Preparation, in Vitro and in Vivo Evaluation of Liposomal/Niosomal Gel Delivery Systems for Clotrimazole

Clotrimazole, which is an imidazole derivative antifungal agent, was widely used for the treatment of mycotic infections of the genitourinary tract. To develop alternative formulation for the vaginal administration of clotrimazole to provide sustained and controlled release of appropriate drug for local vaginal therapy, liposomes/niosomes were evaluated as delivery vehicles. To optimize the preparation of liposomes/niosomes with regard to size and entrapment efficiency, multilamellar liposomes/niosomes containing drug were prepared by lipid hydration method. The prepared liposomes/niosomes were incorporated into 2% carbopol gel, and the systems were evaluated for drug stability in phosphate-buffered saline (pH 7.4) and simulated vaginal fluid at 37 ± 1°C. Further, the vesicle gel system was evaluated by antifungal activity and tolerability on tissue level in rat.     

Preparation and In Vitro Evaluation of pH,Time-Based and Enzyme-Degradable Pellets for Colonic Drug Delivery

The preparation of pH-dependent, time-based and enzyme degradable pellets was investigated for use as an oral colonic drug delivery system. It was expected that drug would be released immediately once the pellets reached the colon. The pellets were prepared using extrusion-spheronizing equipment and subsequently coated with three layers of three functional polymers by an air-suspension technique. The core consisted of 5-aminosalicylic acid (5-ASA) as a model drug, CaP as an enzyme-degradable material and microcrystalline cellulose (MCC) as an additive. As far as the three coated layers were concerned, the outer layer was coated with Eudragit L30D-55 for protection against gastrointestinal juices, the intermediate layer was coated with ethylcellulose (EC) to inhibit drug release during passage through the small intestine, and the inner film was coated with pectin for swelling and enzyme-degradation, which required a 30, 10, and 12% weight gain, respectively. Several micromeritic properties of the core pellets, including particle size distribution, particle size, degree of circularity, and friability, were evaluated to investigate the effects of the formulations of the cores and preparation conditions. Also, dissolution testing of the cores showed that the presence of calcium pectinate (CaP) markedly increased the drug release rate from the cores, as determined by scanning electron microscopy (SEM). In-vitro release studies indicated that the coated pellets completely protected the drug release in 0.1 mol/L HCl, while the drug release was delayed for 3–4 hr in pH 6.8 PBS. A synergistic effect of enzyme dependence for the coated pellets was seen following removal of the coated layer and during contact with colonic enzymes. Consequently, it was possible to achieve colon-specific drug delivery using this triple-dependence system.     

Preparation,Characterization, and Evaluation of Liposomal Ferulic Acid In Vitro and In Vivo

In the present study, various gradients were evaluated for efficient loading of weak acid into liposomes. Several salt gradients showed efficient loading of ferulic acid (FA) into liposomes and the optimized conditions were established in calcium acetate gradient method to obtain 80.2 ± 5.2% entrapment efficiency (EE). Unilamellar vesicles were observed in micrographs and liposomal FA showed good stability. 80% of FA was released from liposomes within 5 h in vitro. There is a novel finding in this study: that drugs could be entrapped with a high solubility in the intraliposomal buffer in contrast to the low solubility in the extraliposomal buffer. The results of body distribution in rats indicated that liposomes could improve the body distribution of FA. For FA liposome, the concentration of FA in brain was two-fold higher than that of free FA. Liposomal FA was a promising approach to improve the body distribution of FA.     

Preparation,Evaluation, and NMR Characterization of Vinpocetine Microemulsion for Transdermal Delivery

A novel microemulsion was prepared to increase the solubility and the in vitro transdermal delivery of poorly water‐soluble vinpocetine. The correlation between the transdermal permeation rate and structural characteristics of vinpocetine microemulsion was investigated by pulsed field gradient nuclear magnetic resonance (PFG‐NMR). For the microemulsions, oleic acid was chosen as oil phase, PEG‐8 glyceryl caprylate/caprate (Labrasol®) as surfactant (S), purified diethylene glycol monoethyl ether (Transcutol P®) as cosurfactant (CoS), and the double‐distilled water as water phase. Pseudo‐ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation. The effects of various oils and different weight ratios of surfactant to cosurfactant (S/CoS) on the solubility and permeation rate of vinpocetine were investigated. Self‐diffusion coefficients were determined by PFG‐NMR in order to investigate the influence of microemulsion composition with the equal drug concentration on their transdermal delivery. Finally, the microemulsion containing 1% vinpocetine was optimized with 4% oleic acid, 20.5% Labrasol, 20.5% Transcutol P, and 55% double‐distilled water (w/w), in which drug solubility was about 3160‐fold higher compared to that in water and the apparent permeation rate across the excised rat skin was 36.4?±?2.1 µg/cm²/h. The physicochemical properties of the optimized microemulsion were examined for the pH, viscosity, refractive index, conductivity, and particle size distribution. The microemulsion was stable after storing more than 12 months at 25°C. The irritation study showed that the optimized microemulsion was a nonirritant transdermal delivery system.     

