Controlled release of therapeutics using interpenetrating polymeric networks

1. Introduction

2. Classification of IPNs

3. Specialty properties of IPNs

4. IPN and semi-IPN systems

5. CR formulations of

therapeutics

6. Conclusion and perspectives

7. Expert opinion

Review

Controlled release of therapeuticsusing interpenetrating polymericnetworksTejraj M Aminabhavi†, Mallikarjuna N Nadagouda, Uttam A More,Shrinivas D Joshi, Venkatrao H Kulkarni, Malleshappa N Noolvi &Padmakar V Kulkarni†Soniya College of Pharmacy, Department of Pharmaceutical Engineering and Chemistry, Dharwad,

India

Introduction: The ever-increasing developments in pharmaceutical formula-

tions have led to the widespread use of biodegradable polymers in various

forms and configurations. In particular, interpenetrating network (IPN) and

semi-IPN polymer structures that are capable of releasing drugs in a controlled

manner have gained much wider importance in recent years.

Areas covered: Recently, IPNs and semi-IPNs have emerged as innovative

materials of choice in controlled release (CR) of drugs as the release from

these systems depends on pH of the media and temperature in addition to

the nature of the system. These networks can be prepared as smart hydrogels

following chemical or physical crosslinking methods to show remarkable drug

release patterns compared to single polymer systems.

Expert opinion: A large number of IPNs and semi-IPNs have been reported in

the literature. The present review is focused on the preparation methods and

their CR properties with reference to anticancer, anti-asthmatic, antibiotic,

anti-inflammatory, anti-tuberculosis and antihypertensive drugs, as majority

of these drugs have been reported to be the ideal choices for using IPNs

and semi-IPNs.

Keywords: controlled release, hydrogels, interpenetrating networks, microspheres, semi-

interpenetrating networks

Expert Opin. Drug Deliv. [Early Online]

1. Introduction

In the area of drug delivery, polymers have been widely used as valuable excipientsin making tablet- and capsule-based formulations [1]. In recent years, to overcomethe poor biological performance and to improve the mechanical strength properties,a new family of polymers called interpenetrating polymer networks (IPNs) havebeen introduced that are prepared from the blending of either natural or syntheticpolymers alone or in combination. IPNs are, thus, a blend of two or more polymersin a network with at least one of the systems synthesized in the presenceof another [2]. Each individual network retains its properties such that any synergis-tic improvements in properties like strength, morphology or toughness can begenerated [3].

An IPN can be distinguished from the regular polymeric blends in a way that theIPN swells, but does not dissolve in solvents and offers improved properties,depending on the composition and degree of crosslinking [4]. In this manner,IPNs are quite different from those of the graft copolymers and other polymer com-plexes that involve either chemical bonds and/or low degree of crosslinking [5].These fascinating network structures were first reported by Aylsworth in 1914 [6],and later termed as IPNs in 1960 by Miller [7]. However, it was not until the late

10.1517/17425247.2014.974871 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 1All rights reserved: reproduction in whole or in part not permitted

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http://informahealthcare.com/journal/EDD

1950s and early 1960s that researchers began to develop inter-est in these complex structures in drug delivery area. IPNspossess a variety of shapes and sizes, depending on the natureof polymerization, type of polymer(s) and synthetic strategies.The chemistry of formation of these structures, their charac-terization and applications in other scientific disciplines hasbeen discussed elsewhere [8-10]. Such biocompatible, nontoxicand biodegradable networks have now acquired a uniqueplace in controlled release (CR) and targeted drug deliveryareas [11].Due to their advantageous physicochemical properties

compared to the conventional polymers, research efforts onIPN and semi-IPN polymer networks have progressed rapidlyin CR area [8,12]. In recent years, researchers have shown muchinterest in these systems to develop formulations in the formof tablets, microparticles, nanoparticles, hydrogels and soon [9]. One of the outstanding achievements of IPN hydrogelsin drug delivery is the development of stimuli-responsivedelivery systems. Such stimuli can be either internal signals(as a result of changes in physiological condition of a livingsubject) or external signals (artificially induced). This sensitivebehavior of hydrogels has sparked interest in their use as drugdelivery vehicles to control the release of a drug. The pH-sensitive IPN hydrogels could be used to target the drug in adesired region. In general, when a hydrophilic polymer isinterpenetrated into a relatively hydrophobic polymer core,the resulting IPN hydrogel exhibits improved capability ofimmobilizing a drug and this has opened up new avenuesfor designing novel CR systems for a variety of drugs [13,14].Particularly, by combining natural polymers with syntheticones through grafting or copolymerization, the range of theirproperties can be broadened. Because of these features anddiversity, IPN and semi-IPN hydrogels have created much

interest in developing CR systems compared to ordinaryhydrogels.

Even though much has been published on the chemistry ofIPN systems, their use as drug delivery systems has not beenwidely published with particular class of drugs considered inthis review. The present review covers available data from2000 hitherto on the IPN and semi-IPN-based formulationsin the CR of anticancer, anti-asthmatic, antibiotic, anti-inflammatory, anti-tuberculosis and antihypertensive drugsthat have been studied using IPNs and semi-IPNs. The avail-ability of data on in vitro and in vivo release kinetics as well aspreparation methods of producing such formulations arediscussed in relation to the nature of polymers used to formsuch systems. It is, however, necessary to briefly understandthe classifications and methods of their production [15,16].

2. Classification of IPNs

The IPN consists of at least one of the constituent polymersthat are crosslinked in the immediate vicinity of other poly-mer such that the network cannot be separated unless chemi-cal bonds are disrupted. If only one polymer of the IPNs iscrosslinked, whereas the others have a linear structure, thensemi-IPN is formed. If all the member polymers are cross-linked, then full-IPN is formed. IPNs are generally classifiedbased on the chemical bonding and arrangement patterns.Based on chemical bonding approach [17], there are two typesnamely, covalent semi-IPN, that is, when two separatepolymer systems that are crosslinked form a single polymernetwork. In the noncovalent semi-IPN, only one of the poly-mer systems is crosslinked. A noncovalent full IPN is formedin which two separate polymers are crosslinked indepen-dently; these systems may be regarded as physical bonding.Based on the arrangement pattern, the four different classesare: full IPN, sequential IPN, simultaneous IPN and semi-IPN.

IPNs can be synthesized by innumerable methods. Thein situ synthesis of IPNs and semi-IPNs involves the mixingof reactants before triggering polymerization reaction or cross-linking. Thus, syntheses of two networks may or may not beinitiated at the same time, leading either to simultaneous orsequential formation of the networks. In these in situ syntheticpathways, morphology of the polymer can be modulatedalmost at will and can be made highly different by alteringthe proportions of two partner polymers, the order and/or rel-ative rates of the formation of two networks [8,9] as shownin Figure 1A.

In the sequential synthesis of IPN, the first polymer net-work is synthesized and subsequently swollen with all theprecursors necessary for the formation of the second network,which is then carried out within the first network. In this pro-cess, the first network determines the morphology of the finalpolymer. In this sense, pore-filling electrolyte membranes canbe considered as IPNs or semi-IPNs, depending on whetheror not the polymer substrate is crosslinked. Pores of the

Article highlights.

. Interpenetrating polymer networks (IPNs) are thepolymeric structures formed when two distinctmultifunctional polymers are entangled at the molecularlevel. Thus, an IPN permits combination of chemical andphysical properties of individual polymers in thesame material.

. The distinctive properties of IPNs or semi-IPNs haveattracted considerable attention and continue to be ofinterest in both fundamental and applied areas.

. IPN hydrogel has more complicated network structureand possesses improved mechanical properties; in suchsystems, the extent of crosslinking can be monitored tocontrol the drug release.

. IPNs have been used extensively in the development ofsmart drug delivery systems. Environment-sensitive IPNsare practically the ideal candidates for developingself-regulated drug delivery systems.

. IPN-based drug delivery systems are designed to deliverdrugs in a zero-order pattern withminimum fluctuations.

This box summarizes key points contained in the article.

T. M. Aminabhavi et al.

2 Expert Opin. Drug Deliv. (2014) ()

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porous polymer substrate are filled with polyelectrolyte pre-cursors and linear or network polyelectrolyte is synthesizedwithin the porous substrate. This synthetic pathway is referredto as ‘impregnation synthesis’ as shown in Figure 1B.

In addition to the abovementioned methods, hydrogels ofIPN and semi-IPN have been prepared by one-pot inverseminiemulsion [18] involving three steps. For instance, in thefirst step, stable droplets of acrylic acid (AA), gelatin (Ge)and NaOH mixture are produced by sonication in the pres-ence of ammonium persulfate initiator for radical generation.In the second step, accelerator tetramethylethylenediamine(TEMED) and crosslinker N,N¢-methylenebisacrylamide(MBA) are used to polymerize and crosslink AA monomer.The semi-IPN thus formed is further used in the third stepto form full-IPN by adding glutaraldehyde (GA) as a cross-linker for Ge. Although GA is considered as a toxic materialfor crosslinking, innumerable studies reported have indicatedtheir safety, since at low concentrations, GA may not be themajor issue.

