Role of Polyphenols, Their Nano-formulations, and Biomaterials in Diabetic Wound Healing.

A diabetic wound is one of the major complications arising from hyperglycemia, neuropathy, and oxidative stress in diabetic patients. Finding effective treatments for diabetic wounds has been difficult owing to the complex pathophysiology of diabetic wound environments. Chronic wounds are notoriously difficult to treat with conventional wound care methods. In recent years, polyphenols found in plants have received much interest as a potential treatment for diabetic wounds. Their key benefits are their safety and the fact that they act through many molecular routes to treat diabetic wounds. However, problems with their formulation development, including lipophilicity, light sensitivity, limited membrane permeability, rapid systemic elimination, and enzymatic degradation, prevented them from gaining clinical attention. This article highlights and discusses the mechanism of polyphenols and various polyphenol-based drug delivery systems used till now to treat diabetic wounds. The consideration that should be taken in polyphenols-based nano-formulations and their prospect for diabetic wounds are also discussed briefly.

Simultaneous Determination of Posaconazole and Hemp Seed Oil in Nanomicelles through RP-HPLC via a Quality-by-Design Approach.

The present study involves the development of a reverse-phase HPLC method employing the quality-by-design methodology for the estimation of posaconazole and hemp seed oil simultaneously in nanomicelles formulation. The successful separation of posaconazole and hemp seed oil was achieved together, and this is the first study to develop and quantify posaconazole and hemp seed oil nanomicelles with linoleic acid as the internal standard and developed a dual drug analytical method employing a quality-by-design approach. The study was performed on a Shimadzu Prominence-I LC-2030C 3D Plus HPLC system with a PDA detector and the Shim-pack Solar C8 column (250 mm × 4.6 mm × 5 µm) for analysis with a mobile phase ratio of methanol:water (80:20% v/v) maintaining the flow rate of 1.0 mL/min. The final wavelength was selected as 240 nm and the elution of hemp seed oil and posaconazole was obtained at 2.7 and 4.6 min, respectively, with a maximum run time of 8.0 min. Box Behnken design was employed to optimize the method, keeping the retention time, peak area, and theoretical plates as dependent variables, while the mobile phase composition, flow rate, and wavelengths were chosen as independent variables. Parameters such as specificity, accuracy, robustness, linearity, sensitivity, precision, ruggedness, and forced degradation study were performed to validate the method. The calibration curves of posaconazole and hemp seed oil were determined to be linear throughout the range for concentration. The suggested approach can be effectively utilized for estimating the content of drugs from their nanoformulation and proved suitable for both in vivo and in vitro research.

Lipid-based nanoparticle-mediated combination therapy for breast cancer management: a comprehensive review.

Breast cancer due to the unpredictable and complex etiopathology combined with the non-availability of any effective drug treatment has become the major root of concern for oncologists globally. The number of women affected by the said disease state is increasing at an alarming rate attributed to environmental and lifestyle changes indicating at the exploration of a novel treatment strategy that can eradicate this aggressive disease. So far, it is treated by promising nanomedicine monotherapy; however, according to the numerous studies conducted, the inadequacy of these nano monotherapies in terms of elevated toxicity and resistance has been reported. This review, therefore, puts forth a new multimodal strategic approach to lipid-based nanoparticle-mediated combination drug delivery in breast cancer, emphasizing the recent advancements. A basic overview about the combination therapy and its index is firstly given. Then, the various nano-based combinations of chemotherapeutics involving the combination delivery of synthetic and herbal agents are discussed along with their examples. Further, the recent exploration of chemotherapeutics co-delivery with small interfering RNA (siRNA) agents has also been explained herein. Finally, a section providing a brief description of the delivery of chemotherapeutic agents with monoclonal antibodies (mAbs) has been presented. From this review, we aim to provide the researchers with deep insight into the novel and much more effective combinational lipid-based nanoparticle-mediated nanomedicines tailored specifically for breast cancer treatment resulting in synergism, enhanced antitumor efficacy, and low toxic effects, subsequently overcoming the hurdles associated with conventional chemotherapy.

Cannabis Sativa in Phytotherapy: Reappraisal of Therapeutic Potential and Regulatory Aspects.

