吸入粉雾剂给药装置的研究进展

综述国际上近年来吸入粉雾剂给药装置的研究进展状况,指出我国应加快对微粉化气雾剂药品的研发,尤其应注重对纳米技术在吸入粉雾剂中的应用.     

肽类和蛋白质类药物口服剂型的进展

本文综述了肽类和蛋白质类药物口服给药研究的新进展,包括给药后的吸收障碍,重点是提高生物膜透过性和突破酶解障碍的方法,同时提出了肽类和蛋白质类药物口服制剂研究的展望。     

肽类和蛋白质类药物口服剂型的进展

本文综述了肽类和蛋白质类药物口服给药研究的新进展，包括给药后的吸收障碍，重点是提高生物膜透过性和突破酶解障碍的方法，同时提出了肽类和蛋白质炎药物口服制剂研究的展望。     

肽类和蛋白质类药物肺部给药的体内外评价方法

目的介绍肽类和蛋白质类药物肺部给药的体内外评价方法。方法对肽类和蛋白质药物肺部给药研究中的给药方法、药动学评价、药效学评价、肺部沉积、体外评价及安全性评价方法进行综述。结果根据研究的不同阶段选择合适的动物给药模型,采用特异性强、灵敏度高的分析方法是肽类和蛋白质药物肺部给药系统体内评价的关键。肺内沉积是对剂型和给药装置递送效果的综合考察。具有良好体内外相关性的体外评价方法的建立与安全性评价在肺部给药制剂开发中具有十分重要的意义。结论肽类和蛋白质类药物肺部给药的体内外评价方法与其他给药途径有较大区别,在研究和开发中应根据需要选取适当的方法。     

肽类和蛋白质类药物肺部给药的体内外评价方法

目的介绍肽类和蛋白质类药物肺部给药的体内外评价方法。方法对肽类和蛋白质药物肺部给药研究中的给药方法、药动学评价、药效学评价、肺部沉积、体外评价及安全性评价方法进行综述。结果根据研究的不同阶段选择合适的动物给药模型,采用特异性强、灵敏度高的分析方法是肽类和蛋白质药物肺部给药系统体内评价的关键。肺内沉积是对剂型和给药装置递送效果的综合考察。具有良好体内外相关性的体外评价方法的建立与安全性评价在肺部给药制剂开发中具有十分重要的意义。结论肽类和蛋白质类药物肺部给药的体内外评价方法与其他给药途径有较大区别,在研究和开发中应根据需要选取适当的方法。     

新型肺部给药系统-吸入粉雾剂

吸入粉雾剂 (又名粉雾吸入剂、干粉吸入剂、粉雾剂) 是一种新型的肺部给药系统, 具有稳定性好, 不含抛射剂氟里昂等优点, 近年来受到人们的广泛关注。粉雾剂由粉末吸入装置和供吸入用的干粉组成。本文就近年来粉雾剂的研究进展, 包括吸收机制, 粉雾剂品种, 吸入装置, 制备技术和评价特征参数等进行了综述。     

呼吸道给药的新剂型——粉雾剂

粉雾剂因不含抛射剂及可避免使用时的协同困难而越来越受到人们的重视，并有取代气雾剂的趋势。早在８０年代初国外即已对偻雾剂进行了深入的研究，而国内尚处于起步阶段。本文概述粉雾剂的发展，比较了粉雾剂与氯雾剂优缺点，对组成粉雾剂的药物粉末的处方设计及呼入装置进行了论述，并指出用于吸入疗法的粉雾剂的研究开发应用从三个文献考虑：粉末的雾化、吸入装置的转运性能和病人的肿气产生的雾化能量。     

肽和蛋白质类药物的给药系统(Ⅱ)

