developing field towards successful clinical translation.

4.
Pharm Res ; 37(2): 21, 2020 Jan 02.
Article in English | MEDLINE | ID: mdl-31897616

ABSTRACT

PURPOSE: Pancreatic cancer (PC) is predicted to become the second leading cause of cancer associated deaths by 2020. Earlier, we confirmed the development and efficacy of our novel Loratadine Self-Microemulsifying-Drug-Delivery-System - Sulforaphane (LOR SMEDDS -SFN) nanoformulation in PC chemoprevention. In this report, we extend our studies to evaluate the PC chemoprevention efficacy of LOR SMEDDS - SFN. METHODS: The nanoformulation was subjected to in vitro colony formation assays, in vivo oral pharmacokinetics and stability studies. RESULTS: The colony formation assay using Panc-1 PC cells demonstrated a survival fraction of 0.74 with LOR-SFN (p < 0.001) which further reduced to 0.35 with LOR SMEDDS-SFN treatment (p < 0.0001) confirming the synergistic chemoprevention efficacy of the nanoformulation. Further, the oral pharmacokinetic studies of LOR SMEDDS-SFN showed 4-fold and 9-fold increase in Cmax (503.2 ± 5.8 ng/mL) and oral bioavailability (20,274.8 ± 3711.0 ng·h/mL) for LOR compared to LOR-SFN combination respectively assuring the enhanced performance by the SMEDDS. Additionally, the formulation exhibited statistically non-significant alteration in globule size, zeta potential, drug content and in vitro drug release during stability studies confirming its stability and pharmaceutical acceptability. CONCLUSION: Our studies have demonstrated a potential of LOR SMEDDS-SFN nanoformulation as an effective PC chemoprevention strategy.


Subject(s)
Loratadine/pharmacology , Loratadine/pharmacokinetics , Pancreas/drug effects , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/prevention & control , Administration, Oral , Animals , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , Chemoprevention/methods , Drug Delivery Systems/methods , Drug Liberation/drug effects , Emulsions/pharmacokinetics , Emulsions/pharmacology , Humans , Male , Rats , Rats, Sprague-Dawley , Solubility/drug effects
5.
Crit Rev Ther Drug Carrier Syst ; 36(1): 59-91, 2019.
Article in English | MEDLINE | ID: mdl-30789818

ABSTRACT

Pancreatic cancer is the fourth leading cause of death in the United States and has a 5-year life expectancy of ~8%. Currently, only a few drugs have been approved by the United States Food and Drug Administration for pancreatic cancer treatment. Despite available drug therapy and ongoing clinical investigations, the high prevalence and mortality associated with pancreatic cancer mean that there is an unmet chemopreventive and therapeutic need. From ongoing studies with various novel formulations, it is evident that the development of smart drug delivery systems will improve delivery of drug cargo to the pancreatic target site to ensure and enhance the therapeutic/chemoprevention efficacy of existing drugs and newly designed drugs in the future. With this in view, nanotechnology is emerging as a promising avenue to enhance drug delivery to the pancreas via both passive and active targeting mechanisms. Research in this field has grown extensively over the past decade, as is evident from available scientific literature. This review summarizes the recent advances that have brought nanotechnology-based formulations to the forefront of pancreatic cancer treatment.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Drug Delivery Systems/methods , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Pancreatic Neoplasms/drug therapy , Animals , Humans
6.
Drug Deliv Transl Res ; 9(3): 641-651, 2019 06.
Article in English | MEDLINE | ID: mdl-30706304

ABSTRACT

Pancreatic cancer (PC), currently the third leading cause of cancer-related deaths in the USA, is projected to become the second leading cause, behind lung cancer, by 2020. The increasing incidence, low survival rate, and limited treatment opportunities necessitate the use of alternative approaches such as chemoprevention, to tackle PC. In this study, we report significant synergistic chemoprevention efficacy for the first time from a low-dose combination of a classical antihistaminic drug, Loratadine (LOR) and a neutraceutical compound, Sulforaphane (SFN) using a self-microemulsifying drug delivery system (SMEDDS) formulation. The formulation was developed using Quality by Design approach (globule size, 95.13 ± 7.9 nm; PDI, 0.17 ± 0.04) and revealed significant (p < 0.05) enhancement in the in vitro dissolution profile confirming the enhanced solubility of BCS class II drug LOR with SMEDDS formulation. The LOR-SFN combination revealed ~ 40-fold reduction in IC50 concentration compared to LOR alone in MIA PaCa-2 and Panc-1 cell lines respectively, confirming the synergistic enhancement in chemoprevention. Further, the nanoformulation resulted in ~ 7-fold and ~ 11-fold reduction in IC50 values compared to LOR-SFN combination. Hence, our studies successfully demonstrate that a unique low-dose combination of LOR encapsulated within SMEDDs with SFN shows significantly enhanced chemopreventive efficacy of PC.


