Assessing the Efficacy of Berberine Hydrochloride-loaded Transethosomal Gel System in Treating Dermatophytosis Caused by Trichophyton Rubrum in ex-vivo, in-vitro, and in-vivo models.

BACKGROUND: Dermatophytosis is the most common dermatological disorder worldwide. Many drugs are available in the market for the treatment of dermatophytosis, but they have had limited success due to the stratum corneum barrier, antifungal resistance, drug permeation, drug retention in skin layers, etc. Thus, there is a constant need for new topical compounds that are effective against dermatophytosis. Berberine-hydrochloride is an attractive candidate to become an antifungal drug, and by using nanotechnology, it achieves deeper penetration in skin layers with enhanced permeability through the stratum corneum. METHODS: In this study, we developed an oleic acid-containing berberine-hydrochloride-loaded transethosomal gel for effective treatment of dermatophytosis by Trichophyton rubrum. Berberine-hydrochloride-loaded transethosomal gels were fabricated using the hot homogenization method, followed by the incorporation of transethosomes into the gel-based system using carbopol 934. Transethosomal gel was characterized by physicochemical properties, in vitro drug release, ex-vivo permeation studies, CLSM visualization, antifungal activity, histopathological evaluation, and dermatokinetic study. RESULTS: Berberine-hydrochloride-loaded transethosomes seemed to be spherical and found in a range between 200-300 nm. Berberine-hydrochloride-loaded transethosomal gel formulation also exhibited controlled ex-vivo permeation of berberine-hydrochloride over 24 hr through excised rat skin, and CLSM confirmed deeper penetration into skin layers. The in vivo study revealed that transethosomal gel had a healing effect on the skin of Wistar rats infected with Trichophyton rubrum and was better than luliconazole cream. The histopathological evaluation confirmed its safety, and the dermatokinetic study showed transethosomal gel superiority over marketed cream. CONCLUSION: Therefore, the incorporation of berberine hydrochloride-loaded transethosomal nanosystems into the gel has the potential to enhance antifungal activity and permeation through transdermal drug delivery.

Development of andrographolide-loaded solid lipid nanoparticles for lymphatic targeting: Formulation, optimization, characterization, in vitro, and in vivo evaluation.

Andrographolide, the primary bioactive constituent of Andrographis paniculata, is a promising natural substance with numerous pharmacotherapy uses. Low water solubility, short half-life, and low permeability necessitate the development of a delivery system that enhances its entrapment efficiency, bioavailability, lymphatic targeting, and by-pass hepatic effect. The andrographolide-loaded solid lipid nanoparticles were fabricated by melt-emulsification and ultrasonication and optimized with Design-Expert software. In the optimal formulation, Glycerol monostearate as the solid lipid and Poloxamer 407 and Span 60 as surfactants were used. Optimum AND-SLN was observed to have a mean particle size, polydispersity index, zeta potential, and entrapment efficiency of 193.84 nm, 0.211, - 22.8 mV, and 83.70% respectively. An optimized formulation was characterized by examining surface morphology, X-ray diffraction, and differential scanning calorimetry. In vitro studies have shown sustained drug release from AND-SLN for up to 24 h. The stability studies showed that there was no significant change in the mean particle size and entrapment efficiency after storage at 4 ± 2 °C and 25 ± 2 °C/60 ± 5% RH. In in vivo pharmacokinetics studies, AND-SLN was found to have enhanced bioavailability and specificity in the spleen and thymus compared to plasma, providing evidence that the formulations could enhance target specificity and bioavailability in comparison to pure drugs. The H&E staining of the liver, spleen, and thymus treated with the AND-SLN revealed no signs of damage histopathologically. Thus, AND-SLN possess a high potential for improved efficacy and are an efficient vehicle for delivering drugs to the lymphatic system.

Glibenclamide-malonic acid cocrystal with an enhanced solubility and bioavailability.