Alternatively, IPNs and semi-IPNs have also been pro-duced by crosslinking with g radiation [19,20]. Photocrosslink-able IPN hydrogels consisting of Ge methacrylate and silkfibroin were formed by sequential polymerization having tun-able structural and biological properties [21,22]. A series ofIPNs of poly(AA) (PAAc)/triazole-modified poly(vinyl alco-hol) have also been prepared by free radical polymerizationin methanol at room temperature with L-ascorbic acid andH2O2 as initiators and trihydroxymethyl propane glycidolether as a crosslinker [23]. These systems were found to bebetter acceptable than those of the GA-crosslinked structures.

3. Specialty properties of IPNs

Their physical and biological characteristics such as enhancedsolubility of hydrophobic drugs, excellent swelling capacityand imparting drug stability during formulation step, inaddition to their biodegradability, biocompatibility, weakantigenicity and targeting of drug in a specific tissue, makehydrogels of IPNs suitable for the CR of drugs. For instance,

Shanmugasundaram et al. [24] prepared biodegradable IPNscaffold composed of collagen and chitosan (CS) for in vitroculture of human epidermoid carcinoma cells (HEp-2), usingGA as a crosslinker. The culture studies performed usingHEp-2 cells on the selected scaffold and its growth morphol-ogy examined by optical photographs, taken at different mag-nifications on various days of culture, suggested that they canbe used as a substrate to culture HEp-2 cells that can be usedas in vitro model for anticancer drugs. Tigli and Gumusdere-lioglu [25] prepared semi-IPN scaffolds composed of sodiumalginate (NaAlg) and CS by freeze-drying using CaCl2 as acrosslinker and analyzed their cellular and structural responsesthat revealed their potential utility as scaffold for improvedcartilage tissue engineering. In addition, structural variationand chemical complexity of the IPNs make them as specialtypolymers in drug delivery area.

4. IPN and semi-IPN systems

Biopolymers have been widely used as building blocks of IPNand semi-IPN systems that are used in drug delivery areabecause of their favorable encapsulation properties and biode-gradability. These polymers, therefore, attracted muchattention in recent years and many research groups haveintensely developed innovative methods to prepare suchsystems with significantly specific properties required for theCR of a variety of drugs than the conventional polymeric sys-tems. The functional groups of IPNs can be derivatized tointroduce new systems, such as networks obtained by cross-linking of the chains [8-11]. Hydrophilic polysaccharides suchas CS, NaAlg, starch, sodium carboxymethyl cellulose(NaCMC), guar gum (GG), konjac glucomannan (KGM),2-hydroxyethyl methacrylate (HEMA), hydroxypropylcellu-lose (HPC), N-(2-hydroxypropyl) methacrylamide, methyl-cellulose (MC) and hydroxyethylcellulose (HEC) havereceived much attention in developing IPNs and semi-IPNsin drug delivery area.

Smart hydrogels of IPN and semi-IPN polymers possessimproved mechanical properties and their response to

Monomer A

Monomer BCrosslinker A

Monomer ACrosslinker A

Monomer AMonomer B

Monomer B

Crosslinker A Crosslinker B

Impregnation

Impregnation

Monomer ACrosslinker A

Polymer BCrosslinker B

IPN

IPN

Semi-IPN

A. In situ synthesis B. Sequential synthesis

Semi-IPN

Figure 1. Schematic representations of in situ and sequential synthesis of IPNs and semi-IPNs.IPN: Interpenetrating network.

CR of therapeutics using interpenetrating polymeric networks

Expert Opin. Drug Deliv. (2014) () 3

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fluctuations in temperature or pH of the medium to tailor therelease of short-lived drugs. Formation of temperature- andpH-responsive IPN hydrogels prepared from poly(N-isopro-pylacrylamide) (PNIPAAm) is widely explored in combina-tion with other crosslinkable biopolymers. Among these,polyacrylamide (PAAm), polyaspartic acid (PAsp), PEG,poly(ethylene oxide) (PEO), polymethacrylate, methacrylicacid), N-acryloylglycine (NAGly), Ge, poly(butyl acrylate),poly("-caprolactone) (PCL) and PAAc were widely explored.In addition to abovementioned polymers, poly(butyl

methacrylate), poly(1,2-butylene oxide), poly(vinyl alcohol)(PVA), NAGly, poly(2-methacryloxyethyltrimethylammo-nium), trisodium trimetaphosphate (TSTMP), TEMED,2-acrylamido-2-methyl-1-propane sulfonic acid (AMPS), N,N¢-MBA, divinyl ester (DVE), PEG diacrylate (PEGDA),poly(acrylamido glycolic acid), N-vinylpyrrolidone (NVP),polyallylammonium chloride (PAAC), low-molecular-weightketene polymer (LMKP), xanthan gum (XG), hydroxyethylchitin (HECH), sodium carboxymethyl locust beangum (SCMLBG), sodium carboxymethyl xanthan (SCMX),poly(3-acrylamidephenylboronic acid-co-(2-dimethylamino)ethyl methacrylate)/(b-cyclodextrin-epichlorohydrin) (P(AAPBA-co-DMAEMA)/(b-CD-EPI)), carboxymethyl cellu-lose (CMC), carrageenan (CG), chondroitin sulfate (ChS)have also been used in developing suitable delivery systems.The systems discussed above have been widely used in drug

delivery area. However, the mechanism(s) by which drugs getimmobilized, retained and delivered through these matrices isquite complex due to the interplay between diffusion and per-meation phenomena at the molecular level [26]. Drug is firstdissolved in the matrix (hydrogel, microsphere or nanoparti-cle) and then distributed uniformly throughout the polymerspace before it is released after the degradation of the matrix.In some cases, due to the complexity of the IPN matrix interms of varying morphology and/or crosslink density in rela-tion to diffusion of drug that may be slow at some point of thematrix domain compared to degradation of the matrix. More-over, drug release depends on the geometry of the system;various theoretical studies have been made [2-5] addressingthis phenomenon and detailed discussion of this is beyondthe objective of this review. In case of coated IPN matrices,erosion of the coat due to pH and enzymatic hydrolysis causesdrug release with certain coat materials such as glyceryl monostearate, beeswax and steryl alcohol and so on [27].

5. CR formulations of therapeutics

Majority of IPNs and semi-IPNs developed to deliver antican-cer, anti-asthmatic, antibiotic, anti-inflammatory, anti-tuberculosis and antihypertensive drugs are discussed in thisreview. Considering the vast amount of literature on suchsystems, we present here typically the well-known systemsthat include the extent of encapsulation and time of releasein addition to safety, biocompatibility and biodegradability.

Published data are critically discussed in relation to the natureof the network polymers.

5.1 Anticancer drugsAmong the many widely used anticancer drugs, 5-fluorouracil(5-FU) stands first for exploring the use of IPN and semi-IPNhydrogels, followed by doxorubicin (DOX), capecitabine(CAP) and oxaliplatin (OXP). Oral CR formulations of thesedrugs have been studied. Typical data are presented in Table 1.

5.1.1 5-FluorouracilThe 5-FU is a widely used drug in clinical chemotherapy [28]

for the treatment of solid tumors in breast [29], gastric [30] andpancreatic [31] cancers. To study its CR properties, tempera-ture- and pH-sensitive IPN hydrogel microsphere (size280 -- 360 µm) blends of NaAlg and N-isopropylacrylamide(NIPAAm) are prepared [32] by w/o in situ polymerizationwith K2S2O8 as an initiator crosslinked with GA in the pres-ence of Tween-80 that showed encapsulation efficiency (EE)of 84% with 90% release of 5-FU in 12 h; but pure NaAlgmatrix gave 100% release in 10 h in acidic and alkaline mediaat 25�C and 37�C. In another study [33], CR of 5-FU fromthe IPN hydrogels prepared by sequential polymerization at25�C was compared with the hydrogel of PNIPAAm whichshowed that release from the IPN hydrogel was slower thanthe latter; both showed a burst release in 30 min with a com-plete release in 4 h. The temperature-sensitive semi-IPNhydrogels of NIPAAm and hydroxylpropyl methyl cellu-lose [34] released 5-FU depending on the nature of blend com-position and temperature. The semi-IPN hydrogelprepared [35] from poly(N-isopropylacrylamide-co-2-acryla-mido-2-methyl-1-propanesulfonic acid) with CS using freeradical addition polymerization gave 76% of EE for 5-FUand released 98% in intestinal pH at 20�C and 100% releaseat 40�C in 12 h.

