抗抑郁药透皮给药系统研究进展

抗抑郁药的传统给药途径如口服给药往往存在生物利用度低、用药成本高、患者依从性较差等缺陷。抗抑郁药透皮给药系统（TDDS）研制可以极大提高药效,减少其不良反应,已成为国内外研究的热点。本文综述抑郁症的发病机制、抗抑郁药类型以及TDDS在抗抑郁药开发中的应用。     

Spray-on transdermal drug delivery systems

Introduction: Transdermal drug delivery possesses superior advantages over other routes of administration, particularly minimizing first-pass metabolism. Transdermal drug delivery is challenged by the barrier nature of skin. Numerous technologies have been developed to overcome the relatively low skin permeability, including spray-on transdermal systems.

Areas covered: A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.

Expert opinion: TSS is easily applied, delivering flexible drug dosage and associated with lower incidence of skin irritation. TSS provides a fast-drying product where the volatile solvent enables uniform drug distribution with minimal vehicle deposition on skin. TSS ensures precise dose administration that is aesthetically appealing and eliminates concerns of residual drug associated with transdermal patches. Furthermore, it provides a better alternative to traditional transdermal products due to ease of product development and manufacturing.     

Passive transdermal drug delivery systems

The skin has evolved as a formidable barrier against invasion by external microorganisms and against the prevention of water loss. Notwithstanding this, transdermal drug delivery systems have been designed with the aim of providing continuous controlled delivery of drugs via this barrier to the systemic circulation. There are numerous systems now available that effectively deliver drugs across the skin. These include reservoir devices, matrix diffusion-controlled devices, multiple polymer devices, and multilayer matrix systems. This review article focuses on the design characteristics and composition of the main categories of passive transdermal delivery device available. Mechanisms controlling release of the active drug from these systems as well as patch size and irritation problems will be considered. Recent developments in the field are highlighted including advances in patch design as well as the increasing number of drug molecules now amenable to delivery via this route. From the early complex patch designs, devices have now evolved towards simpler, matrix formulations. One of the newer technologies to emerge is the delivery-optimized thermodynamic (DOT) patch system, which allows greater drug loading to be achieved in a much smaller patch size. With the DOT technology, drug is loaded in an acrylic-based adhesive. The drug/acrylic blend is dispersed through silicone adhesive, creating a semi-solid suspension. This overcomes the problem with conventional drug-in-adhesive matrix patches, in which a large drug load in the adhesive reservoir can compromise the adhesive properties or necessitate a large patch size. Transdermal drug delivery remains an attractive and evolving field offering many benefits over alternative routes of drug delivery. Future developments in the field should address problems relating to irritancy and sensitization, which currently exclude a number of therapeutic entities from delivery via this route. It is likely that further innovations in matrix composition and formulation will further expand the number of candidate drugs available for transdermal delivery.     

Pressure-sensitive adhesives for transdermal drug delivery systems

Adhesives are a critical component in transdermal drug delivery (TDD) devices. In addition to the usual requirements of functional adhesive properties, adhesives for TDD applications must have good biocompatibility with the skin, chemical compatibility with the drug, various components of the formulation, and provide consistent, effective delivery of the drug. This review discusses the three most commonly used adhesives (polyisobutylenes, polyacrylates and silicones) in TDD devices, and provides an update on recently introduced TDD products and recent developments of new adhesives.     

The skin compliance of transdermal drug delivery systems

This review examines transdermal drug delivery systems (TDS) and focuses on the specific side effects they can have on the skin and how these may be avoided. After a general overview of the structure of skin and its functions, an outline is given of how TDS are composed and how they operate. Upon basic treatment of relevant skin irritation and sensitization phenomena, techniques are described for monitoring them. Subsequently, various specific skin reactions are dealt with; these can be evoked by TDS on both short- and long-term application. Suggestions are then put forward for improving the skin compliance of TDS. For example, it is proposed that hydrogel patches may prove to be a useful alternative for current systems in that they are suitable for long-term applications, having minimal side effects because they are less occlusive.     

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.     

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.     