OBJECTIVE: The objective of the work is to enhance the solubility, dissolution, and pharmacokinetic properties of glibenclamide (GLB) via cocrystallization technique. SIGNIFICANCE: Glibenclamide is an oral hypoglycemic agent used for treating non-insulin-dependent (type II) diabetes mellitus. It exhibits poor aqueous solubility and oral bioavailability, thereby compromising its therapeutic effect. Therefore, utilizing cocrystal approach for enhancing the solubility will modulate the physicochemical properties of GLB without altering its molecular structure. METHODS: Cocrystal was prepared by solution crystallization method using coformer malonic acid. The cocrystal was characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FT-IR) studies. The prepared cocrystal was subjected to solubility, in vitro dissolution, and pharmacokinetic studies. RESULTS: The DSC endotherms, PXRD patterns, and the FT-IR spectra of the cocrystal established the formation of a cocrystal. The formation of eutectic mixture was refuted upon comparing the DSC endotherm and PXRD pattern of the cocrystal with that of the physical mixture. GLB showed a twofold enhancement in solubility and a significant improvement in the rate of dissolution (p < 0.05, independent t-test) after cocrystallization. The pharmacokinetic parameters on male Sprague Drawly rats showed 1.45 enhancement in AUC0-24 and 1.36-fold enhancement in the Cmax of GLB as compared to the pure drug. CONCLUSION: These findings demonstrate that cocrystallization technique was able to tailor the solubility and dissolution profile of GLB leading to an enhanced pharmacokinetic property.

The Epitome of Novel Techniques and Targeting Approaches in Drug Delivery for Treating Lymphatic Filariasis.

BACKGROUND: Lymphatic filariasis is a pervasive and life-threatening disease for human beings. Currently, 893 million people in 49 countries worldwide affected by lymphatic filariasis as per WHO statistics. The concealed aspects of lymphatic diseases such as delayed disease detection, inappropriate disease imaging, the geographical outbreak of infection, and lack of preventive chemotherapy have brought this epidemic to the edge of Neglected Tropical Diseases. Many medications and natural bioactive substances have seen to promote filaricidal activity against the target parasitic species. However, the majority of failures have occurred in pharmaceutical and pharmacokinetic issues. OBJECTIVE: The purpose of the study is to focus on the challenges and therapeutic issues in the treatment of filariasis. The review brings novel techniques and therapeutic approaches for combating lymphatic filariasis. It also offers significant developments and opportunities for such therapeutic interventions. CONCLUSION: Through this review, an attempt has made to critically evaluate the avenues of innovative pharmaceuticals and molecular targeting approaches to bring an integrated solution to combat lymphatic filariasis.

Efficacy of Concanavalin-A conjugated nanotransfersomal gel of apigenin for enhanced targeted delivery of UV induced skin malignant melanoma.

The aim of present study was to develop the efficient targeting of Concanavalin-A conjugated nanotransfersomal gel to bind directly to melanocytes gel layer against UVB induced skin carcinoma. Carbopol loaded nanotransfersomal gel have prepared by modified rotary evaporation sonication technique & conjugated synthesized by carbodiimide method and they were characterized the morphology, zeta potential, penetration and cell viability. In vitro release studies & skin permeation have determined using Franz diffusion cell and confocal laser scanning microscope (CLSM). The conjugated formulation showed vesicles size, polydispersity index, zeta potential and % conjugation efficiency of 179.0 ± 0.32 nm, 0.197 ± 0.07, 35.1 ± 0.21 mV and 89.73 ± 1.29% respectively. The surface morphology was confirmed by transmission electron microscopy (TEM) and FTIR to make sure the compatibility among its ingredients. Con-A conjugated nanotransfersomal gel showed toxicity on melanoma (A375) in a concentration range of 0.4-2.0 mg/mL, but less toxicity toward HaCaT cells. The MTT assay has analyzed against two different cell lines, to determine their anti-cancer potentials and their targeting ability. Conjugated formulation were found to decrease the cell viability, higher skin targeting efficacy in in-vitro & in-vivo. Concanavalin conjugated nanotransfersomal gel of apigenin promise an efficient and economic approach for the skin cancer.

Multicomponent Pharmaceutical Cocrystals: A Novel Approach for Combination Therapy.