Preparation and Evaluation of Self-Microemulsifying Drug Delivery System Containing Vinpocetine

The main purpose of current investigation is to prepare a self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of vinpocetine, a poorly water-soluble drug. Suitable vehicles were screened by determining the solubility of vinpocetine in them. Certain surfactants were selected according to their emulsifying ability with different oils. Ternary phase diagrams were used to identify the efficient self-microemulsifying region and to screen the effect of surfactant/cosurfactant ratio (K_m). The optimized formulation for in vitro dissolution and bioavailability assessment was oil (ethyl oleate, 15%), surfactant (Solutol HS 15, 50%), and cosurfactant (Transcutol^® P, 35%). The release rate of vinpocetine from SMEDDS was significantly higher than that of the commercial tablet. Pharmacokinetics and bioavailability of SMEDDS were evaluated. It was found that the oral bioavailability of vinpocetine of SMEDDS was 1.72-fold higher as compared with that of the commercial tablet. These results obtained demonstrated that vinpocetine absorption was enhanced significantly by employing SMEDDS. Therefore, SMEDDS might provide an efficient way of improving oral bioavailability of poorly water-soluble drugs.     

Synthesis and Biological Evaluation of Ionizable Lipid Materials for the In Vivo Delivery of Messenger RNA to B Lymphocytes

B lymphocytes regulate several aspects of immunity including antibody production, cytokine secretion, and T‐cell activation; moreover, B cell misregulation is implicated in autoimmune disorders and cancers such as multiple sclerosis and non‐Hodgkin's lymphomas. The delivery of messenger RNA (mRNA) into B cells can be used to modulate and study these biological functions by means of inducing functional protein expression in a dose‐dependent and time‐controlled manner. However, current in vivo mRNA delivery systems fail to transfect B lymphocytes and instead primarily target hepatocytes and dendritic cells. Here, the design, synthesis, and biological evaluation of a lipid nanoparticle (LNP) system that can encapsulate mRNA, navigate to the spleen, transfect B lymphocytes, and induce more than 60 pg of protein expression per million B cells within the spleen is described. Importantly, this LNP induces more than 85% of total protein production in the spleen, despite LNPs being observed transiently in the liver and other organs. These results demonstrate that LNP composition alone can be used to modulate the site of protein induction in vivo, highlighting the critical importance of designing and synthesizing new nanomaterials for nucleic acid delivery.     

Preparation and Comparative Clinical Evaluation of Liposomal Gel of Benzoyl Peroxide for Acne

A novel topical benzoyl peroxide (BP) gel formulation containing liposomal BP was shown to significantly reduce local irritation relative to its nonliposomal BP gel (plain BP gel) preparation and also to improve clinical efficacy (almost twofold) in the treatment of acne. BP liposomes were prepared, optimized, and formulated into a carbopol 934 gel base. Drug release evaluated using dialysis membrane has repeatedly shown that a new topical gel formulation containing liposomal BP (liposomal BP gel) significantly reduced BP penetration. Clinical evaluation data were also compared with those obtained with liposomal tretinoin (TRE) gel in an earlier investigation of ours. The overall improvement in terms of percentage reduction in total number of skin lesions demonstrated almost similar results for both BP and TRE. However, variation was observed in the treatment of separate types of lesions in which liposomal TRE gel was found to be more effective in treating comedones and liposomal BP gel in treating papules and pustules. Also, the liposomal gel formulation of both the drugs significantly reduced the local adverse effects, thereby improving patient compliance.     

