Numerical simulation of iontophoresis in the drug delivery system

The architecture and composition of stratum corneum act as barriers and limit the diffusion of most drug molecules and ions. Much effort has been made to overcome this barrier and it can be seen that iontophoresis has shown a good effect. Iontophoresis represents the application of low electrical potential to increase the transport of drugs into and across the skin or tissue. Iontophoresis is a noninvasive drug delivery system, and therefore, it is a useful alternative to drug transportation by injection. In this study, we present a numerical model and effects of electrical potential on the drug diffusion in the buccal tissue and the stratum corneum. The initial numerical results are in good comparison with experimental observation. We demonstrate that the application of an applied voltage can greatly improve the efficacy of localized drug delivery as compared to diffusion alone.     

Future trends in the treatment of urinary incontinence

Anticholinergic drugs act on efferent nerves to counteract overactive bladder (OAB) after it occurs. To prevent the occurrence of OAB, therapies should be directed at blocking the afferent nerves that control the bladder. Tachykinin-receptor antagonists hold great promise in this regard, since they can be administered orally and do not increase the risk of urinary retention that occurs with anticholinergics. Advanced drug delivery systems, such as controlled-release oral oxybutynin (oxybutynin-XL) can reduce the incidence of anticholinergic side effects. In a similar manner intravesical therapy for OAB is site specific, and thus also reduces the occurrence of adverse events. Moreover, the difficulties of intravesical therapy may now be overcome with advanced delivery techniques such as an implantable, long-acting drug-delivery pump. Another intravesical therapy that has met with great acceptance and success is the administration of chili pepper extracts, especially resiniferitoxin, which may be effective for up to 3 months with one application. Finally, gene therapy holds great promise for OAB, because it is possible to access all of the genitourinary organs via endoscopy and other minimally invasive techniques that are ideally suited for gene therapy.     

Perspectives on transdermal ultrasound mediated drug delivery

The use of needles for multiple injection of drugs, such as insulin for diabetes, can be painful. As a result, prescribed drug noncompliance can result in severe medical complications. Several noninvasive methods exist for transdermal drug delivery. These include chemical mediation using liposomes and chemical enhancers or physical mechanisms such as microneedles, iontophoresis, electroporation, and ultrasound. Ultrasound enhanced transdermal drug delivery offers advantages over traditional drug delivery methods which are often invasive and painful. A broad review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for noninvasive drug administration. From a clinical perspective, few drugs, proteins or peptides have been successfully administered transdermally because of the low skin permeability to these relatively large molecules, although much work is underway to resolve this problem. The proposed mechanism of ultrasound has been suggested to be the result of cavitation, which is discussed along with the bioeffects from therapeutic ultrasound. For low frequencies, potential transducers which can be used for drug delivery are discussed, along with cautions regarding ultrasound safety versus efficacy.     

Low-frequency sonophoresis: a noninvasive method of drug delivery and diagnostics

Transdermal drug delivery offers an attractive alternative to injections and oral medications. However, applications of transdermal drug delivery are limited to only a few drugs as a result of low skin permeability. Application of low-frequency ultrasound enhances skin permeability, a phenomenon referred to as low-frequency sonophoresis. In this method, a short application of ultrasound is used to permeabilize skin for a prolonged period of time. During this period, ultrasonically permeabilized skin may be utilized for drug delivery. In addition, a sample of interstitial fluid or its components may be extracted through permeabilized skin for diagnostic applications. In this paper, we report our in vivo studies that demonstrate the principles of both of these concepts. Detailed studies on drug delivery are performed using inulin and mannitol as model drugs. Studies on diagnostics are performed using glucose as a model analyte. Applications of this technology to drug delivery and diagnostics are discussed.     