According to Zhao et al. [36], photo-thermoresponsive andmultifunctional hybrid Au@IPN-PNIPAAm nanogel(50 nm) prepared by growing acrylamide monolayer onto asingle gold nanoparticle (AuNP) followed by in situ poly-merization and crosslinking showed biocompatibility evenat low concentration (< 200 µg/ml) with cellular imagingfunctionality as tested by dark-field microscopy. The uniquescattering properties of AuNP core and reversible thermores-ponsive volume phase transition of IPN-PNIPAAm shelloffered thermo-/photo-triggered release of 5-FU. These sys-tems have much broader opportunities for combined diag-nosis and therapy (theranostics) than the conventionalsystems.

The semi-IPN microspheres (200 µm) [37] of CS and GG-grafted-acrylamide (CS-GG-g-AAm) prepared by w/o emul-sion crosslinking in the presence of GA gave 58% of EEwith 90% release in 12 h in pH 7.4 buffer. The release wasdependent on graft-copolymer composition, crosslinkerconcentration and drug content. Also, the pH-responsiveand thermoresponsive IPN hydrogels containing CS prepared



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by El-Sherbiny et al. [38,39] with NAGly using GA as acrosslinker and 2,2-dimethoxy-2-phenylacetophenone as aphotoinitiator under mild irradiation released 90% of 5-FUin acidic media, but 70% was released in alkaline media at37�C with a maximum EE of 95%. On the other hand,pH-dependent IPN hydrogels prepared [39] by irradiation ofNAGly and PEGDA along with CS using GA crosslinkerand 2,2-dimethoxy-2-phenylacetophenone photoinitiatorreleased 85% of 5-FU at 37�C in pH 2.1 that was higherthan observed in pH 7.4 buffer.

Two types of pH-responsive IPN hydrogels were also pre-pared [40] using CS and PVA crosslinked by GA and g-irradi-ation that showed faster and higher release of 5-FU at highercontent of PVA. The release of 5-FU was 84 -- 96% and57 -- 70%, respectively, in pH 2.1 and 7.4 buffer media atPVA compositions of 50 -- 75% in 5 h. On the one hand,IPN microspheres (80 -- 250 µm) containing PVA andNaCMC [41] prepared by w/o emulsion method and cross-linked with GA showed 62% EE with 60 -- 90% release of5-FU in pH of 1.2 and 7.4 in 12 h. On the other hand,pH-sensitive semi-IPN hydrogels of PVA/poly(acrylamide-co-acrylamidoglycolic acid) [PVA/poly(Am-co-AGA)] pre-pared [42] by free radical polymerization using MBA as acrosslinker showed 61% EE releasing 100% 5-FU in pH7.4 phosphate buffer at 37�C in ~ 12 h.

KGM and PAsp are biodegradable polymers that were usedto form pH-sensitive semi-IPN hydrogels [43,44] for the CR of5-FU using two different crosslinking agents. STMP as acrosslinker [43] released 23% of 5-FU in 3 h, whereas 95%was released in pH 7.4 media at 37�C in 7 h. On the otherhand, pH-sensitive semi-IPN hydrogels of starch and PAspused for colon delivery of 5-FU [44] released almost 100% in13 h in enzyme-free simulated intestinal media containinga-amylase at pH 7.4, whereas in pH 2.2 buffer media, only20% of 5-FU was released in 7 h with 86% of EE. This showsthat natural polymers have high drug release properties due tohigh swelling and are more sensitive to pH of the medium.

5.1.2 CapecitabineCAP, a prodrug, can be converted to 5-FU in the bodyfollowing its oral administration and is used for the treatmentof metastatic colorectal and breast cancers; it is readilyabsorbed from the gastrointestinal tract (GIT). Its recom-mended dose is 2.5 g/m2/day with its short elimination half-life of 0.5 -- 1 h [45] and it has adverse effects like cardiotoxic-ity, diarrhea, nausea, vomiting, stomatitis, dermatitis and soon, which can be minimized by developing its CR dosages [46].In the literature, only one study [47] has dealt with oral formu-lation of semi-IPN hydrogel microspheres (82 -- 168 µm) ofCS-poly(ethylene oxide-g-acrylamide) prepared by emulsion

Table 1. Controlled release formulations of anticancer drugs.

Formulation type Preparation method Carrier system %EE/

%TCR

Release

time (h)

Ref.

5-Fluorouracil (half-life: 10 -- 20 min)Semi-IPN hydrogel microspheres w/o Emulsification NaAlg-NIPAAm 84/90 12 [32]

IPN hydrogels Sequential polymerization PNIPAAm NA/100 4 [33]

Semi-IPN hydrogels Free radical polymerization Poly(NIPAAm-AMPS)-CS 76/100 12 [35]

IPN nanogels In-situ polymerization andcrosslinking

Au@IPN-pNIPAAm NA/85 50 [36]

Semi-IPN microspheres w/o Emulsification CS-guar gum-g-AAm 58/90 12 [37]

IPN hydrogels Photopolymerization Poly(NAGly-CS) 95/90 24 [38]

IPN hydrogels Photopolymerization Poly(NAGly-PEGDA)-CS 78/85 24 [39]

IPN hydrogels g-Irradiation CS/PVA 95/96 5 [40]

IPN microspheres w/o Emulsification PVA/sodiumcarboxymethyl cellulose

62/90 12 [41]

Semi-IPN hydrogels Free radical polymerization (PVA/Poly(Am-co-AGA) 61/100 ~ 12 [42]

Semi-IPN hydrogels Interfacial polymerization PAsp/konjac glucomannan NA/95 7 [43]

Semi-IPN hydrogels Free radical polymerization PAsp/Starch 86/100 13 [44]

Capecitabine (half-life: 0.5 -- 1 h)Semi-IPN microspheres Emulsion crosslinking and

free radicalCS-poly(ethyleneoxide-g-acrylamide)

87/74 10 [47]

Doxorubicin hydrochloride (half-life 15 -- 30 min)IPN hydrogels Emulsion crosslinking Ge/divinyl ester 78/85 6 -- 10 days [49]

Semi-IPN hydrogels Free radical polymerization PAAc/Ge 98/~ 68 30 days [50]

IPN Pluronic P105 micelles Ultrasonic Pluronic P105/N,N¢-diethylarylamide

NA NA [51]

Oxaliplatin (half-life: ~ 10 -- 25 min)Semi-IPN microspheres Direct polymerization Hydroxypropylcellulose-PAAc NA/70 48 [53]

AMPS: 2-acrylamido-2-methyl-1-propane sulfonic acid; CS: Chitosan; EE: Encapsulation efficiency; Ge: Gelatin; IPN: Interpenetrating network; NA: Not available;

NaAlg: Sodium alginate; NAGly: N-acryloylglycine; NIPAAm: N-isopropylacrylamide; PAAc: Poly(acrylic acid); PAsp: Polyaspartic acid; PEGDA: Polyethylene glycol

diacrylate; PNIPAAm: Poly(N-isopropylacrylamide); PVA: Poly(vinyl alcohol); TCR: Total cumulative release.



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crosslinking with GA. PEO was grafted with PAAm byfree radical polymerization using ceric ammonium nitrate(CAN) redox initiator. The EE, release rate, size and mor-phology of the microspheres were studied by factorial designto evaluate the combined effect of independent variables onpercentage drug release at 5 h using regression analysis. TheEE values ranged from 79 to 87% and 74% release in pH1.2 followed by intestinal fluid (pH 7.4) which extended itsrelease time to 10 h.

5.1.3 DOX hydrochlorideDOX is a widely used drug for hematological malignancies,carcinomas and soft tissue sarcomas, since it works by interca-lating DNA. Drug is administered intravenously as its hydro-chloride salt and is sold under the trade names: AdriamycinPFS, Adriamycin RDF or Rubex [48].Only few reports are available on the IPNs containing

DOX to reduce its toxic effects. Of these, biodegradableIPN hydrogels of Ge (hydrophilic) and DVE (hydrophobic)prepared by diffusion method [49] showed low burst releasein 36 h with 85% release in about 6 -- 10 days. At increasedGA concentration, amount of free amino groups werereduced to increase the drug release. At fixed DVE (0.7 g),the release of DOX was 69% in 120 h, but 67% was releasedin 240 h. The authors [50] also reported DOX-loadedsemi-IPN hydrogels of PAAc and Ge crosslinked with poly-caprolactone diacrylate and examined these for post-surgicalantitumor efficacy and biodistribution of implanted hydrogelson Ehrlich’s ascites tumor model using albino mice.Semi-IPNs prepared with 0.2 mol% crosslinker showed deg-radation in 20 days in phosphate buffer of pH 6.5. In vivoanticancer efficacy performed on placebo, and drug-loadedcylindrical implants (65 µg/implant of 10 mg) were insertedinto tumor cavity post-tumor excision to assess biodistribu-tion of DOX for 7, 11, 14, 20 and 25 days, which showedthe highest drug concentration on the 7th day, but negligibleconcentration on the 25th day, at which histopathologyrevealed no signs of tumor recurrence with 100% necrosisand slight inflammation in the treated group. These in vivoresults established their utilization as implants in post-surgicaltherapy for solid tumors.The DOX-loaded Pluronic P105 micelles stabilized with

IPN of N,N¢-diethylarylamide under ultrasonification werealso prepared [51] to determine whether micellar stabilizationis responsible for DOX release as monitored by fluorescencetechnique at 70 kHz of insonation. The amount of drugreleased was different than that released from P105 micelles,suggesting the potential of the system in vivo.