<正>3 蛋白质─聚合物共轭体 重组蛋白因缺乏糖基而使其溶解性和稳定性较差,并且有抗原性,与以聚乙二醇（PEG）为代表的水溶性聚合物通过共价键形成轭合物后,轭合物的性质较之未经修饰的原物质有很大改善,溶解度提高,稳定性增强,生物半衰期延长,毒副作用（免疫原性和过敏反应）降低甚至消除,疗效提高,因此在临床上得到应用。 白细胞介素-2经PEG修饰后的轭合物以适当的剂量和方式给药,可以延长血液中IL-2活性达到最大值的时间,延长循环寿命,减轻免疫原性,提高治疗指数和疗效。PEG-天冬酰胺酶轭合物的半衰期较之天然酶延长了17倍,免疫原性也有所降低,治疗指数得以提高。用PEG修饰,在临床上得到应用的酶还有:SOD（超氧化物歧化酶）、ADA（腺苷脱氨酶）、尿酸酶等,都表现出相似的特性。     

多肽和蛋白质及疫苗类药物干粉吸入给药的研究进展

针对多肽和蛋白质类药物体内过程和药学性质的特殊性，介绍了多肽和蛋白质类药物非注射给药途径研究现状，干粉吸入剂的剂型优点和制剂工艺技术特点，以及多肽和蛋白质类药物干粉吸入剂的研究进展，着重介绍了胰岛素等全身作用类药物、局部作用类药物及疫苗药物的干粉吸入给药的研究现状。     

肺部吸入给药系统的研究进展

肺部给药系统具有起效快、疗效好、同时减少不良反应等优点,已成为一种倍受关注的给药方式.在全球新型给药系统药物市场中,肺部吸入给药系统占有极为重要的地位,特别是在慢性阻塞性肺病和哮喘等与呼吸道相关疾病的治疗方面具有广泛的临床应用价值.本文将从吸入制剂的最新分类、美国FDA已上市产品情况和创新性产品研究进展等方面入手,对目...     

Chitosan-Modified Dry Powder Formulations for Pulmonary Gene Delivery

Purpose Spray-drying is an effective process for preparing micron-dimensioned particles for pulmonary delivery. Previously, we have demonstrated enhanced dispersibility and fine particle fraction of spray-dried nonviral gene delivery formulations using amino acids or absorption enhancers as dispersibility-enhancing excipients. In this study, we investigate the use of the cationic polymer chitosan as a readily available and biocompatible dispersibility enhancer. Methods Lactose-lipid:polycation:pDNA (LPD) powders were prepared by spray-drying and post-mixed with chitosan or spray-dried chitosan. In addition, the water-soluble chitosan derivative, trimethyl chitosan, was added to the lactose-LPD formulation before spray-drying. Results Spray-dried chitosan particles, displaying an irregular surface morphology and diameter of less than 2 μm, readily adsorbed to lactose-LPD particles following mixing. In contrast with the smooth spherical surface of lactose-LPD particles, spray-dried trimethyl chitosan-lactose-LPD particles demonstrated increased surface roughness and a unimodal particle size distribution (mean diameter 3.4 μm), compared with the multimodal distribution for unmodified lactose-LPD powders (mean diameter 23.7 μm). The emitted dose and in vitro deposition of chitosan-modified powders was significantly greater than that of unmodified powders. Moreover, the inclusion of chitosan mediated an enhanced level of reporter gene expression. Conclusions In summary, chitosan enhances the dispersibility and in vitro pulmonary deposition performance of spray-dried powders.     

Formulation of High-Performance Dry Powder Aerosols for Pulmonary Protein Delivery

Purpose

Pulmonary delivery of biologics is of great interest, as it can be used for the local treatment of respiratory diseases or as a route to systemic drug delivery. To reach the full potential of inhaled biologics, a formulation platform capable of producing high performance aerosols without altering protein native structure is required.

Methods

A formulation strategy using Particle Replication in Non-wetting Templates (PRINT) was developed to produce protein dry powders with precisely engineered particle morphology. Stability of the incorporated proteins was characterized and the aerosol properties of the protein dry powders was evaluated in vitro with an Andersen Cascade Impactor (ACI).