The Experimental Evaluation and Molecular Dynamics Simulation of a Heat-Enhanced Transdermal Delivery System

Transdermal delivery systems are useful in cases where preferred routes such as the oral route are not available. However, low overall extent of delivery is seen due to the permeation barrier posed by the skin. Chemical penetration enhancers and invasive methods that disturb the structural barrier function of the skin can be used to improve transdermal drug delivery. However, for suitable drugs, a fast-releasing transdermal delivery system can be produced by incorporating a heating source into a transdermal patch. In this study, a molecular dynamics simulation showed that heat increased the diffusivity of the drug molecules, resulting in faster release from gels containing ketoprofen, diclofenac sodium, and lidocaine HCl. Simulations were confirmed by in vitro drug release studies through lipophilic membranes. These correlations could expand the application of heated transdermal delivery systems for use as fast-release-dosage forms.     

Temperature-Sensitive Microemulsion Gel: An Effective Topical Delivery System for Simultaneous Delivery of Vitamins C and E

Microemulsions (ME)—nanostructured systems composed of water, oil, and surfactants—have frequently been used in attempts to increase cutaneous drug delivery. The primary objective addressed in this work has been the development of temperature-sensitive microemulsion gel (called gel-like ME), as an effective and safe delivery system suitable for simultaneous topical application of a hydrophilic vitamin C and a lipophilic vitamin E. By changing water content of liquid o/w ME (o/w ME), a gel-like ME with temperature-sensitive rheological properties was formed. The temperature-driven changes in its microstructure were confirmed by rotational rheometry, viscosity measurements, and droplet size determination. The release studies have shown that the vitamins’ release at skin temperature from gel-like ME were comparable to those from o/w ME and were much faster and more complete than from o/w ME conventionally thickened with polymer (o/w ME carbomer). According to effectiveness in skin delivery of both vitamins, o/w ME was found the most appropriate, followed by gel-like ME and by o/w ME carbomer, indicating that no simple correlation between vitamins release and skin absorption could be found. The cytotoxicity studies revealed good cell viability after exposure to ME and confirmed all tested microemulsions as nonirritant. This work was supported by a grant of Slovenian Research Agency.     

A review of the tolerability and safety of levocabastine eye drops and nasal spray. Implications for patient management

Levocabastine is a highly potent and selective H(1)-receptor antagonist specifically developed for topical administration by ocular and nasal routes. The clinical effects of levocabastine occur rapidly and are predominantly due to local antihistaminic effects at the site of application. Clinically, levocabastine is well tolerated with an adverse effect profile comparable with that of sodium cromoglycate and placebo. As might be expected from the route of drug administration, local irritation is the most frequent adverse event seen with levocabastine eye drops and nasal spray with an incidence comparable with that in placebo-treated controls. Intranasal application of levocabastine has been shown to have no adverse effect on ciliary activity both in vitro and in vivo, while ocular administration has not been shown to have any significant or consistent adverse effect in both animal and human studies. At therapeutic doses, levocabastine appears to be devoid of significant systemic activity producing no apparent effects on cardiovascular, psychomotor and cognitive function. Since levocabastine undergoes little hepatic metabolism, and only low plasma levels of the drug are attained following topical administration, drug interactions are unlikely.     

生物相容透皮给药微针治疗浅表肿瘤

复杂的肿瘤微环境导致抗肿瘤药物在肿瘤组织内递送效率低下，严重阻碍了药物对浅表肿瘤的治疗效果。生物相容透皮给药微针凭借较高的机械强度，刺穿皮肤角质层，将微针内的药物递送至浅表肿瘤组织内，提高生物利用度，改善静脉注射、口服给药的肝肾毒性等问题。本文介绍了生物相容透皮给药微针的设计及其在癌症化疗、光动力治疗、光热治疗、免疫治疗、基因治疗等领域的研究进展，对浅表肿瘤的微创、局部递药和精准、高效治疗具有重要指导意义。     

