Subcutaneous delivery

DL-polylactic acid 25-75 Subcutaneous delivery of local anesthetics Dibucaine tetracaine... 

Almost 30 routes exist for administration of drugs to patients, but only a handfbl of these are commonly used in preclinical safety studies (Gad, 1994). The most common deviation from what is to be done in clinical trials is the use of parenteral (injected) routes such as IV (intravenous) and SC (subcutaneous) deliveries. Such injections are loosely characterized as bolus (all at once or over a very short period, such as five minutes) and infusion (over a protracted period of hours, days, or even months). The term continuous infusion implies a steady rate over a protracted period, requiring some form of setup such as an implanted venous catheter or infusion port. 

Injection - Administer in a dose of 1 mL IV, IM, or subcutaneously may be repeated as needed at 1-hour intervals to a total dose of 3 mL for IM or subcutaneous delivery or 2 mL for IV delivery in a 24-hour period. Do not exceed a total weekly dosage of 6 mL. Do not use for chronic daily administration. 

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. 

Ward WK, Wood MD, Casey HM, Quinn MJ, Federiuk IF. The effect of local subcutaneous delivery of vascular endothelial growth factor on the function of a chronically implanted amperometric glucose sensor. Diabetes Technology and Therapeutics 2004, 6, 137-145. 

In a pharmacokinetic-based study by Hedin et al. [94], hGH was administered with a nasal permeation enhancer, sodium tauro-24,25-dihydrofusidate (STDHF), in patients deficient in growth hormone (GH) using a reprocessed lyophilized form of hGH. The lyophilized material was formulated with STDHF and all the subjects received the formulation by both the nasal and subcutaneous routes. The dose given by the subcutaneous route was a standard dose of O.lIU/kg body weight (BW), whereas three different doses (of 0.2,0.4, and 0.8 IU/kg BW) of the nasal formulation were given. As compared with the subcutaneous route, all three nasal formulations showed a rapid increase in the plasma levels of hGH, with Y rn ix being reached 15-25 min after administration, as compared with 3-4 h in the case of the subcutaneous route. However, the Cmax was higher in the case of the latter route, and the nasal formulations touched baseline after 3-4 h, as compared with 14-18 h after subcutaneous delivery. 

Zelter et al. [126] compared iontophoretic and subcutaneous delivery of lidocaine and reported that although cutaneous bums were observed in two of the 13 patients for iontophoretic delivery, the majority of the subjects suffered only blanching or mild erythema of the treated site. Other studies also reported blanching and erythema of the skin [127], mild skin irritation [128], sensations of localized heat or cold [111], tingling and itching [126], and allergic contact dermatitis and vims activation [111]. 

Fig. 19 (A) Cross-sectional view of the Alzet osmotic pump, an osmotic pressure-activated drug-delivery system. (B) The effect of 7 days of subcutaneous delivery of antidiuretic hormone (vasopressin) on the daily volume of urinary excretion and urine osmolality in the Brattleboro rats with diabetes insipidus.

Subcutaneous still remains the predictable and controllable route of delivery for peptides and macromolecules. However, there is need for greater convenience and lower cost for prolonged and repeated delivery. An example of refinement of subcutaneous delivery is MEDIPAD (Elan Pharmaceutical Technologies), which is a combination of patch concept and a sophisticated miniaturized pump operated by gas generation. It was described in the report on transdermal drug delivery. 

Implants are a favored subcutaneous delivery system for veterinary formulation scientists as it affords long release of drug, and in contrast to its human counterparts, animals better tolerate the rather invasive administration procedures that are associated with implants. An example of a commercially available subcutaneous implanter is shown in Figure 12. 

Fig. 2 PYY3-36 plasma concentrations up to 96 h after subcutaneous delivery in mice with three different PSi nanocarriers thermally oxidized (TOPSi), thermally hydrocarbonized (THCPSi), and imdecylenic acid treated THCPSi (UnTHCPSi) (Kovalainen et al. 2013) (Reprinted with permission from American Chemical Society)...

Encapsulation of microorganisms, enzymes, plant cells, and animal cells (including mammalian cells) has been accomplished using a mixture of sodium cellulose sulfate with polydiallyldimethyl ammonium chloride (71,72). Encapsulation of hydridoma cells with cellulose sulfate has provided a means of subcutaneous delivery of monoclonal antibodies. The implant vascularized as early as 15 days after implantation and the neoorgan remained an active source of antibodies in mice for several months (73). 

Sartor, O. Dineen, M. K. Perez-Marreno, R. Chu, F. M. Catron, G. J. Tyler, R. C., An eight-month clinical study of LA-2575 30.0 mg a new 4-month, subcutaneous delivery system for leuprohde acetate in the treatment of prostate cancer. Urology, 2003, 62, 319-323. 

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