Cannabis sativa is widely used as a folk medicine in many parts of the globe and has been reported to be a treasure trove of phytoconstituents, including cannabinoids, terpenoids, and flavonoids. Accumulating evidence from various pre-clinical and clinical studies revealed the therapeutic potential of these constituents in various pathological conditions, including chronic pain, inflammation, neurological disorders, and cancer. However, the psychoactive effect and addiction potential associated with cannabis use limited its clinical application. In the past two decades, extensive research on cannabis has led to a resurgence of interest in the clinical application of its constituents, particularly cannabinoids. This review summarizes the therapeutic effect and molecular mechanism of various phytoconstituents of cannabis. Furthermore, recently developed nanoformulations of cannabis constituents have also been reviewed. Since cannabis is often associated with illicit use, regulatory aspects are of vital importance and this review therefore also documented the regulatory aspects of cannabis use along with clinical data and commercial products of cannabis.

Insights into Pharmacological Potential of Apigenin through Various Pathways on a Nanoplatform in Multitude of Diseases.

Apigenin is a natural polyphenolic compound widely distributed as a glycoside in fruits and vegetables. Apigenin belongs to BCS class II with low solubility, which leads to poor absorption and bioavailability. It is mostly absorbed from the small intestine and extensively metabolized through glucuronidation and sulfation processes. Apigenin is known for its antioxidant and anti-inflammatory properties. It is also used as a chemopreventive drug in the management of various cancers. Pharmacological effects of apigenin have a wide range, from neuroprotective to treating renal disorders. Apigenin is non-toxic in nature and acts through various pathways (JAK/STAT, Wnt/ß-catenin, MAPK/ERK, PI3K/Akt, and NF-κB) to exert its therapeutic efficacy. Numerous formulations have been researched to enhance the bioavailability and pharmacological effects of apigenin. Combinatorial therapies are also researched to minimize the side-effects of chemotherapeutic drugs. The review presents pharmacokinetic and pharmacodynamic aspects of apigenin. Apigenin is safe for the treatment and management of numerous diseases. It can be easily incorporated into nanoformulation alone or in combination with other active ingredients to widen the therapeutic window. This review intends to help in drug optimization and therapeutic efficacy maximization for future studies.

Quality by design-based development and validation of an HPLC method for simultaneous estimation of pregabalin and piperine in dual drug-loaded liposomes.

The current research work describes the development of a rapid HPLC method for the concurrent detection of pregabalin and piperine in dual drug-loaded nanoformulations. The primary goal was to recognize the chromatographic conditions wherein propitious segregation of the integrants with quality peaks can be attained. An attempt to expound the target analytical profile was made to accomplish this goal, and critical method attributes (CMAs), viz. percentage acetonitrile content, injection volume and pH, which affect critical quality attributes (CQAs), were identified using systemic risk analysis. Box-Behnken design was employed to develop a relationship between CMAs and CQAs, which engenders an analytical design space. Efficient chromatographic separation for pregabalin and piperine was attained using an analytical C18 column and mobile phase comprising acetonitrile-water (pH 6.9; 70:30%, v/v) in an isocratic elution mode with a 1 ml/min flow rate. The elution was descried at an isosbestic wavelength of 221 nm using a photodiode array detector. The International Conference on Harmonization guidelines were adopted for the developed HPLC method. The validated HPLC method can be further utilized for the simultaneous quantification and detection of pregabalin and piperine in other lipid-based nanopharmaceuticals such as polymeric nanoparticles, nanocrystals, solid-lipid nanoparticles, metallic nanoparticles, etc., in in vitro and in vivo studies.

Combinatorial Chemosensitive Nanomedicine Approach for the Treatment of Breast Cancer.

