5 DRUG DELIVERY THROUGH THERMODYNAMICALLY STABLE
5.5 Gels
The use of gels in pharmaceutics depends to some extent of the structure of the particular gel being considered.
The term "gel" is frequently used in pharmaceutical research and development to describe "thick" or "non-flowing" systems. This means that different systems may have drastically different compositions, even consisting of entirely different kinds of sub-units, therefore hav-ing widely different structures. (In fact, some gels of interest to pharmaceutical applications are two-phase systems, and therefore not even thermodynamically sta-ble.) More often than not, however, the gels used in pharmaceutical applications contain water-soluble poly-mers. While some are suitable for molecular solubiliza-tion of sparingly soluble drugs due to the presence of hydrophobic domains, others are not capable of this due to the absence of such domains. However, although the solubilization capacity may be an important aspect in a particular drug delivery system, it is generally other aspects, e.g. the rheological properties or their conse-quences (e.g. relating to the drug release rate, bioad-hesion, etc.), which make these systems particularly interesting from a drug delivery point of view, and there-fore these systems are discussed together here.
One type of "gel" which has been extensively inves-tigated in relation to pharmaceutical applications is that formed by certain PEO-PPO-PEO block copolymers (153). These systems are particularly interesting since even a concentrated polymer solution is quite low-viscous in nature at low temperature, whereas a very abrupt "gelation" (liquid crystal formation (25, 187, 188)) occurs on increasing the temperature. The precise value of the transition temperature depends on the poly-mer molecular weight, composition and concentration, the concentration and nature of the drug, etc., but by
combining these aspects, the gelation temperature can be straightforwardly controlled.
Such systems have the capacity to solubilize par-ticularly hydrophilic or moderately hydrophobic drugs.
Apart from this, however, they are also interesting from the point of view of drug delivery, e.g. since they can be easily administered at low temperatures through their low viscosities, whereas they gel rapidly at the admin-istration site. One area where this is of obvious impor-tance is in topical, dermal and buccal administration.
As an example of this, Scherlund et al. investigated the gels formed by two PEO-PPO-PEO block copolymers (Lutrol F68 and Lutrol Fl 27) and the local anaesthetic agents, lidocaine and prilocaine. By a suitable choice of composition, the low viscosity of a refrigerator-chilled or room-temperature formulation can be combined with gelation at the administration site, bioadhesion in the oral cavity, and a suitable release rate of the active ingre-dients, with the latter being an important aspect of these types of formulation (Figure 1.14) (28).
One reason for the use of gel-based drug delivery formulations is that they allow sustained and controlled release. As expected for PEO-PPO-PEO-based gels, the drug release rate depends on the drug hydropho-bicity. More precisely, the drug release rate has been found to decrease with increasing drug hydrophobic-ity for these types of formulations (see Figure 1.9).
For example, Wang and Johnston investigated the sus-tained release of interleukin-2 (IL-2) after intramuscular injection in rats (189). This substance has been found promising in the treatment of several cancers in both experimental animal models and in humans, in which the toxicity of IL-2 is a major problem. However, the
antitumour effect of IL-2 has been found to correlate with the time that this substance remains in the serum, rather than with the peak serum concentration, and there-fore a sustained-release formulation could be expected to improve the therapeutic efficiency and reduce toxic side-effects. Therefore, the reduced peak serum IL-2 con-centration and the longer circulation of IL-2 observed after intramuscular administration for a gel formulation (Pluronic F127), when compared to the aqueous IL-2 solution, is promising for IL-2 intramuscular therapy.
Apart from effectively increasing the solubility of hydrophobic drugs and achieving a controlled release of the drug after administration, block copolymer gels may be used to improve the chemical stability of the active substance (cf. micellar and cyclodextrin solubilization (see Figure 1.10)). For example, Tomida etai investigated PEO-PPO-PEO block copolymer gels containing indomethacin regarding their suitability as topical drug delivery systems, and found that the hydrolysis rate of indomethacin was reduced in the gels when compared to the aqueous solution (190).
This protective property make these gels interesting, e.g.
for oral administration of substances sensitive to acid-catalysed hydrolysis.
