Vehicles intramuscular administration

Ethyl oleate is primarily used as a vehicle in certain parenteral preparations intended for intramuscular administration. It has also been used as a solvent for drugs formulated as biodegradable capsules for subdermal implantation and in the preparation of microemulsions containing cyclosporin. ... 

One somewhat different, but critical, parameter in animal health sterile products compared with human health care products is the irritation and residue at the injection site. For companion animals, the pain upon injection should be minimal, and any lasting reactions that cause either pain or visual lumps to a pet will not be tolerated by many owners. For food-producing animals such as cattle, pigs, and poultry, the added challenge is that of ensuring the residue levels at the injection site have been depleted adequately by the time the animal is harvested. The formulation scientist thus may need to carefully observe the viscosity and polarity of the vehicle as they can affect residue times. Volumes injected and the route can also have an impact. Oftentimes subcutaneous administration is used instead of intramuscular administration to minimize residues in the tissue and potential damage to meat (i.e., muscle). 

The most important requirement is that the salt possesses sufficient solubility at physiologically compatible pH values to permit incorporation into the dosage form. Buffering the solution to an appropriate pH can often enhance solubility. Salts may also be prepared in situ in the formulation. This is particularly useful when the main route of administration utilizes the parent drug form. Where the aqueous solubility of the salt is not sufficiently high, co-solvents may need to be added to enhance solubility (e.g. propylene glycol is used as the vehicle in phe-nobarbitone sodium injection). Parenteral solutions based on co-solvent vehicles normally cannot be directly injected intravenously because there is the risk of precipitation at the injection site. Therefore, such products are diluted with isotonic saline or 5%w/v dextrose solution to produce a lower concentration that remains soluble and can be safely administered by infusion. Alternative delivery routes are by subcutaneous or intramuscular administration by which, in... 

Poorly soluble drugs for intramuscular administration can be formulated in a non-aqueous vehicle this can have the additional benefit of providing a slow release of the active moiety. Oily vehicles have been used historically the most commonly encountered is sesame oil, and... 

Figure 7.37 Plasma diazepam levels following intramuscular administration of diazepam O in propylene glycol vehicle x in a Cremophor EL vehicle compared with intravenous administration of the propylene glycol preparation. From Kan to [171] with permission.

Dimercaprol (BAL, British Anti-Lewisite) was developed in World War 11 as an antidote against vesicant organic arsenicals (B). It is able to chelate various metal ions. Dimercaprol forms a liquid, rapidly decomposing substance that is given intramuscularly in an oily vehicle. A related compound, both in terms of structure and activity, is di-mercaptopropanesulfonic acid, whose sodium salt is suitable for oral administration. Shivering, fever, and skin reactions are potential adverse effects. 

Intravenous aqueous injections provide an excellent means of achieving a rapid therapeutic response. Parenteral product design, e.g., vehicle and other excipient selection, as well as choice of route of administration, can prolong therapeutic activity and increase onset times, Thus, oily solutions, suspensions, or emulsions can be administered by subcutaneous or intramuscular routes to create prolonged effect, i.e., depot injection. 

Several types of CDD systems have been designed based on various mechanisms of drug release (Table I). These mechanisms are dependent on the required site of drug delivery, the physicochemical properties of the drug and also of the delivery vehicle (13), Modes of administration can be oral, sublingual, transdermal, rectal, intrauterine, ocular, or parenteral (intramuscular, peritoneal, and subcutaneous routes of injection). 

Following intramuscular (IM) administration, drugs must cross one or more biological membranes in order to enter the systemic circulation. Intramuscular injection is used mainly for drugs and vaccines that are not absorbed orally, for example, aminoglycosides, insulin, and hepatitis vaccine. The IM route is often used for sustained medication and specialized vehicles, such as aqueous suspensions, oily vehicles, complexes and microencapsulation, which has been developed for slow delivery of drugs by this route. ... 

