Optimization and evaluation of pluronic lecithin organogels as a transdermal delivery vehicle for sinomenine

The purpose of the present study was to prepare and optimize sinomenine (SIN) pluronic lecithin organogels system (PLO), and to evaluate the permeability of the optimized PLO in vitro and in vivo. Box–Behnken design was used to optimize the PLO and the optimized formulation was pluronic F127 of 19.61%, lecithin of 3.60% and SIN of 1.27%. The formulation was evaluated its skin permeation and drug deposition both in vitro and in vivo compared with gel. Permeation and deposition studies of PLO were carried out with Franz diffusion cells in vitro and with microdialysis in vivo. In vitro studies, permeation rate (J_ss) of SIN from PLO was 146.55?±?2.93?μg/cm²/h, significantly higher than that of gel (120.39?μg/cm²/h) and the amount of SIN deposited in skin from the PLO was 10.08?±?0.86?μg/cm², significantly larger than that from gel (6.01?±?0.04?μg/cm²). In vivo skin microdialysis studies showed that the maximum concentration (C_max) of SIN from PLO in “permeation study” and “drug-deposition study” were 150.27?±?20.85?μg/ml and 67.95?μg/ml, respectively, both significantly higher than that of SIN from gel (29.66 and 6.73?μg/ml). The results recommend that PLO can be used as an advantageous transdermal delivery vehicle to enhance the permeation and skin deposition of SIN.     

Electric field assisted transdermal drug delivery from salicylic acid-loaded polyacrylamide hydrogels

The apparent diffusion coefficients, D_app, and the release mechanisms of salicylic acid from polyacrylamide hydrogels through pigskin were investigated. D_app increases with increasing electric field strength and reaches the maximum value at electric field strength of 0.1 V; beyond that it decreases with increasing electric field strength and becomes saturated at 5?V. The increase in D_app at low electric field strength can be attributed to the combination of iontophoresis, electroporation of matrix pore, and induced pathway in pigskin. D_app obeys the scaling behavior D_app/D_o = (drug size/pore size)^m with m equal to 0.67 and 0.49 at the electric field strengths of 0 and 0.1?V, respectively.     

Solid lipid nanoparticles incorporated in dextran hydrogels: a new drug delivery system for oral formulations

Solid lipid nanoparticles (SLN) containing or not (S)-(+)-2-(4-isobutylphenyl)propionic acid (ibuprofen) were prepared with Preciol ATO 5 as lipid phase by the hot homogenization technique and characterized through particle size analyses and zeta potential measurements. DSC experiments carried out on the freeze-dried samples of loaded SLN showed a shift of the melting endotherm of the lipid phase, with the maximum at a temperature value higher then that of the "empty" SLN. (1)H NMR of the nanosuspension allowed to calculate the encapsulation efficiency of the particles that was 52+/-3%. By adding dextran methacrylate (DEX-MA) to the aqueous phase and submitting the mixture to UV irradiation, systems of SLN (drug-loaded and unloaded) incorporated into a dextran hydrogel were prepared. Finally, dissolution studies of ibuprofen from the freeze-dried samples were performed. The comparison among the release profiles of ibuprofen from SLN, DEX-MA hydrogel and SLN/DEX-MA-hydrogel allows to affirm that this last system, retaining about 60% of the drug after 2h in acid medium and releasing it slowly in neutral solution, is suitable for modified delivery oral formulations.     

Preparation and characterization of microemulsion formulations of nicotinic acid and its prodrugs for transdermal delivery

