Subcutaneous extended release

Cox M C, Scripture C D, Figg W D (2005). Leuprolide acetate given by a subcutaneous extended-release injection Less of a pain Expert Rev. Anticancer. Ther. 5(4) 605-611. 

Skin Asymptomatic subcutaneous nodules have frequently been reported and local inflammation demonstrated. Extensive fat necrosis at injection sites has been attributed to subcutaneous extended-release lameo-tide [73 ]. 

In this work we will focus on the use of the cubic phase as a delivery system for oligopeptides - Desmopressin, Lysine Vasopressin, Somatostatin and the Renin inhibitor H214/03. The amino acid sequences of these peptides are given in Table I. The work focuses on the cubic phase as a subcutaneous or intramuscular depot for extended release of peptide drugs, and as a vehicle for peptide uptake in the Gl-tract. Several examples of how the peptide drugs interact with this lipid-water system will be given in terms of phase behaviour, peptide self-diffusion, in vitro and in vivo release kinetics, and the ability of the cubic phase to protect peptides from enzymatic degradation in vitro. Part of this work has been described elsewhere (4-6). 

Perez-Marrero R, Tyler RC. A subcutaneous delivery system for the extended release of leuprolide acetate for the treatment of prostate cancer. Expert Opin Pharmacother. 2004 5 447 157. 

Bioavailability studies quantify rate and extent of absorption. They compare the efficiency of the disposition of several drug formulations, e.g. immediate-release vs. extended-release or capsule vs. tablet or tablet A vs. tablet B etc., or they compare the disposition of different routes of administration, e.g. oral vs. subcutaneous or oral vs. intravenous. According to the definition, a comparison to the intravenous bolus injection yields the absolute bioavailability. 

An 80-year-old woman with acromegaly developed extensive fat necrosis in both buttocks after three deep subcutaneous doses of lameo-tide 60 mg extended release. The lesions first became apparent about 4 months after the first injection and developed over several months. There was central necrosis with surrounding inflammatory tissue. The CRP concentration and white cell count were normal and bacterial cultures were negative. Once the lesions were clearly demarcated they were excised. 

A 47-year-old HIV-infected man with dilated cardiomyopathy, a prolonged QT interval, and an automatic implantable cardiovascular defibrillator device was given subcutaneous enfuvirtide 90 mg bd and oral extended-release niacin 500 mg/day. After 1 week he developed extreme redness, edema, and swelling at the injection site that corresponded with the flushing sensation due to niacin. The niacin was withdrawn and no further problems occurred with enfuvirtide alone. 

Insulin suspensions. When the hormone is injected as a suspension of insulin-containing particles, its dissolution and release in subcutaneous tissue are retarded (rapid, intermediate, and slow insulins). Suitable particles can be obtained by precipitation of apolar, poorly water-soluble complexes consisting of anionic insulin and cationic partners, e.g the polycationic protein protamine or the compound aminoqui-nuride (Surfen). In the presence of zinc and acetate ions, insulin crystallizes crystal size determines the rate of dissolution. Intermediate insulin preparations (NPH or isophane, lente or zinc insulin) act for 18 to 26 h, slow preparations (protamine zinc insulin, ultralente or extended zinc insulin) for up to 36 h. 

Detemir needs some special attention here. Insulin detemir differs from human insulin in that one amino acid has been omitted from the end of the B chain, and a fatty acid has been attached. Detemir s action is extended because its altered form makes that it is slowly released from the subcutaneous depot. More than 98% of detemir in the bloodstream is bound to albumin. Because it slowly dissociates from the albumin, it is available to the body over an extended period. 

In drug delivery, injectable systems can be administered systemically or topically, producing dosage forms that can have an extended circulation (dispersed systems) or provide a localized reservoir of an active ingredient (depot systems). Different combinations of route of administration and physical nature of the formulation can be used to spatially (biodistribution) and temporally (kinetics of release) control the concentration of the active principle and thus its bioavailability. For example, the characteristics of the administration (e.g. subcutaneous or intravenous) and the size of the carrier (e.g. capable or not of... 

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