Another application where PEO-PPO-PEO block copolymer gels have shown promise is as wound dress-ings in the treatment of thermal burns. Such dressdress-ings should be easy to apply, and should adhere to the uninjured skin surrounding the wound, but also come off easily when removed. Furthermore, the adherence should be uniform since small areas of non-adherence may lead to fluid-filled pockets where bacteria could proliferate. Moreover, dressings should absorb fluid and
Figure 1.14. (a) Elastic modulus (G') of formulations containing 14.5 wt% Lutrol F127, 5 wt% Lutrol F68 and 5 wt% of a 50/50 mixture of lidocaine and prilocaine. (b) The effect of the concentration of the active ingredients on the gelation temperature of a formulation containing 15.5 wt% Lutrol F127 and 4 wt% Lutrol F68 at pH 5 (squares), pH 7 (diamonds), pH 8 (circles), and pH 10 (triangles). The pATa of lidocaine (lido) and prilocaine (prilo) are 7.86 and 7.89, respectively (267) (data from ref. (28))
T(0C) ^lido+prilc/^tot
W
C>
G'(Pa )
maintain a high humidity at the wound, and should also provide a bacterial barrier, either on their own or by the inclusion of antibacterial agents, the release of which should preferably be sustained. Although it is dif-ficult to meet all of these requirements, PEO-PPO-PEO block copolymer gels have been found useful for such wound dressings. For example, Nalbandian et al. found that Pluronic F127 is an efficient formulation for bac-teriocidal silver nitrate and silver lactate following full-thickness thermal burns in rats (191). No inhibition of skin growth and repair was noted and the dressings were equally efficient against Pseudomonas aeruginosa and Proteus mirabilis. The dressings also showed promise regarding electrolyte imbalances, heat loss and bacterial invasion.
While the "gels" formed by the PEO-PPO-PEO block copolymers are generally liquid crystalline phases (187, 188), those formed by polysaccharides occur as a consequence of network formation, frequently involving coil-helix transitions, and in at least some cases, helix aggregation (192-195). For example, pectin and galac-tomannan are of interest, e.g. for specific targeting of the drug to the large intestine, due to their enzymatic degra-dation in the colon (see below) (196, and refs therein).
Furthermore, in situ-forming polysaccharide gels are interesting for sustained drug release in the stomach (197, and refs therein). A relatively frequently inves-tigated type of polysaccharide gels are those formed by alginates or gellan gum in the presence of calcium ions. Irrespective of the nature of these types of gels, however, they lack substantial hydrophobic domains.
As such, they can only solubilize either fully soluble (hydrophilic) drugs, or dispersed drug (-containing) col-loids. Nevertheless, a considerable drug loading can be reach by utilizing poor solvency conditions for the drug.
For example, Kedzierewicz et al. were able to achieve very high drug loading capacities of propranolol in gel-lan gum microgel particles by increasing the pH prior to particle formation to above the pKa of propanolol (198).
Yet another class of gels of some interest in drug delivery is that formed by polymer-surfactant mixed aggregates. Thus, on mixing polymers and surfactants, there is frequently surfactant binding to the polymer backbone, as well as polymer-induced surfactant self-assembly (199, 200). Although the polymer-surfactant aggregates so formed may have different structures, frequently they are described with the so-called bead-necklace structure, in which surfactant micelles are
"bound" along the polymer chains. Considering this, it is not surprising that the surfactant micelles may act as transient cross-links, and that an effective "gelation"
can result under at least certain specific conditions (137-139, 199-203).
Polymer systems which have been found to be particularly interesting in this context are cellulose ethers and hydrophobe-modified cellulose ethers. In the presence of ionic surfactants, some cellulose ethers, e.g. ethyl(hydroxyethyl)cellulose (EHEC), display a reversible temperature-induced gelation on heating (137-139, 202, 203). Thus, while such polymer systems are relatively low-viscous in nature at low temperatures, they form loose gels at elevated temperatures. As an example of this, Figure 1.15 shows the temperature-induced gelation of a local anaesthetic formulation, intended for the periodontal pocket, consisting of lidocaine/prilocaine, EHEC and myristoylcholine bromide, the latter being a readily biodegradable and antibacterial cationic surfactant.
In a couple of investigations, Lindell and Engstrom studied the in situ gelation of EHEC/surfactant systems in the presence of timolol maleate and timolol chloride, where the former is a potent ^-blocker (202, 203). It was found that timolol maleate could be incorporated in the thermogelling EHEC system at a concentration rele-vant to commercial eye drops, thus indicating a potential use of these systems in ocular drug delivery. Further-more, by comparison of formulations containing timolol maleate and timolol chloride, as well as those with dif-ferent surfactants, it was inferred that for a gel to form at a low concentration of ionic surfactant, (i) the ionic drug should typically be a co-ion to the surfactant, (ii) the counterion of the drug and the surfactant should be inorganic and have a low polarizability, and (iii) the sur-factant should have a low CMC, but a Krafft temperature not higher than ambient.
Figure 1.15. Elastic modulus (G') of formulations containing EHEC (1 wt%) and myristoylcholine bromide (3 mM) in the presence (circles) and absence (squares) of 0.5 wt% prilo-caine/lidocaine (50/50), at pH 9.8 (data from ref.(139))
G'(Pa)
T(0C)