Liposomes — microscopic phospholipid bubbles with a bilayered membrane structure — have received a lot of attention during the past 30 years as pharmaceutical carriers of great potential. More recently, many new developments have been seen in the area of liposomal drugs — from clinically approved products to new experimental applications, with gene delivery and cancer therapy still being the principal areas of interest. For further successful development of this field, promising trends must be identified and exploited, albeit with a clear understanding of the limitations of these approaches.

Recent advances with liposomes as pharmaceutical carriers.

Current challenges in non-invasive insulin delivery systems: a comparative review.

Attempts at replicating physiological insulin secretion, as a means of restoring the normal metabolic milieu and thereby minimizing the risk of diabetic complications, has become an essential feature of insulin treatment. However, despite advances in the production, purification, formulation and methods of delivery of insulin which have occurred in recent years, this has met with limited success. The current advocacy of intensive insulin therapy regimens involving multiple daily subcutaneous injection places a heavy burden of compliance on patients and has prompted interest in developing alternative, less invasive routes of delivery. To date, attempts to exploit the nasal, oral, gastrointestinal and transdermal routes have been mainly unsuccessful. The respiratory tree, with a large surface area, offers the greatest potential for the delivery of polypeptide drugs and there is renewed interest in administrating insulin by the intrapulmonary route. Current pulmonary drug delivery systems include a variety of pressurized metered dose inhalers, dry powder inhalers, nebulizers and aqueous mist inhalers. Recent clinical studies suggest a possible role for inhaled insulin in fulfilling meal-related insulin requirements in persons with Type 1 and Type 2 diabetes. Most experience with inhaled insulin has been obtained using either dry powder formulation in the Nektar Pulmonary Inhaler/Exubera device (Nektar Therapeutics Inc., San Carlos, CA, Aventis, Bridgewater, NJ, Pfizer, NY) or a liquid aerosol formulation in the AERx® Insulin Diabetes Management System (Aradigm Corp., Hayward, CA, NovoNordisk A/S, Copenhagen, Denmark). If long-term safety and efficacy is confirmed, inhalation may become the first non-subcutaneous route of insulin administration for widespread clinical use. Despite overwhelming interest and investment in administering insulin via the oral route, success is not expected in the short term. Attempts at utilizing the buccal mucosa and skin are also continuing. Pancreatic transplantation will remain limited to those patients receiving a kidney transplant and immunotherapy. Islet cell transplantation is at an early though encouraging stage following the availability of new less toxic immunosuppressive agents. True insulin independence will require further advances in the combined fields of cell biology and genetics to ensure freedom from both the need for lifelong administration of insulin and the complications of diabetes.

Alternative routes of insulin delivery

The Need for Drugs and Drug Delivery Systems.- Overview of Controlled Release Mechanisms.- Hydrophobic Polymers of Pharmaceutical Significance.- Hydrogels.- Biodegradable Polymers in Drug Delivery Systems.- Diffusion Controlled Drug Delivery Systems.- Swelling Controlled Drug Delivery Systems.- Degradable Polymeric Carriers for Parenteral Controlled Drug Delivery Systems.- Porous Systems.- Targeted Delivery Using Biodegradable polymeric Nanoparticles.- Liposomes in Drug Delivery.- Receptor Mediated Delivery Systems for Cancer Therapeutics.- Biological Rhythms, Drug Delivery, and Chronotherapeutics.- Site Specific Controlled Release for Cardiovascular Disease - Translational Direction.- Drug Delivery Systems to Fight Cancer.- Applications of Vaccine Delivery in Infectious Diseases.- Tissue Engineering in Drug Delivery.- The Shaping of Controlled Release Drug Product Development by Emerging Trends in the Commercial, Regulatory and Political Macro-Environment

Fundamentals and applications of controlled release drug delivery

Liquid filled nanoparticles as a drug delivery tool for protein therapeutics.

To investigate the possibility of the enhancing effect of deformable vesicles on buccal delivery of insulin, two kinds of vesicles with and without the presence of sodium deoxycholate (deformable vesicles and conventional vesicles) were prepared by reverse phase evaporation methods. The liposomal entrapment efficiency was determined by column chromatography. The particle size and morphology of the vesicles were also evaluated. The hypoglycemic effects, insulin concentrations, and residual amounts of insulin deposited in the buccal membrane after buccal administration of insulin vesicles to rabbits were investigated. Compared with subcutaneous administration of insulin solution, the relative pharmacological bioavailability and the relative bioavailability of buccal administration of insulin vesicles were determined. The results showed that the entrapment efficiencies of the deformable and conventional vesicles were 18.87±1.78% (n=3) and 22.07±2.16% (n=3), respectively. The particle sizes of the deformable and conventional vesicles were 42.5±20.5 nm and 59.7±33.8 nm, respectively. There were no significant differences in appearance between the two types of vesicle. Compared with subcutaneous administration of insulin solution, the relative pharmacological bioavailability and the relative bioavailability in the insulin-deformable vesicles group were 15.59% and 19.78%, respectively, which were higher than in the conventional insulin vesicles (p<0.05), blank deformable vesicles and insulin mixture groups (p<0.05). Deformable vesicles have an enhancing effect on buccal delivery of insulin and may be a better carrier than conventional vesicles for buccal delivery of protein drugs.

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Phospholipid deformable vesicles for buccal delivery of insulin.

To investigate the absorption of recombinant hirudin-2 (rHV2) after oral administration to rats and its possible absorption mechanism, a series of experiments were carried out. The degradation of 125 I-rHV2 in the luminal contents and variant mucosal subcellular fractions, as well as the effect of degradation inhibition of some adjuvant was investigated. The bioavailability of rHV2, with or without degradation inhibitor after oral administration to rats was estimated, whereas the in situ loop test and everted sac experiment were also conducted to understand more about the gastrointestinal absorption of rHV2 in rats. It was demonstrated that the rHV2 was not stable in the luminal contents and subfraction of the intestinal mucosa. Some enzyme inhibitor, such as bacitracin or casein, could inhibit the degradation to certain degrees. The intact rHV2 molecules were found in the rat plasma after oral administration, and the bioavailability varies obviously, dependent on the analytical method. Some of the enzyme inhibitor could enhance the rHV2 oral absorption. There is no site difference on rHV2 absorption in different segments of small intestine. The possible transport mechanism of rHV2 across the gastrointestinal tract is concerned with the endocytosis process.

https://jpet.aspetjournals.org/content/jpet/early/2003/11/10/jpet.103.056655.full.pdf

Xiang-Tao Wang

Papers

Phospholipid deformable vesicles for buccal delivery of insulin.

Gastrointestinal Absorption of Recombinant Hirudin-2 in Rats