New transdermal and transmucosal nitroglycerin delivery systems in patients with ischaemic heart disease

Summary The efficacy of a transdermal (Nitroderm-TTS) and a transmucosal (Trinitrolong) nitroglycerin (NG) formulation has been compared with sublingual NG in 9 patients with ischaemic heart disease and stable angina pectoris. The duration and the degree of anti-ischaemic effect were assessed in terms of similar, individually adjusted work loads performed prior to and repeatedly after drug application in comparison with placebo. The anti-ischaemic effect of nitroderm appeared in 0.5–3 h after administration, reached a maximum in about 3.8 h and persisted for 7.9 h. The maximal nitroderm effect was significantly lower than that of sublingual NG or Trinitrolong. The effect of Trinitrolong was less variable and lasted for 4.6 h. It was evident in all patients 0.5 h after drug administration. Plasma NG levels were monitored in 9 patients after sublingual NG and trinitrolong and in 4 following Nitroderm. The relative bioavailability of Nitroderm and Trinitrolong according to the pharmacokinetic data was 29% and 256%, respectively, of sublingual NG tablets. A therapeutic NG level in blood (0.5 ng/ml) after Trinitrolong appeared much earlier (2 min) than after Nitroderm (1 h). A significant reduction in the effect of sublingual NG was observed during Nitroderm application. Thus, the transdermal NG formulation did not exhibit an antianginal effect lasting for 24 h; transmucosal NG had a relatively short, but more pronounced and stable antianginal effect.     

凝集素修饰透黏膜微粒给药系统

通过对近年来相关文献的检索,本文介绍了凝集素修饰的微球、纳米粒和脂质体,以及凝集素对不同微粒系统的修饰机制,综述凝集素修饰微粒给药系统在透黏膜给药中的应用,认为凝集素修饰微粒给药系统有较好的应用前景。     

Transdermal and transmucosal powdered drug delivery.

High-velocity powder injection is a promising new drug-delivery technique that provides needle- and pain-free delivery of traditional drugs, drugs from biotechnology such as proteins, peptides, and oligonucleotides as well as traditional and genetic vaccines. The energy of a transient helium gas jet accelerates fine drug particles of 20 microns-100 microns diameter to high velocities and delivers them into skin or mucosal sites. This review describes the configuration and operating principles of devices that accelerate the particles, the required properties of the particles, the characteristics of the target tissues, and features of the developmental test methods. Preclinical and clinical results that best characterize the technology and introduce its potential as a drug-delivery platform are presented.     

Chitosan and its salts for mucosal and transmucosal delivery

This review considers the application of chitosan and its salts in the delivery of drugs intended to act locally towards diseases of the mucosa itself (mucosal delivery), and to undergo systemic absorption by means of transmucosal routes (transmucosal delivery). Those chitosan properties that are particularly useful in mucosal and transmucosal delivery have been reviewed, such as mucoadhesion, penetration enhancement and peptidase inhibition behaviour. Chitosan bioactive properties have also been considered, such as anti-infective, haemostatic, wound healing and immune-stimulating activity. Chitosan is available with a wide range of molecular mass and deacetylation degree: the influence of these properties on polymer performance and solubility has been taken into account. As solubility in particular can strongly limit the results obtained at pH values close to neutrality, particular attention has been paid to chitosan salts and derivatives with modified solubility. Thanks to the presence of positively charged amino groups of the polymer, a subject of increasing interest is the exploitation of its interaction with acidic molecules having potential synergistic behaviour towards bioactive properties, or even with acidic drugs. The aim of the review is to describe not only some properties of chitosan, but also the way they can be modified by the acidic moiety.     