At pharmacological doses, nicotinic acid has a lipid-regulating effect and is in use clinically for that purpose. However, despite of all features, its utility is strongly limited by several disadvantages such as, extensive hepatic metabolism and flushing. Transdermal delivery of nicotinic acid may, therefore, be the solution to reducing side effects associated with oral administration, and to maintaining constant therapeutic blood levels for longer duration. The aim of this investigation was to develop a suitable formulation or select a suitable vehicle for the transdermal delivery of highly lipophilic prodrugs of nicotinic acid (dodecyl and myristyl nicotinate) designed to deliver nicotinic acid through skin without causing vasodilatation and flushing and optimizing its delivery to the blood stream. A microemulsion system and penetration enhancers have been attempted in this study. The microemulsion system was composed of isopropyl myristate (IPM), water and a 4:1 (w/w) mixture of Labrasol and Peceol where a pseudoternary phase diagram was constructed. Furthermore, the microemulsion formulations with different component ratios were characterized by determination of conductivity, pH, particle size, viscosity and refractive index. According to the particle size analysis, conductivity and viscosity measurements, the microemulsion formulations that formed were of oil-in-water type. The transdermal permeability of nicotinic acid and its prodrugs was evaluated in vitro using Franz diffusion cells fitted with mice skin and nicotinic acid concentration was analyzed by high performance liquid chromatography. A theoretical design of percutaneous penetration optimization in which prodrugs derivation and enhancer application are combined based on the skin diffusion model was experimentally verified. The selected formulations seemed promising for developing a transdermal drug delivery system of nicotinic acid from dodecyl nicotinate that would offer advantages like possible controlled drug release, reduced flushing, increased drug stability and ease of large-scale production.     

Microstructured bicontinuous phase formulations: their characterization and application in dermal and transdermal drug delivery

Introduction: The development of approaches to increase drug solubility and partitioning into the skin is an active area of research in topical and transdermal delivery. In addition to forming spherical aggregates, e.g., conventional oil in water or water in oil microemulsions, the combination of an oil, surfactant and water can create bicontinuous structures where the self-assembly properties of surfactants mean that the boundaries between oil and water are no longer random. This leads to the formation of specific microstructures whose intrinsic properties and interactions with the drug will determine the ability to formulate a given drug, its stability once formulated and its subsequent delivery.

Areas covered: The review explores the relationship between the microstructure of biphasic formulations, present in microemulsions and liquid crystalline phases, and drug delivery into the skin. An overview of possible internal microstructures is followed by a summary of the methods used for structure characterization. The final section presents the work to-date and discusses the efficacy of such vehicles in enhancing dermal and transdermal delivery.

Expert opinion: The combination of water, surface agent and oil generates a broad range of three dimensional structures differing in both chemical and physical proprieties. Knowledge of the microstructure is important in understanding the behavior of a formulation and its effect on drug delivery into the skin. Microstructure complexity, interactions between the drug and the vehicle (i.e., location and mobility) and those between the vehicle and the skin are key determinants of drug delivery.     

Effect of mixed micelle formulations including terpenes on the transdermal delivery of diclofenac

The significant inhibitory action of diclofenac formulated in mixed micelles of lecithin with cholate or deoxycholate was observed on the rat hind paw edema induced by carrageenan. In the primary stage, mixed micelle formulation of deoxycholate was more effective compared with that of cholate. However, in the final term, the inhibitory action was similar in both formulations. In a previous study, the flux of diclofenac was greater in the mixed micelle formulation of deoxycholate compared with that of cholate. It was suggested that the permeation rate of diclofenac through skin was proportional to the pharmacological activity. The hind paw edema was quickly inhibited when cyclic monoterpene such as d-limonene or l-menthol was included in the formulations. All the micelle formulations significantly decreased the value of AUC estimated the hind paw thickness-time profile. This suggests that the micelle formulation of cholate in addition to deoxycholate showed significant anti-inflammatory activity to hind paw edema of rats. Incorporation of d-limonene or l-menthol was more effective on the decrease of AUC. A pharmacological study revealed that micelle formulations were able to reduce the skin irritation of chemicals.     

有机凝胶在药物传递系统中的应用

目的介绍有机凝胶的分类及其在药学中的应用情况。方法参阅国内外代表性文献资料,以其中的53篇为依据对其进行分析、归纳和整理。结果阐明了不同种类有机凝胶的分子特点、结构类型及凝胶形成机理,并对其在经皮给药、皮下植入、口服和黏膜给药等方面的应用加以综述。结论有机凝胶在药学领域具有广阔的应用及发展前景。     