5.1.4 OxaliplatinOXP is a hydrophilic antitumor drug discovered in 1976 [52]

and licensed by Debiopharm that is used for treatingadvanced colorectal cancer. Later, it was licensed to Sanofi-Aventis in 1994 and was approved by US FDA in 2002.The drug has a half-life of ~ 10 -- 25 min. Semi-IPN

nanoparticles (100 nm to 1 µm) were prepared [53] by poly-merizing AA in the presence of HPC; AA and MBA exhibitedthermo-responsive and pH-responsive properties. In vitrocytotoxicity assay indicated high antitumor activity, andrelease was 70% in 48 h, showing higher anticancer activitythan the free drug at higher drug dose.

5.2 Anti-asthmatic drugsTheophylline (THP), an anti-asthmatic drug (biological half-life of 5 -- 6 h) with dose-related drug (> 20 µg/ml) has sideeffects like nausea, ulcers, cardiac arrhythmia and epigastriapain [54,55]. It is the only drug under anti-asthmatic categoryfor which IPN-based CR oral formulations were prepared[56-62]. In our own research [56-59], IPN microspheres using dif-ferent blend polymers were developed. The microspheres(120 -- 300 µm) of CS with MC prepared [56] by emulsioncrosslinking using GA as a crosslinker by varying the ratio ofMC to CS, percentage drug loading and concentration ofGA showed 82% EE with 85 to 90% release of THP in about12 h in pH 1.2 and pH 7.4 buffer media. On the other hand,IPN microspheres (4 -- 60 µm) of PVA and MC prepared [57]

by w/o emulsion method and crosslinked with GA showed84% EE and released 80% THP in pH 1.2 and 7.4 buffermedia in 32 h. Here, the presence of PVA helped to reducethe matrix swelling.

The semi-IPN microspheres (10 -- 15 µm) of PVA withHEC crosslinked with GA were also prepared [58] by w/oemulsion method that gave 69% EE for THP with in vitrorelease of 70 -- 75% in 12 h. Similarly, semi-IPN hydrogelblend microspheres (100 -- 140 µm) of Ge with HEC [59] pre-pared by w/o emulsion method gave EE of 74%, but byemploying Ge in place of PVA, and resulted in 85% releaseof THP in 24 h, due to the presence of Ge (hydrophilic) [58].On the other hand, semi-IPN microspheres of CS-(dextran-g-acrylamide) prepared [60] by emulsion free-radical polymeriza-tion crosslinked with GA and CAN initiator showed50 -- 80% EE with 90% release of THP in pH 1.2 and7.4 media in 18 h at 37�C.

When IPN hydrogels of CS with NVP and its copolymerwith HEMA prepared [61] by photopolymerization without aphotoinitiator or a crosslinking agent were tested for biocom-patibility with human epidermal keratinocyte cells (HaCaT),it showed positive cell growth, suggesting non-toxicity tohuman keratinocytes. On the other hand, pH-sensitive semi-IPN hydrogels of crosslinked copolymer of acrylamide/AA[P(Am-co-AA)] and linear PAAC prepared [62] by templatecopolymerization in the presence of MBA as a crosslinkerreleased 100% THP in 150 min at 37�C in pH 7.4 media.

5.3 AntibioticsTypical antibiotic drugs and their CR formulations developedusing IPNs and semi-IPNs as hydrogels are summarizedin Table 2.



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5.3.1 CefadroxilCefadroxil (CF) is an antibiotic drug with a biological half-lifeof 1.2 -- 2 h at doses of 0.5 and 1.5 g and is used for treatingbacterial infections. Reported data on CR formulations of CFare very rare. In our own research, CR formulations of CFwere prepared by w/o emulsion method using pH-sensitiveIPN microgels (40 -- 180 µm) of CS and acrylamide-g-PVAcrosslinked with GA [63] that showed EE of 95% with 98%release in 10 h in alkaline pH, but with a much lower releasein acidic media, suggesting its potential for colon delivery totreat bacterial infections. The CS and GG blend semi-IPNmicrospheres prepared by w/o emulsion method and cross-linked with GA [64] released 90% of CF in pH 7.4 buffer in10 h with EE of 69 -- 78%, depending on the blend compo-sition, GA concentration and initial loading of CF. Noticethat matrices discussed in Ref. [63] are superior than thosereported in Ref. [64].

5.3.2 CiprofloxacinCiprofloxacin (CFX) is a wide spectrum antibiotic belongingto fluoroquinolone family, with a plasma half-life of 4 h and isused for treating bacterial infections caused in enteric, respira-tory, urinary tract, GIT, typhoid, gonorrhea, osteomyelitisand septicemia [65,66]. For encapsulating CFX, IPN micro-spheres of acrylamide-g-GG (PAAm-g-GG) blended with

CS [67] were prepared by w/o emulsion crosslinking methodusing GA that showed 74% EE with 90% release of CFX in12 h in pH 7.4 media at 37�C. However, blend IPN micro-spheres prepared by w/o emulsion method using hydroxyl-propyl methyl cellulose and PVA [68] showed 95% in vitrorelease of CFX in pH 7.4 buffer media at 37�C in 10 h.Swarnalatha et al. [69] synthesized novel semi-IPN nanohydro-gels (140 -- 225 nm) using hydrophobic LMKP and hydro-philic PAAm in the presence of benzoyl peroxide initiatorand MBA as a crosslinker, which released 50% of CFX in18 h at pH 7 and 37�C.

5.3.3 AmoxicillinAmoxicillin (a-amino-hydroxybenzylpenicillin) (AMX) is anantibiotic with a half-life of 61 min that is used for treatingHelicobacter pylori occurring in peptic ulcers [70]. Risbudet al. [71] prepared pH-sensitive CS/polyvinylpyrrolidone(PVP) blend semi-IPN hydrogels (40 µm) crosslinked byGA to investigate the CR of AMX. Freeze-dried membranesreleased 73% of AMX (33% by air-dried) in 3 h at pH1.2 that showed superior drug release than air-dried hydro-gels, suggesting that freeze-dried formulations are potentialfor antibiotic delivery in acidic environment.

According to Ekici and Saraydin [72], ternary IPN hydrogelsprepared by using CS, PVP and PAAm by free radical poly-merization of acrylamide monomers in the presence of GA

Table 2. Controlled release formulations of antibiotics.


%TCR

Release

time (h)

Ref.

Cefadroxil (half-life: 1.2 -- 2 h)IPN microgels w/o Emulsification CS-Am-g-PVA 95/98 10 [63]

Semi-IPN microspheres w/o Emulsification CS-GG 78/90 10 [64]

Ciprofloxacin (half-life: 4 h)IPN hydrogel microspheres w/o Emulsification CS-polyacrylamide-g-GG 74/90 12 [67]

IPN microspheres w/o Emulsification HPMC/poly(vinyl alcohol) 76/95 10 [68]

Semi-IPN nanohydrogels Surface-initiatedanionic/free radicalpolymerization

Low molecular weightketene polymer/AAm

NA/50 18 [69]

Amoxicillin (half-life: 61 min)Semi-IPN hydrogels Crosslinking, freeze-drying CS/PVP NA/73 3 [71]

IPN hydrogels Free radical polymerization CS-PVP-polyacrylamide NA/98 11 [72]

IPN hydrogels Simultaneous polymerization CS-PVP-PAAc NA/100 20 [73]

Vancomycin (half-life: 4 -- 11 h)Sequential IPN-grafted films g-Radiation net-PP-g-PNIPAAm-inter-net-AAc NA/90 8 [75]

IPN-grafted films g-Radiation net-PP-g-PNIPAAm-inter-net-PAAc NA/95 8 [76]

IPN-grafted films g-Radiation net-PP-g-PNIPAAm-inter-net-PAAc NA/90 8 [77]

Ofloxacin (half-life: 4 -- 5 h)IPN beads Emulsion crosslinking CS-sodium alginate 86/95 24 [79]

Clarithromycin (half-life: 3 -- 4 h)IPN hydrogels Chemical crosslinking CS-PAAc-PVP 96/89 12 [80]

Gentamicin sulfate (half life: ~ 10 -- 25 min)Full and semi-IPN hydrogels Polymerizing and crosslinking PAA-Ge NA/85 7 days [82]

IPN hydrogels Polymerizing and crosslinking PAA-Ge NA/NA NA [83]

IPN hydrogels Polymerizing and crosslinking PAA-Ge NA/NA NA [84]

CS: Chitosan; EE: Encapsulation efficiency; Ge: Gelatin; GG: Guar gum; HPMC: Hydroxylpropyl methyl cellulose; IPN: Interpenetrating network; NA: Not available;

PAAc: Poly(acrylic acid); PNIPAAm: Poly(N-isopropylacrylamide); PP: Polypropylene; PVP: Polyvinylpyrrolidone; TCR: Total cumulative release.