Permeation enhancers in the transmucosal delivery of macromolecules

The present article presents a compilation of information regarding various chemical permeation enhancers useful for transmucosal delivery of macromolecules. In the recent past, biotechnology has provided a great number of macromolecules for treatment of various disorders. With the rise in importance of macromolecules, especially proteins and peptides, an enormous volume of research on various novel routes of drug delivery has been carried out. Inspite of its giving the highest and fastest bioavailability, the parenteral route is not a preferred option, due to its inconvenience and the noncompliance of patients. Mucosal surfaces are the most common and convenient routes for delivering drugs to the body. However, macromolecular drugs such as peptides and proteins are unable to overcome the mucosal barriers and/or are degraded before reaching the blood stream. Transmucosal drug delivery with various bioavailability enhancers is receiving increasing attention as a possible alternative to parenteral delivery of macromolecules. Among the various bioavailability enhancers, chemical permeation enhancers have been most studied. Permeation enhancers reversibly modulate the permeability of the barrier layer in favor of drug absorption. Newer permeation enhancers like zonula occludin toxin, poly-L-arginine, chitosan derivatives etc have shown a significant increase in drug absorption through transmucosal routes without serious damage to the barrier layer. In particular delivery of macromolecules via the nasal and pulmonary routesusing newer permeation enhancers has emerged as a possible alternative to the parenteral delivery ofmacromolecules.     

The performance of nanocarriers for transmucosal drug delivery

Most of the newly designed drug molecules are characterised by low solubility in aqueous medium, low permeability through biological membranes and/or an insufficient stability in the biological environment. Fundamental studies have provided proof-of-concept of the potential of particulate nanocarriers for overcoming these unsuitable properties. For example, it is known that polymeric nanosystems may enhance transmucosal transport of drugs with poor penetration capacities while preserving their biological activity. Moreover, in recent years it has become clear that through an appropriate selection of the nanosystem components it is possible to enhance its affinity for the mucosa and, hence, the residence time of the drug in contact with the absorptive epithelium. These properties, combined with a suitably tailored release profile can markedly increase the efficacy of pharmaceuticals. Overall, the properties that have been identified as critical for the performance of these delivery systems are particle size, surface charge and surface chemical composition. These properties are known to affect the physical and chemical stability of the nanoparticles in the biological environment as well as their ability to interact (unspecific bioadhesion, receptor-mediated interaction and so on) and, eventually, overcome biological barriers. The present article aims to critically review the latest advances in this area and to provide some insights into these complex issues. Thus, herein the most widely investigated transmucosal drug delivery nanosystems and their most promising applications are reported.     

The performance of nanocarriers for transmucosal drug delivery

Most of the newly designed drug molecules are characterised by low solubility in aqueous medium, low permeability through biological membranes and/or an insufficient stability in the biological environment. Fundamental studies have provided proof-of-concept of the potential of particulate nanocarriers for overcoming these unsuitable properties. For example, it is known that polymeric nanosystems may enhance transmucosal transport of drugs with poor penetration capacities while preserving their biological activity. Moreover, in recent years it has become clear that through an appropriate selection of the nanosystem components it is possible to enhance its affinity for the mucosa and, hence, the residence time of the drug in contact with the absorptive epithelium. These properties, combined with a suitably tailored release profile can markedly increase the efficacy of pharmaceuticals. Overall, the properties that have been identified as critical for the performance of these delivery systems are particle size, surface charge and surface chemical composition. These properties are known to affect the physical and chemical stability of the nanoparticles in the biological environment as well as their ability to interact (unspecific bioadhesion, receptor-mediated interaction and so on) and, eventually, overcome biological barriers. The present article aims to critically review the latest advances in this area and to provide some insights into these complex issues. Thus, herein the most widely investigated transmucosal drug delivery nanosystems and their most promising applications are reported.     

Recent trends in oral transmucosal drug delivery systems: an emphasis on the soft palatal route

Introduction: The oral mucosa is an appropriate route for drug delivery systems, as it evades first-pass metabolism, enhances drug bioavailability and provides the means for rapid drug transport to the systematic circulation. This delivery system offers a more comfortable and convenient delivery route compared with the intravenous route. Although numerous drugs have been evaluated for oral mucosal delivery, few of them are available commercially. This is due to limitations such as the high costs associated with developing such drug delivery systems.