Nanoparticle delivery for transdermal HRT

Nanomedicine is an emerging technology and the first nano-engineered medical products have come to light in the last decade. Transdermal drug delivery has significant advantages compared to other routes of drug administration. Nanoparticles unique physical and chemical properties enable transport of substances directly into the skin. The objective of this paper is to review different aspects of nanoparticle delivery, generally, and discuss its current use for transdermal hormone therapy. Transdermal estrogen therapy remains the most effective treatment for bothersome menopausal symptoms, particularly in those women for whom the potential adverse effects associated with “first pass” hepatic metabolism are to be avoided. Available alternatives for transdermal estrogen delivery include patches, gels, sprays and lotions. Other non-oral therapies which likewise avoid “first pass” hepatic metabolism include: subcutaneous implants and vaginal rings. Some of the transdermal products are associated with mild adverse skin effects such as redness and irritation, but more severe and bothersome consequences include blistering and tattooing. Even the mild adverse skin effects are frequently cited as reasons for discontinuation. Micellar nanoparticle estradiol emulsion (MNPEE) is a lotion-like therapy which constitutes an alternative transdermal delivery system not requiring the permeation enhancers or temporary skin digestion, both of which increase the possibility of irritation. MNPEE's advantages include low fluctuation of plasma estradiol concentrations, infrequent skin related adverse effects, and pleasant cosmetic-like moisturizing properties. The efficacy of MNPEE for management of menopausal vasomotor symptoms has been demonstrated in a randomized placebo controlled trial,¹ and the product is FDA approved for management of moderate to severe vasomotor symptoms. None of the observed adverse effects in the MNPEE group were statistically different from the placebo group.¹ Studies addressing inadvertent transference of estradiol to the male partners of menopausal women using this delivery technology have demonstrated small, but real amounts of transference, which do not exceed the normal physiological male estradiol range. MNPEE is safe and effective for treatment of vasomotor symptoms and represents the commercial validation of nanoparticle technology for transdermal delivery of estrogen therapy (ET) for postmenopausal women with vasomotor symptoms.     

Transfersomes for transdermal drug delivery

Transfersomes^® (Idea AG) are a form of elastic or deformable vesicle, which were first introduced in the early 1990s. Elasticity is generated by incorporation of an edge activator in the lipid bilayer structure. The original composition of these vesicles was soya phosphatidyl choline incorporating sodium cholate and a small concentration of ethanol. Transfersomes are applied in a non-occluded method to the skin and have been shown to permeate through the stratum corneum lipid lamellar regions as a result of the hydration or osmotic force in the skin. They have been used as drug carriers for a range of small molecules, peptides, proteins and vaccines, both in vitro and in vivo. It has been claimed by Idea AG that intact Transfersomes penetrate through the stratum corneum and the underlying viable skin into the blood circulation. However, this has not been substantiated by other research groups who have extensively probed the mechanism of penetration and interaction of elastic vesicles in the skin. Structural changes in the stratum corneum have been identified, and intact elastic vesicles visualised within the stratum corneum lipid lamellar regions, but no intact vesicles have been ascertained in the viable tissues. Using the principle of incorporating an edge-activator agent into a bilayer structure, a number of other elastic vesicle compositions have been evaluated. This review describes the research into the development and evaluation of Transfersomes and elastic vesicles as topical and transdermal delivery systems.     

Transfersomes for transdermal drug delivery

Transfersomes (Idea AG) are a form of elastic or deformable vesicle, which were first introduced in the early 1990s. Elasticity is generated by incorporation of an edge activator in the lipid bilayer structure. The original composition of these vesicles was soya phosphatidyl choline incorporating sodium cholate and a small concentration of ethanol. Transfersomes are applied in a non-occluded method to the skin and have been shown to permeate through the stratum corneum lipid lamellar regions as a result of the hydration or osmotic force in the skin. They have been used as drug carriers for a range of small molecules, peptides, proteins and vaccines, both in vitro and in vivo. It has been claimed by Idea AG that intact Transfersomes penetrate through the stratum corneum and the underlying viable skin into the blood circulation. However, this has not been substantiated by other research groups who have extensively probed the mechanism of penetration and interaction of elastic vesicles in the skin. Structural changes in the stratum corneum have been identified, and intact elastic vesicles visualised within the stratum corneum lipid lamellar regions, but no intact vesicles have been ascertained in the viable tissues. Using the principle of incorporating an edge-activator agent into a bilayer structure, a number of other elastic vesicle compositions have been evaluated. This review describes the research into the development and evaluation of Transfersomes and elastic vesicles as topical and transdermal delivery systems.     