超声介导镇痛药物透皮吸收研究进展

现阶段,临床中常用的镇痛药物多采用口服或注射给药的方式,具全身不良反应多,患者依从性差等缺点,透皮给药作为一种非侵入性给药方式,相对于这些有很多显著的优势,如使用方便,患者痛苦少等。但是,如何克服皮肤的低渗透性一直是该种给药方式发展的瓶颈。近年来,使用超声能量增强镇痛药物在皮肤上的的渗透性成为新的研究热点,各项研究发现,低频超声对药物的增透效果尤为显著。本文通过检索各国文献,对超声介导镇痛药物透皮吸收的原理,临床前试验和临床试验进行综述。     

Formulation and optimization of porous osmotic pump-based controlled release system of oxybutynin

The aim of the current study was to design a porous osmotic pump-based drug delivery system for controlled release of oxybutynin. The porous osmotic pump contains pore-forming water-soluble additives in the coating membrane, which after coming in contact with water, dissolve, resulting in an in situ formation of a microporous structure. The dosage regimen of oxybutynin is one 5-mg tablet 2 to 3 times a day. The plasma half-life ranges from ∼2 to 3 hours. Hence, oxybutynin was chosen as a model drug with an aim to develop a controlled release system for a period of 24 hours. Linear and reproducible release similar to that of Ditropan XL was achieved for optimized formulation (f2>50) independent of hydrodynamic conditions. The effect of different formulation variables, namely, ratio of drug to osmogent, membrane weight gain, and level of pore former on the in vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. It was found that drug release rate increased with the amount of osmogent because of the increased water uptake, and hence increased driving force for drug release. Oxybutynin release was inversely proportional to the membrane weight gain; however, directly related to the level of pore former, sorbitol, in the membrane. This system was found to deliver oxybutynin at a zero-order rate for 20 hours. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per International Conference on Harmonisation (ICH) guidelines and formulations were stable after a 3 month study. Published: July 13, 2007     

Transdermal delivery of scopolamine by natural submicron injectors: in-vivo study in pig

Transdermal drug delivery has made a notable contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. While transdermal delivery systems would appear to provide an attractive solution for local and systemic drug delivery, only a limited number of drugs can be delivered through the outer layer of the skin. The most difficult to deliver in this way are hydrophilic drugs. The aquatic phylum Cnidaria, which includes sea anemones, corals, jellyfish and hydra, is one of the most ancient multicellular phyla that possess stinging cells containing organelles (cnidocysts), comprising a sophisticated injection system. The apparatus is folded within collagenous microcapsules and upon activation injects a thin tubule that immediately penetrates the prey and delivers its contents. Here we show that this natural microscopic injection system can be adapted for systemic transdermal drug delivery once it is isolated from the cells and uploaded with the drug. Using a topically applied gel containing isolated natural sea anemone injectors and the muscarinic receptor antagonist scopolamine, we found that the formulated injectors could penetrate porcine skin and immediately deliver this hydrophilic drug. An in-vivo study in pigs demonstrated, for the first time, rapid systemic delivery of scopolamine, with T(max) of 30 minutes and C(max) 5 times higher than in controls treated topically with a scopolamine-containing gel without cnidocysts. The ability of the formulated natural injection system to penetrate a barrier as thick as the skin and systemically deliver an exogenous compound presents an intriguing and attractive alternative for hydrophilic transdermal drug delivery.     

Selecting a medical therapy for overactive bladder

Immediate-release oxybutynin was the gold standard for pharmacologic treatment of overactive bladder for nearly 30 years. Intolerable systemic side effects, in particular dry mouth, limited its clinical utility, resulting in poor patient compliance with dosing regimens. Multiple studies have demonstrated the vastly superior tolerability of tolterodine, extended-release tolterodine, and extended-release oxybutynin over that of immediate-release oxybutynin at equivalent doses, and in the case of extended-release oxybutynin even to twice the dose of the original immediate-release form. With different drug delivery systems and, perhaps, with better bladder selectivity, these new oral agents have favorable side effect profiles, which translate into higher patient compliance and fewer treatment withdrawals or dosage reductions.     

Lidocaine-loaded fish scale-nanocellulose biopolymer composite microneedles

Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36 h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture.     

