Mannosylated-Chitosan-Coated Andrographolide Nanoliposomes for the Treatment of Hepatitis: In Vitro and In Vivo Evaluations.

A key diterpene lactone of Andrographis paniculata, i.e., andrographolide (AG), exhibits a variety of physiological properties, including hepatoprotection. The limited solubility, short half-life, and poor bioavailability limits the pharmacotherapeutic potential of AG. Therefore, in this study we aimed to formulate and optimize AG-loaded nanoliposomes (AGL) using the Design of Experiment (DOE) approach and further modify the surface of the liposomes with mannosylated chitosan to enhance its oral bioavailability. Physical, morphological, and solid-state characterization was performed to confirm the formation of AGL and Mannosylated chitosan-coated AGL (MCS-AGL). Molecular docking studies were conducted to understand the ligand (MCS) protein (1EGG) type of interaction. Further, in vitro release, ex vivo drug permeation, and in vivo pharmacokinetics studies were conducted. The morphological studies confirmed that AGL was spherical and a layer of MCS coating was observed on their surface, forming the MCS-AGL. Further increase in the particle size and change in the zeta potential of MCS-AGL confirms the coating on the surface of AGL (375.3 nm, 29.80 mV). The in vitro drug release data reflected a sustained drug release profile from MCS-AGL in the phosphate buffer (pH 7.4) with 89.9 ± 2.13% drug release in 8 h. Ex vivo permeation studies showed higher permeation of AG from MCS-AGL (1.78-fold) compared to plain AG and AGL (1.37-fold), indicating improved permeability profiles of MCS-AGL. In vivo pharmacokinetic studies inferred that MCS-AGL had a 1.56-fold enhancement in AUC values compared to plain AG, confirming that MCS-AGL improved the bioavailability of AG. Additionally, the 2.25-fold enhancement in the MRT proves that MCS coating also enhances the in vivo stability and retention of AG (stealth effect). MCS as a polymer therefore has a considerable potential for improving the intestinal permeability and bioavailability of poorly soluble and permeable drugs or phytoconstituents when coated over nanocarriers.

2D Hetero-Nanoconstructs of Black Phosphorus for Breast Cancer Theragnosis: Technological Advancements.

As per global cancer statistics of 2020, female breast cancer is the most commonly diagnosed cancer and also the foremost cause of cancer death in women. Traditional treatments include a number of negative effects, making it necessary to investigate novel smart drug delivery methods and identify new therapeutic approaches. Efforts for developing novel strategies for breast cancer therapy are being devised worldwide by various research groups. Currently, two-dimensional black phosphorus nanosheets (BPNSs) have attracted considerable attention and are best suited for theranostic nanomedicine. Particularly, their characteristics, including drug loading efficacy, biocompatibility, optical, thermal, electrical, and phototherapeutic characteristics, support their growing demand as a potential substitute for graphene-based nanomaterials in biomedical applications. In this review, we have explained different platforms of BP nanomaterials for breast cancer management, their structures, functionalization approaches, and general methods of synthesis. Various characteristics of BP nanomaterials that make them suitable for cancer therapy and diagnosis, such as large surface area, nontoxicity, solubility, biodegradability, and excellent near-infrared (NIR) absorption capability, are discussed in the later sections. Next, we summarize targeting approaches using various strategies for effective therapy with BP nanoplatforms. Then, we describe applications of BP nanomaterials for breast cancer treatment, which include drug delivery, codelivery of drugs, photodynamic therapy, photothermal therapy, combined therapy, gene therapy, immunotherapy, and multidrug resistance reversal strategy. Finally, the present challenges and future aspects of BP nanomaterials are discussed.

Advancements in cell membrane camouflaged nanoparticles: A bioinspired platform for cancer therapy.

The idea of employing natural cell membranes as a coating medium for nanoparticles (NPs) endows man-made vectors with natural capabilities and benefits. In addition to retaining the physicochemical characteristics of the NPs, the biomimetic NPs also have the functionality of source cell membranes. It has emerged as a promising approach to enhancing the properties of NPs for drug delivery, immune evasion, imaging, cancer-targeting, and phototherapy sensitivity. Several studies have been reported with a multitude of approaches to reengineering the surface of NPs using biological membranes. Owing to their low immunogenicity and intriguing biomimetic properties, cell-membrane-based biohybrid delivery systems have recently gained a lot of interest as therapeutic delivery systems. This review summarises different kinds of biomimetic NPs reported so far, their fabrication aspects, and their application in the biomedical field. Finally, it briefs on the latest advances available in this biohybrid concept.

