Hindawi Publishing Corporation Journal of Drug Delivery Volume 2014, Article ID 583612, 11 pages http://dx.doi.org/10.1155/2014/583612

Review Article Interpenetrating Polymer Networks as Innovative Drug Delivery Systems

Alka Lohani, Garima Singh, Shiv Sankar Bhattacharya, and Anurag Verma

School of Pharmaceutical Sciences, IFTM University, Moradabad, Uttar Pradesh 244102, India

Correspondence should be addressed to Alka Lohani; [email protected]

Received 10 January 2014; Accepted 27 March 2014; Published 14 May 2014

Academic Editor: Sven Frøkjær

Copyright © 2014 Alka Lohani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Polymers have always been valuable excipients in conventional dosage forms, also have shown excellent performance into the parenteral arena, and are now capable of offering advanced and sophisticated functions such as controlled drug release and drug targeting. Advances in polymer science have led to the development of several novel drug delivery systems. Interpenetrating polymer networks (IPNs) have shown superior performances over the conventional individual polymers and, consequently, the ranges of applications have grown rapidly for such class of materials. The advanced properties of IPNs like swelling capacity, stability, biocompatibility, nontoxicity and biodegradability have attracted considerable attention in pharmaceutical field especially in delivering bioactive molecules to the target site. In the past few years various research reports on the IPN based delivery systems showed that these carriers have emerged as a novel carrier in controlled drug delivery. The present review encompasses IPNs, their types, method of synthesis, factors which affects the morphology of IPNs, extensively studied IPN based drug delivery systems, and some natural polymers widely used for IPNs.

1. Introduction whenpolymerchainsofthesecondsystemareentangled with or penetrate the network formed by the first polymer. In the present scenario polymers are among the largest vol- Each individual network retains its individual properties umechemicalproductsintheworldandtheglobalmarketfor so synergistic improvements in properties like strength or polymer products is growing rapidly. Polymers have always toughness can be seen [7]. An IPN can be distinguished from been valuable excipients in tablet and capsule formulations polymer blend in the way that an IPN swells but does not [1] and also have shown excellent performance into the dissolve in solvents and creep and flow are suppressed8 [ ]. parenteral arena as blood circulation time enhancers [2] They are also different from graft copolymers and polymer and are now capable of offering advanced and sophisticated complex that involve either chemical bonds and/or low functions such as controlled drug release and drug targeting degree of cross-linking. From this point of view only, IPN can [3]. In the recent decades, an ever growing demand for be generally named “polymer alloys” through which polymer improved polymer properties has paved the development of blends can be made chemically compatible to achieve the the blending of polymer mixtures [4, 5]. In order to overcome desired phase morphology [9]. IPN can be distinguished the poor biological performance and to improve mechanical from the other multiple systems through their bicontinuous strength a new class of polymers has been introduced which structure ideally formed by cross-linking of two polymers are based on blending of either natural or synthetic polymers that are in intimate contact but without any chemical contact alone or in combinations. and yields a material with improved properties depending An interpenetrating polymer network (IPN) is defined as on the composition and degree of cross-linking (Figure 1). a blend of two or more polymers in a network with at least The concept of IPN goes back at least as far as 1914 when one of the systems synthesized in the presence of another [6]. the first interpenetrating polymer network was invented by This results in a formation of physically cross-linked network Aylsworth [10]. This was a mixture of natural rubber, sulphur, 2 Journal of Drug Delivery and partly reacted phenol-formaldehyde resins. The term theyarethermosets.Onewaytoovercomethisproblem IPN was introduced for the first time by Miller in 1960s in is to use latex IPN. They are also called interpenetrating a scientific study about polystyrene networks11 [ ]. Since that elastomericnetworksespeciallywhenbothpolymersare time the field of IPN has expended dramatically. above the glass transition temperature. In latex type IPN Advances in polymer science have led to the development both networks are included in a single latex particle, usually of several novel drug delivery systems. IPNs have shown by polymerization of the second monomer together with superior performances over the conventional individual thecross-linkingagentandactivatorintheoriginalseed polymers and, consequently, the ranges of applications have latex of the first cross-linked monomer [6]. Latex IPNs are grown rapidly for such class of materials. The advanced formed from a mixture of two lattices, frequently exhibiting properties of IPNs have attracted considerable attention in a“core”and“shell”structure.Inasequentialmethod,ifthe pharmaceutical field especially in the area of drug delivery. monomers corresponding to the second polymer react near These biocompatible, nontoxic, and biodegradable polymer the surface of the first polymer, latex IPN with shell/core networks are now acquiring unique place in delivering morphology will be obtained [13]. bioactive molecules, particularly in controlled and targeted drug delivery applications. Various research investigations 2.2.4. Thermoplastic IPN. These IPNs have completely erased have shown that a variety of drugs can be delivered effectively the idea of chemical cross-linkers and use physical cross- via IPN based delivery systems (Table 1). linkers, like thermoplastic elastomers. The thermoplastic IPNs are combination of two physically cross-linked poly- 2. Classification of IPN mers [6, 7]. Typical physical cross-links arise from ionic groups,crystallinity,orglassydomains.Thus,thesematerials 2.1. Based on Chemical Bonding [12] flow at elevated temperatures, similar to the thermoplas- tic elastomers, while behaving like conventional thermoset 2.1.1. Covalent Semi-IPN. When two separate polymer sys- IPNs and at their application temperature usually at least tems that are cross-linked form a single polymer network, it one component is a block copolymer and the other one is called covalent semi-IPN. a semicrystalline or glassy polymer [9]. Depending on the continuity and proportion of phases, this kind of IPNs can 2.1.2. Noncovalent Semi-IPN. In noncovalent semi-IPNs only exhibit a wide range of properties, from reinforced rubber to one of the polymer systems is cross-linked. high impact plastics.