Areas covered: The present review covers recent developments and applications of oral transmucosal drug delivery systems. More specifically, the review focuses on the suitability of the oral soft palatal site as a new route for drug delivery systems.

Expert opinion: The novelistic oral soft palatal platform is a promising mucoadhesive site for delivering active pharmaceuticals, both systemically and locally, and it can also serve as a smart route for the targeting of drugs to the brain.     

Recent trends in oral transmucosal drug delivery systems: an emphasis on the soft palatal route

INTRODUCTION: The oral mucosa is an appropriate route for drug delivery systems, as it evades first-pass metabolism, enhances drug bioavailability and provides the means for rapid drug transport to the systematic circulation. This delivery system offers a more comfortable and convenient delivery route compared with the intravenous route. Although numerous drugs have been evaluated for oral mucosal delivery, few of them are available commercially. This is due to limitations such as the high costs associated with developing such drug delivery systems. AREAS COVERED: The present review covers recent developments and applications of oral transmucosal drug delivery systems. More specifically, the review focuses on the suitability of the oral soft palatal site as a new route for drug delivery systems. EXPERT OPINION: The novelistic oral soft palatal platform is a promising mucoadhesive site for delivering active pharmaceuticals, both systemically and locally, and it can also serve as a smart route for the targeting of drugs to the brain.     

Muco-adhesive multivesicular liposomes as an effective carrier for transmucosal insulin delivery

Considering limitations of conventional insulin therapies, the present study characterizes usefulness of novel mucoadhesive multivesicular liposomes as a mucoadhesive sustained release carrier of insulin via nasal and ocular routes, thus attempts to develop non-invasive carrier system for the controlled release of bioactives. Multivesicular liposomes (MVLs) of 26–34 μm were prepared with a high protein loading (58–62%) and were coated with chitosan and carbopol. These mucoadhesive carriers were characterized by zeta potential studies, in vitro mucoadhesion test and insulin protective ability against nasal aminopeptidase. In vitro, mucoadhesive carriers released insulin for a period of 7–9 days compared to 24 h of conventional liposomes. After intranasal administration to STZ induced diabetic rats, the mucoadhesive MVLs (chitosan coated MVLs) effectively reduced plasma glucose level up to 2 days (35% reduction), compared to non-coated MVLs (32% at 12 h) and conventional liposomes (34% at 8 h). Although the differences are statistically insignificant, chitosan coated formulation has shown a better hypoglycemic profile as the effects were prolonged compared to carbopol coated formulation. When compared to ocular route, chitosan formulation after nasal administration has shown better therapeutic profile as the hypoglycemic effects were prolonged until 72 h. The effectiveness of this chitosan coated MVLs was further demonstrated by the significant quantities of ELISA detectable insulin levels after nasal (334.6 μIu/ml) and ocular (186.3 μIu/ml) administration. These results demonstrate that mucoadhesive carrier is a viable option for a sustained release transmucosal insulin carrier, and open an avenue to develop a non-invasive carrier platform for the controlled release of bioactives.     

Muco-adhesive multivesicular liposomes as an effective carrier for transmucosal insulin delivery

Considering limitations of conventional insulin therapies, the present study characterizes usefulness of novel mucoadhesive multivesicular liposomes as a mucoadhesive sustained release carrier of insulin via nasal and ocular routes, thus attempts to develop non-invasive carrier system for the controlled release of bioactives. Multivesicular liposomes (MVLs) of 26-34 microm were prepared with a high protein loading (58-62%) and were coated with chitosan and carbopol. These mucoadhesive carriers were characterized by zeta potential studies, in vitro mucoadhesion test and insulin protective ability against nasal aminopeptidase. In vitro, mucoadhesive carriers released insulin for a period of 7-9 days compared to 24 h of conventional liposomes. After intranasal administration to STZ induced diabetic rats, the mucoadhesive MVLs (chitosan coated MVLs) effectively reduced plasma glucose level up to 2 days (35% reduction), compared to non-coated MVLs (32% at 12 h) and conventional liposomes (34% at 8 h). Although the differences are statistically insignificant, chitosan coated formulation has shown a better hypoglycemic profile as the effects were prolonged compared to carbopol coated formulation. When compared to ocular route, chitosan formulation after nasal administration has shown better therapeutic profile as the hypoglycemic effects were prolonged until 72 h. The effectiveness of this chitosan coated MVLs was further demonstrated by the significant quantities of ELISA detectable insulin levels after nasal (334.6 microIu/ml) and ocular (186.3 microIu/ml) administration. These results demonstrate that mucoadhesive carrier is a viable option for a sustained release transmucosal insulin carrier, and open an avenue to develop a non-invasive carrier platform for the controlled release of bioactives.     