Stimuli responsive and receptor targeted iron oxide based nanoplatforms for multimodal therapy and imaging of cancer: Conjugation chemistry and alternative therapeutic strategies.

Cancer being one of the most precarious and second most fatal diseases evokes opportunities for multimodal delivery platforms which will act synergistically for efficient cancer treatment. Multifunctional iron oxide magnetic nanoparticles (IONPs) are being studied for few decades and still attracting increasing attention for several biomedical applications owing to their multifunctional design and intrinsic magnetic properties that provide a multimodal theranostic platform for cancer therapy, monitoring and diagnosis. The review article aims to provide brief information on various surface chemistries involved in modulating IONPs properties to exhibit potential therapy in cancer treatment. The review addresses structural, magnetic, thermal and optical properties of IONPs which aids in the fabrication of efficient multimodal nanoplatform in cancer therapy. The review discussed the pharmacokinetics of IONPs and attributes influencing them. This review inculcates recent advancements in therapies, focused on tumor-microenvironment-responsive and targeted therapy along with their eminent role in cancer diagnosis. The concept of stimuli-responsive including endogenous, exogenous and dual/multi stimuli-based delivery platform demonstrated significantly enhanced anticancer therapy. Several therapeutic approaches viz. chemotherapy, radiotherapy, immunotherapy, hyperthermia, gene therapy, sonodynamic therapy, photothermal, photodynamic-based therapy along with biosensing and several toxicity aspects of IONPs have been addressed in this review for effective cancer treatment.

Liposomes as Versatile Platform for Cancer Theranostics: Therapy, Bio-imaging, and Toxicological Aspects.

Liposomes are nano-sized formulations having the benefits of site-specificity, biocompatibility, and biodegradability, which make them useful for the therapy and diagnosis of major diseases like cancer. In this review, various synthetic strategies of liposomes and their biomedical application in special concern to cancer are discussed. In context to the biomedical application, this article gives a detailed insight into subcellular targeted therapy and several therapeutic modifications like immunotherapy, receptor-based therapy, phototherapy, and combination therapy. The review also describes the liposome-based imaging platforms and the toxicity associated with liposomes. Owing to a significant amount of benefits of this carrier system, several products have been approved to be launched in the market and several others have already been marketed for clinical use.

Surface-engineered nanoliposomes with lipidated and non-lipidated peptide-dendrimeric scaffold for efficient transdermal delivery of a therapeutic agent: Development, characterization, toxicological and preclinical performance analyses.

The current study aimed to develop novel peptide dendrimer (PD)-conjugated nanoliposomal formulations of asenapine maleate (ASP) for improvement in the transdermal delivery and pharmacokinetic profile of the drug. Novel arginine-terminated PDs (+/-lipidation) were prepared by solid phase peptide synthesis, followed by conjugation onto ASP nanoliposomes. The nanoliposomes were characterized for particle size (and polydispersity index), zeta potential (ZP), drug entrapment efficiency, shape and morphology, differential scanning calorimetry and FT-IR spectroscopy. Ex vivo skin permeation and retention studies demonstrated considerably higher percutaneous permeation of ASP from the developed nanoliposomes (Q24 = 794.31 ± 54.89 µg/cm2, Jss = 105.40 ± 4.8 µg/cm2/h, ER = 36.85 ± 2.89 for liposomes with lipidated peptide dendrimer (Lipo-PD2)) in comparison with passive diffusion studies (Q24 = 63.09 ± 3.56 µg/cm2, Jss = 3.01 ± 0.23 µg/cm2/h). Confocal Laser Scanning Microscopy (CLSM) confirmed the higher percutaneous penetration of Lipo-PD2 in comparison with liposomes without the dendrimer. In vitro cytotoxicity determined on HaCaT cell line demonstrated CTC50 of >1000 µg/mL for both the synthesized PDs and Lipo-PD2. Pharmacokinetic studies in male Sprague Dawley rats revealed considerably and significantly higher t1/2 = 82.32 ± 14.48 h and AUC0-t = 4403.34 ± 367.10 h.ng/mL, from the developed formulation, compared to orally administered ASP (t1/2 = 21.64 ± 2.53 h and AUC0-t = 2303.55 ± 444.5 h.ng/mL), demonstrating higher bioavailability and longer retention in vivo. Additionally, in vivo skin retention, brain uptake studies and pharmacodynamics of the developed formulations were investigated. Stability studies indicated that the formulations were stable up to relatively stable with respect to size, ZP and drug content for 4 months at the tested conditions. This study demonstrates that the developed PD-conjugated nanoliposomal formulations can effectively serve as a transdermal delivery strategy for ASP.