Subject(s)
Anticarcinogenic Agents/administration & dosage , Drug Delivery Systems , Histamine Antagonists/administration & dosage , Isothiocyanates/administration & dosage , Loratadine/administration & dosage , Pancreatic Neoplasms/prevention & control , Anticarcinogenic Agents/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Chemoprevention , Drug Liberation , Drug Synergism , Emulsions , Histamine Antagonists/chemistry , Humans , Isothiocyanates/chemistry , Loratadine/chemistry , Sulfoxides
7.
Crit Rev Ther Drug Carrier Syst ; 36(1): 59-91, 2019.
Article in English | MEDLINE | ID: mdl-30806206

ABSTRACT

Pancreatic cancer is the fourth leading cause of death in the United States and has a 5-year life expectancy of ~8%. Currently, only a few drugs have been approved by the United States Food and Drug Administration for pancreatic cancer treatment. Despite available drug therapy and ongoing clinical investigations, the high prevalence and mortality associated with pancreatic cancer mean that there is an unmet chemopreventive and therapeutic need. From ongoing studies with various novel formulations, it is evident that the development of smart drug delivery systems will improve delivery of drug cargo to the pancreatic target site to ensure and enhance the therapeutic/chemoprevention efficacy of existing drugs and newly designed drugs in the future. With this in view, nanotechnology is emerging as a promising avenue to enhance drug delivery to the pancreas via both passive and active targeting mechanisms. Research in this field has grown extensively over the past decade, as is evident from available scientific literature. This review summarizes the recent advances that have brought nanotechnology-based formulations to the forefront of pancreatic cancer treatment.

8.
Am J Cancer Res ; 8(10): 2005-2019, 2018.
Article in English | MEDLINE | ID: mdl-30416852

ABSTRACT

The current work studied the chemopreventive efficacy of orally administered chitosan coated solid-lipid nanoparticle (c-SLN) encapsulated aspirin (ASP), curcumin (CUR) and free sulforaphane (SFN), ACS-cSLN, in the LSL-Kras G12D/+; Pdx-1 Cre/+ transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC). In vitro uptake study and intracellular localization of ODA-FITC labeled ASP and CUR c-SLNs were performed in Panc-1 and MIA PaCa-2 cells by fluorescence microscopy. LSL-Kras G12D/+; Pdx-1 Cre/+ transgenic mice (n = 30) were randomly divided into 5 groups. Treatment groups were orally gavaged with ACS c-SLNs in three doses: low (2 + 4.5 + 0.16 mg/kg), medium (20 + 45 + 1.6 mg/kg) and high (60 + 135 + 4.8 mg/kg), respectively. After 20 weeks of treatment, mice pancreas were harvested, stained with dye and scored according to various pancreatic intraepithelial neoplasms (PanIN) categories by an independent observer. In vitro, cellular uptake evaluated on Panc-1 and MIA PaCa-2 cells resulted in higher fluorescence intensities, indicating increased cellular uptake of ASP and CUR c-SLNs. For further evidence, the addition of lysoID (red fluorescence) demonstrated location and uptake of ASP and CUR c-SLNs into the lysosome. In vivo, treatment with ACS c-SLN for 20-weeks did not cause obvious adverse effects on growth and no statistically significant differences in body weight were observed between groups. However, the weight (mean ± SEM) of pancreas at the end of the study was higher in blank c-SLN group (223.6 ± 42.2 mg) compared to low (138.0 ± 26.0 mg; not significant [NS]), medium (145.0 ± 9.0 mg; NS), and high (133.8 ± 20.3 mg; NS) ACS c-SLN treated groups, demonstrating the efficacy of ACS c-SLN nanoformulations. The low, medium and high dose of ACS c-SLN combinations exhibited a reduction in tumor incidence (PanIN count) by 16.6% (P < 0.01), 66.8% (P < 0.01), and 83.4% (P < 0.01), respectively. These studies provide further proof for the use of an oral, low dose nanotechnology-based combinatorial regimen for the chemoprevention of PDAC.

