Nanotechnology and therapeutic delivery: a drug regulation perspective

Nanotechnology is expected to contribute to the therapeutic delivery field in the coming decade. Although the US FDA has multiple guidance documents in place to deal with novel drug products, nanoparticles may produce issues that have not been previously encountered with small drug molecules. This regulatory focus highlights some current guidance documents and thinking of the FDA as applied to nanoparticles used for therapeutic delivery.     

Industrial perspective in ocular drug delivery

In the development of a commercial drug product, the formulator must consider various perspectives. The bioavailability of the active drug substance is often the major hurdle to overcome. In the past it has been common to add viscosity-enhancing agents or mucoadhesive polymers into formulations to improve ocular bioavailability. In addition to these conventional approaches, non-conventional technologies such as nanotechnology, microspheres and prodrugs could be considered to optimize the product. Along with bioavailability, the formulator must also consider the tolerability and stability of the final drug product. Quite often, the final formulation is the ideal compromise between the three. Authorities in different parts of the world have set strict requirements and guidelines for development and approval of drug products. In order to secure an expeditious development process and the shortest possible review and approval time, the formulator should be familiar with the current requirements and regulations.     

A vaginal drug delivery model

Efficient drug delivery at vaginal cavity is often a challenge owing to its peculiar physiological variations including vast differences in pH. Keeping in view this attribute of the target site, the current work was aimed at developing formulation strategies which could overcome this and successfully deliver molecules like itraconazole through SLNs. Optimized SLNs with the given composition was selected for further development into mucoadhesive and thermosensitive gel. Stearic acid and Compritol 888 (1:1, w/w ratio) as lipid, a mixture of 3% Poloxomer 188 and 0.5% sodium taurocholate as surfactant and organic to aqueous ratio of 10:50 was taken. Carbopol 934 and Pluronic F 127 were taken for the development of gel. Optimized gel exhibited a desired gelling temperature (35?°C); viscosity (0.920 PaS) and appreciable in vitro drug release (62.2% in 20?h). MTT assay did not show any cytotoxic effect of the gel. When evaluated in vivo, it did not exhibit any irritation potential despite appreciable bioadhesion. A remarkable decrease in CFUs was also observed in comparison with control and marketed formulation when evaluated in rat infection model. Thus, the proposed study defines the challenges for developing a suitable formulation system overcoming the delivery barriers of the vaginal site.     

pH-Sensitive nanospheres for colon-specific drug delivery in experimentally induced colitis rat model

Novel pH-sensitive nanospheres designed for colon-specific delivery were prepared using polymeric mixtures of poly (lactic-co-glycolic) acid (PLGA) and a pH-sensitive methacrylate copolymer. Budesonide (BSD), a topically active corticosteroid, was entrapped as a model drug. The therapeutic efficacy of the prepared nanospheres was assessed using the trinitrobenzenesulfonic acid (TNBS) colitis rat model, in comparison with conventional enteric microparticles. In addition, the colon targeting properties, systemic bioavailability, and specific uptake by the inflamed colon mucosa were evaluated using coumarin-6 (C-6)-loaded nanospheres. The prepared nanospheres showed strongly pH-dependent drug release properties in acidic and neutral pH values followed by a sustained release phase at pH 7.4. Animal experiments revealed the superior therapeutic efficiency of BSD-loaded nanospheres in alleviating the conditions of TNBS-induced colitis model. The in vivo studies using C-6-loaded nanospheres displayed higher colon levels and lower systemic availability of the fluorescent marker when compared with simple enteric coating. Moreover, quantitative analysis of the fluorescent marker and confocal laser scanning studies showed strong and specific adhesion of the nanospheres to the ulcerated and inflamed mucosal tissue of the rat colon. In conclusion, the proposed nanosphere system combined the properties of pH-sensitivity, controlled release, and particulate targeting that could be useful for colon-specific delivery in inflammatory bowel disease.     

Validation of a biophysical drug absorption model by the PATQSAR system

Absorption rate constants (in situ rat gut technique) and in vitro antibacterial activities of twenty fluoroquinolones have been evaluated. A biophysical model that relates the absorption of the compounds with their lipophilicity was fitted. The model considers the absorption process from the intestinal lumen as the sum of two resistances in series: aqueous diffusional barrier and lipoidal membrane. Even if partitioning into the membrane and membrane diffusion are both enhanced for lipophilic compounds, the absorption rate constant is limited by the aqueous diffusion. To estimate the influence of structural modifications on each property and to establish the role of lipophilicity in controlling in situ absorption and in vitro antibacterial activity, the PATQSAR search system is used to construct structure-property relationships. The structural models, which explain 99% of the total variance of each physicochemical property and 96% of each in vitro biological activity, provide an explicit and precise interpretation of lipophilicity, absorption, and antimicrobial activity. The results confirm the important role of lipophilicity in controlling absorption, as pointed out by the biophysical model for the piperazinyl series, and suggest the introduction of electronic factors in order to extend the model to heterologues. They also justify the mechanism by which quinolones are assumed to induce antibacterial activity.     

Polymeric particulate technologies for oral drug delivery and targeting: a pathophysiological perspective

The oral route for delivery of pharmaceuticals is the most widely used and accepted. Nanoparticles and microparticles are increasingly being applied within this arena to optimize drug targeting and bioavailability. Frequently the carrier systems used are either constructed from or contain polymeric materials. Examples of these nanocarriers include polymeric nanoparticles, solid lipid nanocarriers, self-nanoemulsifying drug delivery systems and nanocrystals. It is the purpose of this review to describe these cutting edge technologies and specifically focus on the interaction and fate of these polymers within the gastrointestinal system.     