Development of sponge-like dressings for mucosal/transmucosal drug delivery into vaginal cavity

The aim of the present work was the development of vaginal sponge-like dressings based on chitosan ascorbate (CS) and on hyaluronic acid sodium salt/lysine acetate (HAS) combination. Sponge-like dressings were prepared by freeze-drying and characterized for mechanical resistance and mucoadhesion. CS dressings show higher mechanical and mucoadhesion properties in comparison with HAS dressing. The enzymatic inhibition properties of the dressings were evaluated in vitro against carboxipeptidase A in view of their employment for vaginal delivery of peptidic drugs. All the dressings were able to inhibit carboxipeptidase activity; CS dressings, independently of polymer MW, completely inhibited enzyme activity. Release and penetration enhancement properties of the dressings loaded with a high molecular weight hydrophilic molecule, fluorescein isothiocyanate dextran (FD4), were assessed. CS dressings were able to prolong FD4 release. All the dressings showed penetration enhancement properties into pig vaginal mucosa although to a different extent: greater for dressings based on CS than for that containing HAS. Moreover, CS dressings demonstrated intrinsic antimicrobial properties. The suitability of sponge-like systems for the treatment of vaginal infections was assessed by loading the CS dressing characterized by the best mechanical and antimicrobial properties with an antibiotic drug (clyndamicin-2-phosphate) and by checking drug release.     

Nutraceutics and delivery systems

Medical treatment has been shifted to being more prophylactic as a recent trend. Postgenomic research has unveiled the fact that nutritional intervention has been strongly associated with genetic expressions, which are responsible for a variety of biological functions. Based on these findings, the prophylactic effects of dietary supplement and nutrient have been enthusiastically investigated. Preventing or retarding the onset of diseases has become a more attractive and cost effective strategy in the medical arena. Among other approaches to prevent diseases, antioxidants, which are found in many phytochemicals, have received much attention. However, most natural antioxidants such as alpha-tocopherol, ascorbic acid and others are biologically unstable, poorly soluble in water, and poorly distributed to target sites. Because of these shortcomings further prophylactic applications of dietary supplements have stagnated. This is partially due to a lack of basic awareness of drug delivery system for dietary supplements and nutrients. In this article, we strongly advocate serious consideration of the bioavailability of dietary supplements. Currently, there are some challenging works to improve their bioavailability using delivery systems such as liposomal formulations. We will discuss the target molecules of dietary supplements for prevention of diseases and also introduce the pioneering works of delivery systems for dietary supplements to promote their therapeutic value.     

药物传递系统（DDS）Ⅳ腔道给药传递系统

腔道给药是能起全身作用、避开肝首过代谢作用、患者便于自用的非损伤性给药途径。本文着重介绍影响鼻腔、阴道给药药物吸收的生物因素和剂型因素及正在开发的腔道给药传递系统。     

Site-specific drug delivery systems II. Buccal delivery systems

Buccal route can be used for systemic delivery because the mucosa has a rich blood supply and it is relatively permeable. This route of drug delivery has many advantages, including the bypass of first pass effect and the avoidance of presystemic elimination within the GIT. Buccal delivery systems enable the systemic delivery of peptides and proteins. The present study summarizes their formulation possibilities.     