Cocrystallization is a technique for modifying the physicochemical and pharmacokinetic properties of an active pharmaceutical ingredient (API) embodying the concept of supramolecular synthon. Most of the examples cited in the literature are of cocrystals formed between an API and a coformer chosen from the generally recognized as safe (GRAS) substance list; however few examples exist where a cocrystal consists of two or more APIs. These cocrystals are commonly known as multi API, multi-drug or drug- drug cocrystals. The formation of such cocrystals is feasible by virtue of non covalent interactions between the APIs, which help them in retaining their activity. In addition, drugdrug cocrystals also offer potential solution to the limitations such as solubility, stability differences and chemical interaction between the APIs which is often faced during the traditional combination therapy. Cocrystallization of two or more APIs can be employed for delivery of combination drugs for the better and efficacious management of many complex disorders where existing monotherapies do not furnish the desired therapeutic effect. This review on the existing drug-drug cocrystals is to gain an insight for better designing of multi API cocrystals with improved physicochemical and pharmacokinetic profile and its application in multiple target therapy.

Antipsoriatic and Anti-inflammatory Studies of Berberis aristata Extract Loaded Nanovesicular Gels.

OBJECTIVE: Novel nanovesicular gel of Berberis aristata extract was developed and evaluated for its anti-inflammatory and antipsoriatic activity. MATERIALS AND METHODS: Transferosomes were prepared using soya phosphatidylcholine and edge activators (Tween 80, Span 80, and sodium deoxycholate) by a modified lipid film hydration technique using rotary evaporator and evaluated for various parameters. The quantification and standardization of extract have been carried out using its alkaloid content as berberine as biomarker. Topical application of imiquimod (IMQ) (immune modifier) on the shaved back of mice developed psoriasis-like inflammation followed by histopathological study of inflamed skin. RESULTS: The size of transferosomes was in the range of 265-345 nm whereas polydispersity index ranges from 0.10 to 0.63, and for zeta potential, it was from -19.3 to -43.3 mV. Transferosomes were further added to Carbopol 934P for gel formation and subsequently evaluated for their physicochemical properties. Their efficacy against inflammation, IMQ-induced psoriasis, and skin sensitivity was compared with conventional formulation (commercial formulation-Angle Gloss, Phytolab Pvt. Ltd.). Percent inhibition of edema by transferosomal gel (55.76%) was more as compared to conventional gel of extract (33.5%) found out by Carrageenan-induced paw edema method. Primary irritation index was found to be <0.4 inferring its safe use for topical formulation. CONCLUSION: Histopathological report showed that, in psoriasis-induced animal treated with topical application of extract loaded transferosomal gel showed a marked reduction in thickness of epidermis, length of rete ridges as compared to conventional gel formulation. It can be inferred that B. aristata extract loaded transferosomal gel can function as potential anti-inflammatory and antipsoriatic formulation. SUMMARY: The objective of the present research work was to prepare Berberis aristata extracts (roots, ethanolic 70%v/v) loaded transferosomal gel, to perform in vitro characterization and in vivo evaluation of their efficacy against inflammation as well as imiquimod (IMQ)-induced psoriasis in animalsThe remarkable enhancement in the in vitro release efficiency of B. aristata extract loaded transferosomal gel resulted in improved anti-inflammatory activity. The prepared novel formulation of B. aristata has also shown its efficacy against IMQ-induced psoriasis. Abbreviations used: SPC: Soyaphosphatidylcholine, PDI: Polydispersity index, IMQ: Imiquimod, EA: Edge activator, BE: Berberine, TEM: Transmission electron microscopy, PBS: Phosphate buffered saline, H and E: Hematoxylin and eosin, ZP: Zeta potential, EE: Entrapment efficiency.

Targeting of herbal bioactives through folate receptors: a novel concept to enhance intracellular drug delivery in cancer therapy.

Targeted drug delivery through folate receptor (FR) has emerged as a most biocompatible, target oriented, and non-immunogenic cargoes for the delivery of anticancer drugs. FRs are highly overexpressed in many tumor cells (like ovarian, lung, breast, kidney, brain, endometrial, and colon cancer), and targeting them through conjugates bearing specific ligand with encapsulated nanodrug moiety is undoubtedly, a promising approach toward tumor targeting. Folate, being an endogenous ligand, can be exploited well to affect various cellular events occurring during the progress of tumor, in a more natural and definite way. Thus, the aim of the review lies in summarizing the advancements taken place in the drug delivery system of different therapeutics through FRs and to refine its role as an endogenous ligand, in targeting of synthetic as well as natural bioactives. The review also provides an update on the patents received on the folate-based drug delivery system.