Epigallocatechin-3-gallate (EGCG) protects the oocytes from methyl parathion-induced cytoplasmic deformities by suppressing oxidative and endoplasmic reticulum stress.

Methyl parathion (MP) is a commonly used organophosphorus insecticide in commercial farming. It is well known that MP exposure can affect the function of nervous, respiratory, cardiovascular and reproductive systems. In our previous report we have demonstrated that MP exposure results in poor oocyte maturation and defective embryo development which is mainly mediated through oxidative stress. The present investigation was designed to explore whether using a potent free radical scavenger like Epigallocatechin-3-gallate (EGCG) can help in reducing the detrimental effects of MP on the oocytes. For the study, germinal vesicle (GV) stage oocytes collected from the ovaries of adult Swiss albino mice were subjected to in vitro maturation (IVM) in the presence or absence of MP (100 µg/mL) and/or EGCG (0.25 µM). MP significantly reduced the nuclear maturation rate, and resulted in poor cytoplasmic organization which was evident from the altered distribution pattern of mitochondria, endoplasmic reticulum and abnormal spindle organization. These changes were associated with significant elevation in oxidative stress and expression of ER stress markers such as 78 kDa Glucose regulated protein (GRP78) as well as X-box binding protein-1 (XBP1) in the oocytes. Further, the oocytes exposed to MP had lower activation rate and developmental potential. Supplementation of EGCG during IVM not only improved the nuclear maturation rate but also reduced the cytoplasmic abnormalities. These beneficial effects appear to be due to mitigation of oxidative and ER stress in oocytes. In conclusion, results of our study indicate that EGCG can help in alleviating MP-induced oocyte abnormalities.

Ethanolic extract of Moringa oleifera leaves alleviate cyclophosphamide-induced testicular toxicity by improving endocrine function and modulating cell specific gene expression in mouse testis.

ETHNOPHARMACOLOGICAL RELEVANCE: Moringa oleifera Lam. is known for its nutritional and ethno medicinal values due to the presence of wide array of phytochemicals with multiple biological activities. We have previously reported that ethanolic extract of Moringa oleifera leaves (MOE) ameliorated cyclophosphamide (CP)-induced testicular toxicity and improved functional integrity of spermatozoa as well as spermatogenic cells. AIM OF THE STUDY: The present study was planned to investigate whether the mitigation of CP-induced testicular toxicity by MOE is mediated via modulation of endocrine profile, genes associated with function of different cell types and enhancement of DNA repair response in spermatogonial cells. MATERIALS AND METHODS: Adult Swiss albino mice (8 week) were injected with CP (100 mg/kg, one dose in a week for 3 weeks) and MOE (100 mg/kg, 5 doses in a week for 4 weeks) either alone or in combination intraperitoneally. At 35 day post CP injection (first dose), the functional characteristics such as count, motility, head morphology and DNA integrity were assessed in epididymal spermatozoa. Key reproductive hormones like testosterone, follicle stimulating hormone (FSH) and Inhibin B concentration were analyzed in serum and testis. In addition, mRNA expression of genes pertaining to the function of Leydig, Sertoli and spermatogonial cells as well as antioxidant enzymes were evaluated in the testis. To understand the DNA damage and repair process in germ cells, prepubertal (2 week) mice were administered with single dose of CP (200 mg/kg) and/or MOE (100 mg/kg) and analyzed for expression of DNA damage (γ-H2AX, P53 and Caspase3) and repair genes (Rad51 and Ku80) in isolated spermatogonial cells at various time points after treatment. RESULTS: CP administration resulted in decrease in count, motility and increase in morphological defects and DNA damage in spermatozoa. Testosterone level was marginally decreased while there was a significant increase in FSH (p < 0.001) and decrease in inhibin B (p < 0.05) observed in CP treated mice. Administration of MOE prior to CP, improved sperm functional characteristics, decreased FSH and increased inhibin B levels. Expression of Abp was down-regulated while Transferrin, Fshr and Gata4 (Sertoli cell specific genes) were up-regulated in testis treated with CP. Administration of CP down-regulated the expression of Oct4 and Ddx4 (Spermatogonia specific genes). MOE administration was shown to ameliorate CP-induced damage by modulating the expression of genes specific to Sertoli and spermatogenic cells. Furthermore, MOE treatment reduced CP-induced DNA damage as evident from lower percentage of γ-H2AX positive spermatogonial cells. CONCLUSION: Administration of MOE mitigated CP-induced testicular damage by improving blood and, intra-testicular hormonal milieu as well as modulating the expression of genes pertaining to Sertoli and spermatogonial cells.