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and MBA as crosslinkers showed the pH-dependent release ofAMX that was higher in acidic media than in basic media.The IPNs released 98, 88 and 84% of AMX at pH 1.1compared to 83, 73 and 71% release in pH 7.4 at 37�C. Ina later study [73], the authors prepared IPN hydrogels bysimultaneous polymerization and crosslinking of CS, PVPand PAAc with GA and MBA for gastrointestinal delivery ofAMX. These matrices showed 100% release of AMX in pH7.4, whereas 77% was released in pH 1.1 in 20 h at 37�C.

5.3.4 VancomycinVancomycin (VNM) is another antibiotic drug used for treat-ing MRSA infections associated with the use of catheters [74].Sequential IPN films of PAAc and PNIPAAm grafted ontopolypropylene (PP) were prepared [75] and loaded withVNM that showed 90% release in pH 7.4, adequate to killbacteria adhered to the surface of the films. To furtherimprove its CR characteristics and reduce the risk of biofilmformation, surface-modified PP (PP-g-PNIPAAm-inter-net-PAAc) was prepared [76] by grafting and crosslinkingNIPAAm onto PP films followed by redox polymerizationand crosslinking acrylic acid to form IPN. Drug-loaded filmsshowed the pH-dependent CR in pH 7.4 media at 37�C forseveral hours. However, stimuli-responsive performance ofPP substrates grafted with IPNs of NIPAAm and acrylicacid monomer crosslinked, as shown in Figure 2 [77], under10 -- 100 kGy doses of g-radiation in the presence or absenceof chemical crosslinker (MBA) when loaded with VNMshowed 90% release in 48 h to prevent the bacterial growth.

5.3.5 OfloxacinOfloxacin HCl (OFX) is a synthetic antimicrobial drug that isactive against Gram-negative bacteria and certain anae-robes [78]. Only one [79] IPN formulation of CS-NaAlg beads(150 -- 240 µm) was investigated that showed EE of 76 -- 86%with 95% release of OFX in 24 h at 37�C.

5.3.6 ClarithromycinClarithromycin (CLM) is a macrolide antibiotic drug that isused for treating pharyngitis, tonsillitis, acute maxillary sinus-itis, acute bacterial exacerbation of chronic bronchitis, pneu-monia (especially atypical pneumonias associated withChlamydophila pneumoniae) and skin infections. CLM pre-vents bacteria from growing by interfering with their proteinsynthesis. Only one oral formulation [80] was developed forin vitro release of CLM using IPN hydrogels of CS, PAAcand PVP crosslinked with GA and MBA by varying theconcentration of GA, keeping the polymer composition con-stant. The effect of GA concentration on in vitro release wasstudied by which IPN hydrogels released 89% of CLM ingastric environment in 12 h at 37�C with a EE of 96%.

5.3.7 Gentamicin sulfateThe aminoglycoside gentamicin sulfate (GS) is a broad spec-trum antibiotic used for antimicrobial activity [81].Changez et al. [82] prepared the IPN hydrogels of PAAc andGe crosslinked with GA and MBA to investigate the CR ofGS in water (pH 5.8), phosphate buffer (pH 7.4) and citratebuffer (pH 4) at 37�C. Drug release in phosphate buffer was

Pre-irradiation oxidativemethod

Radiation dose: 30 kGy

AAc + MBAAmDirect method

Radiation dose: 2.5 kGy

(Method A)

PP-g-PNIPAAm

net-PP-g-PNIPAAm

net-PP-g-PNIPAAm-inter-net-PAAc

Radiation dose:10, 40, 70 or 100 kGy

or γ + MBAAm(Method B)

PP

+

NIPAAm

γ

γ

γ

H2C

H3C

OH

OO

NH

CHCH3

Figure 2. Schematic representation of polymerization steps in the preparation of net-PP-g-PNIPAAm-inter-net-poly(acrylic

acid).Reprinted from [77], Copyright � 2012, with permission from Elsevier.

PNIPAAm: Poly(N-isopropylacrylamide); PP: Polypropylene.



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faster than in water or citrate buffer. At increased Ge compo-sition of the matrix, 85% release occurred in 7 days inphosphate buffer (pH 7.4). The safety and efficacy of thesesystems were evaluated [83] for the treatment of osteomyelitisin rabbit. Sequential radiography, histology and microbiologyassay suggested suitability to heal the infection after 6 weeks.The same systems when subjected [84] to in vitro and in vivorelease of GS showed that local skin tissue concentration of50 and 100% GS-loaded IPNs were higher than minimumbactericidal concentration for Staphylococcus aureus andPseudomonas aeruginosa, respectively within 60 days.

5.4 Anti-inflammatory drugsResearch efforts on the CR of anti-inflammatory drugs usingIPN or semi-IPN systems as oral dosage formulations areextensive and typical data are presented in Table 3.

5.4.1 Ketorolac tromethamineKetorolac tromethamine (KT) is a member of pyrrolopyrrolegroup of NSAID, a racemic mixture of - S and [+] R forms,whose biological activity is associated with S-form. The half-life of S-enantiomer is ~ 2.5 h compared to 5 h for R-enantio-mer. The half-life of racemate is around 4 -- 6 h [85]. Formu-lations based on semi-IPN microspheres (247 -- 535 µm)prepared from Ge and NaCMC, crosslinked with GA, wereused [86] to encapsulate KT by varying the composition ofGe and NaCMC, percentage drug loading and amount ofGA. The EE of the matrix was 67% and in vitro release was78% in 10 h at 37�C.

5.4.2 Diclofenac sodiumDiclofenac sodium (DS) NSAID is insoluble in acidic solu-tion (pKa = 4.0) but dissolves in intestinal fluid. Its daily

Table 3. Controlled release formulations of anti-inflammatory drugs.


%TCR

Release

time (h)

Ref.

Ketorolac tromethamine (half-life: 4 -- 6 h)Semi-IPN microspheres Emulsion crosslinking Ge-sodium carboxymethyl cellulose 67/78 10 [86]

Diclofenac sodium (half life: 1 -- 2 h)Sequential IPN microspheres w/o Emulsification PVA-PAAc 91/98 6 [88]

IPN microspheres w/o Emulsification NaAlg-PVP 72/90 11 [89]

Semi-IPN microspheres Emulsion crosslinking AAm-g-hydroxyethylcellulose 83/75 12 [90]

IPN microgels Emulsion crosslinking XG-PVA 83/90 12 [91]

IPN microbeads Water-in-water (w/w)emulsification

Sodium carboxymethyl locust beangum-NaCMC

99/95 8 [92]

IPN hydrogel microspheres w/o Emulsification NaCMC-PVA 75/100 8 [93]

IPN hydrogels Chemical crosslinking Hydroxyethyl chitin/PAAc NA/95 12 [94]

Tramadol hydrochloride (half-life: 6 -- 7 h)IPN microgels Chemical crosslinking NaAlg-Ge 87/90 12 [96]

Ibuprofen (half-life: 1 -- 3 h)IPN beads Chemical crosslinking NaAlg-SCMX NA/99.5 4 -- 5 [99]

IPN hydrogel beads Chemical crosslinking NaAlg-SCMX 98/100 5 [100]

Semi-IPN hydrogels Chemical crosslinking Poly(3-acrylamidephenylboronic acid-co-(2-dimethylamino) ethyl methacrylate)/(b-cyclodextrin-epichlorohydrin)

NA/95 24 [101]

Sequential IPN hydrogels Chemical crosslinking PAAc-g-b-CD NA/85 12 [102]

IPN microgels w/o Emulsification NaAlg-AAc 84/100 12 [103]

Indomethacin (half-life: 1 -- 3 h)Semi-IPN hydrogel beads Chemical crosslinking NaAlg-poly(N-acryloylglycinate) NA/68 10 [105]

Semi-IPN hydrogel beads Redox polymerization Calcium alginate-poly(N-isopropylacrylamide)