Topical Analgesic Nanolipid Vesicles Formulation of Capsaicinoids Extract of Bhut Jolokia (Capsicum chinense Jacq): Pharmacodynamic Evaluation in Rat Models and Acceptability studies in Human Volunteers.

Capsicum fruit is used for treating skeletomuscular disorders as a counterirritant analgesic around the globe. But its concentration-dependent irritation and concomitant withdrawal of therapy by the patients hampers its therapeutic usefulness. In the present study, a novel nanolipid approach based on elastic phospholipid vesicles was employed to encapsulate a semipurified extract of Bhut Jolokia for topical drug delivery application. The working hypothesis was that encapsulation of irritant extract into nanolipid vesicles may prevent the initial rejection of formulation and the elastic vesicles may facilitate deeper skin penetration over a shorter time period. Surface response methodology was adopted to study the effect of selected independent formulation variables on dependent variables like vesicle size and entrapment efficacy. The prepared formulations were characterized for various physicochemical parameters. The efficacy of the newly developed nonolipid vesicle formulation loaded with semipurified extract of Bhut Jolokia was tested on carrageenan and formaldehyde-induced inflammation as well as Freund's adjuvant-induced arthritis model. The novel formulations were tested on human volunteers in a Phase I clinical trial and were found to be acceptable. The study indicates that this strategy holds immense potential for topical delivery of the bioactive from Bhut Jolokia and can pave the way for its clinical applications.

Formulation, characterization, and evaluation of ligand-conjugated biodegradable quercetin nanoparticles for active targeting.

The aim of this study was to design a targeted drug delivery system carrying a natural anticancer drug Quercetin (Qu), specifically for skin cancer. A central composite design was applied separately for each ligand, and the quadratic model was used for the process. The surface morphology was confirmed by transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR), and in vitro release studies were also performed. The MTT assay was performed against two different cell lines, to measure their anticancer potentials and their targeting ability. The study thus reveals that MA-Qu-PLGA and FA-Qu-PLGA nanoparticles (NPs) can be used as effective drug delivery systems for skin cancer treatment encompassing natural drugs.

Dermatological consequences of photosensitization with an approach to treat them naturally.

Photosensitization is a process in which the skin reacts to exposure to ultraviolet radiations. There are various associated dermatological consequences like photoxicity and photoallergic reactions which make the disease more complicated. There are various drugs which together with solar radiations worsen the situation of photosensitivity and hence termed as photosensitizers. The developments on the use of phytoconstituents from the herbal extract is the ardent need for fighting against the deleterious photosensitization reactions. This review attempts to highlight the problems of photosensitivity its pathological manifestation with the approach to treat them naturally with the help of skin rejuvenating herbs.

Matrix metalloproteinase enzymes and their naturally derived inhibitors: novel targets in photocarcinoma therapy.

The continuous exposure of skin to ultraviolet radiations generates reactive oxygen species leading to photoaging in which degradation of dermal collagen and degeneration of elastic fibers occurs. Matrix metalloproteinase [MMP] enzymes are the proteolytic enzymes which have significant potentiality of cleaving extracellular matrix [ECM] against Ultraviolet [UV] radiation. The important MMPs are MMP1, MMP2 and MMP7 which promote skin cancer when irradiated by UV rays. In lieu of this, the investigation of MMPs and their inhibitors are constantly being studied for successive results. Recent researches have focused on some traditionally used bioactive moieties as natural matrix metalloproteinases inhibitors (MMPIs) and emphasized on the need of more extensive and specific studies on MMPIs, so that a good combination of natural or synthetic MMPIs with the conventional drugs can be evolved for cancer chemotherapy. In this review, we discuss the current view on the feasibility of MMPs as targets for therapeutic intervention in cancer. This review also summarizes the role of small molecular weight natural MMPIs and a clinical update of those natural MMPIs that are under clinical trial stage.

Biocompatible nanoparticles for sustained topical delivery of anticancer phytoconstituent quercetin.

