Parenteral administration dose volume

Currently, pentamidine in the form of aerosol is used for the prophylaxis of PCP with apparent success [163-166]. Initially no renal side effects were described with its use. However, two reports of acute renal dysfunction raised the possibility of a systemic absorption of aerosolized pentamidine [167, 168]. One of the patients received a previous large dose of TMP-SMZ and the other appears to have had concomitant volume depletion caused by severe diarrhea while an elevation of serum creatinine occurred. We have been unable to find additional reports of renal toxicity associated with aerosol pentamidine administration[169]. Likewise, no renal side effects were reported with the use of aerosolized pentamidine for the prophylaxis of PCP in patients who received bone marrow, renal or hepatic transplants [165, 166]. Although the use of aerosolized pentamidine may be associated with renal dysfunction, this seems much less frequent compared to the parenteral administration of this drug. 

Homogeneous solutions are the preferred formulation systems for parenteral administration because they can be easily visually inspected for the absence of particulate matter. For this reason, cosolvent solubilization is the first choice for parenteral products once purely aqueous systems provide insufficient solvency. The compositions of three commercial, injectable products are given in Table 39.5. The first product (1) has a low percentage of cosolvent in the separate solvent ampoule. The drug substance is provided as a dry powder because of its limited stability in solution. The second one (2) is solubiUzed with two cosolvents amounting to 50% of the total volume, whereas in the third product the drug dose is dissolved in a water-free mixture of cosolvents. This draws the attention to a further point to consider when cosolvents are employed in formulations. The formulation has to be devised such that the effect of dilution of... 

The cost of parenteral administration can be high due to the need for frequent dosing and the requirement for aseptic/sterile conditions for preparation of the doses. Moreover, dosing errors due to calculation and/or dilution errors are not uncommon, especially in neonates and infants, as they require frequent dose adaptation, serial dilutions to achieve measurable volumes or withdrawal of a dose volume that is less... 

With the aid of the three methods described in Sect. 18.5.4 it can be calculated whether or not a pharmaceutical preparation is iso-osmotic. Hypo-osmolarity can usually be avoided as it can be compensated by the addition of excipients in calculated quantities. Hyper-osmolarity may be inevitable due to dosage reasons, for example when a high dose of an active substance has to be administered in a small volume. The extent to which hyper-osmolarity is tolerated will depend on the route of administration and administration site. The tolerance for parenteral administration, for example, increases in the order subcutaneous < intramuscular < intravenously. This has to do with the fact that of these three routes, the intravenously administered dose spreads most rapidly, and thus dilutes most rapidly in the body and the subcutaneously administered dose most slowly. For the same reason, the tolerance is greater when the solution is injected into a large blood vessel than in a small blood vessel. The tolerance is also determined by the volume infused. In Sects. 

The AUC is a measure of bioavailability, i.e. the amount of substance in the central compartment that is available to the organism. It takes a maximal value under intravenous administration, and is usually less after oral administration or parenteral injection (such as under the skin or in muscle). In the latter cases, losses occur in the gut and at the injection sites. The definition also shows that for a constant dose D, the area under the curve varies inversely with the rate of elimination kp and with the volume of distribution V. Figure 39.6 illustrates schematically the different cases that can be obtained by varying the volume of distribution Vp and the rate of elimination k both on linear and semilogarithmic diagrams. These diagrams show that the slope (time course) of the curves are governed by the rate of elimination and that elevation (amplitude) of the curve is determined by the volume of distribution. 

The total fluid volume that must be filled into a unit parenteral container is typically greater than the volume that would contain the exact labeled dose. The fill volume is dependent on the viscosity of the solution and the retention of the solution by the container and stopper. The USP provides a procedure for calculating the fill dose that is necessary to ensure the delivery of the stated dose. It also provides a table of excess volumes that are usually sufficient to permit withdrawal and administration of the labeled volume. 

Distribution - Following a 1 mg parenteral dose, nalmefene was rapidly distributed. A 1 mg dose blocked more than 80% of brain opioid receptors within 5 minutes after administration. The apparent volumes of distribution centrally and at steady state are 3.9 and 8.6 L/kg, respectively. Over a concentration range of 0.1 to 2 mcg/mL, 45% is bound to plasma proteins. 

The use of cosolvents in small-volume parenteral preparations is often critical due to the limited volume of solution that can be administered by a single injection. Thus, the required dose of drug must often be incorporated in 1 or 2mL of solution. Table 6 lists parenteral products containing cosolvents. The cosolvents most often used include ethanol, propylene glycol, glycerin, PEG 400, and, sometimes, dimethylacetamide. Other cosolvents, such as DMSO, have been used as solvents for parenteral formulations of experimental anticancer agents however, their use is restricted due to toxicity and potential incompatibilities with plastic administration devices. ... 

Large Volume Parenterals A sterile single dose injectable product intended for administration through the skin with a nominal fill volume of more than 100ml. It may be packed in glass or suitable plastic material. 

B. Parenteral injection is an alternate route of administration, but is not likely to result in more rapid reversal of anticoagulant effects, and is associated with potentially serious side effects. If hemorrhage is present, use fresh frozen plasma for rapid replacement of coagulation factors. Subcutaneous administration is preferred over IM injection, although both can cause hematomas. The maximum volume is 5 mL or 50 mg per dose per injection site. The adult dose is 10-25 mg, and that tor children is 1-5 mg this may be repeated in 6-8 hours. Switch to oral therapy as soon as possible. Intravenous administration is rarely used because of the risk of anaphylactoid reaction. The usual dose is 10-25 mg (0.6 mg/kg in children under 12 years), depending on the severity of anticoagulation, diluted in preservative-free dextrose or sodium chloride solution. Give slowly at a rate not to exceed 1 mg/min or 5% of the total dose per minute, whichever is slower. 

The nurse who prepares parenterals prior to administration to a patient sometimes only needs a small part of an injection solution from an ampoule or has to take the appropriate amount from the ampoule for further dilution to achieve the appropriate dose. She will take out the desired volume from the ampoule with a syringe and probably use other syringes for further dilution (see also Sect. 29.1.7). 

An example of calculating the limits for endotoxins A morphine containing injection solution with the strength of 100 mg/5 mL has been prepared. Because the product will be administered parenterally a bacterial endotoxins test has to be performed. Therefore the administration route has to be known is this intravenous or intrathecal or epidural. For endotoxins in intravenous administration the requirement is maximally 5 EU/kg body weight during 1 h. Based on a body weight of 70 kg this means 350 EU/h. Secondly the maximal dose (in volume of the product per hour) will determine the actual limit. This depends on the need of the patient as well. If he needs the full 5 mL, this makes the requirement for the product to be 350 EU/5 mL = 70 EU/mL. 

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