The U.S. Pharmacopoeia (USP) classifies injections into five different types. The dosage form selected for a particular drug product is dependent upon the characteristics of the drug molecule (e.g., stability in solution, solubility, and injectability), the desired therapeutic effect of the product (e.g., immediate vs. sustained release), and the desired route of administration. Solutions and some emulsions (e.g., miscible with blood) can be injected via most parenteral routes of administration. Suspensions and solutions that are not miscible with blood (e.g., injections employing oleaginous vehicles) can be administered via intramuscular or subcutaneous injection but should not be given intravenously. 

The solids content of parenteral suspensions is usually between 0.5 and 5.0%, except for insoluble forms of penicillin, in which concentrations of the antibiotic may exceed 30%. These sterile preparations are designed for intramuscular, intradermal, intra-lesional, intra-articular, or subcutaneous administration. The viscosity of a parenteral suspension should be low enough to facilitate injection. Common vehicles for parenteral suspensions include preserved 0.9% saline... 

The solubility of a drug and the compatibility of a particular solvent with the site of injection are interrelated factors governing the suitability of this route of administration and the pharmaceutical formulation that is employed. The route of administration may also be governed by tolerability aspects associated with the formulation. If a drug cannot be dissolved in a concentrated manner in a suitable vehicle, then often dose size must increase. For example, intravenous injections of penicillin-type antibiotics are much more comfortable than when the same dose is administered intramuscularly. 

Ideally, the kinetics of the prodrug and the active moiety should be studied in the same patients or healthy volunteers. It is not possible to provide generally valid guidelines for study design because, as described in the previous sections, many factors may influence the analysis of the data, and consequently the way in which data must be collected. For example, it is certainly very different to study a prodrug such as bacampicillin with a very fast release of ampicillin after oral administration, or the decanoic ester of haloperidol given intramuscularly as a depot preparation in an oily vehicle. 

For the intramuscular and subcutaneous routes, the use of non-aqueous vehicles may be considered as a method of avoiding hydrolysis. For IV administration, the use of an oil-in-water emulsion is a possible, although little used, option. These approaches are discussed in the section Strategies for Formulating Poorly Soluble Drugs . 

Phenytoin may be administered either orally or intravenously and is absorbed slowly after oral administration, with peak plasma levels achieved after 3 to 12 hours. It is extensively plasma protein bound ( 90%), and the elimination half-life is between 15 and 30 hours. These large ranges reflect the considerable variability observed from patient to patient. Parenteral administration of phenytoin is usually limited to the intravenous route. Phenytoin for injection is dissolved in a highly alkaline vehicle (pFI 12). This alkaline vehicle is required because phenytoin is weakly acidic and has very poor solubility in its un-ionized form. Reportedly, however, its phosphate ester fosphenytoin has water solubility advantages over phenytoin for injection. Intramuscular phenytoin generally is avoided, because it results in tissue necrosis at the site of injection and erratic absorption because of high alkalinity. In addition, intermittent intravenous infusion is required to reduce the incidence of severe phlebitis. 

Unlike the much-shorter-acting scopolamine, BZ s effectiveness by the oral route of administration is about 80% that of the intravenous or intramuscular routes (which are virtually identical). By inhalation, if disseminated at an optimal particle size (diameter about 1.0 pm), BZ is approximately 40% to 50% as effective as it is by injection. When applied to the skin dissolved in propylene glycol (a common vehicle for transdermal administration), apparent absorption is only 5% to 10% and the effects are delayed approximately 24 hours. (This is surprising since historical treatises suggest that belladonna drugs are readily absorbed from poultices.31)... 

Gene delivery constitutes an interesting approach to treat diseased striated muscles. Administration of pDNA coding for the dystrophin protein has been extensively studied in animal models of Duchenne or Becker muscular dystrophy and even evaluated in Phase 1 clinical trials. Although most of the cationic vehicles appeared to be relatively inefficient in promoting transgenic expression in the muscle tissue, D-SPM polycations were reported to show a transient increase in reporter gene expression after direct intramuscular injection in skeletal muscles with maximum efficiency. 

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