76/95 7 [106]

Semi-IPN microspheres w/o Emulsification CS-hydroxyethyl methacrylate 83/100 12 [107]

Naproxen (half-life: 15 h)IPN microspheres w/o Emulsification NaAlg-PVA 68/92 10 [108]

Ketoprofen (half-life: 2 -- 4 h)IPN hydrogel beads Ionotropic gelation/

covalent crosslinkingPolyacrylamide-g- carrageenan/NaAlg 90/90 7 [109]

Semi-IPN hydrogels Chemical crosslinking Chs-AAc NA/100 12 [110]

IPN hydrogel beads Free radical polymerization CMC/PAm-g-NaAlg 90/95 12 [111]

IPN hydrogel beads Free radical polymerization NaCMC/PAm-g-XG 93/90 10 [112]

Semi-IPNs Polymerization ChS/PAAc NA/80 7 [113]

ChS: Chondroitin sulfate; CMC: Carboxymethyl cellulose; CS: Chitosan: EE: Encapsulation efficiency; Ge: Gelatin; IPN: Interpenetrating network; NA: Not available;

NaAlg: Sodium alginate; NaCMC: Sodium carboxymethyl cellulose; PAAc: Poly(acrylic acid); PVA: Poly(vinyl alcohol); PVP: Polyvinylpyrrolidone; SCMX: Sodium

carboxymethyl xanthan; TCR: Total cumulative release; XG: Xanthan gum.



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doses vary between 75 and 200 mg/person given in three orfour divided portions. Its adverse effects are gastritis, pepticulceration, hypersensitivity reactions and depression of renalfunctions [87]. In our own study [88], sequential pH-sensitivemicrospheres of IPN hydrogels of PVA and PAAc that arecrosslinked with GA delivered DS to the intestine and therelease was dependent on pH, concentration of crosslinkerand amount of drug loaded. In another study [89], IPNs ofNaAlg and PVP microspheres (472 -- 157 µm) prepared byw/o emulsion method, crosslinked with GA, gave EE valueof 72%, with 90% release of DS at pH 7.4 in 11 h.Other studies dealt with pH-sensitive semi-IPN micro-

spheres (190 -- 300 µm) prepared from CS and acrylamide-g-HEC (AAm-g-HEC) [90] by emulsion crosslinking in thepresence of GA crosslinker. These matrices gave EE of 83%with 75% in vitro release of DS in pH 7.4 media in 12 h.Another study [91] dealt with pH-sensitive IPN microgels(300 -- 500 µm) of XG and PVA prepared by emulsion cross-linking with GA as a crosslinker for releasing DS to intestine.These formulations gave 83% of EE with in vitro release of90% in pH 1.2 and 6.8, depending on the extent of crosslink-ing at the ratio of XG:PVA. In vivo pharmacokinetic evalua-tion in rabbits suggested slow and prolonged release of DS.IPN microbeads of SCMLBG and NaCMC loaded with

DS were prepared [92] by water-in-water (w/w) emulsion gela-tion method using AlCl3 as a crosslinker in aqueous mediathat released DS in alkaline media, but trivalent ion cross-linked beads improved the drug’s EE to enhance drug releasein phosphate buffer. On the other hand, IPN hydrogel micro-spheres of NaCMC and PVA prepared [93] by w/o emulsioncrosslinking method offered 100% in vitro release in 8 h,whereas IPN blend of HECH and PAAc based [94] tempera-ture and pH-sensitive hydrogels showed 95% in vitro releaseof diclofenac potassium in 12 h. It appears that for all theCR formulations developed using IPNs or semi-IPNs, deliv-ery route for DS was always through oral tract.

5.4.3 TramadolTramadol hydrochloride (TMH) is a centrally acting analge-sic marketed as a mixture, of which (+)- is approximatelyfour times more potent than (-)-enantiomer in terms of µ-opioid receptor affinity and 5-HT reuptake; the (-)-enantio-mer is responsible for noradrenaline reuptake effects [95].TMH-loaded IPN of NaAlg microgels (44 -- 102 µm) cross-linked with GA gave EE of 87% [96] and their mucoadhesiveproperties were evaluated. The 90% of TMH release occurredin 12 h at pH 7.4 that was dependent on the extent of cross-linking and composition of Ge in IPN.

5.4.4 IbuprofenIbuprofen (IBP) is a NSAID used in the treatment of variousmusculoskeletal disorders and painful conditions. The drug isused for the treatment of rheumatoid arthritis, osteoarthritisand ankylosing spondylitis for a quick relief of pain [97].Its plasma half-life of 1 -- 3 h following oral dosing [98] and

necessitates frequent administration and the drug is readilyabsorbed throughout GIT with a rapid elimination. IPNbeads were prepared from SCMX and NaAlg using AlCl3 asa crosslinker and tested for ulcerogenic and anti-inflammatoryactivity of IBP [99,100]. In vivo data tested on rats suggesteddecrease in ulcerogenicity with sustained release of 98 --99.5% in 4 -- 5 h in simulated intestinal fluid [99]. Anotherstudy [100] showed nearly 98% of EE with 100% release ofIBP from the hydrogel beads, for which the release was higherin phosphate buffer than in acidic media.

Recently, P(AAPBA-co-DMAEMA)/(b-CD-EPI) semi-IPN hydrogel was prepared by chemical crosslinking [101]

and used for the CR of IBP. Its performance was affected byb-CD content, which exhibited much higher drug-loadingratio for IBP. In contrast to the conventional P(AAPBA-co-DMA-EMA) hydrogel, release of IBP from b-CD containinghydrogel was slower than that was influenced by pH, temper-ature, glucose concentration as well as release media at physi-ological pH. Such multi-responsive hydrogels are attractivefor self-regulated drug delivery.

A sequential IPN thermoresponsive hydrogel composed ofPAAc-g-b-cyclodextrin (PAAc-g-b-CD) and PAAm was pre-pared that showed 85% release at 37�C, whereas at 25�C,only 30% IBP was released in pH 7.4 media [102]. Swelling/deswelling kinetics of these IPN hydrogels exhibited improvedCR properties compared to normal hydrogels for IBP and therelease was faster at 37�C than at 25�C. Our own results onIBP containing pH-sensitive IPN microgels (45 -- 150 µm)prepared from NaAlg and AAc [103] using w/o emulsiongave an EE of 84%, with 100% release in 12 h in pH7.4 media and these data are superior to those of the earlierreports [99,100,102,103].

5.4.5 IndomethacinIndomethacin (IDM) is used for treating local and systemicinflammatory pathologies. Drug has side ulcerogenic effectin GIT but is effective in the management of rheumatoidarthritis, ankylosing spondylitis, osteoarthritis and acutegout [104]. For encapsulating IDM, pH/temperature-sensitivehydrogel beads of semi-IPN composed of NaAlg and poly(N-acryloylglycinate) were prepared [105] and their CR proper-ties in pH 2.3 phosphate buffer showed only 9% release in610 min but 68% release in pH 7.4. Drug release was higherat 37�C than that at 20�C that increased with increasing poly(N-acryloylglycinate) content of the matrix.

The semi-IPN pH/temperature-sensitive hydrogel beadscomposed of calcium alginate and PNIPAAm [106] showed10% IDM release in pH 2.1 in 400 min and 95% release inpH 7.4. The release was higher at 37�C than at 25�C, whichincreased with increasing PNIPAAm content of the matrix(Figure 3). On the other hand, semi-IPN microspheres(75 -- 185 µm) prepared [107] by w/o emulsion method bypolymerizing HEMA in the presence of CS using K2S2O8 ini-tiator and crosslinked with GA gave 83% EE by releasing100% IDM at 37�C in pH 7.4 at 12 h.



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5.4.6 NaproxenNaproxen sodium (NS) has analgesic properties producingGIT side effects like bleeding, ulceration or perforation.Drug’s bioavailability was improved by preparing the IPNmicrospheres of NaAlg and PVA, crosslinked with GA [108],by w/o emulsion method that showed 92% release in 10 hat pH 7.4 giving EE of 68%. These oral formulations of NSminimized the toxic effects of NS.

5.4.7 KetoprofenKetoprofen (KTP) is one of the propionic acid class NSAIDshaving analgesic and antipyretic effects. Of the many studiesutilizing hydrogels, Kulkarni et al. [109] investigated the pH-responsive IPN hydrogel beads of PAAm-g-k-CG (PAAm-g-CG) and NaAlg prepared by ionotropic gelation/covalentcrosslinking for the release of KTP to the intestine. The beadsshowed 10% release in acidic media and 90% release in alka-line pH 7.4. Stomach histopathology of albino rats indicatedretarded release of KTP in stomach, leading to reduced ulcer-ation, hemorrhage and erosion of gastric mucosa. Anotherstudy [110] dealt with semi-IPN hydrogels of ChS and AA asa colon-specific carrier for KTP that delivered KTP to thecolon. The soluble ChS was extracted in semi-IPNs thatgave 100% release in pH 7.4 at 700 min. Drug-release ratesdecreased with increasing concentrations of DEGDA; at pH1.2, the release was < 40% within 1400 min, indicating thepH-sensitivity of the semi-IPNs.