Liposomal systems as viable drug delivery technology for skin cancer sites with an outlook on lipid-based delivery vehicles and diagnostic imaging inputs for skin conditions'

Skin cancer is among one of the most common human malignancies wide-spread world-over with mortality statistics rising continuously at an alarming rate. The increasing frequency of these malignancies has marked the need for adopting effective treatment plan coupled with better and site-specific delivery options for the desired therapeutic agent's availability at the affected site. The concurrent delivery approaches to cancerous tissues are under constant challenge and, as a result, are evolving and gaining advancements in terms of delivery modes, therapeutic agents and site-specificity of the therapeutics delivery. The lipid-based liposomal drug delivery is an attractive and emerging option, and which is meticulously shaping up beyond a threshold level to a promising, and viable route for the effective delivery of therapeutic agents and other required injuctions to the skin cancer. An update on liposomal delivery of chemotherapeutic agents, natural-origin compounds, photosensitizer, and DNA repair enzymes as well as other desirable and typical delivery modes employed in drug delivery and in the treatment of skin cancers is discussed in details. Moreover, liposomal delivery of nucleic acid-based therapeutics, i.e., small interfering RNA (siRNA), mRNA therapy, and RGD-linked liposomes are among the other promising novel technology under constant development. The current clinical applicability, viable clinical plans, future prospects including transport feasibility of delivery vesicles and imaging techniques in conjunction with the therapeutic agents is also discussed. The ongoing innovations in liposomal drug delivery technology for skin cancers hold promise for further development of the methodology for better, more effective and site-specific delivery as part of the better treatment plan by ensuring faster drug transport, better and full payload delivery with enough and required concentration of the dose.     

A Review About the Drug Delivery from Microsponges

Microparticulate drug delivery systems have shown a great interest in the pharmaceutical area. They allow the increase of drug therapeutic efficacy and the reduction of side effects. In this context, microsponges represent a new model of porous polymer microspheres, which allow the entrapment of a wide range of active agents. During the development, it is necessary the characterization of the system and among of the most important tests are the release and permeation profile analysis. They can demonstrate the behavior of drug in a specific site with a particular application condition and are related to therapeutic efficacy. Therefore, this review provides an overview of drug delivery profile from microsponges. Methods for determination of in vitro release and ex vivo permeation studies are detailed. Examples of drug delivery from microsponges administered in different sites are also discussed with aim to provide an understanding of the use of this strategy to modify the drug delivery.     

Drug-delivering nerve conduit improves regeneration in a critical-sized gap

Autologous nerve grafts are the current “gold standard” for repairing large nerve gaps. However, they cause morbidity at the donor nerve site and only a limited amount of nerve can be harvested. Nerve conduits are a promising alternative to autografts and can act as guidance cues for the regenerating axons, without the need to harvest donor nerve. Separately, it has been shown that localized delivery of GDNF can enhance axon growth and motor recovery. FK506, an FDA approved small molecule, has also been shown to enhance peripheral nerve regeneration. This paper describes the design of a novel hole-based drug delivery apparatus integrated with a polytetrafluoroethylene (PTFE) nerve conduit for controlled local delivery of a protein such as GDNF or a small molecule such as FK506. The PTFE devices were tested in a diffusion chamber, and the bioactivity of the released media was evaluated by measuring neurite growth of dorsal root ganglions (DRGs) exposed to the released drugs. The drug delivering nerve guide was able to release bioactive concentrations of FK506 or GDNF. Following these tests, optimized drug releasing nerve conduits were implanted across 10 mm sciatic nerve gaps in a BL6 yellow fluorescent protein (YFP) mouse model, where they demonstrated significant improvement in muscle mass, compound muscle action potential, and axon myelination in vivo as compared with nerve conduits without the drug. The drug delivery nerve guide could release drug for extended periods of time and enhance axon growth in vitro and in vivo.     