Breast cancer is the most commonly diagnosed type of cancer and ranks second among cancer that leads to death. From becoming the foremost reason for global concern, this multifactorial disease is being treated by conventional chemotherapies that are associated with severe side effects, with chemoresistance being the ruling reason. Exemestane, an aromatase inhibitor that has been approved by the US FDA for the treatment of breast cancer in post-menopausal women, acts by inhibiting the aromatase enzyme, in turn, inhibiting the production of estrogen. However, the clinical application of exemestane remains limited due to its poor aqueous solubility and low oral bioavailability. Furthermore, the treatment regimen of exemestane often leads to thinning of bone mineral density. Thymoquinone, a natural compound derived from the oil of the seeds of Nigella sativa Linn, possesses the dual property of being a chemosensitizer and chemotherapeutic agent. In addition, it has been found to exhibit potent bone protection properties, as evidenced by several studies. To mitigate the limitations associated with exemestane and to deliver to the cancerous cells overcoming chemoresistance, the present hypothesis has been put forth, wherein a natural chemosensitizer and chemotherapeutic agent thymoquinone will be incorporated into a lipid nanocarrier along with exemestane for combinatorial delivery to cancer cells. Additionally, thymoquinone being bone protecting will help in ousting the untoward effect of exemestane at the same time delivering it to the required malignant cells, safeguarding the healthy cells, reducing the offsite toxicity, and providing potent synergistic action.

Engineering of QbD driven and ultrasonically shaped lyotropic liquid crystalline nanoparticles for Apigenin in the management of skin cancer.

Treatment of skin cancer demands targeted delivery without minimal systemic circulation for maximum therapeutic window. Dermal delivery with nano-formulation offers such advantages. Therefore, present study aims to formulate Lyotropic liquid crystalline nanoparticles (LLC NPs) loaded with Apigenin (API) for dermal delivery using quality by design (QbD) approach for effective permeation resulting in improved bioavailability. Apigenin loaded LLC NPs (API-LLC NPs) were formulated and optimized by applying risk assessment and design of experiments (Box-Behnken Design). The optimized API-LLC NPs showed particle size, PdI and entrapment efficiency of 287.7 ± 9.53 nm, 0.152 ± 0.051 and 80 ± 2.2 % respectively. The optimized API-LLC NPs were characterized for morphology and crystallinity using optical microscopy, TEM, DSC and PXRD. In vitro and ex vivo studies showed sustained release and better permeation profile. CLSM study presented better penetration of API-LLC NPs which were quantitatively confirmed with dermatokinetics. Cytotoxic efficacy assessed on B16F10 cell lines showed a dose-dependent efficacy of API-LLC NPs with an IC50 of 45.74 ± 0.05. In a nutshell, the developed API-LLC NPs exhibit excellent potential for targeting deeper skin layers thereby can be considered a promising topical drug delivery nanocarrier in the treatment and management of skin cancer.

Brain targeted delivery of carmustine using chitosan coated nanoparticles via nasal route for glioblastoma treatment.

This study aims to develop chitosan-coated PLGA nanoparticles intended for nose-to-brain delivery of carmustine. Formulations were prepared by the double emulsion solvent evaporation method and optimized by using Box-Behnken Design. The optimized nanoparticles were obtained to satisfactory levels in terms of particle size, PDI, entrapment efficiency, and drug loading. In vitro drug release and ex-vivo permeation showed sustained release and enhanced permeability (approx. 2 fold) of carmustine compared to drug suspension. The AUC0-t of brain obtained with carmustine-loaded nanoparticles via nasal administration in Albino Wistar rats was 2.8 and 14.7 times that of intranasal carmustine suspension and intravenous carmustine, respectively. The MTT assay on U87 MG cell line showed a significant decrease (P < 0.05) in the IC50 value of the formulation (71.23 µg ml-1) as compared to drug suspension (90.02 µg ml-1).These findings suggest chitosan coated nanoparticles could be used to deliver carmustine via intranasal administration to treat Glioblastoma multiforme.

Repurposing pentosan polysulfate sodium as hyaluronic acid linked polyion complex nanoparticles for the management of osteoarthritis: A potential approach.

Osteoarthritis is still a disease burden for pharmaceutical scientists and strategy makers. It is associated with the chronic inflammation of joints especially weight-bearing joints like knee, hip, backbone, and phalanges. NSAIDs that are used for the management of inflammation associated with osteoarthritis have high side effects related to gastric upset, gastric ulcer, and long term treatment associated with liver and kidney damage. Nanotechnology has gained a huge scope for the management of arthritis as it can reach out to the deep inside the cell and alter cellular physiology as desired. The present study hypothesizes the use of polyion complex nanoparticles of hyaluronic acid linked Pentosan polysulfate sodium, a disease-modifying agent for the treatment of osteoarthritis administered through transdermal route. The hypothesis involves the use of drug repurposing as the drug was initially approved for interstitial cystitis, a condition of the urinary bladder associated with pain and swelling. Being very low oral bioavailability and gastric irritation profile, the transdermal route would be beneficial. To overcome the problem associated with the oral route, there is a need for the targeted approach that will particularly reach at inflammatory sites. Thereby transdermal delivery of hyaluronic acid linked Pentosan polysulfate sodium through polyion complex nanoparticle therapy will be a novel therapeutic approach to combat osteoarthritis.