9.
Curr Pharm Des ; 24(21): 2438-2455, 2018.
Article in English | MEDLINE | ID: mdl-29773055

ABSTRACT

BACKGROUND AND OBJECTIVE: Pulmonary drug delivery has transformed over a past few decades from being a platform for local pulmonary disease treatment to systemic drug delivery opportunities. In case of pulmonary delivery systems, particle properties are critical as they affect inhalation efficacy, pulmonary deposition, drug delivery and overall performance. With this in view, particle engineering has emerged as an advanced science that helps in designing of efficacious pulmonary delivery systems. Among various particle engineering branches, crystal engineering is being extensively explored as it provides an opportunity to optimize particles at morphological, physicochemical and molecular levels which are essential to understand the role of crystal engineering in pulmonary drug delivery. METHODS: A thorough literature survey in the field of crystal engineering approaches explored for pulmonary drug delivery was conducted and the collected data was meticulously studied and summarized. RESULTS: In the review, pulmonary system is discussed with respect to various sites for drug deposition in respiratory tract, mechanism of drug deposition and clearance. Further, critical crystal parameters are discussed in-depth and various crystal engineering methods are summarized with emphasis on their impact on pulmonary delivery. Also, inhalation devices are overviewed to understand their performance in relation to crystal based pulmonary formulations. CONCLUSION: The review enabled a detailed insight on crystal engineering approaches for design of pulmonary delivery systems.


Subject(s)
Drug Delivery Systems , Dry Powder Inhalers , Lung Diseases/drug therapy , Pharmaceutical Preparations/administration & dosage , Administration, Inhalation , Crystallization , Humans
10.
J Pharm Sci ; 107(4): 1143-1156, 2018 04.
Article in English | MEDLINE | ID: mdl-29183742

ABSTRACT

Curcumin, a potent antioxidant polyphenol with neuroprotective and antiamyloid activities, has significant potential in the treatment of neurodegenerative disorders such as Alzheimer's disease. However, its clinical translation is delayed due to poor bioavailability. For effective use of curcumin in Alzheimer's disease, it is imperative to increase its bioavailability with enhanced delivery at a therapeutic site that is, brain. With this objective, pharmaceutical cocrystals of curcumin were developed and incorporated in micellar nanocarriers for nose-to-brain delivery. For cocrystals, an antioxidant hydrophilic coformer was strategically selected using molecular modeling approach. The cocrystals were formulated using a planetary ball mill, and the process was optimized using 32 factorial design followed by characterization using differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy analysis. The cocrystal micelles exhibited globule size of 28.79 ± 0.86 nm. Further, curcumin cocrystal and co-crystal micelles exhibited a significantly low (p value <0.01) IC50 concentration for antioxidant activity as compared to curcumin corroborating superior antioxidant performance. In vivo studies revealed about 1.7-fold absolute bioavailability of curcumin cocrystal micelles with Cmax of 1218.38 ± 58.11 ng/mL and showed significantly high brain distribution even beyond 6 hours of dosing. Thus, the studies confirmed enhanced bioavailability, higher brain uptake, retention, and delayed clearance with curcumin cocrystal micellar nanocarriers.


Subject(s)
Alzheimer Disease/drug therapy , Curcumin/chemistry , Curcumin/pharmacology , Nanocomposites/chemistry , Antioxidants/chemistry , Antioxidants/pharmacology , Biological Availability , Brain/drug effects , Calorimetry, Differential Scanning/methods , Cell Line, Tumor , Crystallization/methods , Drug Carriers/chemistry , Humans , Micelles , Solubility/drug effects , Spectroscopy, Fourier Transform Infrared/methods , X-Ray Diffraction/methods
11.
Drug Deliv Transl Res ; 6(4): 354-64, 2016 08.
Article in English | MEDLINE | ID: mdl-26712123

ABSTRACT

Amphotericin B, a gold standard broad spectrum antibiotic used in treatment of systemic fungal infections and visceral leishmaniasis, though is effective parenterally offers severe nephrotoxicity whereas the oral delivery is reported to give very meager oral bioavailability. Thus, to alleviate the toxicity and to improve oral bioavailability, an effective oral delivery approach in the form of solid lipid nanoparticles of amphotericin B (AmbiOnp) was reported earlier by our group. In this investigation, we report the predominant formation of nontoxic superaggregated form of amphotericin B, resulting from the probe sonication-assisted nanoprecipitation technique. The developed formulation was further confirmed to retain this nontoxic form and was found to be stable over the varied gastrointestinal conditions. Further, in vitro antifungal activity of AmbiOnp against Candida albicans showed minimum inhibitory concentration value of 7.812 µg/mL attributed to controlled release of drug from nanoparticulate matrix. In vivo pharmacokinetic studies revealed a relative bioavailability of AmbiOnp to be 1.05-fold with a Cmax of 1109.31 ± 104.79 ng/mL at the end of 24 h which was comparable to Cmax of 1417.49 ± 85.52 ng/mL achieved with that of marketed formulation (Fungizone®) given intravenously establishing efficacy of AmbiOnp. In vivo biodistribution studies indicated very low levels of Amphotericin B in kidneys when given as AmbiOnp as compared to that of marketed formulation proving its safety and was further corroborated by renal toxicity studies. Further, the formulations were found to be stable under refrigeration condition over a period of 3 months.