Microneedles for transdermal drug delivery

The success of transdermal drug delivery has been severely limited by the inability of most drugs to enter the skin at therapeutically useful rates. Recently, the use of micron-scale needles in increasing skin permeability has been proposed and shown to dramatically increase transdermal delivery, especially for macromolecules. Using the tools of the microelectronics industry, microneedles have been fabricated with a range of sizes, shapes and materials. Most drug delivery studies have emphasized solid microneedles, which have been shown to increase skin permeability to a broad range of molecules and nanoparticles in vitro. In vivo studies have demonstrated delivery of oligonucleotides, reduction of blood glucose level by insulin, and induction of immune responses from protein and DNA vaccines. For these studies, needle arrays have been used to pierce holes into skin to increase transport by diffusion or iontophoresis or as drug carriers that release drug into the skin from a microneedle surface coating. Hollow microneedles have also been developed and shown to microinject insulin to diabetic rats. To address practical applications of microneedles, the ratio of microneedle fracture force to skin insertion force (i.e. margin of safety) was found to be optimal for needles with small tip radius and large wall thickness. Microneedles inserted into the skin of human subjects were reported as painless. Together, these results suggest that microneedles represent a promising technology to deliver therapeutic compounds into the skin for a range of possible applications.     

Thermosensitive hydrogels for drug delivery

INTRODUCTION: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels. AREAS COVERED: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration. EXPERT OPINION: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

Thermosensitive hydrogels for drug delivery

Introduction: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels.

Areas covered: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration.

Expert opinion: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

Environment-sensitive hydrogels for drug delivery

Environmentally sensitive hydrogels have enormous potential in various applications. Some environmental variables, such as low pH and elevated temperatures, are found in the body. For this reason, either pH-sensitive and/or temperature-sensitive hydrogels can be used for site-specific controlled drug delivery. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. Light-sensitive, pressure-responsive and electro-sensitive hydrogels also have the potential to be used in drug delivery and bioseparation. While the concepts of these environment-sensitive hydrogels are sound, the practical applications require significant improvements in the hydrogel properties. The most significant weakness of all these external stimuli-sensitive hydrogels is that their response time is too slow. Thus, fast-acting hydrogels are necessary, and the easiest way of achieving that goal is to make thinner and smaller hydrogels. This usually makes the hydrogel systems too fragile and they do not have mechanical strength necessary in many applications. Environmentally sensitive hydrogels for drug delivery applications also require biocompatibility. Synthesis of new polymers and crosslinkers with more biocompatibility and better biodegradability would be essential for successful applications. Development of environmentally sensitive hydrogels with such properties is a formidable challenge. If the achievements of the past can be extrapolated into the future, however, it is highly likely that responsive hydrogels with a wide array of desirable properties can be made.     

Topical delivery of aceclofenac from lecithin organogels: preformulation study

The purpose of this research is to evaluate the suitability of lecithin organogels containing aceclofenac for topical application. The present article focuses on the preformulation part of the whole research work. Thin layer chromatography was carried out to determine lecithin's purity. The excipients for formulating lecithin organogel were screened. Lecithin organogels are thermo reversible in nature and hence gelation temperature study was carried out to determine the temperature where Sol-Gel and Gel-Sol transformation takes place. Partition coefficient of the drug was estimated. Drug solubility in plain oil and organogel containing reverse micelles was estimated. Effect of water added on the properties of lecithin organogels such as X-ray diffraction pattern, conductivity and viscosity were determined. Microscopy of the gel sample has been carried out at different magnifications. The pseudo ternary phase diagram has been constructed to determine the organogel existence region. The permeation study of aceclofenac from different concentrations of lecithin organogels [200 mM, 300 mM and 400 mM] has been determined using cellulose acetate membrane (0.45 micro) and excised rat skin. Lecithin organogel in ethyl oleate has desired stability and consistency. A single spot on the TLC plate confirms the purity of soy lecithin to be used in organogel formation. Aceclofenac solubility was found to be more in lecithin/oil reverse micellar system as compared to its solubility in oil. The X-ray diffraction pattern confirms the incorporation of water in micellar gel network. The physical properties of organogels are affected by water incorporated and concentration of gelator. The permeation of aceclofenac through artificial membrane and excised rat skin demonstrated the same trend and were in the following order 200 mM>300 mM>400 mM. The results showed that organogel exhibits useful pharmaceutical properties.     