Fisetin loaded binary ethosomes for management of skin cancer by dermal application on UV exposed mice.

Fisetin loaded binary ethosomes were prepared and optimized using Box-Behnken design for dermal application to alleviate skin cancer. The prepared formulations were evaluated for vesicle size, entrapment efficiency and flux of fisetin. Additionally, the optimized formulation was further evaluated by transmission electron microscopy, confocal laser microscopy, vesicles-skin interaction, dermatokinetic study and DPPH (2, 2-diphenyl-1-picryl-hydrazyl) assay. The in vivo study was carried out for the evaluation of tumor incidence, pro-inflammatory cytokines such as TNF-α and IL-1α, lipid peroxidation values, glutathione content and catalase activity in mice. The optimized binary ethosomes formulation presented sealed unilamellar shaped vesicles, with vesicles size, entrapment efficiency and flux of 99.89 ±â€¯3.24 nm, 89.23 ±â€¯2.13% and 1.01 ±â€¯0.03 µg/cm2/h respectively. The confocal images of rat skin clearly illustrated the deeper penetration of rhodamine B loaded binary ethosomes formulation. Further, the binary ethosomes gel treated rat skin showed substantial increase in CSkin max and AUC0-8 in comparison to rat skin treated with conventional gel. In vivo study revealed that the mice pre-treated with fisetin binary ethosomes gel caused marked decrease in the levels of TNF-α and IL-1α as compared to the mice exposed to UV only. Further the binary ethosomes gel treated mice group had demonstrated less percentage of tumour incidences (49%) as compared to mice treated with UV only (96% tumour incidence). The novelty of the work lies in successful optimization of formulation using Box-Behnken design and characterization of binary ethosomes carrier of fisetin and demonstration of improved dermal delivery of the same. The overall data suggest that the fisetin loaded binary ethosomes formulation is a potential dermal delivery system for the management of skin cancer.

Ursolic acid loaded intra nasal nano lipid vesicles for brain tumour: Formulation, optimization, in-vivo brain/plasma distribution study and histopathological assessment.

The aim was to formulate an optimized ursolic acid (UA) loaded lipid vesicle using formulation by design approach (FbD) for improving the drug targeting by nasal route for brain tumor. Three factors were evaluated at three different levels using anethole (terpene) (A), ethanol (B) and phospholipid90 G (C) as independent variables and their individual and combined effects were observed for PDI (Y1), vesicle size (Y2) and encapsulation efficiency (Y3) to select an optimal system (UALVopt). The optimized formulation was further converted into gel and evaluated for drug release, nasal permeation study, brain/plasma uptake and histopathology study. The UALVopt formulation containing anethole as terpene (1% as A), ethanol (2.6% as B) and phospholipid90 G (8.8 mg as C) showed low PDI (0.212), vesicle size (115.56 nm) and high entrapment efficiency (76.42%). The in-vitro drug release and ex-vivo permeation study results revealed prolonged drug release and permeation. The brain/blood ratio for UALVGopt remained significantly higher at all the time points with respect to UALVopt indicating higher and prolonged retention of drug at site of action. The histopathological study of the nasal mucosa and brain confirmed non-toxic nature of developed formulation. The formulation UALVGopt could serve as a better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its efficacy.

Temozolomide loaded nano lipid based chitosan hydrogel for nose to brain delivery: Characterization, nasal absorption, histopathology and cell line study.