壳聚糖衍生物及其胶束：特性、功能化修饰和在药物传递系统中的应用

壳聚糖是一种天然多糖,具有无毒、可生物降解、生物相容性等诸多优点,但水溶性差的自身特点限制了其在药剂学中的应用,而其经合理的结构设计、修饰和优化,可获得性能良好的两亲性壳聚糖衍生物,这些衍生物在水溶液中能自组装成具有良好药物传输性能（如载药量、稳定性、刺激敏感性、靶向性等）的胶束,并被广泛应用于构建药物传递系统,以改善药物的溶解性、靶向性、生物利用度及耐药性,降低药物的毒副作用。综述壳聚糖衍生物结构对其胶束药物传输性能的影响以及壳聚糖衍生物及其胶束的功能化修饰和在药物传递系统中的应用。     

Local topical delivery of drugs: a model incorporating simultaneous diffusion and metabolic interconversion between drug and a single metabolite in the skin

A comprehensive biophysical model for the topical delivery of a drug and its single, locally active metabolite is proposed. This elaboration of the simpler case, in which the drug converts irreversibly to a pharmacologically active metabolite in the tissue, allows for enzymatic interconversion between drug and metabolite. Exact mathematical expressions give concentration-distance relationships of drug and metabolite as well as fluxes of the two molecules in terms of concentration of drug applied to the stratum corneum, permeability coefficient of drug in the stratum corneum, diffusion coefficients of drug and metabolite in the viable tissues (epidermis and dermis), rate constants for the two enzyme systems, and the thickness of the viable tissue. Constants included in the mathematical expressions can be evaluated independently by appropriate in vitro experiments with freshly excised animal skin. The model can then predict what physiochemical drug constants will lead to maximal levels of active metabolite at the site of activity within the skin.     

Immunostimulant adjuvant patch enhances humoral and cellular immune responses to DNA immunization

The focus of this report is on the development of an improved DNA immunization protocol, which takes advantage of the strengths of DNA immunization, as well as those associated with adjuvant delivered by transcutaneous immunostimulatory (IS) patches. Because transcutaneous delivery of adjuvants to the skin at the vaccination site has been shown to amplify the immune response to protein antigens, we hypothesized that the same IS patch when placed on the skin at the site of DNA injection could further enhance the immune response to a DNA influenza vaccine. We have combined an influenza DNA vaccine, hemagglutinin fused with three copies of complement C3d, to enhance uptake and antigen presentation, with an IS patch containing heat-labile enterotoxin from Escherichia coli. Coadministration of a potent adjuvant in IS patches placed on the skin at the site of DNA vaccination dramatically amplifies anti-influenza antibody immune response. Supplementing DNA vaccines with IS patches may be a particularly valuable strategy because DNA vaccines can be rapidly modified in response to mutations in pathogens, and individuals with compromised immune systems such as transplant patients and the elderly will benefit from the enhanced antibody response induced by the IS patches.     

Molecular mechanism of transdermal co-delivery of interferon-alpha protein with gold nanoparticle – a molecular dynamics study

The transdermal route provides numerous advantages over conventional drug delivery routes. However, passive delivery of large molecules such as proteins through the skin is challenging due to its barrier function. Therefore, to design a successful formulation, molecular interaction of these proteins with constituent molecules present in the skin responsible for its barrier function, is necessary. In this study, we have shown through extensive computer simulations that the therapeutic protein, interferon alpha (INF), can be co-delivered through the skin using the gold nanoparticle. We carried out both steered (umbrella sampling) and unrestrained coarse-grained molecular dynamics simulation to show the molecular mechanism of absorption/permeation of protein on/through skin layer in the absence/presence of gold nanoparticle. According to the steered simulations, when INF was taken alone, the free energy minimum was observed at the head group of the skin layer, whereas, when co-delivered with AuNP, it was observed in the interior of the bilayer. Unrestrained simulations have also shown that INF was adsorbed on the skin lipid bilayer head group, while in presence of AuNP, it first complexed with the AuNP and then breached the barrier. The MD simulations thus established the transdermal delivery as a possible pathway for delivery of INF protein.