Kulkarni and Sa [111] also prepared the pH-sensitive IPNhydrogel beads of CMC and PAAm-g-NaAlg for investigatingthe CR of KTP. These beads prepared by ionotropic gelationcovalently crosslinked with GA exhibited 90% EE with 95%release of KTP in pH 7.4, but in pH 1.2, about 25% lesserrelease occurred than in alkaline media at 37�C. The same

authors [112] further developed another type of pH-sensitiveIPN hydrogel beads from PAAm-g-xanthan (PAAm-g-XG)and NaCMC for the CR of KTP, which showed almost iden-tical results as in Ref. [111] with 93% EE and 90% release ofKTP in pH 7.4 at 37�C. However, semi-IPNs of ChS/PAAc [113] crosslinked with AA and diethylene glycol diacry-late demonstrated a significant reduction in swelling in bothgastric and intestinal fluids compared to pure ChS and ChS-AA blend without crosslinking. These matrices released nearly30% of KTP in pH 1.2 and 80% release in pH 7.4 in 7 h.

5.5 Anti-tubercular drugsOf the many anti-tubercular drugs, isoniazid (INH) is theonly drug for which oral CR formulations have been devel-oped using microspheres and hydrogels. INH is used in thefirst-line therapy of tuberculosis and has a short half-life of1 -- 4 h [114]. Drug is freely soluble in water, but severe meta-bolic acidosis, acetonuria and hyperglycemia are reported [115].Novel pH-sensitive stearic acid-coated IPN blend micro-spheres (52 µm -- 502 nm) of CS and Ge developed [116] byemulsion crosslinking method using GA as a crosslinkershowed EE of 65 -- 78%, but in vitro release in pH 1.2 and7.4 indicated a dependence on crosslinking, blend ratio andstearic acid coating. Here, the coated microspheres helped inreducing the burst release in gastric stomach media to enhancein the intestinal media as shown in Figure 4. The coated par-ticles exhibited after 24 h of slow release, a step functionalrelease was observed followed by a gradual release. Typically,complete release of INH was achieved in about 30 h.

Among other systems developed for INH, the IPN blendmicrospheres (66 -- 82 µm) prepared from CS and HEC pol-ymers crosslinked with GA [117] have shown the EE of50 -- 66%. The INH was released to the extent of 75% in16 h at 37�C in pH 7.4. In another study [118], tempera-ture-responsive IPN hollow nanohydrogels (117 -- 413 nm)of PAA and PNIPAAm prepared by two-step sequential col-loidal template polymerization, the INH release was faster at37�C than at 25�C. Drug release in pH 1.2 was 80% in2 h, but was 50% in pH 7.4 at the same time. On the otherhand, semi-IPN microspheres of CS and PEG prepared [119]

for the oral delivery of INH showed EE of 93%, with 58%release in pH 2 at 37�C, but 31% was released in pH 7.4 at37�C in 48 h; but semi-IPN beads of CS and PEG [120]

showed 82% EE with 60% release of INH in pH 2 at 37�C.

5.6 Antihypertensive drugsSeveral natural polymers and their various combinations havebeen employed as IPN and semi-IPN hydrogels for investigat-ing the CR of antihypertensive drugs. These are mainly devel-oped as oral formulations as compiled in Table 4.

5.6.1 AtenololAtenolol (ATL), a cardiovascular drug, having its biologicalhalf-life of 4 h is used to treat hypertension and angina pecto-ris. Only one study was reported for the CR of ATL using

100

80

60

40

20

0

100

80

60

40

20

0

pH 2.1

pH 7.4pH 7.4 37°C

37°C

25°C

25°C 37°C

Time (min)

Dru

g r

elea

se (

%)

0 0200 200100 100300 300400 400

Figure 3. Temperature- and pH-dependent swelling and

release of indomethacin from semi-IPN beads of calcium

alginate and PNIPAAm are shown.Reprinted from [106], Copyright � 2006, with permission from WILEY-VCH

Verlag GmbH & Co. KGaA, Weinheim. PNIPAAm: Poly(N-isopropylacrylamide)



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hydrogels of thermoresponsive semi-IPN microspheres (34 --76 µm) prepared from gellan gum-PNIPAAm, that is,GLG-P(NIPAAm) [121] by ionic crosslinking that released90% of ATL with EE of 71% in pH 7.4 media at 25�C and37�C for 12 h. The formulations containing 50:50 ratio ofP(NIPAAm) to GG exhibited lower release rates than30:70 composition at 37�C and at 25�C; the release washigher at 25�C than at 37�C.

5.6.2 CarvedilolCarvedilol is a noncardioselective b-blocker used in the man-agement of hypertension and angina pectoris. It is wellabsorbed by GIT with a low bioavailability of 25% andplasma half-life of 6 h [122]. IPN microspheres (230 --346 µm) of gellan gum and PVA prepared [123] by emulsioncrosslinking showed 87% EE, with 95% release of carvedilolin intestine at 37�C in 12 h.

5.6.3 Diltiazem hydrochlorideDiltiazem hydrochloride (DTZ) is a benzothiazepine calciumchannel antagonist that is widely used in the treatment ofangina pectoris and hypertension [124], having a short half-life of 3 -- 4 h. Drug is administered 3 -- 4 times daily witha low dose of 30 -- 60 mg [125] and is an ideal candidate forcolon targeting. Among few attempts to encapsulate DTZ,the IPN hydrogels of PVA and PAAc prepared [126] by non-conventional emulsion method using benzoyl peroxide

initiator and NaCl as additive gave EE of 79% in acidic mediawith 95% release in 24 h at 37�C. In vivo studies were doneby inducing hypertension in normotensive rats by methylprednisolone acetate administration that showed reductionin mean blood pressure (BP) in rats for PVA:AA formulationscontaining 25:75 ratio and released 40% of DLZ in 24 h.

For IPN matrix tablets of DTZ-HCl prepared [127] by wetgranulation method using PAAm-g-NaAlg copolymer andNaAlg, the release was controlled by swelling of the hydrogel.Swelling was due to the presence of alginate core and in vitrorelease in pH 1.2 for 2 h followed by pH 6.8 media indicatedslow release with increasing composition of copolymer:NaAlgratio. Decrease in swelling and increase in viscosity of hydro-gel was responsible for low CR from the tablets. Thus, theblend of PAAm-g-NaAlg and NaAlg cross-linked with Ca2+

ions prepared as IPN tablets gave 98% release of DTZ withEE of 99% in 12 h at 37�C in pH 6.8 media.

DTZ-HCl was bound to Indion 254�, a cation exchangeresin that was entrapped within IPN microcapsules (841 --1118 µm) of gellan gum and egg albumin prepared [128] byionotropic gelation and covalent crosslinking method. Puredrug showed rapid and complete dissolution within 60 min,whereas drug release from drug--resinate complex wasextended to 3 h and that from IPN microcapsules was stillslower. Ionically crosslinked microcapsules released 95% ofdrug in 9 h, whereas dual crosslinked microcapsules extendedup to 15 h with EE of 89%. In a similar study, IPN

A. B.

pH = 1.2 pH = 1.2

pH = 7.4

COO–

COO–

COO–

COO–

pH = 7.4

Swollen matrix

Swollen matrix

Drug

Burst release of drug

Controlled release of drug

Drug release

Drug release

Drug

Drug

Drug

Stom

achIntestine

IntestineS

tomach

Oraladministration

Oraladministration

Figure 4. Schematic representation of the drug release from (A) uncoated and (B) coated microspheres in different pH media.Reprinted from [116], Copyright � 2011, with permission from American Chemical Society.



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microbeads of tamarind seed polysaccharide and NaAlg pre-pared by ionotropic gelation and covalent crosslinkingmethod extended the CR of DTZ-HCl [129] by up to 2.5 h,but the unformulated drug showed complete dissolutionwithin 1 h. Ionically crosslinked and dual crosslinkedmicrobeads (986 -- 1257 µm) gave 92% EE that released98% of drug in 6 and 9 h, respectively; the microbeads con-taining higher amount of GA released much slower in pH7.4 at 37�C. In vivo pharmacokinetics studies performed inWistar rats containing pure drug and drug-loaded IPNmicrobeads demonstrated Cmax of 171 and 136 ng/ml, Tmax

of 1 and 4 h at half-life of 3.55 and 5.79 h, respectively.

