DRUG ABSORPTION FROM DRUG CARRIER SYSTEMS

3. DRUG ABSORPTION FROM DRUG CARRIER SYSTEMS

Drugs that are rapidly eliminated from the blood yield quickly declining blood drug levels and result in a short duration of

50 Oussoren et al. Table 2 Testosterondecanoate Fat =Phosphate Buffer Partition

and Absorption Rate Expressed as Half-Life in the Muscle Solvent

t 1 =2 in the muscle (h) Ethyloleate

Part coeff.

6.3 10.3 Octanol

5.3 9.7 Isopropylmyristate

4.3 7.8 Light liquid paraffin

1.3 3.2 Source: From Ref. 18.

therapeutic response. For a number of drugs, it is desirable to maintain the concentration of the drug in blood within the therapeutic range for a long period of time and avoid toxic levels. In these cases, the use of drug delivery systems that provide slow release of the drug over an extended period of time is useful. Several drug carrier systems, e.g., liposomes and microspheres, are currently being developed as sustained systems following s.c. or i.m. administration (19).

Absorption of drugs encapsulated in carrier systems after s.c. and i.m. administration is more complicated than absorption from conventional formulations. Not only absorp- tion of the free drug but also absorption of the carrier and release of the drug from the carrier are important issues to

be considered. After release, the drug will behave similarly to drug administered in conventional formulations and gen- eral biopharmaceutical principles will be applicable. How- ever, if the drug is not released from the carrier, and the carrier is absorbed from the injection site as an intact entity, the drug will follow the kinetics and biodistribution of the carrier, which is generally very different from the kinetics of the free drug. Moreover, slow release of drug from the circulating carrier will also affect drug concentration in the blood circulation.

This section will deal with the absorption of s.c. and i.m. administered drug carriers. First absorption of the carrier as an intact entity from the local site of injection will be discussed. Then attention will be paid to release mechanisms of drugs from several carriers at the local injection site.

Injectable Dispersed Systems 51

3.1. Absorption of Drug Carrier Systems Following local administration, large molecules and particu-

late matter do not have direct access to the bloodstream as the permeability of blood capillaries in the interstitium is restricted to water and small molecules. Instead, large mole- cules and particulate matter may be taken up by lymphatic capillaries (16). Figure 5 presents a schematic illustration of drug absorption following s.c. injection of liposome-encapsu- lated drugs. Similar mechanisms hold for the i.m. route of administration. Lymphatic absorption is described for several carrier systems. Here absorption of liposomes will be discussed as a model for other drug carriers. Generally, simi- lar phenomena occur for the other carrier systems.

Figure 5 Schematic representation of drug release and absorp- tion of injectable dispersed systems from the site of injection after s.c. or i.m. injection. Small molecules can enter the blood circulation either by entering blood capillaries or via lymphatic capillaries, whereas larger molecules and drug encapsulated in small particles can enter the blood circulation only via lymphatic capillaries. (From Ref. 19.)

52 Oussoren et al.

Absorption of particles from the injection site after local parenteral administration depends mainly on one important carrier-related factor, particle size. For liposomes, several reports refer to a cut-off value of 0.1 mm, above which lipo- somes fail to appear in the blood to any substantial extent. Larger liposomes will remain at the s.c. injection site for a long period of time (20–23). This size-dependent retention at the injection site is likely to be related to the process of particle transport through the interstitium. The structural organization of the interstitium dictates that larger particles will have more difficulty to pass through the interstitium and will remain at the site of injection to a large, almost complete extent. Gradual release of the encapsulated drug from liposomes remaining at the injection site results in very low but prolonged drug levels in the blood. Therapeutic drug levels have been reported to last for several days (24–27). When smaller liposomes are administered, they will migrate through the aqueous channels in the interstitium and will be taken up by the lymphatic capillaries. Small liposomes that have been taken up by the lymphatic capillaries reach the general circulation where they behave as if administered by the i.v. route (23). Obviously, if sustained drug release is intended, larger particles that remain at the site of injec- tion are preferred. Other liposome-related factors such as liposome charge, liposome composition, and surface modifica- tion appear to be of less importance for liposome absorption (23,28).

