Ii

Figure 2.4 Absorption of drugs from intramuscular injections

Formulation considerations

Since the formulation does not have to be miscible with water, it is possible to inject a much wider range of materials than those which can be administered intravenously. The possible formulations include aqueous solutions, aqueous suspensions, oily solutions, oil in water emulsions, water in oil emulsions, oily suspensions, and dispersions in polymer or solid implants. These are listed approximately in order of release rate, as aqueous solutions can be absorbed in minutes, while implants can deliver drugs for several months.

In addition a range of other factors can influence the absorption rate. If the drug is extremely hydrophobic it will not dissolve in the ICF, while if it is strongly ionized or extremely water soluble it will not be able to cross the capillary membrane. Drugs which are strongly protein-bound will also be slowly absorbed since their activity in solution will be reduced. A number of drugs administered in solutions may be absorbed anomalously slowly if the composition of the formulation changes after injection. For example, phenytoin is formulated as an injection at pH 12 due to its low solubility. On injection the ICF quickly reduces the pH to normal levels, and the drug precipitates. As a result it may then take several days for the dose to be fully absorbed.

SUBCUTANEOUS DELIVERY Physiology

A subcutaneous injection (SC) is made into the connective tissue beneath the dermis, and should be contrasted with an intradermal injection which is made into the dermal layer, often between the dermis and the epidermis (Figure 2.5). This is a critical distinction because the subcutaneous tissues have a significant volume of interstitial fluid into which the drug can diffuse, while the epidermal tissue has relatively little available fluid, nor is it well perfused by blood. As a result an intradermal injection persists at the site for a long period and the available volume for injection is small; it is normally used for antigens (e.g. tuberculin) and vaccines (smallpox).

Drugs injected subcutaneously dissolve in the interstitial fluid and gain entry to the bloodstream by two routes. They may be absorbed directly into blood vessels, but the subcutaneous tissues are often adipose and poorly perfused. Alternatively the interstitial

Figure 2.5. Physiology of parenteral administration routes

fluid is collected by lymphatic capillaries and these drain into the regional lymph nodes and then into the bloodstream. These pathways are both relatively slow and depend on the local vascularure, so absorption from subcutaneous sites can be slow and unpredictable. To some extent this allows a sustained release effect to be obtained; however it is not particularly satisfactory to design a dose form in this way because of the inherent variability of the pharmacokinetics. A better strategy is to make the release from the dose form rate-limiting (as is the case for intramuscular depot delivery systems) so that biological variation then has little influence on the drug pharmacokinetics. A large number of delivery systems have been devised which work in this way; probably the best known being Zoladex® (AstraZeneca) which releases the hormone goserelin, a chemical castrating agent used in the treatment of androgen-dependent tumours. The hormone is incorporated into a small rod of biodegradable poly (D, L lactide) polymer about 5mm long and implanted subcutaneously in the abdomen. A single injection lasts for 28 days; the cost (over £100 per injection at the time of writing) reflects the difficulty of manufacturing the device in a totally aseptic environment. Technology of this type is particularly suited to peptide hormones in which the dose is small and the size of the device can be minimized. A number of other interesting examples of this depot technique can be found in the literature, including the use of emulsion depots for methotrexate17, hydrogels18 and block copolymer gels19.

Subcutaneous colloidal delivery systems

It has already been indicated that materials injected subcutaneously may be carried by the lymphatic flow into the regional lymph nodes and then into the blood. Colloidal particles which are injected subcutaneously can follow the same route, although their large size (tens to hundreds of nanometres) relative to drug molecules will reduce their diffusion rate considerably. On reaching the lymph nodes they will be taken up by macrophages rather than passing to the bloodstream.

Most of the research in this area has been performed in rats, with the foot and footpad being the most closely studied injection sites. Ousseren and Storm20 used this technique to study the lymphatic uptake of liposomes from SC injection, and found relatively high lymphatic localization (60% of injected dose). However, injections into the flank produced only a slight uptake, and the suspicion is that footpad injections cause a large increase in local interstitial pressure due to the small volume of the site, and that this drives the injection into the lymphatic vessels. Consequently the targeting effect may not be so pronounced if the technique were used in man. The same study showed that the liposomes needed to be small (>0.2 pm) or they could not be moved from the injection site, and that highly charged liposomes were taken up more efficiently than weakly charged ones. Interestingly, liposomes made from the 'stealth phospholipid' with grafted PEG-chains were taken up to a similar extent to normal liposomes of the same size. Although this study was performed exclusively with liposomes there seems to be no reason why the results should not broadly apply to other colloidal particles.

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