Heterogeneous surface-modified nanoplatforms for the targeted therapy of haematological malignancies.

Here, we focus on nanoparticle (NP)-based platforms for the targeted therapy of haematological malignancies (HMs), providing an overview of surface-modified nanoplatforms, such as aptamer-, metal-, nucleic acid-, toxin, and peptide-modified NPs, for the efficient targeting of tumor cells. We discuss NPs targeting subcellular compartments, including mitochondria, nucleus and Golgi apparatus, for enhanced therapy of HMs. We also review stimuli-responsive nanoplatforms for modulating site-specific release of drugs. We provide insight into alternative modes of therapy, such as phototherapy, gene therapy, dendritic cell (DC) therapy, and radiotherapy, highlighting recent advances in the treatment of HMs.

Supplementation of biotin to sperm preparation medium enhances fertilizing ability of spermatozoa and improves preimplantation embryo development.

PURPOSE: Motility of spermatozoa helps not only in planning the type of infertility treatment but also directly reflects the success rate in assisted reproductive technology (ART). Previously, biotin, a water-soluble vitamin, has been shown to increase the motility and longevity of cryopreserved human spermatozoa. The present study was designed to understand the molecular basis of the beneficial effects of presence of biotin in sperm wash medium on early embryo development. METHODS: The effect biotin supplementation to sperm wash medium on the sperm parameters were assessed in swim-up fraction of normozoospermic and asthenozoospermic ejaculates collected from infertile men. Fertilization and early embryo development was studied using Swiss albino mice. RESULTS: Even though both biotin and pentoxifylline (PTX) enhanced the motility of spermatozoa from normozoospermic and asthenozoospermic samples, biotin group exhibited higher in vitro survival. Using mouse model, we observed that presence of biotin or PTX in sperm wash medium improved the fertilization rate and blastocyst rate compared to control. Blastocysts from these groups had significantly higher total cell number (P < 0.01) and lower apoptotic index. In silico target prediction revealed that GTPase HRas (HRas), tyrosine-protein phosphatase nonreceptor type 1 (PTP1B), and glucokinase are the probable targets for biotin. Solution-state Nuclear Magnetic Resonance (NMR) studies confirmed that biotin interacts both with human HRas and PTP1B. CONCLUSION: Our results indicate that presence of biotin in sperm wash medium can improve the fertilization potential and preimplantation embryo development and can be considered as a safe alternate to PTX.

Supplementing zinc oxide nanoparticles to cryopreservation medium minimizes the freeze-thaw-induced damage to spermatozoa.

The sperm DNA integrity post cryopreservation of human semen samples is one of the serious concerns in human infertility treatment. In the present study, the beneficial effects of zinc oxide nanoparticles in preserving the functional ability of spermatozoa was explored. Ejaculates of normozoospermic men cryopreserved along with Zinc oxide nanoparticles (ZnONPs) exhibited non-significantly higher percentage of total and progressive motility in frozen-thawed samples compared to control. The sperm chromatin damage and malondialdehyde (MDA) level was significantly lower in ZnONPs group (P < 0.01 and P < 0.05 respectively) and the spermatozoa's ability to undergo acrosome reaction was also unaltered. Fluorescence microscopy and High resolution transmission electron microscopy analysis demonstrated that the ZnONPs do not penetrate the membrane of spermatozoa but stay around the spermatozoa. In conclusion, the presence of ZnONPs during cryopreservation appears to be beneficial to the spermatozoa as they withstand freeze-thaw process competently better than control, without any adverse effect shown.