Results

Model proteins bovine serum albumin (BSA) and lysozyme were micromolded into 1 μm cylinders composed of more than 80% protein, by mass. Extensive characterization of the incorporated proteins found no evidence of alteration of native structures. The BSA formulation produced a mass median aerodynamic diameter (MMAD) of 1.77 μm ± 0.06 and a geometric standard deviation (GSD) of 1.51 ± 0.06 while the lysozyme formulation had an MMAD of 1.83 μm ± 0.12 and a GSD of 1.44 ± 0.03.

Conclusion

Protein dry powders manufactured with PRINT could enable high-performance delivery of protein therapeutics to the lungs.

     

Pulmonary Absorption of Peptides and Proteins

Pulmonary delivery provides a promising route for absorption of peptides and proteins having poor oral bioavailability due to inefficient transport across the gastrointestinal epithelium or high levels of first-pass hepatic clearance. Efficient absorption after inhalation has been demonstrated for compounds varying substantially in size and other physicochemical characteristics. However, understanding of the relationship of structure to absorption efficiency is incomplete. Limited data regarding mechanisms of permeation across respiratory epithelium suggest passive transport of small peptides, with a contribution from vesicle-mediated transcytosis in the relatively slow transport of large proteins such as albumin and peroxidase. Lack of absorption of some peptides is most likely due to their susceptibility to protease degradation, since high levels of some exopeptidases are present in lung tissue. Effects of chronic exposure to potentially antigenic molecules delivered to the lung will need to be assessed on a case by case basis before the potential for pulmonary peptide delivery can be determined. Formulation/device development for proteins is in early stages: the susceptibility of many proteins to denaturation and oxidation presents special difficulties in small particle aerosol generation. The relative inefficiency and volume limitations of inhalation delivery currently limit this approach to molecules of relatively high potency. More widespread exploitation of pulmonary polypeptide delivery will depend on successful development of reproducible dry powder systems allowing inhalation of a greater amount of drug.     

Freeze-Dried Mannitol for Superior Pulmonary Drug Delivery via Dry Powder Inhaler

Purpose

To show for the first time the superior dry powder inhaler (DPI) performance of freeze dried mannitol in comparison to spray dried mannitol and commercial mannitol.

Methods

Different mannitol powders were sieved to collect 63–90 μm particles and then analyzed in terms of size, shape, surface morphology, solid state, density, flowability. Salbutamol sulphate-mannitol aerosol formulations were evaluated in terms of homogeneity, SS-mannitol adhesion, and in vitro aerosolization performance.

Results

Freeze dried mannitol demonstrated superior DPI performance with a fine particle fraction believed to be highest so far reported in literature for salbutamol sulphate under similar protocols (FPF?=?46.9%). To lesser extent, spray dried mannitol produced better aerosolization performance than commercial mannitol. Freeze dried mannitol demonstrated elongated morphology, α-+β-+δ- polymorphic forms, and poor flowability whereas spray dried mannitol demonstrated spherical morphology, α-+β- polymorphic forms, and excellent flowability. Commercial mannitol demonstrated angular morphology, β- polymorphic form, and good flowability. Freeze dried mannitol demonstrated smoother surface than spray dried mannitol which in turn demonstrated smoother surface than commercial mannitol. FPF of SS increased as mannitol powder porosity increase.

Conclusions

Freeze drying under controlled conditions can be used as a potential technique to generate aerodynamically light mannitol particles for superior DPI performance.     