Subject(s)
Amphotericin B/administration & dosage , Amphotericin B/pharmacology , Administration, Oral , Amphotericin B/chemistry , Amphotericin B/pharmacokinetics , Animals , Biological Availability , Candida albicans/drug effects , Chemistry, Pharmaceutical , Delayed-Action Preparations/chemical synthesis , Delayed-Action Preparations/pharmacokinetics , Delayed-Action Preparations/pharmacology , Drug Stability , Female , Kidney/drug effects , Kidney/metabolism , Microbial Sensitivity Tests , Nanoparticles/chemistry , Rats , Tissue Distribution
12.
Drug Dev Ind Pharm ; 41(3): 398-405, 2015 Mar.
Article in English | MEDLINE | ID: mdl-24384027

ABSTRACT

The present investigation is aimed at development and characterization of sumatriptan succinate orodispersible tablets (ODTs) prepared by freeze drying technology. The tablet excipients were screened and the composition was optimized based on parameters which involved general appearance, tablet size and shape, uniformity of weight, mechanical properties, surface pH, moisture analysis, drug content, wetting time, in vitro and in vivo disintegration time. Furthermore, fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron micrograph of cross-section of the tablet and in vitro dissolution studies were performed. Studies revealed that formulation containing gelatin-mannitol (3.75% w/v and 3.5% w/v, respectively) with camphor as a volatile pore forming agent exhibited superior properties with disintegration time of less than 10 s. Furthermore, in vitro release studies revealed 90% release of drug from developed dosage form within 10 min, thus suggesting rapid drug dissolution followed by faster onset of action, which forms a strong rationale for development of ODTs of sumatriptan succinate. The developed technology is simple, which involves few steps and can be easily scaled up. Thus, it holds enormous potential for commercial exploitation.


Subject(s)
Chemistry, Pharmaceutical/methods , Sumatriptan/chemical synthesis , Sumatriptan/metabolism , Administration, Oral , Freeze Drying/methods , Humans , Mouth Mucosa/drug effects , Mouth Mucosa/metabolism , Sumatriptan/administration & dosage , Tablets
13.
J Control Release ; 189: 25-45, 2014 Sep 10.
Article in English | MEDLINE | ID: mdl-24960225

ABSTRACT

The medical device industry is growing at a very fast pace and has recorded great research activity over the past decade. The interdisciplinary nature of this field has made it possible for researchers to incorporate principles from various allied areas like pharmaceutics, bioengineering, biotechnology, chemistry, electronics, biophysics etc. to develop superior medical solutions, offering better prospects to the patient. Moreover, micro and nanotechnology have made it possible to positively affect at the sub-micron scales, the cellular processes initiated upon implantation. Literature is rife with findings on various implants and this review comprehensively summarizes the recent advances in micro/nanoscale implantable medical devices - particularly cardiovascular implants, neural implants, orthopedic and dental implants and other miscellaneous implants. Over the years, medical implants have metamorphosed from mere support providing devices to smart interventions participating positively in the healing process. We have highlighted the current research in each area emphasizing on the value addition provided by micro/nanoscale features, its course through the past and the future perspectives focusing on the unmet needs.


Subject(s)
Prostheses and Implants , Animals , Biocompatible Materials , Humans , Nanotechnology
14.
J Chromatogr Sci ; 52(8): 872-9, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24036005

ABSTRACT

A simple, rapid, sensitive and specific liquid chromatographic method was developed and validated for the determination of curcumin in human plasma. Berberine was used as the internal standard. Chromatographic separation was achieved on a Zorbax Eclipse C18 column at 40 °C, with a mobile phase consisting of 1% acetic acid (pH 3 adjusted with 50% triethanolamine): acetonitrile (55:45), at a flow rate of 1.25 mL/min. The method was validated for precision, accuracy, linearity, lower limit of quantification (LLOQ) and extraction efficiency according to the International Conference on Harmonization guidelines. The method was successfully developed with an LLOQ of 10 ng/mL and a runtime of 9 min. Linearity range was from 10 to 1000 ng/mL. Curcumin and Berberine were well separated with retention times of 8.2 ± 0.2 and 1.4 ± 0.1 min, respectively. Further, the method was successfully employed to study the pharmacokinetic parameters of curcumin, following oral administration of curcumin-loaded hydroxy propyl cellulose (HPC) nanoparticles and curcumin suspension in female Wistar rats. Curcumin-loaded HPC nanoparticles (Cmax: 106.01 ± 20.11 ng/mL) showed significant improvement in pharmacokinetic parameters when compared with curcumin suspension (Cmax: 30.13 ± 0.47 ng/mL) indicating 43.73-fold increase in relative bioavailability.


Subject(s)
Chromatography, Liquid/methods , Curcumin/pharmacokinetics , Administration, Oral , Animals , Curcumin/administration & dosage , Female , Humans , Rats , Rats, Wistar , Reproducibility of Results
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