Liposome-encapsulated diacyl glycerol and inositol triphosphate-induced delayed oocyte activation and poor development of parthenotes.

OBJECTIVE: To explore the ability of diacyl glycerol (DAG) and inositol triphosphate (IP3), two major secondary messengers in the calcium signaling pathway, in activating oocytes. MATERIAL AND METHODS: Oocyte cumulus complex obtained from superovulated Swiss albino mice were incubated in M16 medium with liposome-encapsulated 1,2-Dipalmitoyl-sn-glycerol (LEDAG) and/or IP3 for 3 h. Strontium chloride was used as positive control. The activation potential, ploidy status, and blastocyst rate was calculated. RESULTS: Both DAG and IP3, individually, induced activation in ~98% of oocytes, which was significantly higher (p<0.01) than activation induced by strontium chloride (60%). Delayed pronucleus formation and a higher percentage of diploid parthenotes was observed in oocytes activated with LEDAG and/or IP3. However, these embryos failed to progress beyond the 6-8-cell stage. Only when the medium was supplemented with LEDAG (5 µg/mL) and IP3 (10 µg/mL) could activated oocytes progress till the blastocyst stage (5.26%), which was lower than the blastocyst rate in the positive controls (13.91%). CONCLUSION: The results of the present study indicate that DAG and IP3 can induce delayed oocyte activation and poor development of parthenotes in vitro.

Indian propolis ameliorates the mitomycin C-induced testicular toxicity by reducing DNA damage and elevating the antioxidant activity.

Development of excellent curative therapy for most of the malignancies has resulted in a growing population of cancer survivors who are at increased risk for a variety of health problems including infertility. Therefore, fertility preservation has become an important issue during cancer treatment in recent years. Combination therapy with natural agents such as vitamins, antioxidants, dietary supplements, and plant products are considered as an attractive option to mitigate normal tissue toxicity imparted by chemotherapy. The aim of the present study was to explore the beneficial effect of hydroethanolic extract of Indian propolis (HEIP) on mitigating mitomycin C (MMC)-induced testicular damage and its mechanism of action. Healthy adult male mice were injected intraperitoneally with saline, MMC, HEIP and HEIP followed by MMC after 1h. The animals were dissected at 35days after various treatments to analyze testicular function. MMC administration resulted in significant reduction in testicular function in a dose-dependent manner at 35days after treatment which significantly improved by HEIP pre-treatment. At 24h after treatment, MMC induced significant increase in oxidative stress, γ-H2AX foci and expression of RAD51 and KU80 in testicular cells. Prior treatment with HEIP decreased the oxidative stress, reduced DNA damage and restored the testicular testosterone and inhibin B level. In conclusion, co-administration of Indian propolis extract may play a promising beneficial role in fertility preservation of males undergoing chemotherapy.

Ethanolic extract of Moringa oleifera Lam. leaves protect the pre-pubertal spermatogonial cells from cyclophosphamide-induced damage.

ETHNOPHARMACOLOGICAL RELEVANCE: Moringa oleifera Lam. is widely cultivated in Asian and African countries for its medicinal and dietary significance. The leaves are highly nutritious and are known to possess various biological activities. MATERIALS AND METHODS: Pre-pubertal Swiss albino male mice were injected with single dose of cyclophosphamide (CP, 200mg/kg body weight) or ethanolic extract of Moringa oleifera leaves (MOE, 100mg/kg body weight) intraperitoneally. In combination group, MOE was administered 24h prior to CP injection. RESULTS: CP induced a significant decrease in testicular weight (p<0.01) and depletion of germ cells (p<0.001) and higher level of DNA damage (p<0.001) compared to control. The expression of P53, Bax, Cytochrome C (Cyt C) was increased while there was a decrease in the expression of Bcl2, c-Kit and Oct4. Administration of MOE 24h prior to CP treatment ameliorated the depletion (p<0.001), DNA damage (p<0.001) and apoptosis (p<0.01) of germ cells induced by CP. The mitigating effect of MOE appears to be mediated by up-regulating the expression of c-Kit and Oct4 transcripts in P53-independent manner. CONCLUSION: MOE protects the spermatogonial cells from CP-induced damage by modulating the apoptotic response elicited by CP and therefore can be considered as an efficient method of male fertility preservation.