Development and characterization of transdermal drug delivery systems for diltiazem hydrochloride

Transdermal drug delivery system of diltiazem hydrochloride was developed to obtain a prolonged controlled drug delivery. Both the matrix diffusion controlled (MDC) and membrane permeation controlled (MPC) systems were developed. The matrix diffusion controlled systems used various combinations of hydrophilic and lipophillic polymers, whereas membrane permeation controlled systems were developed using the natural polymer chitosan. The MDC systems were prepared using the cast film method and the MPC systems by an adhesive sealing technique. Both the systems were characterized for in vitro and in vivo performance. The MDC systems were characterized for physicochemical properties such as tensile strength, moisture content, and water vapor transmission. The in vitro release studies showed that the release from the matrix diffusion controlled transdermal drug delivery systems follows a nonfickian pattern and that from the membrane permeation controlled transdermal drug delivery systems follow zero-order kinetics. The release from the matrix systems increased on increasing the hydrophilic polymer concentration, but the release from the membrane systems decrease on cross-linking of the rate controlling membrane and also on addition of citric acid to the chitosan drug reservoir gel. The in vivo studies of the selected systems showed that both systems are capable of achieving the effective plasma concentration for a prolonged period of time. The MPC system achieved effective plasma concentration a little more slowly than the MDC system, but it exhibited a more steady state plasma level for 24 hr.     

Optimal process design for the manufacture of transdermal drug delivery systems

In a pharmaceutical market characterized by increasing competition, assessment criteria related to system design are assuming greater importance. This is true for both conventional dosage forms and drug delivery systems (DDS), as manufacturers strive to achieve adequate patient convenience and compliance. At the same time, the process design for the manufacture of DDS must comply with current good manufacturing practices, and give sufficient consideration to associated environmental issues. Related problems must be solved under social and safety pressures, which, in turn, become economic pressures, such as the consideration of control methods. In addition, both the system design and the process design have a major impact on the cost of goods, as well as on the levels of complexity or risk associated with development.     

Pulsed release of nitroglycerin from transdermal drug delivery systems

Non-ionic surfactant vesicles (niosomes) formed by a hexadecyl diglycerol ether (C16G2) and a series of polyoxyethylene alkyl ethers exhibit a variety of shapes dependent on their membrane composition. These surfactants form with an equimolar amount of cholesterol a mixture of largely spherical and tubular niosomes. In the absence of cholesterol, they form faceted polyhedral structures. The physicochemical and biological differences between polyhedral and spherical/tubular niosomes were studied. Polyhedral niosomes undergo a reversible shape transformation into spherical structures on heating above their phase transition temperature (Tm). The viscosity of polyhedral niosomes at room temperature is higher than their spherical counterparts due to their faceted and relatively rigid shape, and is more dependent on temperature due to shape transformation. At room temperature, polyhedral niosomes possess more rigid gel phase membranes and are less osmotically sensitive; however, they are more permeable because of a lack of or low levels of cholesterol in their membranes. Polyhedral niosomes loaded with luteinising hormone releasing hormone (LHRH), nonetheless, slow the release of drug compared to solution, albeit to a small extent.     

Current landscape and trends in transdermal drug delivery systems

"Generic pharmaceutical marketers are increasingly keen to have a presence in generic patches as they represent high-margin, high entry-barrier opportunities with a smaller field of competition".     

Novel engineered systems for oral,mucosal and transdermal drug delivery

Abstract

Technological advances in drug discovery have resulted in increasing number of molecules including proteins and peptides as drug candidates. However, how to deliver drugs with satisfactory therapeutic effect, minimal side effects and increased patient compliance is a question posted before researchers, especially for those drugs with poor solubility, large molecular weight or instability. Microfabrication technology, polymer science and bioconjugate chemistry combine to address these problems and generate a number of novel engineered drug delivery systems. Injection routes usually have poor patient compliance due to their invasive nature and potential safety concerns over needle reuse. The alternative non-invasive routes, such as oral, mucosal (pulmonary, nasal, ocular, buccal, rectal, vaginal), and transdermal drug delivery have thus attracted many attentions. Here, we review the applications of the novel engineered systems for oral, mucosal and transdermal drug delivery.     

