It would be most desirable for drug release to match a patient’s physiological needs at the proper time and/or the proper site. This is why there is a great interest in the development of controlled delivery systems [81]. In particular, the application of polymeric systems provides, in a great number of selected cases, a clear optimization in the dosage methods to get the desired therapeutic result in the required target, as well as the optimization of the control drug release in order to obtain the maximum result and the minimum adverse effects. The release of a drug incorporated in a polymeric system takes place by migration of the solute to the medium that surrounds the system by molecular diffusion through the support or by diffusion through micropores of the polymeric matrix.
This makes the solute solubility in the polymer an important factor in the control of its migration. Drug diffusion from monolithic systems can be analyzed using Fick's Second Law of Diffusion [82].
Diffusion-controlled polymeric matrix devices have been among the most widely used drug delivery systems, mainly due to their low manufacturing cost. However, in conventional matrix devices, where the drug to be released is dispersed or dissolved uniformly through the polymer, the diffusional distance increases with time (as drug is released), and hence, the release rate decreases. To circumvent this disadvantage of first-order diffusion behavior, various approaches have been developed to achieve constant release rates in polymeric matrix devices, including variations in geometry [83], development of surface eroding polymers [84], and design of devices combining several release mechanisms [85]. Swelling-controlled release systems [86] are capable of delivering
delivery is controlled by the balance between drug (solute) diffusion across a concentration gradient, the polymer relaxation occurring as the cross-linked polymer imbibes water, and the osmotic pressure occurring during the swelling process [87]. Swelling-controlled release systems are based on the principles, where a polymeric carrier can counterbalance normal Fickian diffusion by hindering the release of an imbedded solute or drug, leading to an extended period of drug delivery under zero-order release conditions, Case II transport [88].
Swelling and relaxational behavior of p(HEMA-co-MMA)) polymers were observed by Davidson and Peppas [89] who determined polymer relaxation times by mechanical stress relaxation experiments and used them to calculate the diffusional Deborah number (De), a dimensionless parameter relating solvent uptake to macromolecular relaxation. Franson and Peppas [90] observed the swelling front motion using polarized light to view stressed regions in p(HEMA-co-MMA) and related gels when exposed to water. They noted the importance of gel history on the swelling behavior. After a dry sample was swollen to equilibrium, some macromolecular chains could be disentangled to yield a different structure and different swelling kinetics upon subsequent swelling processes. In addition, Water and solute or drug transport in p(HEMA-co-MMA) was investigated to determine the effects of polymer morphology, composition and solute properties on transport behavior [91]. Anseth et al. [92] developed a novel approach to immobilize nonuniform initial drug concentration profiles in multilaminated matrix devices utilizing photopolymerization techniques. Solution polymerization of HEMA and diethylene glycol dimethacrylate (DEGDMA) in the presence of a model compound, acid orange 8 (AO8), was conducted using UV light and photoinitiators to construct a laminated matrix device. The results indicate that a zero-order release pattern can be approximated by employing a suitable nonuniform initial drug concentration profile. Penetrant uptake behavior into crosslinked polymers has been investigated over the past several decades, with notable contributions made to the understanding of deviations from classical Fickian diffusion [93, 94]. This
general behavior, known as anomalous transport, is bound by pure Fickian diffusion and Case II transport which have been observed in several polymer/penetrant systems [95].
Another powerful approach for controlling drug delivery is to incorporate the drug into biodegradable polymeric matrix, which can achieve a controlled and sustained fashion through the drug diffusion or/and the polymeric carrier degradation. Sustained drug release from a degrading hydrogel is obtained when the initial mesh size of the network is smaller than the size of the drug molecules, since the latter cannot leave the gel before the network has been degraded [96]. Currently, there is a major interest in pulsed drug delivery in which the pharmaceutical device releases the drug at a preprogrammed time [97]. Pulsed drug release can be achieved by creating a rigid, semipermeable membrane around the degradable gel particle. During degradation the gel gradually liquefies, and the swelling pressure Πsw increases. When Πsw exceeds the tensile strength of the membrane, it ruptures [98], followed by a sudden release of the drug. Demeester et al. [99] had demonstrated that the chemical composition of the network (dex-HEMA content and the number of HEMA groups on the dextran chains) strongly affects the degradation rate of dex-HEMA hydrogels.
These observations are important to design degrading hydrogel systems with tailored swelling pressure profile for pulsed drug delivery.
Drug delivery technology can be brought to the next level by the fabrication of smart materials into a single assembled device that is responsive to the individual patient’s therapeutic requirements and able to deliver a certain amount of drug in response to a biological state. Such smart therapeutics should possess one or more properties such as proper drug protection, local targeting, precisely controlled release, self-regulated therapeutic action, permeation enhancing, enzyme inhibiting, imaging, and reporting. This is clearly a highly challenging task and it is difficult to add all of these functionalities in a single device. Hence, Lee et al. [100] attemped to develop an intelligent system for drug
hydrogels. In the study, a pH-sensitive hydrogel together with a pHEMA barrier was used as a gate to control drug release. In addition, pHEMA coated with poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO–PPO–PEO) surfactant was utilized to enhance mucoadhesion on the device surface. Herein, the pHEMA layer not only affects the folding direction but also serves as a barrier to protect the model drugs. In addition, Roma´n et al. [101] designed one kind of “polymeric drugs” based on copolymers of HEMA, and five methacrylic derivatives which incorporate ibuprofen or ketoprofen in their chemical structure by means of labile ester bonds. The use of polymeric systems with pharmacological activity provides very good local activities reducing the toxicological risks, and in addition could act as release systems of the pharmacological active residue, controlled by chemical reactions, mainly hydrolytic processes under enzymatic catalysis [102].
Recently, much attention has been focused on delivery systems which can deliver drugs on demand in response to an external signal. In these systems, release could be pulsatile, periodic or in direct response to some signal generated by the disease state itself.
Intelligent materials have been a focus for therapeutic and diagnostic uses [103]. The concept of intelligent drug-delivery systems for clinical therapy could be considered by combining the homeostasis theory and chronopharmacology of drugs [104]. Therefore, intelligent drug-delivery systems not only act as a rate-controlling system for drug release but also deliver the drug when it is required, i.e. they are time-controlled [105]. The use of thermoresponsive hydrogels has received much attention in recent years. Ansari et al. [106]
reported the use of thermotropic liquid crystals (LCs) embedded in pHEMA membranes as a temperature-controlled drug release system. The use of thermoresponsive liquid-crystal-embedded membranes has also been studied before [107]. However, the use of thermotropic liquid crystals as thermoresponsive drug-delivery systems is rare.
Temperature-related properties of thermotropic liquid crystals are both sharp and positive,
i.e. they can control drug release in response to minute temperature changes.