This study describes the release and retention of a herbal lipophilic drug in sustained and controlled manner in skin layers, given topically, intended for skin cancer. Quercetin -loaded nanoparticles were prepared by nanoprecipitation technique using ethylcellulose as polymer. Ethylcellulose was selected as it is biocompatible, but non-biodegradable and hence can act as a reservoir in skin furrows and ducts. It was observed that the Quercetin: Ethylcellulose: Tween 80 at different ratios affects particle sizes along with yield and entrapment efficiency. It was found that the size of nanoparticles could be varied by changing the speed of agitation and sonication. The nanoparticles were prepared in particle size range 228.77 +/- 2.0 nm and the zeta potential of the selected formulation were found to be -16.7 mV, which shows the stability of the preparation. The percent entrapment efficiency was found to be in the range from 51.96 to 53.93% and percent loading capacity in the range 34.19 to 5.12%. The amount of drug release from nanoparticles and of drug retained in skin was compared using ex vivo study which shows that the drug being lipophilic could be retained in the skin for longer duration thus reducing the dose and frequency of drug administration. Further the amount of drug reaching to other organs is also reduced since the systemic absorption of drug was low. Thus, Quercetin loaded nanoparticles were prepared for topical use.

Development of photochemoprotective herbs containing cosmetic formulations for improving skin properties.

Botanical photochemoprotectives are used because they act on various stages to prevent skin cancer and photoaging. The aim of this study was to prepare herbal creams from various photochemoprotective herbs and to perform efficacy studies on them by using physicochemical, microbiological, safety, psychometric, biophysical, and sun protection factor measurements. Herbal creams were prepared by incorporating hydroalcoholic extracts of Curcuma caesia (rhizome), Areca catechu (seeds), Centella asiatica (leaves) Cinnamon zeylanicum (dried bark), and Tamarindus indica (fruit pulp) in varied concentrations (1-5% w/w) in a base cream. The efficacy of all formulations was checked out for four weeks on 60 normal subjects on the volar forearm for evaluation of biophysical properties, and for psychometric evaluations (fragrance, lathery feel, softness, irritation, stickiness, smoothness, and aftereffect on the skin) and safety measurements. In the biophysical characterization, a cutometer for viscoelasticity, a mexameter for melanin content, a corneometer for hydration, and a sebumeter for sebum determination were used. All the cream formulations with 1% and 3% w/w extracts showed positive results and passed physicochemical, microbiological, and safety tests. The SPF values increased as the concentration of extract was increased up to a limit in the formulations. The SPF values were significantly higher (p < 0.01) in formulations with 3% herbal extract than with 1% herbal extract. Increased skin hydration, sebum levels, viscoelasticity, and decreased melanin values were obtained. The Cinnamon, Centella, and Tamarindus formulations were found more effective as photoprotectives than the Areca and Curcuma formulations.

Topical vesicular formulations of Curcuma longa extract on recuperating the ultraviolet radiation-damaged skin.

BACKGROUND: Ultraviolet radiations generate reactive oxygen species, leading to adverse effects on skin properties. Botanical extracts are multifunctional in nature having various properties like photoprotection, anti-aging, moisturizing, antioxidant, astringent, anti-irritant, and antimicrobial activity. AIMS: The aim of this study was to formulate creams having Curcuma longa extract loaded novel vesicular systems (liposomes, ethosomes, and transfersomes) and study their photoprotective effect by assessment of skin hydration (Cutometer) and sebum content (Sebumeter). METHODS: The alcoholic C. longa extract loaded liposomes, ethosomes, and transfersomes having 0.5-2.0% w/w extract were prepared, evaluated for size, entrapment efficiency, and incorporated into the cream. Their long-term interaction with skin (6 weeks) was compared in terms of their effects on skin hydration and sebum content. RESULTS: Vesicular size obtained was in the range 167.3 ± 3.0 to 262.4 ± 2.4 nm with low polydispersity index (0.2-0.3) and high entrapment efficiency. The efficacy was in the order C. longa extract loaded transfersomal creams > C. longa extract loaded ethosomal creams > C. longa extract loaded liposomal creams > C. longa extract loaded creams > Empty transfersome loaded cream > Empty ethosome loaded cream > Empty liposome loaded cream > Base cream. CONCLUSIONS: The photoprotective properties of the constituents of C. longa extract and hydrant, moisturizing lipid components of nano vesicles with better skin penetration resulted in improvement in skin properties like skin hydration and sebum content. The herbal extract loaded nano vesicles incorporated in cream could be used as photoprotective formulations.