Wearable patches for transdermal drug delivery

Transdermal drug delivery systems (TDDs) avoid gastrointestinal degradation and hepatic first-pass metabolism, providing good drug bioavailability and patient compliance. One emerging type of TDDs is the wearable patch worn on the skin surface to deliver medication through the skin. They can generally be grouped into passive and active types, depending on the properties of materials, design principles and integrated devices. This review describes the latest advancement in the development of wearable patches, focusing on the integration of stimulus-responsive materials and electronics. This development is deemed to provide a dosage, temporal, and spatial control of therapeutics delivery.     

Application of methyl methacrylate copolymers to the development of transdermal or loco-regional drug delivery systems

Introduction: Methyl methacrylate copolymers (Eudragit®) have been exploited to develop transdermal patches, medicated plasters (hereinafter patches) and, more recently, film-forming sprays, microsponges and nanoparticles intended to be applied on the skin.

Areas covered: The article reviews the information regarding the application of Eudragits in the design and development of these dosage forms focusing on the impact of formulative variables on the skin drug penetration and the patch adhesive properties.

Expert opinion: Eudragits combined with a large amount of plasticizers are used to design the pressure-sensitive adhesives, specialized materials used in the patch development. They have to assure the drug skin penetration and the contact with the skin. Most of the studies mainly deal with the former aspect. The authors used a Eudragit type opportunely plasticized to merely investigate the in vitro or in vivo skin permeability of a loaded drug. However, the summa of these data evidenced that a strict connection between the matrix hydrophilicity and drug penetration probably exists. The criticisms of adhesion are addressed in a limited number of papers reporting data on technological properties, namely tack, shear adhesion and peel adhesion, while the structural data of the Eudragit adhesives, rheology and surface free energy are not described, excepting the case of Eudragit E. Among other applications, micro- and nanosystems exploiting the ionizable nature of some Eudragits can offer novel opportunities to develop pH-sensitive drug delivery systems suitable for triggering its release onto the skin.     

Carbon nanotubes for transdermal drug delivery

In this study, drug carrier properties through skin and penetration enhancement effects of carbon nanotubes (CNTs) are presented. Multi-walled and double-walled carbon nanotubes were used. Penetration enhancement into the skin following passive diffusion and iontophoresis were determined. Possible solubility enhancement effects and drug adsorption properties of CNTs were investigated. CNTs were found to be a useful drug carrier system and they can provide a high loading and enhanced transdermal penetration for especially hydrophobic drugs. The electroconductive nature of CNTs allows easy application of iontophoresis and the additional advantage of CNTs appears to be using them as electrodes.     

Micro-scale devices for transdermal drug delivery

Skin makes an excellent site for drug and vaccine delivery due to easy accessibility, immuno-surveillance functions, avoidance of macromolecular degradation in the gastrointestinal tract and possibility of self-administration. However, macromolecular drug delivery across the skin is primarily accomplished using hypodermic needles, which have several disadvantages including accidental needle-sticks, pain and needle phobia. These limitations have led to extensive research and development of alternative methods for drug and vaccine delivery across the skin. This review focuses on the recent trends and developments in this field of micro-scale devices for transdermal macromolecular delivery. These include liquid jet injectors, powder injectors, microneedles and thermal microablation. The historical perspective, mechanisms of action, important design parameters, applications and challenges are discussed for each method.     

透皮吸收促进剂在经皮给药系统中的质控和评价方法

透皮吸收制剂是国际上第三代药物制剂的研究重点领域。透皮吸收促进剂在处方中的合理应用和质量控制及其评价方法日益重要。通过对透皮促进机理、协同作用等的探讨,介绍透皮吸收促进剂的选用原则,并对透皮给药制剂和局部用药局部起效的皮肤外用制剂处方中使用的要求加以讨论,介绍了现有的评价方法和基本的技术要求。     

空心微针透皮给药技术的研究进展

空心微针类似于微米级的注射针,具有注射给药和透皮给药的双重特点.作为一种新型的透皮给药技术,空心微针近年来在疫苗和胰岛素等生物大分子药物的递送方面显示出极大的潜力.笔者根据近年来国内外相关的研究报道,对空心微针的促透机制、常用制备材料及工艺和在透皮给药中的应用等进行归纳总结,以期为空心微针技术的研究和发展提供参考借鉴.