Twin-Screw Continuous Mixing Can Produce Dry Powder Inhalation Mixtures for Pulmonary Delivery

The feasibility of twin-screw corotating extruder as a continuous process mixer to prepare dry powder inhalation (DPI) powders was investigated. Interactive mixtures of 1% micronized budesonide, 0.3% magnesium stearate and 98.7% alpha-lactose monohydrate were manufactured using a Leistritz Nano-16 extruder at various processing conditions. One set of GFM (grooved mixing) elements were included in the screw profile to provide distributive mixing of conveyed powders with the goal of resulting in a homogeneous mixture. Residence time in the twin-screw mixer was modelled to quantify mixing efficiency. Comparative powders were also prepared using either low or high-shear batch mixing to compare the effect of mixing methods on the properties of the budesonide dry powder inhalation formulation. Twin screw mixing results in homogeneous mixtures with aerosol performance comparable to that of high-shear batch mixing. Scanning electron microscopy confirmed that twin screw mixing produces particles with morphology like that of low and high-shear batch mixing. X-ray diffraction (XRD) analysis verified that there was no form change of the drug due to twin-screw processing. Statistical regression was used to probe the relationship between twin screw mixing process parameters such as screw speed and feed rate and aerosol performance. The twin screw mixing process was found to be robust, as no significant differences in aerosol performance were found for various processing parameters.     

A Delivery System for Oral Administration of Proteins/Peptides Through Bile Acid Transport Channels

Proteins and peptides are poorly absorbed via oral administration because of the gastrointestinal tract environment and lysosomal digestion after apical endocytosis. A delivery system, consisting of a deoxycholic acid–conjugated nanometer-sized carrier, may enhance the absorption of proteins in the intestine via the bile acid pathway. Deoxycholic acid is first conjugated to chitosan. Liposomes are then prepared and loaded with the model drug insulin. Finally, the conjugates are bound to the liposome surface to form deoxycholic acid and chitosan conjugate–modified liposomes (DC-LIPs). This study demonstrates that DC-LIPs can promote the intestinal absorption of insulin via the apical sodium-dependent bile acid transporter, based on observing fluorescently stained tissue slices of the rat small intestine and a Caco-2 cell uptake experiment. Images of intestinal slices revealed that excellent absorption of DC-LIPs is achieved via apical sodium-dependent bile acid transporter, and a flow cytometry experiment proved that DC-LIPs are a highly efficient delivery carrier. Caco-2 cells were also used to study the lysosome escape ability of DC-LIPs. We learned from confocal microscopy photographs that DC-LIPs can protect their contents from being destroyed by the lysosome. Finally, according to pharmacokinetic analyses, insulin-loaded DC-LIPs show a significant hypoglycemic effect with an oral bioavailability of 16.1% in rats with type I diabetes.     

Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases

The blood–brain barrier (BBB) is a major impediment to the therapeutic delivery of peptides and proteins to the brain. Intranasal delivery often provides a non-invasive means to bypass the BBB. Advantages of using intranasal delivery include minimizing exposure to peripheral organs and tissues, thus reducing systemic side effects. It also allows substances that typically have rapid degradation in the blood time to exert their effect. Intranasal delivery provides the ability to target proteins and peptides to specific regions of the brain when administered with substrates like cyclodextrins. In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP. We have described their rationale for use, distribution in the brain after intranasal injection, how intranasal administration differed from other modes of delivery, and their use in clinical trials, if applicable. Intranasal delivery of drugs, peptides, and other proteins could be very useful in the future for the prevention or treatment of brain related diseases.KEY WORDS: blood–brain barrier, cognition, intranasal, memory     

Dextran Mass Ratio Controls Particle Drying Dynamics in a Thermally Stable Dry Powder Vaccine for Pulmonary Delivery

Pharmaceutical Research - Thermally stable, spray dried vaccines targeting respiratory diseases are promising candidates for pulmonary delivery, requiring careful excipient formulation to...     

Development of a Spray-Dried Formulation of Peptide-DNA Nanoparticles into a Dry Powder for Pulmonary Delivery Using Factorial Design

Pharmaceutical Research - Gene therapy via pulmonary delivery holds the potential to treat various lung pathologies. To date, spray drying has been the most promising method to produce inhalable...