Wax-Matrix Tablet for Time-Dependent Colon-Specific Delivery System of Sophora Flavescens Aiton: Preparation and In Vivo Evaluation

A wax-matrix time-dependent colon-specific tablet (WM-TDCS) was studied. Wax-matrix tablet core consisting of semi-synthetic glycerides, as a wax polymeric expanding agent, carboxymethyl starch sodium (CMS-Na), and NaCl was prepared, and Sophora flavescens Aiton (ASF, extracts of traditional Chinese medicine) was used as model drug. The wax-matrix ASF tablets core was coated with Eudragit NE 30 D as the inner coating materials and with Opadry OY-P-7171 as the outer coating materials. The in vitro release behaviors of the coated tablets were examined and then in vivo absorption kinetics of the coated tablets in dogs was further investigated. The volume of the tablet core was markedly increased at 37°C because of the expand effect of polymer semi-synthetic glycerides and CMS-Na. The drug release from WM-TDCS was more stable than TDCS in vitro and in vivo. The lag time of ASF release was also controlled by the thickness of the inner coating layer. In vivo evaluation demonstrated that in vivo lag time of absorption was in a good agreement with in vitro lag time of release. ASF wax-matrix tablets coated with Eudragit NE 30 D and Opadry OY-P-7171 using the regular coating technique could be designed to achieve a lag time of 3 h in the small intestinal tract.     

Preparation and Comparative Clinical Evaluation of Liposomal Gel of Benzoyl Peroxide for Acne

A novel topical benzoyl peroxide (BP) gel formulation containing liposomal BP was shown to significantly reduce local irritation relative to its nonliposomal BP gel (plain BP gel) preparation and also to improve clinical efficacy (almost twofold) in the treatment of acne. BP liposomes were prepared, optimized, and formulated into a carbopol 934 gel base. Drug release evaluated using dialysis membrane has repeatedly shown that a new topical gel formulation containing liposomal BP (liposomal BP gel) significantly reduced BP penetration. Clinical evaluation data were also compared with those obtained with liposomal tretinoin (TRE) gel in an earlier investigation of ours. The overall improvement in terms of percentage reduction in total number of skin lesions demonstrated almost similar results for both BP and TRE. However, variation was observed in the treatment of separate types of lesions in which liposomal TRE gel was found to be more effective in treating comedones and liposomal BP gel in treating papules and pustules. Also, the liposomal gel formulation of both the drugs significantly reduced the local adverse effects, thereby improving patient compliance.     

Glucose-Responsive Insulin and Delivery Systems: Innovation and Translation

Type 1 and advanced type 2 diabetes treatment involves daily injections or continuous infusion of exogenous insulin aimed at regulating blood glucose levels in the normoglycemic range. However, current options for insulin therapy are limited by the risk of hypoglycemia and are associated with suboptimal glycemic control outcomes. Therefore, a range of glucose-responsive components that can undergo changes in conformation or show alterations in intermolecular binding capability in response to glucose stimulation has been studied for ultimate integration into closed-loop insulin delivery or “smart insulin” systems. Here, an overview of the evolution and recent progress in the development of molecular approaches for glucose-responsive insulin delivery systems, a rapidly growing subfield of precision medicine, is presented. Three central glucose-responsive moieties, including glucose oxidase, phenylboronic acid, and glucose-binding molecules are examined in detail. Future opportunities and challenges regarding translation are also discussed.     

In Vitro and In Vivo Adhesion Testing of Mucoadhesive Drug Delivery Systems

Bioadhesive tablets were prepared by physical mixing of polymers and drug, then granulating and compressing into a tablet. The mucoadhesion was evaluated by shear stress measurement, detachment force measurement, and X-ray photography of the rabbit gastrointestinal tract. The strong interaction between the polymer and the mucous lining of the tissue helps increase contact time and permit localization. Polymers like hydroxypropyl methylcellulose K4M (HPMC K4M), hydroxypropyl methylcellulose 100 cps (HPMC 100 cps), carbopol-934, sodium carboxy methylcellulose (Na CMC), guar gum, and polyvinylpyrrolidone (PVP) were tested by shear stress measurement and detachment force measurement methods. HPMC K4M, showing maximum bioadhesion, was used in further studies. Adhesion was maximum between pH 5 and pH 6. Maximum adhesion was observed in the duodenum, followed by the jejunum and ileum. Barium sulfate (BaSO₄) matrix tablets containing polymer and drug were subjected to X-ray studies in rabbits, and it was found that the tablet was mucoadhesive even after 8 hr. Enteric coating did not show any effect on mucoadhesion after passing from the stomach.     

Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

With the recent FDA approval of the first siRNA‐derived therapeutic, RNA interference (RNAi)‐mediated gene therapy is undergoing a transition from research to the clinical space. The primary obstacle to realization of RNAi therapy has been the delivery of oligonucleotide payloads. Therefore, the main aims is to identify and describe key design features needed for nanoscale vehicles to achieve effective delivery of siRNA‐mediated gene silencing agents in vivo. The problem is broken into three elements: 1) protection of siRNA from degradation and clearance; 2) selective homing to target cell types; and 3) cytoplasmic release of the siRNA payload by escaping or bypassing endocytic uptake. The in vitro and in vivo gene silencing efficiency values that have been reported in publications over the past decade are quantitatively summarized by material type (lipid, polymer, metal, mesoporous silica, and porous silicon), and the overall trends in research publication and in clinical translation are discussed to reflect on the direction of the RNAi therapeutics field.     

Formulation and In Vivo Evaluation of Niosome-Encapsulated Daunorubicin Hydrochloride

ABSTRACT

The central aim of this present study was to modify the reverse evaporation process, such that an enhanced entrapment, with increased storage stability and prolonged release, could be achieved, and to translate these advantages to increased therapeutic efficacy of daunorubicin hydrochloride on Dalton's ascitic lymphoma. Niosomes prepared exhibited entrapment efficiency 20% higher than theoretically possible by the reverse evaporation process. The niosomes were found to be very stable at a storage temperature of 4°C for a duration of three months. Even the drug leakage was restricted to just 10%. The in vivo studies suggested a prolonged release of 20 hr. Niosomal daunorubicin hydrochloride exhibited an enhanced anti-tumor efficacy when compared to free drug. The niosomal formulation was able to destroy the Dalton's ascitic lymphoma cells in the peritoneum within the third day of treatment, while free drug took around six days and the process was incomplete. The hematological studies also prove that the niosomal formulation was superior to free drug treatment. An enhanced mean survival time was achieved by the niosomal formulation that finally substantiates the overall efficacy of the niosomal formulation. This study suggests that the multilamellar vesicles obtained by the presently utilized reverse evaporation process resulted in vesicles that resisted the immediate lysis in the Kupffer cells, whereby a prolonged drug concentration was achieved which enhanced the cell lysis. But the major factor responsible for the quicker onset of action could be the increased permeability of the niosomes into the cell membrane and the cytoplasm of the Dalton's ascitic lymphoma cells.     

A Molecular Hero Suit for In Vitro and In Vivo DNA Nanostructures

Precise control of DNA base pairing has rapidly developed into a field full of diverse nanoscale structures and devices that are capable of automation, performing molecular analyses, mimicking enzymatic cascades, biosensing, and delivering drugs. This DNA‐based platform has shown the potential of offering novel therapeutics and biomolecular analysis but will ultimately require clever modification to enrich or achieve the needed “properties” and make it whole. These modifications total what are categorized as the molecular hero suit of DNA nanotechnology. Like a hero, DNA nanostructures have the ability to put on a suit equipped with honing mechanisms, molecular flares, encapsulated cargoes, a protective body armor, and an evasive stealth mode.     

Elastic Liposomal Formulation for Sustained Delivery of Antimigraine Drug: In Vitro Characterization and Biological Evaluation

The aim of this study was to prepare and characterize a topical formulation for sustained delivery of rizatriptan. Elastic liposomal formulation of rizatriptan was prepared and characterized for different characteristics by evaluating in vitro and in vivo parameters. The in vivo performance of optimized formulation was evaluated for antimigraine activity in mice using morphine withdrawal-induced hyperalgesia. The in vitro skin permeation study across rat skin suggested carrier-mediated transdermal permeation for different elastic liposomal formulation to range between 18.1 ± 0.6 and 42.7 ± 2.3 μg/h/cm², which was approximately 8–19 times higher than that obtained using drug solution. The amount of drug deposited was 10-fold higher for elastic liposome (39.9 ± 3.2%) than using drug solution (3.8 ± 1%); similarly the biological activity of optimized elastic liposome formulation was found to be threefold higher than the drug solution. On the basis of the results, it can be concluded that the elastic liposomal formulation provided sustained action of rizatriptan due to depot formation in the deeper layer of skin.