The circling training rat model as a behavioral teratology test

The properties of circling training (CT) for detecting behavioral teratologic drug-induced effects was evaluated by prenatal administration of two behavioral teratogenic drugs: vitamin A (80,000 IU/kg/day) and haloperidol (2.5 mg/kg/day). The circling training was started at 30 days of age and performed for 8 days in an automated apparatus. Statistically significant differences between drug-treated and control animals regarding the measured response (turns per minute) were found. Two components may affect the response measured by the CT: associative learning and motor performance. The incidence of these components was discriminated with behavioral and mathematical approaches. In the experimental conditions used the most affected parameter was motor performance. The results indicate that CT can be used as an instrumental conditioning test where the quantifiable endpoint is the on-going motor performance. Further applications of the CT for neurochemical evaluation of drug induced effects are also discussed.     

Triggered drug delivery from biomaterials

Importance of the field: Conventional dosing methods are frequently unable to deliver the clinical requirement of the patient. The ability to control the delivery of drugs from implanted materials is difficult to achieve, but offers promise in diverse areas such as infection-resistant medical devices and responsive implants for diabetics.

Areas covered in this review: This review gives a broad overview of recent progress in the use of triggers that can be used to achieve modulation of drug release rates from implantable biomaterials. In particular, these can be classified as being responsive to one or more of the following stimuli: a chemical species, light, heat, magnetism, ultrasound and mechanical force.

What the reader will gain: An overview of the potential for triggered drug delivery to give methods for tailoring the dose, location and time of release of a wide range of drugs where traditional dosing methods are not suitable. Particular emphasis is given to recently reported systems, and important historical reports are included.

Take home message: The use of externally or internally applied triggers of drug delivery to biomaterials has significant potential for improved delivery modalities and infection resistance.     

从社会学视角探索分娩计划的意义

目的从社会学视角了解分娩计划在中国助产生育服务中的意义。方法从社会学角度,利用质性研究,深度访谈3位助产士和8位有分娩计划的生育妇女,访谈结果采用主题分析法。结果升华出4个主题:分娩计划可以激发产妇对生育健康知识的兴趣;帮助助产士与产妇构建互信合作关系;在分娩时促进双方有效沟通,是助产士在孕期服务专业团队中的生存策略。结论分娩计划在中国助产服务意义重大,应给于普及。     

Iontophoretic delivery of model inorganic and drug ions

The in vitro delivery of the inorganic ions Li+, Na+, K+, Mg2+, and Ca2+, and the model organic ions pyridostigmine and propranolol through various types of excised skin was investigated using a constant current iontophoretic system. The drug delivery rate was found to be linearly dependent on current for each ion. The slope of this linear dependence is defined as the iontophoretic flux and was used to calculate the efficiency of drug delivery which was found to be virtually independent of the type of skin employed. However, the efficiency of drug delivery was affected by the anode material and drug counterion employed in the iontophoretic system. In addition, the efficiency of delivery for divalent magnesium and calcium ions was found to be less than half that observed for the monovalent sodium and potassium ions. The in vivo iontophoretic delivery of pyridostigmine using the domestic weanling pig is also reported. The in vivo results were found to be similar to those observed in vitro.     

Factors affecting drug delivery from a syringe-pump infusion set

In vitro testing of drug delivery via dual-lumen, small-volume i.v. extension tubing designed for use with a syringe pump was conducted. From a dual-lumen extension set with intraluminal diameters of 0.020 inch, effluent samples were collected at 5, 10, and 20 minutes after injection of a 1-mL volume of drug solution intended for delivery over 20 minutes by a syringe infusion pump. Variables were flow rate (5 or 25 mL/hr) of the primary infusion, tubing position (vertical or horizontal), and density of the drug solution (penicillin G potassium 250,000 units/mL and aminophylline 25 mg/mL represented high and low specific gravities, respectively). Each drug solution was labeled with radioactive carbon and the drug content of the effluent was analyzed by liquid scintillation. For each set of variables, samples were also tested after the tubing was flushed with 5% dextrose injection 0.2-0.6 mL. Similar procedures were followed to determine delivery of the labeled penicillin G potassium solution via a dual-lumen extension set with intraluminal diameters of 0.020 inch (for drug) and 0.060 inch (for the primary infusion); a 13-mm-diameter, 0.2 micron filter was attached to the smaller-lumen tubing. A primary infusion flow rate of 5 mL/hr and flush volumes of 0.3 and 0.6 mL were used in this study. To determine the influence of intraluminal diameter on the flush volume required for delivery of a dose of aminophylline (1-mL volume), single-lumen extension tubings with different diameters were tested. The final percentage of the drug dose delivered via the dual-lumen extension set with 0.020-inch lumens was affected only by flush volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hydrophilic silica aerogels as dermal drug delivery systems - Dithranol as a model drug.

A special class of porous silica materials, silica aerogels, was recently shown to be a potential candidate for oral drug delivery systems. It was demonstrated, that stability of drugs and their dissolution rate can essentially be improved through the adsorption on to these materials. In this work, drug loaded silica aerogels are firstly applied as dermal drug delivery systems. Dithranol is used as a representative drug since there is a need to enhance its dermal availability. The unstable and nearly water-insoluble drug exhibits a poor penetration. Release of dithranol from aerogels into various semi-solid formulations and its dissolution as well as the release and penetration into artificial membranes were investigated by Fourier-transform infrared attenuated total reflection (FTIR-ATR) spectroscopy. Two model membranes (one hydrophilic and one lipophilic) were applied. Several formulations were tested and the most promising one was used in order to study the penetration of dithranol into human stratum corneum (SC). Dithranol adsorbed on hydrophilic silica aerogels exhibited superior penetration behaviour compared to that of the standard ointment (dithranol in white soft paraffin).