The present study was designed to develop and optimize Temozolomide nano lipid chitosan hydrogel formulations (TMZNLCHG) to target the brain through nasal route. The formulation was developed using chitosan as a gelling agent and Vit E: gelucire 44/14 blend as lipid. The formulations were evaluated for particle size, encapsulation efficiency (%EE), drug loading (DL), morphology, drug release, nasal diffusion, cell line study, and histopathology study. The particle size, PDI, %EE, %DL, and drug release were found to be 134 nm, 0.177, 88.45% ±â€¯4.45%, 9.12% ±â€¯0.78%, and 84.23% ±â€¯2.78%, respectively. The enhancement ratio was more than two folds higher than TMZCHG formulation (control) suggesting the superiority of chitosan with lipid as permeability enhancer. The microscopic image of lyophilized TMZNLCHGopt displayed the spherical and rough surface morphology. IC50 was found to be 3.34 µg/ml for TMZNLCHGopt and was 160 µg/ml for pure TMZ. Further, No structural damage was observed with TMZNLCHGopt treated nasal mucosa upon histopathological examination. Overall, the present study produces encouraging findings in the formulation of a non-invasive intranasal route for brain targeting as an alternate to other route for TMZ.

Glial Cell: A Potential Target for Cellular and Drug Based Therapy in Various CNS Diseases.

Glial cells are integrated part of neurovascular unit of blood brain barrier (BBB). They undergo mitosis and mainly classified as astrocytes, oligodendrocytes, microglia, ependymal cells and nerve glial antigen 2 cells. Being a most versatile glial cell, astrocytes provide structural support to neurons, maintain brain homeostasis, take part in neuronal communication, and perform some housekeeping functions. Oligodendrocytes myelinate the neuronal axons for proper transmission of nerve impulse and microglia are brain immune cells. Multiple sclerosis is a prototype glia mediated disease that manifests demyelination. Fingolimod is already being marketed for this disease, while guanabenz and ibudilast are facing clinical trials. Many researches revealed the role of glial cells in Alzheimer's disease, in which riluzole (a glutamate modulator already in market for amyotrophic lateral sclerosis-ALS) was found to be effective. Q-cells® are glial cell-based therapeutic agent to treat ALS that only produce astrocytes and oligodendrocytes, when transplanted in vivo. hIL13-PE is a gene based therapeutic agent that has been smartly designed for the treatment of glioma. Although for CNS diseases, drugs are available, still it is not easy to extract satisfactory therapeutic effect of most of the drugs due to the presence of BBB. This barrier can be overcome by implanting a drug reservoir in brain parenchyma (wafer), by judicious selection of drug delivery system (nanoparticulate system), or by using an alternative route of administration (intranasal route). This review revolves around cellular and drug based modulation of glial cells to achieve maximum therapeutic benefit for some of the CNS diseases.

Development and validation of stability-indicating high performance liquid chromatography method to analyze gatifloxacin in bulk drug and pharmaceutical preparations.

Quantitative determination of gatifloxacin in tablets, solid lipid nanoparticles (SLNs) and eye-drops using a very simple and rapid chromatographic technique was validated and developed. Formulations were analyzed using a reverse phase SUPELCO® 516 C-18-DB, 50306-U, HPLC column (250 mm × 4.6 mm, 5 µm) and a mobile phase consisting of disodium hydrogen phosphate buffer:acetonitrile (75:25, v/v) and with orthophosphoric acid pH was adjusted to 3.3 The flow rate was 1.0 mL/min and analyte concentrations were measured using a UV-detector at 293 nm. The analyses were performed at room temperature (25 ± 2 °C). Gatifloxacin was separated in all the formulations within 2.767 min. There were linear calibration curves over a concentration range of 4.0-40 µg.mL(-1) and correlation coefficients of 0.9998 with an average recovery above 99.91%. Detection of analyte from different dosage forms at the same Rt indicates the specificity and stability of the developed method.

Novel carbopol-based transfersomal gel of 5-fluorouracil for skin cancer treatment: in vitro characterization and in vivo study.

5-fluorouracil (5-Fu) is an antineoplastic drug, topically used for the treatment of actinic keratosis and nonmelanoma skin cancer. It shows poor percutaneous permeation through the conventionally applicable creams and thus inefficient for the treatment of deep-seated skin cancer. In the present article, transfersomal gel containing 5-Fu was investigated for the treatment of skin cancer. Different formulation of tranfersomes was prepared using Tween-80 and Span-80 as edge activators. The vesicles were characterized for particle size, shape, entrapment efficiency, deformability and in vitro skin permeation. Optimized formulation was incorporated into 1% carbopol 940 gel and evaluated for efficacy in the treatment of skin cancer. 5-Fu-loaded transfersomes (TT-2) has the size of 266.9 ± 2.04 nm with 69.2 ± 0.98% entrapment efficiency and highest deformability index of 27.8 ± 1.08. Formulation TT-2 showed maximum skin deposition (81.3%) and comparable transdermal flux of 21.46 µg/cm(2) h. The TT-2-loaded gel showed better skin penetration and skin deposition of the drug than the marketed formulation. Composition of the transfersomal gel has been proved nonirritant to the skin. We concluded that the developed 5-Fu-loaded transfersomal gel improves the skin absorption of 5-Fu and provide a better treatment for skin cancer.