5.6.4 Propranolol HClPropranolol (PPL) is a sympatholytic nonselective b-blockerhaving a low bioavailability of 10 -- 20% when administeredby oral/intravenous routes due to rapid biotransformation inliver. It has a biological half-life of 4.2 h. Only two studieswere done on the CR formulations of PPL using IPNs. IPNhydrogel tablets of tamarind tree seed polysaccharide andNaAlg prepared [130] as tablets and loaded with PPL orPPL--resin complex (resinate) by wet granulation/covalentcrosslinking method showed 98% release in 24 h in pH7.4 at 37�C with EE of 98%. On the other hand, plaindrug showed complete release within 1 h, whereas drug releasefrom the resinate occurred in 2.5 h. However, IPNs of NaAlgand CG containing PPL--resin complex (resinate) prepared bywet granulation/covalent crosslinking method and com-pressed into tablets [131] released 98% drug in 2.5 h comparedto pure drug release in 60 min, but IPN tablet prolonged therelease by up to 18 h. Crosslinking time of granules affectedthe release of PPL in pH 7.4 at 37�C with EE of 99.5%.

6. Conclusion and perspectives

For over the past two decades, IPNs and semi-IPNs wereintroduced in pharmaceutical and biomedical fields. Sincethen, several CR formulations have been developed and testedto investigate in vitro release of therapeutics to extend theirshort half-life. This review summarizes published results onthe CR of therapeutics through formulations containingmicro/nanoparticulate hydrogels. The selected classes of drugsnamely, anticancer, anti-asthmatic, antibiotic, anti-inflamma-tory, anti-tuberculosis and antihypertensive have been widelyreported before and these data are critically discussed. Eventhough many potential applications of these systems areenvisioned, considerable challenges and issues are yet to beresolved, such as heterogeneity which remains a major prob-lem, and it is hard to precisely control the functionality ofthese systems. The importance of biocompatible and biode-gradable hydrophilic polymers have wide applications indrug delivery, because of their propensity to combine withother polymers to form crosslinked three-dimensional IPNnetwork hydrogels that tend to swell in water or biologicalfluids.

7. Expert opinion

The IPN or semi-IPN systems are often prepared using natu-ral polymers in combination with synthetic polymers to formtemperature- or pH-sensitive hydrogels. Due to the progres-sive developments in stimuli-responsive hydrogels in recentyears, standard methods of improving hydrogel propertiessuch as enhanced physical properties compared to normalpolymer blends or their components along with valuablesynergistic effect are required to be developed. Such usefulproperties of IPNs can be combined to overcome the

Table 4. Controlled release formulations of antihypertensive drugs.


%TCR

Release

time (h)

Ref.

Atenolol (half-life: 4 h)Semi-IPN microspheres Ionic crosslinking Guar gum-P(NIPAAm) 71/90 12 [121]

Carvedilol (half-life: 6 h)IPN microspheres Emulsion crosslinking Gellan gum/PVA 87/95 12 [123]

Diltiazem HCl (half-life: 3 -- 4 h)IPN hydrogels Non-conventional emulsion PVA/poly(acrylic acid) 79/95 24 [126]

IPN matrix tablets Wet granulation Polyacrylamide-g-NaAlg 99/98 12 [127]

IPN microcapsules Ionotropic gelation andcovalent crosslinking

Gellan gum/egg albumin 89/95 15 [128]

IPN microbeads Ionotropic gelation andcovalent crosslinking

Tamarind seedpolysaccharide/NaAlg

92/98 9 [129]

Propranolol (half-life: 4 h)IPN hydrogel tablets Wet granulation/

covalent crosslinkingTamarind seedpolysaccharide/NaAlg

98/98 24 [130]

IPN matrix tablets Wet granulation/covalent crosslinking

NaAlg/carrageenan 99/98 18 [131]

EE: Encapsulation efficiency; IPN: Interpenetrating network; NaAlg: Sodium alginate; PVA: Poly(vinyl alcohol); TCR: Total cumulative release.



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drawbacks of individual components in delivering therapeu-tics. In these aspects, studies on molecular chain dynamicsto predict the exact morphology and/or estimate the level ofmixing between the two components are needed to helpfuture researchers. This aspect is very useful in understandingdrug release phenomenon in terms of miscibility of polymercomponents, composition, crosslink density, polymerizationsequence (i.e., which polymer network is polymerized firstas a pure network and which one is polymerized in the pres-ence of the other component) as well as the kinetics of poly-merization processes.IPN-based drug delivery systems are designed to deliver

drugs in zero-order pattern with minimum fluctuations.Whenever an IPN hydrogel is formed from two polymers ata given temperature, the physical phase separation betweenthe component polymers would be almost impossible becauseof the infinite zero-viscosity of the gel. Therefore, formationof IPN hydrogel is still the better approach. Synthesis ofnew polymers and crosslinkers with better biocompatibilityand biodegradability will be essential for their successfulapplications in drug delivery area. If the achievements of thepast can be extrapolated to the future, it is likely that respon-sive hydrogels with a wide array of desirable properties can bemade to deliver therapeutics to the site of action.Currently, various formulation techniques involving single

unit dosage form, multiparticulate unit dosage form, transder-mal drug delivery systems and so on are developed and evalu-ated. Even though no major breakthrough is in prospect,these IPN-based formulations have sufficient potential andwill take prevention of diseases to a new scientific level inthe upcoming drug delivery area. Therefore, to achieve rapiddevelopment of IPN-based drug delivery technology plat-form, collaborations between regulators, industry, practi-tioners and academia are required. One importantconsequence of this fact is the difficulty to assess commercialanalysis of the market. From this viewpoint, IPN remains tobe one of the few major groups of chemical products withsignificant discrepancies between industrial, commercial andscientific nomenclatures.IPN-based devices must be prepared under good

manufacturing practice conditions and sterilized or disin-fected before their medical use. However, sterilization method(wet or dry heat, chemical treatment or radiation) should notcause any structural changes or lead to chain scission, cross-linking or a significant alteration in their mechanical proper-ties. Chemical sterilization with ethylene oxide gas offers theadvantage of effective treatment at ambient temperature andis useful for hydrolytically unstable polymers. Nevertheless,

its popularity is decreasing due to the toxicity and flammabil-ity of ethylene oxide.

The major challenge of research and development of IPNsfor drug delivery is their large-scale production as there is aneed to scale-up laboratory or pilot technologies to the com-mercial scale. Maintaining the composition of polymers atlarge scale is also a challenge. Despite the number of researchefforts and patent literature on IPN drug delivery technolo-gies, commercialization is still at its early stage as majoritystudies are still at the academic platform. Therefore, greatereffort is needed to bring IPN-based drug delivery systemsfrom an experimental level to the pilot or commercial scaleproduction in order to extend their practical applications.This can be achieved by addressing several aspects, whichinclude boosting the selectivity without compromisingbiocompatibility and stability, optimizing polymer modifica-tion techniques, using proper engineering configurations,understanding the mechanism of drug transport and usingcost-effective materials and methods.

Finally, researchers need to focus on developing improvedstrategies for producing IPNs with precise composition,reproducible functionalization and molecular weight distribu-tion. Compared to in vitro data, in vivo studies on these sys-tems are not much and more studies in this direction areneeded. For successful in vivo biomedical applications, theirpurity, dispersity and stability in physiological environmentsas well as FDA approval are necessary.

Acknowledgments

TM Aminabhavi dedicates this review to Professor PVKulkarni on the eve of his retirement from 40 years ofcontinuous service and initiating this field of research some30 years ago. The authors are indebted to S Rame Gowda,Research Institute of Science and Technology, Dharwad,India, for a partial support of this study as well as in creatingthe needed infrastructure. The authors also thank Shrikant ATiwari for technical assistance.

Declaration of interest

This review was partially supported by S Rame Gowda,Research Institute of Science and Technology, Dharwad,India. The authors have no other relevant affiliations or finan-cial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter ormaterials discussed in the manuscript apart from thosedisclosed.



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AffiliationTejraj M Aminabhavi†1,

Mallikarjuna N Nadagouda1, Uttam A More1,

Shrinivas D Joshi1, Venkatrao H Kulkarni1,

Malleshappa N Noolvi2 &

Padmakar V Kulkarni3

†Author for correspondence1Soniya College of Pharmacy, Department of

Pharmaceutical Engineering and Chemistry,

S.R. Nagar, Dharwad 580 002, India

Tel: +91 9449821279;

Fax: +91 836 2467190;

E-mail: [email protected];

[email protected] Dhanvantary Pharmacy College,

Surat 394110, India3UT Southwestern Medical Center, Radiology

Department, Harry Hines Blvd, Dallas, TX, USA



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Controlled release of therapeutics using interpenetrating polymeric networks

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