Crisaborole-Enthused Glycerosomal Gel for an Augmented Skin Permeation.

BACKGROUND: Crisaborole (CB), a boron-based compound, is the first topical PDE4 inhibitor to be approved by the US Food and Drug Administration (2016) for the treatment of Atopic Dermatitis. It is marketed as a 2% ointment (Eucrisa, Pfizer). However, CB is insoluble in water; therfore, CB glycersomes were formulated to enhance its permeation flux across the skin. OBJECTIVE: We developed a glycerosomal gel of CB and compared its in vitro release and permeation flux with the 2% conventional ointment. METHODS: Glycerosomes were prepared using a thin film hydration method employing CB, soya phosphatidylcholine, and cholesterol. The formed film was further hydrated employing a mixture of phosphate buffer pH 7.4 /glycerin solution containing varying percentages (20,30, 40, and 50 %) of glycerol. The glycerosomes obtained were characterized by their size, polydispersity index (PDI), and Zeta potential. The entrapment efficiency of the optimized formulation (F 1) was determined. The in vitro release of F1 was compared with its 2% conventional ointment. F1 was further incorporated into carbopol 934 P gel. The gel was characterized by pH, viscosity, spreadability, and drug content. The permeability flux of the glycerosomal gel was compared with its 2% conventional ointment. RESULTS: The optimized CB glycerosomes had a vesicle size of 137.5 ± 50.58 nm, PDI 0.342, and zeta potential -65.4 ± 6.75 mV. CB glycerosomal gel demonstrated a 2.13-fold enhancement in the permeation flux. CONCLUSION: It can thereby be concluded that glycerosomes can be an effective delivery system to enhance the penetration of CB across the skin.

A Comprehensive Review on Polyphenols Based Nanovesicular System for Topical Delivery.

BACKGROUND: Polyphenols are naturally occurring compounds having more than one hydroxy functional group. They are ubiquitous secondary plant metabolites possessing a wide range of pharmacological activity. Brightly colored fruits and vegetables are the natural source of polyphenols. Majorly, they possess antioxidant, anti-inflammatory and antimicrobial properties which make them suitable candidates to target skin related disorders. OBJECTIVE: This study is focused to explore the potential of polyphenols loaded nanovesicles for skin related disorders. The aim of the study is to review the applicability and efficacy of different vesicular systems encapsulated with various classes of polyphenols for skin related disorders, thus opening the opportunity for future studies based on these drug delivery systems. METHOD: Web of Science, PubMed, Scopus database, and the search engine Google Scholar were accessed for the literature search. The results were then filtered based on the titles, abstracts, and accessibility of the complete texts. RESULTS: The expository evaluation of the literature revealed that various nanovesicles like liposomes, niosomes, ethosomes and transferosomes incorporating polyphenol have been formulated to address issues pertaining to delivery across the skin. These developed nano vesicular systems have shown improvement in the physicochemical properties and pharmacological action. CONCLUSION: Polyphenol based nano-vesicular formulations have proved to be an effective system for topical delivery and henceforth, they might curtail the use of other skin therapies having limited applicability.

Crisaborole loaded nanoemulgel for the mitigation of atopic dermatitis in mice model.

OBJECTIVE: The present work aims to formulate nanoemulgel of crisaborole (CB) and evaluate its effectiveness against 2,4-Di-nitrochlorobenzene induced (DNCB) atopic dermatitis (AD) in mice. SIGNIFICANCE: AD is a chronic inflammation of the skin affecting the quality of life. CB is a topical PDE4 inhibitor marketed as a 2% ointment. It, however, possesses poor aqueous solubility. An o/w nanoemulsion shall exhibit an enhanced therapeutic effect owing to the increased solubility of CB and an augmented skin penetration. The addition of a gelling agent to form a nanoemulgel further provides ease of application to the patients. METHODS: Nanoemulsion was prepared by aqueous titration method using caproyl PGMC, cremophore EL and propylene glycol as the oil, surfactant, and cosurfactant respectively. The formulations were characterized by their size, zeta potential and polydispersity index (PDI). 1% Carbopol 934 was used as the gelling agent to formulate nanoemulgel comprising of optimized nanoemulsion (NE 9). Ex vivo skin permeation of the CB nanoemulgel was compared with the CB ointment. Its therapeutic effect was evaluated in Balb/c mice. RESULTS: NE 9 comprised of 7.49% oil, 37.45% Smix (1:3) and water 55.06%. Its particle size, PDI and zeta potential were 15.45 ± 5.265 nm, 0.098 and -17.9 ± 8.00 mV respectively. The nanoemulgel exhibited a 3-fold higher permeation flux as compared to the ointment. In vivo studies demonstrated that the nanoemulgel provided better therapeutic effect than the ointment. CONCLUSION: We can thereby conclude that nanoemulgel formulation can be a successful drug delivery strategy for enhancing the therapeutic effect of CB.

A Discursive Review of Recent Development and Patents on Glycerosomes.