Seroepidemiology of Strongyloides stercoralis in Dhaka, Bangladesh.

Human strongyloidiasis is a neglected tropical disease with global distribution and this infection is caused by the parasitic nematode Strongyloides stercoralis. The aim of this study was to determine the prevalence of strongyloidiasis in Dhaka, Bangladesh. Sera from 1004 residents from a slum (group A) and 299 from city dwellers (group B) were tested for total IgG and IgG subclasses to Strongyloides antigen. There was a significant difference (P < 0·001) in IgG seroprevalence between group A (22%) and group B (5%). Reactive IgG subclasses (IgG1 and IgG4) were also higher in group A (P < 0·05). The seroprevalence of strongyloidiasis in group A increased with age but was unrelated to sex. The presence of reactive IgG to Strongyloides antigen had no correlation with either socio-economic or personal hygiene factors. However, a history of diarrhoea in a family member, in the past 6 months, but not in the respondents was associated with detection of antibodies to S. stercoralis (P < 0·01). None of the sera from either group had an HTLV-I reaction. This study demonstrates that strongyloidiasis is prevalent in Dhaka, especially among slum dwellers, but concurrent infection with HTLV-I was not found. Future epidemiological studies should identify individual risk factors and other communities at risk so that appropriate interventions can be planned.

Pharmacodynamics of a losartan transdermal system for the treatment of hypertension.

AIMS: Transdermal therapeutic systems were developed using the polymers, Eudragit E 100 and polyvinyl pyrrolidone VA 64 in a film casting assembly. The medicated films were evaluated for physical properties, in vitro drug release studies, in vitro skin permeation studies, and pharmacodynamic studies. RESULTS: The physical parameters were found to be very satisfactory with high drug content (>99%). The in vitro drug release studies were performed using paddle-over-disc assembly specified in USP XXIII. The pharmacodynamic studies were carried out using tail cuff method in Wistar albino rats. Hypertension was induced by methyl prednisolone acetate subcutaneously for 2 weeks. The developed matrix patch was found to decrease the blood pressure (25.42% reduction in mean systolic blood pressure of rats) significantly (P < 0.001) in proximity of the normal value and it was maintained for 24 hours. CONCLUSION: It can be concluded that the developed transdermal matrix patch holds promise for the management of hypertension that needs to be validated by clinical trials.

Effect of pre-treatment of almond oil on ultraviolet B-induced cutaneous photoaging in mice.

BACKGROUND: Ultraviolet (UV) radiation has been implicated in photoaging and various types of skin carcinomas. Although the human skin has evolved several defense mechanisms to survive the insults of actinic damage like keratinization, melanin pigmentation, etc., it is still subjected to the harmful effects of sunlight. AIMS: In this study, the role of almond oil in reducing the degradative changes induced in skin upon exposure to UV radiation was investigated. METHODS: Mice were divided in four groups of 20 animals. Group I was the control group. Group II was negative control, which received almond oil treatment alone. Group III was exposed to UV radiation only and Group IV received both UV treatment and almond oil treatment. Visible skin grading assessed the changes based on a rating scale, biochemical tests (glutathione estimation and lipid peroxidation), and histopathologic studies. RESULTS: Upon exposure of mice to UV radiation, it was found that pronounced visible skin changes were seen after 12 weeks of exposure. The results of the biochemical tests, glutathione estimation, and lipid peroxidation showed that almond oil reduced the effect of UV light-induced photoaging on the skin. Histopathologic studies also indicated a photoprotective effect of almond oil on the skin after UV exposure. CONCLUSIONS: It was concluded that topical almond oil is capable of preventing the structural damage caused by UV irradiation and it was also found useful in decelerating the photoaging process.