Development and evaluation of sunscreen creams containing morin-encapsulated nanoparticles for enhanced UV radiation protection and antioxidant activity.

The objective of present work was to develop novel sunscreen creams containing polymeric nanoparticles (NPs) of morin. Polymeric NPs containing morin were prepared and optimized. The creams containing morin NPs were also prepared and evaluated. Optimized NPs exhibited particle size of 90.6 nm and zeta potential of -31 mV. The entrapment efficiency of morin, within the polymeric NPs, was found to be low (12.27%). Fourier transformed infrared spectroscopy and differential scanning calorimetry studies revealed no interaction between morin and excipients. Transmission electron microscopy and atomic force microscopy revealed that the NPs were spherical in shape with approximately 100 nm diameter. Optimized NPs showed excellent in vitro free radical scavenging activity. Skin permeation and deposition of morin from its NPs was higher than its plain form. Different sunscreen creams (SC1-SC8) were formulated by incorporating morin NPs along with nano zinc oxide and nano titanium dioxide. SC5 and SC8 creams showed excellent sun protection factor values (≈40). In vitro and in vivo skin permeation studies of sunscreen creams containing morin NPs indicated excellent deposition of morin within the skin. Morin NPs and optimized cream formulations (SC5 and SC8) did not exhibit cytotoxicity in Vero and HaCaT cells. Optimized sunscreen creams showed excellent dermal safety. SC5 and SC8 creams demonstrated exceptional in vivo antioxidant effect (estimation of catalase, superoxide dismutase, and glutathione) in UV radiation-exposed rats. The optimized sunscreen creams confirmed outstanding UV radiation protection as well as antioxidant properties.

Liposome encapsulated soy lecithin and cholesterol can efficiently replace chicken egg yolk in human semen cryopreservation medium.

Cryopreservation of spermatozoa plays a significant role in reproductive medicine and fertility preservation. Chicken egg yolk is used as an extender in cryopreservation of human spermatozoa using glycerol egg yolk citrate (GEYC) buffered medium. Even though 50% survival of spermatozoa is generally achieved with this method, the risk of high levels of endotoxins and transmission pathogens from chicken egg yolk is a matter of concern. In the present study we attempted to establish a chemically defined cryopreservation medium which can replace the chicken egg yolk without affecting sperm survival. Ejaculates from 28 men were cryopreserved with GEYC based freezing medium or liposome encapsulated soy lecithin-cholesterol based freezing medium (LFM). The semen samples were subjected to rapid thawing after 14 days of storage in liquid nitrogen. Post-thaw analysis indicated significantly higher post-thaw motility and sperm survival in spermatozoa cryopreserved with LFM compared to conventional GEYC freezing medium. The soy lecithin and cholesterol at the ratio of 80:20 with sucrose showed the highest percentage of post-thaw motility and survival compared to the other compositions. In conclusion, chemically defined cryopreservation medium with liposome encapsulated soy lecithin and cholesterol can effectively replace the chicken egg yolk from human semen cryopreservation medium without compromising post-thaw outcome.

Transdermal delivery of lercanidipine hydrochloride: effect of chemical enhancers and ultrasound.

The effects of permeation enhancers and sonophoresis on the transdermal permeation of lercanidipine hydrochloride (LRDP) across mouse skin were investigated. Parameters including drug solubility, partition coefficient, drug degradation and drug permeation in skin were determined. Tween-20, dimethyl formamide, propylene glycol, poly ethylene glycol (5% v/v) and different concentration of ethanol were used for permeation enhancement. Low frequency ultrasound was also applied in the presence and absence of permeation enhancers to assess its effect on augmenting the permeation of drug. All the permeation enhancers, except propylene glycol, increased the transdermal permeation of LRDP. Sonophoresis significantly increased the cumulative amount of LRDP permeating through the skin in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in presence of permeation enhancers. The results suggest that the formulation of LRDP with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver LRDP across the skin for a prolonged period (i.e., 24 h). The application of ultrasound in association with permeation enhancers could further serve as non-oral and non-invasive drug delivery modality for the immediate therapeutic effect.