In vitro sun protection factor determination of herbal oils used in cosmetics.

The aim of this study was to evaluate ultraviolet (UV) absorption ability of volatile and nonvolatile herbal oils used in sunscreens or cosmetics and express the same in terms of sun protection factor (SPF) values. Sun protection factor is a laboratory measure of the effectiveness of sunscreen; the higher the SPF, the more protection a sunscreen offers against the ultraviolet radiations causing sunburn. The in vitro SPF is determined according to the spectrophotometric method of Mansur et al. Hydroalcoholic dilutions of oils were prepared, and in vitro photoprotective activity was studied by UV spectrophotometric method in the range of 290-320 nm. It can be observed that the SPF values found for nonvolatile oils were in between 2 and 8; and for volatile oils, in between 1 and 7. Among the fixed oils taken, SPF value of olive oil was found to be the highest. Similarly among essential oils, SPF value of peppermint oil was found to be the highest. The study will be helpful in the selection of oils and fragrances to develop sunscreens with better safety and high SPF. Oily vehicles are more effective for producing a uniform and long-lasting film of sunscreen on the skin, and their emollient properties protect the skin against the drying effects of exposure to wind and sun. Volatile oils are used as perfumes in cosmetics.

Comparative measurement of hydration effects of herbal moisturizers.

Improvements of skin hydration properties by the use of polyherbal moisturizers are the recent advances in cosmetic preparations to avoid the harmful effects of chemical moisturizers. The main aim of the study was to establish selection preference of different available marketed herbal moisturizers on the basis of the efficiency of constituents for their hydration effects. The criteria for the selection of formulations were presence of herbal constituents, wheat germ oil and Aloe vera extract. Initially, physiochemical and psychometric studies were performed to visualize the compliance of moisturizers with the skin. The clinical study was carried out in six groups of six healthy human volunteers (aged 20-25 years) each applying moisturizers twice daily over a period of 3 weeks in their forearm. The skin properties measured were conductance, glow and appearance. The results indicated that all the moisturizers show moisturizing effect in a time-dependent pattern and the maximum increase in skin conductance was 168.125 and 165.24% for A2 and A1, respectively. Ranking of moisturizers based on conductance as well as physicochemical analysis is A2 > A1 > A4 > A3 > A5 > A6. It was found that the formulation A2 having wheat germ oil, Aloe vera extract and turmeric extract in combination showed best results due to their synergistic effect and wheat germ oil or Aloe extract, when present separately produced skin hydration to lesser extent.

Lymphatic targeting of zidovudine using surface-engineered liposomes.

The present investigation was aimed at lymphatic targeting of zidovudine (ZDV)-loaded surface-engineered liposomes (SE liposomes). Surface of liposomes was engineered by incorporation of charges (positive or negative) and site-specific ligand (mannose) in order to enhance localization to lymphatics, specifically to lymph node and spleen. Positively and negatively charged nanosized SE liposomes (120 +/- 10 nm) were prepared using stearylamine (SA) and dicetyl phosphate (DCP), respectively, while ligand-coated SE liposomes were prepared using mannose-terminated SA (mannose conjugate). The SE liposomes were characterized for shape and surface morphology, size, entrapment efficiency, and in vitro drug release. All the SE liposomes formulations showed biphasic ZDV release, whereas mannose-coated liposomes (MAN-Lip) significantly reduced (p < 0.05) drug release compared with conventional liposome (Lip). The organ distribution pattern of the SE liposomes exhibited significant reduction in free ZDV concentration in serum, whereas significantly increased quantity was detected in the spleen and lymph nodes (p < 0.05). Fluorescent microscopy suggested enhanced uptake and localization of the SE liposomes in the lymph nodes and spleen, which were in the order: mannose coated > negatively charged > positively charged > Lip. Thus, the SE liposomes appeared to be promising novel vesicular system for enhanced targeting of ZDV to lymphatics, in AIDS chemotherapy.