The effects of iontophoresis and electroporation on transdermal delivery of buprenorphine from solutions and hydrogels

The in-vitro permeation of buprenorphine across skin was investigated to assess the effects of iontophoresis and electroporation on drug permeation from solutions as well as from hydrogels. Iontophoresis (0.3 mA cm(-2)) increased the buprenorphine permeation from solution by a factor of 14.27 as compared with passive diffusion; the application of electroporation increased the buprenorphine permeation from solutions by a factor of 8.45. The permeation experiments using cellulose membrane and stratum corneum (SC)-stripped skin as permeation barriers suggested that the enhancement with iontophoresis was primarily due to strong electrophoretic drift of buprenorphine molecules, whereas the enhancement seen with electroporation was mainly attributed to the creation of transient aqueous pores in the SC layer. Application of high-voltage pulses followed by iontophoresis resulted in a shorter permeation onset time from both solutions and hydrogels as compared with iontophoresis or electroporation alone. The charge repulsion between buprenorphine and chitosan vehicles as well as the competition effects of counter-ions for carboxymethylcellulose (CMC)-based polymers may account for the different permeation rates under electrical field. This study demonstrates the feasibility of using hydrogels for delivery of buprenorphine under the application of iontophoresis or electroporation, separately or together.     

A transdermal delivery system for glipizide

Glipizide is one of the most commonly prescribed drugs for treatment of type 2 diabetes. Oral therapy with glipizide comprises problems of bioavailability fluctuations and may be associated with severe hypoglycaemia and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glipizide. For this purpose, inclusion complexes of the drug in beta-cyclodextrin (beta-CyD), dimethyl-beta-cyclodextrin (DM-beta-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CyD) were prepared. Several percutaneous formulations of the drug and the prepared complexes in different bases (o/w emulsion, polyethylene glycol, carboxymethyl cellulose and Carbopol) were developed. Release studies revealed an improved release of the drug from formulations containing glipizide-CyD complexes. Ex vivo permeation studies through full thickness rat abdominal skin were conducted, whereby the effect of several conventional penetration enhancers (propylene glycol [PG], oleic acid, urea, dimethyl sulfoxide, menthol, limonene and cineole) was monitored. Highest flux was obtained from ointments prepared with Carbopol gel base containing a combination of PG and oleic acid as well as ointments prepared in the same base utilizing glipizide-DM-beta-CyD complex and urea. In vivo studies on diabetic male Wistar rats revealed a marked therapeutic efficacy sustained for about 48 hours. In this respect, two formulations showed best biological performance. In the first formulation, the drug was incorporated in Carbopol gel base in the presence of 20% PG together with 15% oleic acid. The second was prepared by incorporating glipizide-DM-beta-CyD complex in Carbopol gel base in presence of 15% urea. The glucose tolerance test showed suppression of hyperglycaemia induced in glucose-loaded rats. The above-mentioned results might shed a strong beam of light on the feasibility of using glipizide in a transdermal delivery system for treatment of type 2 diabetes with the aim of improving both patient compliance and pathophysiology of the disease.     

Dermal and transdermal delivery: prodrugs

Attempts to deliver drugs into and through the skin (dermal and transdermal delivery) have not been very successful because the physicochemical properties of drugs are often not optimal. Prodrugs can be used to optimize those physicochemical properties of drugs and optimize their delivery by transiently masking their polar functional groups. For a drug to cross the rate-limiting barrier to delivery (the stratum corneum) it must dissolve in and cross multiple lipid and aqueous phases within the stratum corneum. Prodrugs can be designed to exhibit increased lipid and aqueous solubilities resulting in increased delivery. In order to identify the optimal prodrugs, they must be evaluated as saturated solutions where their thermodynamic activities are maximal in the solution and in the skin. If prodrugs are evaluated at concentrations less than at saturation, inaccurate conclusions about the optimal physicochemical properties may result. Prodrugs must be designed to optimize both their lipid and aqueous solubilities to optimize their delivery into and through the skin.