3.2. Drug Release from Carrier Systems Drugs encapsulated in carrier systems that remain at the site

of injection will be gradually released from the carrier. Drug release rates are determined by both the carrier and the drug characteristics.

The release mechanism of drugs from microspheres is dependent on the polymer and formulation technique used. From polyester microspheres, the drug is generally released by diffusion through aqueous channels or pores in the poly- mer matrix and by diffusion across the polymer barrier

Injectable Dispersed Systems 53

following erosion of the polymer. Surface erosion or bulk ero- sion occurs parallel with the hydrolytic degradation of the polymer, which influences the release pattern and stability of incorporated drugs after injection. Anderson and Shive summarized the factors affecting the hydrolytic degradation behavior of biodegradable polyesters and described their bio- compatibility (29). These factors are shown in Table 3.

Hydrogel particles are considered to be interesting systems for peptide and protein delivery because of their good tissue compatibility and possibilities to manipulate the permeability for solutes. The release rate is dependent on the molecular size of the drug, the degree of cross-linking of the gel, and the water content (30).

Liposomes and microspheres often show a burst effect combined with sustained release. Several mechanisms of drug release from liposomes following local administration have been suggested. Liposomes remaining at the site of injection might gradually erode and eventually disintegrate completely (e.g., as a result of attack by enzymes, destruc- tion by neutrophils). During this process, the entrapped drug is released. After release, free drug enters the blood circulation by either direct absorption into the blood capillaries or via lymphatic capillaries. As release of the

Table 3 Factors Influencing Hydrolytic Behavior of Biodegradable Polyesters a

Water permeability and solubility (hydrophilicity =hydrophobicity) Chemical composition Mechanism of hydrolysis (noncatalytic, autocatalytic, enzymatic) Additives (acidic, basic, monomers, solvents, drugs) Morphology (crystalline, amorphous) Device dimensions (size, shape, surface-to-volume ratio) Porosity Glass transition temperature (glassy, rubbery) Molecular weight and molecular weight distribution Physico-chemical factors (ion exchange, ionic strength, pH) Sterilization Site of implantation

a From Ref. 29.

54 Oussoren et al.

encapsulated drug may occur during an extended period of time, concentrations in the blood will be prolonged. The rate and duration of release from liposomes depends on plasma factors and liposome stability. Serum proteins, enzymes, phagocytosing cells, shear stress, and liposome aggregation at the injection site play a role in the destabilization or degradation of liposomes at the injection site and subsequent leakage of liposomal contents (31–37).

Stable liposomes composed of saturated lipids are known to release their content slower than liposomes with higher membrane fluidity. Schreier et al. reported the same relation between liposome stability and drug release after i.m. admin- istration of liposomes (38). The rate of release of encapsulated drug as well as the erosion of liposomes at the injection site were found to be a function of the fluidity of the lipid mem- branes. The release rate of gentamicin from egg phosphatidyl- choline liposomes was about seven times slower than from soy phosphatidylcholine liposomes with more fluid (unsaturated) bilayers when injected i.m. In line with these observations, Koppenhagen reported that after intratumoral injection of

111 Indium-labeled desferal encapsulated in ‘‘solid’’ liposomes, the amount of label remaining at the injection site was about

10-fold higher than when encapsulated in ‘‘fluid’’ liposomes, 6 days post-injection (39). From these observations, it may be concluded that drug absorption rates may be controlled (within certain limits) by using lipids with different degrees of bilayer fluidity.

Other liposome-related factors seem to be of less impor- tance for drug release from the injection site. Several papers studied retention of differently charged liposomes at the injec- tion site after i.m. injection. Results suggest that release from negatively charged liposomes at the i.m. injection site is somewhat less than the release of neutral and positively charged liposomes (27,40,41). Recently, the influence of liposome charge on the fate of methotrexate encapsulated in neutral, positively, and negatively charged liposomes was studied after i.m. injection (42,43). Plasma concentrations of methotrexate were not substantially influenced by liposome charge.

Injectable Dispersed Systems 55