Subcutaneous administration liposomes

Prolonged hypoglycemic effect in diabetic dogs due to subcutaneous administration of insulin liposomes, Diabetes, 31. 506-511. 

Oussoren C, Storm G. Liposomes to target the lymphatics by subcutaneous administration. Adv Drug Delia Rev 2001 50 143-56. 

The insulin solution and Ch-coated liposomes and plain liposomes containing insulin were tested for their influence on the blood glucose level after intragastric administration to normal rats. When compared with the change in the blood glucose level caused by the subcutaneous administration of insulin solution, Ch-coated liposomes had a pharmacological effect of approximately 5% (Figure 3.2). The effect of the plain liposomes and insulin solution was... 

FIGURE 3.2 Blood glucose concentration-time profiles in normal rats after oral administration of insulin-containing chitosan-coated liposomes, insulin-containing plain liposomes and insulin solution, and subcutaneous administration of insulin solution. Sol, solution Lip, liposomes Ch, chitosan s.c., subcutaneous. The results are expressed as the mean values. 

Subcutaneous Administration As for the use of PEGylated liposomes subcutaneously, there is not much reported. In one paper the influence of the administration either s.c. or i.m. of mitoxantrone-loaded liposomes was studied. It was reported that mitoxantrone showed reduced irritation when the formulation was administered i.m. rather than s.c. However, when PEG was incorporated on the liposome surface, there was no apparent protective effect of the liposomes [240]. 

Qi, X.-R. Maitani, Y. Shimoda, N. Sakaguchi, K. Nagai, T. Evaluation of liposomal erythropoietin prepared with reverse-phase evaporation vesicle method by subcutaneous administration in rats. Chem.Pharm.Bull, 1995, 43, 295-299... 

Liposomes tend to remain at the injection site when they are administered intramuscularly or subcutaneously. Therefore, these administration routes are useful for slow and sustained release of drugs at the injection site. 

To review, in an experimental mouse model, LPDI/E7 vaccination both prevents the establishment of metastatic E7-expressing tumors in naive mice through an induced E7-specific T-cell immune response and, in mice with previously established E7-expressing tumors, causes tumor regression with one subcutaneous injection of LPDI/E7 [Han SJ, et al. Subcutaneous antigen loading of dendritic cells by liposome-protamine-DNA (LPD) nanoparticles results in their activation and induction of specific antitumor immune response (impublished)]. A robust immune response follows administration of LPDI/ peptide particles, which can be used as either a preventative or therapeutic cancer vaccination strategy due to the ability of the particles to prevent and eliminate tumors, respectively, in mouse models. 

In this chapter we will provide information about the basic characteristics of liposomes staring from their building blocks, that is, phospholipids. After this, liposome structure, physicochemical properties, and stability, which are most important for their in vivo performance, will be discussed as well as methods used for liposome preparation, characterization, and stabilization. Following this first part which is more technological, we will move into the biological part and talk about the fate of conventional liposomes and sterically stabilized liposomes, as well as liposomal drugs, after in vivo administration by different routes [mainly intravenous (i.v.), intraperitoneal (i.p.), or subcutaneous (s.c.)] and also give some information about other possible routes for in vivo administration of liposomes. Finally, specific applications of liposomes in therapeutics will be presented, some in more detail, mainly for the therapy of different types of cancer. 

Successful treatment depends not only on the formulation characteristics but also on the route of administration. For example, the schistosomicidal drug tartar emetic incorporated in PEGylated liposomes was delivered either intraperitoneally or subcutaneously (27mgSb/kg) to mice infected with Schisostoma mansoni [189]. Indeed, 82 and 67% reduction levels of worm were obtained, respectively. However, the efficacy of the formulation given by either administrative route was not significantly different. The only difference was the slower liposome absorption by the subcutaneous route. 

Parenteral is defined as situated or occurring outside the intestine, and especially introduced otherwise than by way of the intestines —pertaining to essentially any administration route other than enteral. This field is obviously too broad for an adequate focus in one book, let alone one chapter. Many have nonetheless used the term synonymously with injectable drug delivery. We restrict ourselves to this latter usage. This would thus include intravenous, intramuscular, subcutaneous, intrathecal, and subdural injection. In this chapter we discuss the theoretical and practical aspects of solubilizing small molecules for injectable formulation development and will examine the role of surfactants and other excipients in more recent parenteral delivery systems such as liposomes, solid-drug nanoparticles and particulate carriers. 

The reversibility of radiation fibrosis in skin and subcutaneous tissues in response to antioxidants is supported by regression of indnration reported in a French non-randomized pilot study involving intramuscnlar administration of bovine liposomal Cu/Zn superoxide dismutase (SOD), 5 mg twice weekly for 3 weeks, to 34 patients with 42 distinct zones of superficial fibrosis. Softening of snbcutaneous induration was noted in 86% of fibrotic zones, with an actuarial response rate of 70% by 5 years. Complete regressions were noted in 7 of 42 (17%) of the fibrotic zones. Supportive data are reported with topical apphcations of SOD over a period of several months in 40 patients with fibrosis after postmastectomy radiotherapy for early breast cancer. These studies were not pursued after bovine spongiform encephalopathy (BSE) was recognized and bovine products withdrawn. 

Enzymes may also be immobilized by microencapsulation. In this technique, which has medical applications, enzymes are enclosed by various types of semi-permeable membrane, e.g. polyamide, polyurethane, polyphenyl esters and phospholipids. Microcapsules of phospholipids are also called liposomes. The micro-encapsulated enzymes and proteins inside the micro-capsule cannot pass the membrane envelope, but low M, substrates can pass into it, and products can leave. Such encapsulated proteins do not elicit an antigenic response, and they are not attacked by proteases outside the microcapsule. They are therefore suitable for the delivery of enzymes for therapeutic purposes. This area of application is still at an early stage of development, but positive results have been reported from animal experiments and clinical studies, e.g. treatment of inherited catalase deficiency with encapsulated catalase. There are various methods of administration intramuscular, subcutaneous or intraperito-neal injection. However, their major area of application is outside the body. For example, microencapsulated urease can be employed as an artificial kidney in hemodiffusion (Rg.2). 

Nanoparticles with insulin adsorbed onto the surface (Douglas et al, 1987) or liposomes loaded with insulin have also been utilized for sustained release after subcutaneous, intramuscular, or intraperitoneal administration (Patel and Ryman, 1976 Couvreur et al, 1980 Stevenson et al., 1982 Weiner eta/., 1985 Spangler, 1990). However, most injected liposomes and their content of insulin apparently remained at the subcutaneous injection site(Spangler, 1990). 

Deformable vesicles of phospholipids, known as transfersomes, have recently been investigated for buccal delivery of insulin [83]. Transfersomes are morphologically identical to liposomes, but these vesicles can respond to external stresses by rapid shape transformations requiring low energy. This high deformability allows them to deliver therapeutics across buccal barriers. Sodium cholate or sodium deoxycholate is incorporated into the vascular membrane to prepare transfersomes. Pharmacological bio availability of insulin after administration of deformable vesicles is higher relative to subcutaneous insulin and buccal conventional insulin vesicles. 

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