Development of mucoadhesive buccal films for the treatment of oral sub-mucous fibrosis: a preliminary study.

The objective of the present study was to develop the mucoadhesive buccal film of valdecoxib for the treatment of oral sub mucous fibrosis, a localized buccal disease. Valdecoxib, a novel COX-2 inhibitor has been reported to be used in various osteopathic and rheumatoid conditions as oral therapy. The films were made out of chitosan and HPMC K4M as polymers. Sodium taurocholate was used as a permeation enhancer. All the formulations were examined for film thickness, swelling properties, drug content, weight variation, in vitro release studies, bioadhesive force, tensile strength, diffusion studies using pig mucosa and pharmacokinetic study in healthy male volunteers. Prepared films were thin, flexible, smooth and transparent. Bioadhesive force and tensile strength of the optimized formulation were found to be 75 +/- 4 kg m(-1) S(-2) and more than 2.5 kg/3 cm(2), respectively. The percent drug content was 98.5 +/- 1.3%. The in vitro drug release from the selected formulation showed that about 69.34% of the drug payload was released up to 6 hours. The drug permeation through the dialysis sac and pig buccal mucosa was found to be 62.70% and 54.39%, respectively. Pharmacokinetic studies of the buccal mucoadhesive film showed that the drug was released locally at the target site of action, and a very small amount might have absorbed systemically.

A combined approach of chemical enhancers and sonophoresis for the transdermal delivery of tizanidine hydrochloride.

The effects of chemical enhancers and sonophoresis on the transdermal permeation of tizanidine hydrochloride (TIZ) across mouse skin were investigated. Parameters including drug solubility, apparent partition coefficient (APC), drug permeation, and degradation in skin were determined. Low frequency ultrasound was also applied in the presence and absence of chemical enhancers to assess whether drug permeation improved. APC values indicated that TIZ preferentially partitions into intercellular spaces and does not form a reservoir, with the drug also exhibiting good enzymatic stability in skin. Most of the enhancers studied significantly increased the permeation rate of TIZ through full thickness mouse skin in comparison with TIZ formulated in phosphate buffer. Maximum enhancement was observed for TIZ formulated as a suspension in 50% v/v aqueous ethanol containing 5% v/v citral. Sonophoresis significantly (p < 0.05) increased the cumulative amount of TIZ permeating through the skin at 15 and 30 min in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in the presence of chemical enhancers. The results suggest that the formulation of TIZ with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver TIZ across the skin for a prolonged period, i.e. 24 hr. The application of ultrasound in association with chemical enhancers, such as the combination of 5% v/v citral in 50% v/v aqueous ethanol, could further serve as a non-oral and non-invasive drug delivery modality for the immediate therapeutic effect of muscle relaxants such as TIZ.

Chronotherapeutic drug delivery for early morning surge in blood pressure: a programmable delivery system.

The purpose of the study was to develop pulsatile capsule dosage form of valsartan for controlled delivery. In the majority of individuals blood pressure rises in the early morning hours, which lead to serious cardiovascular complications. Formulations with constant/programmable delivery rates make it possible to deliver drug at definite time or controlled rate in chronopharmacokinetic studies. The prepared system contained swellable polymer (l-hydroxypropyl cellulose (L-HPC), xanthan gum, polyethylene oxide or sodium alginate) together with drug tablet and erodible tablet (L-HPC or guar gum) in a pre-coated capsule. Various formulation factors were investigated through series of tests, in vitro dissolution and ex vivo continuous dissolution-absorption studies. We found that the type, amount of polymers and erodible tablet influenced the drug release. The formulation containing 200 mg sodium alginate and erodible tablet (150 mg) containing 50% guar gum and 46% lactose showed 5-6 h lag time and 10+/-2.1% drug release in initial 6 h following rapid release (99+/-1.7% release in 12 h) of drug was observed. The continuous dissolution-absorption study conducted using everted rat intestinal segment indicated delay in absorption of drug. Thus this approach can provide a useful means for timed release of valsartan and may be helpful for patients with morning surge.