Oral transmucosal delivery of domperidone from immediate release films produced via hot-melt extrusion technology

The objective of the study was to prepare and characterize the domperidone (DOM) hot-melt extruded (HME) buccal films by both in vitro and in vivo techniques. The HME film formulations contained PEO N10 and/or its combination with HPMC E5 LV or Eudragit RL100 as polymeric carriers, and PEG3350 as a plasticizer. The blends were co-processed at a screw speed of 50 rpm with the barrel temperatures ranging from 120–160°C utilizing a bench top co-rotating twin-screw hot-melt extruder using a transverse-slit die. The HME films were evaluated for drug content, drug excipient interaction, in vitro drug release, mechanical properties, in vivo residence time, in vitro bioadhesion, swelling and erosion, ex vivo permeation from HME films and the selected optimal formulation was subjected for bioavailability studies in healthy human volunteers. The extruded films demonstrated no drug excipient interaction and excellent content uniformity. The selected HME film formulation (DOM2) exhibited a tensile strength (0.72 Kg/mm²), elongation at break (28.4% mm²), in vivo residence time (120 min), peak detachment force (1.55 N), work of adhesion (1.49 mJ), swelling index (210.2%), erosion (10.5%) and in vitro drug release of 84.8% in 2 h. Bioavailability from the optimized HME buccal films was 1.5 times higher than the oral dosage form and the results showed statistically significant (p < 0.05) difference. The ex vivo–in vivo correlation was found to have biphasic pattern and followed type A correlation. The results indicate that HME is a viable technique for the preparation of DOM buccal-adhesive films with improved bioavailability characteristics.     

Rumen-stable delivery systems

Ruminants have a distinct digestive system which serves a unique symbiotic relationship between the host animal and predominantly anaerobic rumen bacteria and protozoa. Rumen fermentation can be both beneficial by enabling utilization of cellulose and non-protein nitrogen and detrimental by reducing the nutritive value of some carbohydrates, high biological value proteins and by hydrogenating unsaturated lipids. In addition it can also result in the modification and inactivation of many pharmacologically active ingredients administered to the host animal via the oral route. The advances in ruminant nutrition and health demand a rumen-stable delivery system which can deliver the active ingredient post-ruminally while simultaneously meet efficacy, safety and cost criteria. In contrast to drug delivery systems for humans, the demand for low-cost has hindered the development of effective rumen-stable delivery systems. Historically, heat and chemical treatment of feed components, low solubility analogues or lipid-based formulations have been used to achieve some degree of rumen-stability, and products have been developed accordingly. Recently, a polymeric pH-dependent rumen-stable delivery system has been developed and commercialized. The rationale of this delivery system is based on the pH difference between ruminal and abomasal fluids. The delivery system is composed of a basic polymer, a hydrophobic substance and a pigment material. It can be applied as a coating to solid particles via a common encapsulation method such as air-suspension coating. In the future, the delivery system could be used to deliver micronutrients and pharmaceuticals post-ruminally to ruminant animals. A further possible application of the delivery system is that it could also be combined with other controlled delivery devices/systems in order to enhance slow release or to achieve targeted delivery needs for ruminants. This paper discusses the rumen protection and the abomasal release mechanism of the polymeric coating. It also reviews other rumen stable delivery systems and methods for evaluating their in vitro and in vivo performance.     

Fullerene-based delivery systems

Innovative therapeutic methods can comprise a series of pioneer strategies to deliver substances to a specific target in the body. In this regard, fullerene derivatives due to their exceptional abilities are able to effectively deliver many molecules to targeted organs.

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Acyclovir delivery systems

Herpes viruses (herpes simplex, varicella zoster, cytomegalovirus) are the main cause of a wide variety of human infections. Although the development of successful antiviral agents against infections caused by herpes viruses had been slow until the last decade, the production of delivery systems for acyclovir are a promising alternative. The present review summarizes the principal advances made in developing carriers for the delivery of acyclovir by different routes of administration.