Hydrogel nanoparticles(4)

faster than hydrogel distention,swelling is considered to be controlling for the release behavior[60,61].Finally,chemically-controlled release is determined by chemical reactions occurring within the gel matrix.These reactions include polymeric chain cleavage via hydrolytic or enzymatic degradation,or reversible/irreversible reactions occurring between the polymer network and the releasing drug.In addition to the above-mentioned release mechanisms,under certain circumstances,surface or bulk erosion of hydrogels or the binding equilibrium among the drug-binding moieties incorporated within the hydrogels,are two different mechanisms reported as controlling the rate of drug release.[53,55,62].

2.3.Controlled-release hydrogel systems

Controlled-release or controlled-delivery systems are intended to provide the drug or compound of interest at a speci?c predetermined temporal and/or spatial manner within the body to ful?ll the speci?c therapeutic needs.Hydrogels,among the different controlled-release systems exploited so far,have particular properties which make them to be potentially considered as one of the ideal future controlled-release systems.The hydrogel-based delivery systems are of two major categories:i)time-controlled systems and ii)stimuli-induced release systems[51,63].The latter,stimuli-induced release systems, are also referred to as‘stimuli-sensitive’,‘stimuli-responsive’,‘envir-onment-sensitive’,‘environment-responsive’,or‘responsive’hydrogel systems.Responsive hydrogel systems are developed to deliver their content(s)in response to a?uctuating condition in a way that desirably coincides with the physiological requirements at the right time and proper place[51].Despite the huge attraction centered towards the novel drug delivery systems based on the environment-sensitive hydrogels in the past and current times,these systems have disadvantages of their own.The most considerable drawback of stimuli-sensitive hydrogels is their signi?cantly slow response time, with the easiest way to achieve fast-acting responsiveness being to develop thinner and smaller hydrogels which,in turn,bring about fragility and loss of mechanical strength in the polymer network and the hydrogel device itself[64].

Dependent on changes in the nature of the external environment, responsive hydrogels undergo drastic alterations in their structure/ behavior[33,63,65].The environment(stimuli)-sensitive hydrogel systems which are also famous as‘intelligent’or‘smart’systems,can be further sub-classi?ed to:

i)Physically-induced release systems;

ii)Chemically-induced release systems;and

iii)Other stimuli-induced release systems.

Temperature,electricity,light,pressure,sound,and magnetic?eld are among the physical stimuli of interest in this context,while pH, solvent composition,ions,and speci?c molecular recognition events are chemical stimuli reported so far[63–65].Temperature-sensitive (thermoresponsive)hydrogels have gained considerable attention due to their ability for repeated swelling–deswelling conversion in response to the environmental temperature changes[66,67].A series of studies on application of these hydrogels in the pharmaceutical ?eld has shown promising results[68–76].On the other hand, chemical-responsive hydrogel systems propose several classes of hydrogels which can trigger drug release from a depot with respect to changes in the concentration of a speci?c molecule or bioactive compound in the surrounding media[63–65,77–84].Furthermore,the challenge of potential need for chronotherapy has currently resulted in the development of electrically assisted release technologies using hydrogels,as well[85–90].These technologies include iontophoresis, infusion pumps,and sonophoresis[85,190,191].pH-responsive hydro-gel systems are of great importance due to their unique pH dependant swelling–deswelling behavior[33,73,74,72,92–97].Several environ-mental stimuli are being exploited extensively in drug delivery researches.As typical examples,physical stimuli such as light[98], magnetic?eld[99],electric current[100,101],and ultrasound[102]as well as chemical stimuli such as ionic species[103,104]can be listed among others.Finally,a series of studies on development of novel infection-responsive drug release systems has been performed by Suzuki et al.[105–108].

2.4.Hydrogels for pharmaceutical applications

Hydrogels have been attempted extensively to achieve ideal drug delivery systems with desirable therapeutic features[109].The unique attractive physicochemical and biological characteristics of hydrogels, along with their huge diversity,collectively,have led to considerable attention to these polymeric materials as excellent candidates for delivery systems of therapeutic agents[19–21,110].Pharmaceutical hydrogels have been categorized according to a variety of criteria mainly including,rout of administration[111–115],type of material being delivered[22,51,53],release kinetics[23,63–65],etc.Therefore, a common classi?cation system for the therapeutic hydrogel formula-tions might not be found within the literature.Nonetheless,a classi?cation based on the route of administration of the hydrogel drug delivery systems,seems to include the vast area of these therapeutic materials.Accordingly,the pharmaceutical hydrogels can be classi?ed as:i)oral hydrogel systems[116–120],ii)transdermal and implantable hydrogel systems[35,121–124],iii)topical and transder-mal hydrogel systems[125–129],iv)hydrogel devices for gastro-intestinal(GI)drug delivery[130–136],and v)hydrogel-based ocular delivery systems[137–139].Furthermore,hydrogel-based formula-tions applied via other routs are also noteworthy.In this regard,novel approaches to improve bioavailability through nasal[140,141]and vaginal[142,143]routes using hydrogels have been presented.

Valuable articles reviewing different aspects of hydrogel polymeric materials,their classi?cations and applications are available in the literature[49–51,53,54,91,92,94,95,63–65].

3.Hydrogel nanoparticles(Nanogels?)

As a family of nanoscale particulate materials,hydrogel nanopar-ticles(NPs)(recently referred to as nanogels1)have been the point of convergence of considerable amount of efforts devoted to the study of these systems dealing with drug delivery approaches.Interestingly, hydrogel nanoparticulate materials would demonstrate the features and characteristics hydrogels and NPs separately posses,at the same time.Therefore,it seems that the pharmacy world will bene?t from both the hydrophilicity,?exibility,versatility,high water absorptivity, and biocompatibility of these particles and all the advantages of the NPs,mainly long life span in circulation and the possibility of being actively or passively targeted to the desired biophase,e.g.tumor sites. Different methods have been adopted to prepare NPs of hydrogel consistency.Besides the commonly used synthetic polymers,active research is focused on the preparation of NPs using naturally occurring hydrophilic polymers.The remainder of this text presents various types of nanogels prepared and characterized,using a classi?cation based on the type of polymeric materials used in preparation of the NPs.Although this review covers the literature up-to-date in the?eld signi?cantly,the reader is referred to the original literature in order to get more technical detail.

3.1.Chitosan-based hydrogel nanoparticles

Chitosan,α(1-4)-2-amino-2-deoxyβ-D-glucan,is a deacetylated form of chitin,an abundant polysaccharide present in crustacean shells.Even though the discovery of chitosan dates back from19th 1A registered trademark of Superateck Pharma Inc.(Montreal,Canada).

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M.Hamidi et al./Advanced Drug Delivery Reviews60(2008)1638–1649

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