BACKGROUND: To achieve a target-based drug delivery with minimal side effects, novel drug delivery systems are being continuously explored. Vesicular systems are one such system that can ameliorate the bioavailability of the encapsulated drug by delivering the drug at the targeted site and can minimize the side effect. OBJECTIVE: The objective of this patent review is to provide a vivid description of glycerosomes and their applications. Glycerosomes are sphere-shaped versatile vesicles consisting of one or more phospholipid bilayers similar to liposomes but contain a high concentration of glycerol, which modifies the liposome bilayer fluidity. Glycerosomes can encapsulate both hydrophobic and hydrophilic drugs, which makes them the promising vehicle in the field of drug delivery. CONCLUSION: Most of the glycerosome formulations prepared were targeted for topical delivery and in particular, a cutaneous route where they have shown promising results. These vesicles are biocompatible and due to the high glycerol concentration, they have improved spreadability and penetrability. It is therefore imperative to explore the other topical routes such as ocular, vaginal, nasal, and rectal for delivery of drugs.

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.

Phytochemical: a treatment option for heavy metal induced neurotoxicity.

Heavy metals are known to be carcinogenic, mutagenic, and teratogenic. Some heavy metals are necessary while present in the growing medium in moderate concentrations known to be essential heavy metals as they required for the body functioning as a nutrient. But there are some unwanted metals and are also toxic to the environment and create a harmful impact on the body, which termed to be non-essential heavy metals. Upon exposure, the heavy metals decrease the major antioxidants of cells and enzymes with the thiol group and affect cell division, proliferation, and apoptosis. It interacts with the DNA repair mechanism and initiates the production of reactive oxygen species (ROS). It subsequently binds to the mitochondria and may inhibit respiratory and oxidative phosphorylation in even low concentrations. This mechanism leads to damage antioxidant repair mechanism of neuronal cells and turns into neurotoxicity. Now, phytochemicals have led to good practices in the health system. Phytochemicals that are present in the fruits and herbs can preserve upon free radical damage. Thus, this review paper summarized various phytochemicals which can be utilized as a treatment option to reverse the effect of the toxicity caused by the ingestion of heavy metals in our body through various environmental or lifestyles ways.

Efficacy of Flavonoids in Combating Fluconazole Resistant Oral Candidiasis.

BACKGROUND: Candida is an opportunistic fungus often present in the oral mucosa. In the compromised immune system, it may become pathogenic and cause oral candidiasis. This infection is more common with Candida albicans; though, non-albicans Candida spp also have significant relevance. Current treatment guidelines include polyenes, azoles and echinocandins, where fluconazole is the primary therapeutic option. However, both inherited and acquired resistance to fluconazole is exhaustively reported. The development of resistance has resulted in the worsening of the original and re-emergence of new fungal diseases. Thus, the development of an anti-candidiasis therapy with a satisfactory outcome is the urgent need of the hour. OBJECTIVE: This review article aims to stimulate research in establishing the synergistic efficacy of various flavonoids with fluconazole to combat the resistance and develop an effective pharmacotherapy for the treatment of oral candidiasis. Further, in this article, we discuss in detail the mechanisms of action of fluconazole, along with the molecular basis of the development of resistance in Candida species. METHODS: PubMed and other databases were used for literature search. RESULTS: The designing of natural drugs from the plant-derived phytochemicals are the promising alternatives in modern medicine. The challenge today is the development of alternative anti-oral candidiasis drugs with increased efficacy, bioavailability and better outcome which can combat azole resistance. Identifying the flavonoids with potential antifungal action at low concentrations seems to meet the challenges. CONCLUSION: Phyto-active constituents, either alone or in combination with conventional antibiotics may be an effective approach to deal with global antimicrobial resistance. The efficacy of herbal therapy for decades suggests that bacteria, fungi, and viruses may have a reduced ability to adapt and resistance to these natural antimicrobial regimes.

Pharmaceutical Cocrystal: A Novel Approach to Tailor the Biopharmaceutical Properties of a Poorly Water Soluble Drug.

BACKGROUND: The present study reports the formation of a cocrystal of candesartan with the coformer methyl paraben, its characterization and determination of its bioavailability. Candesartan is a poorly water-soluble drug having an anti-hypertensive activity. The recent patents on the cocrystals of the drugs Progesterone (US9982007B2), Epalrestat (EP2326632B1), Gefitinib (WO2015170345A1), and Valsartan (CN102702118B) for enhancement of solubility, helped in selection of the drug for this work. METHODS: Candesartan cocrystal was prepared by solution crystallization method. The formation of a new crystalline phase was characterized by Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) and Powder X-ray Diffraction (PXRD) studies. Saturation solubility studies were carried out in ethanol: water (50:50 % v/v) mixture. The dissolution studies were conducted in 900 ml of phosphate buffer at pH 7.4(I.P.) with 0.7% w/w of Tween 20 at 50 rpm, maintained at a temperature of 37±0.5°C in a USP type II dissolution apparatus. The pharmacokinetic behavior of candesartan and its cocrystal was thereof investigated in male Wistar rats. RESULTS: There was 6.94 fold enhancement in the solubility of candesartan after its cocrystallization. The dissolution profile of the cocrystal exhibited significant improvement in solubility at 60 and 120 minutes and it remained stable in ethanol: water (50:50%v/v) mixture for 48 h as confirmed by PXRD studies. The AUC0-24of the cocrystal was found to be increased by 2.9 fold in terms of bioavailability as compared to the pure drug. CONCLUSION: The prepared cocrystal was found to be relatively more soluble than the pure drug and also showed an enhanced oral bioavailability as compared to the pure drug.

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.