2.1.3. Noncovalent Full IPN. AnoncovalentfullIPNisonein 2.2.5. Gradient IPN. Gradient IPNs have compositions which which the two separate polymers are cross-linked indepen- vary as a function of position in the sample. They are formed dently. as a result of the swelling of the first monomer network in the network of the second monomer. Before equilibrium is 2.2. Based on Method of Synthesis. IPNs are of different types: established a stage comes where swelling is terminated and sequential IPN, subsequent IPN, latex IPN, gradient IPN, and polymerization is carried out to produce the IPN. In this type thermoplastic IPN. of system the concentration of second monomer network has a gradient over the first monomer network [6, 7, 30]. 2.2.1. Sequential IPN. In sequential IPN, the first cross- linked polymer network is swollen by the monomer of the 3. Preparation of IPN second polymer that is polymerized and/or cross-linked afterwards. In this class an IPN is formed by polymerizing 3.1. Casting Evaporation. This method has been used widely the first mixture of monomer (I), cross-linker, and initiator to form cross-linked polymer network. In this method each to form a network. The network is swollen with the second polymer constituent is heated until it is dissolved and then combination of monomer (II) and cross-linker which is added to cross-linker solution [31]. In case of sequential polymerized to form an IPN [6]. Sequential IPNs are easy process, solution of polymer I is added to the cross-linker to synthesize. The primary requirement is that monomer solution followed by addition of polymer II solution. In both (II) and coreactants swell properly into polymer network I. cases the solution is heated and mixed and then casted and Usually elastomers are used for network I because they swell dried. IPN gels can be prepared by this technique. easily compared to glassy network (Figure 2). 3.2. Emulsification Cross-Linking. Thismethodisbasedon 2.2.2. Simultaneous IPN. An IPN is formed by polymer- phase separation. Generally single emulsion cross-linking ization of two different monomer and cross-linking agent technique is based on w/o emulsion but recently w/w emul- pairs together in one step [6, 7]. The key to the success of sion method has also been developed to form IPN [32]. The this process is that the two components must polymerize main advantage of w/w emulsion method is that there is no simultaneously by noninterfering routes (Figure 3). use of organic solvents which might leave toxic residue that is incompatible with IPN biomaterials. 2.2.3. Latex IPN. The common problem associated with most In w/o emulsification method the water soluble materials IPNs is the difficulty in molding after they are formed since are dissolved in aqueous phase at specific temperature to Journal of Drug Delivery 3

(a) (b) (c)

Polymer Ι Polymer Ι Polymer Ι Polymer ΙΙ Polymer ΙΙ Polymer ΙΙ Cross-links Cross-links Cross-links

(d) (e) (f)

Figure 1: (a) A polymer blend; (b) a graft copolymer; (c) a block copolymer; (d) semi-IPN; (e) full IPN; F- cross-linked copolymer.

1 1111 Polymerize Monomer 1 PPolymero network 1

1 1111 Cross-linker 1

2 2 2 2 2 Monomer 2

2 2 2 2 2 Cross-linker 2

2 2

Polymerize 2 2 SwSwell in monomer 2 IPN 2 and cross-linker 2 2

Sequential IPN

Figure 2: Sequential IPN formation. 4 Journal of Drug Delivery

1 1111 Monomer 1

1 1111 Cross-linker 1 Stepwise and chain polymerization

2 2 2 2 2 Monomer 2 Simultaneous IPN

2 2 2 2 2 Cross-linker 2

Figure 3: Formation of simultaneous IPN.

Synthesis of IPN particles from hydrophobic monomers via direct miniemulsion process

Costablizer Initiator Sonication Polymerization Monomer(s)

Surfactant Water

Aqueous and Hydrophobic monomer IPN particles nonaqueous phase dispersed in water dispersed in water

Figure 4: Synthesis of IPN particles by miniemulsion polymerization.

form homogenous solution by stirring. This aqueous phase represents the formation of IPN particles by the process of is added to oil phase to prepare w/o emulsion [33]butin direct (oil in water) miniemulsion polymerization. w/w emulsion technique an aqueous solution of water soluble In case of inverse miniemulsion (water in oil), hydrophilic polymers is emulsified as a dispersed phase in an aqueous monomers can be easily polymerized. In this case the solution of another polymer that acts as continuous phase. monomer solution is miniemulsified in a continuous Then the dispersed polymer phase is cross-linked to form IPN hydrophobic phase. The polymerization process can network [32]. beinitiatedeitherfromthecontinuousphaseorfrom the droplet. Koul et al. synthesized novel IPN nanogels 3.3. Miniemulsion/Inverse Miniemulsion Technique. This composed of poly(acrylic acid) and gelatin by inverse technique allows one to create small stable droplets in a miniemulsion technique. Acrylic acid monomer stabilized continuous phase by the application of high shear stress [34]. around the gelatin macromolecules in each droplet was The idea of miniemulsion polymerization is to initiate the polymerized using ammonium persulfate and tetramethyl polymerineachofthesmallstabilizeddroplets.Toprevent ethylene diamine and cross-linked with N, N-methylene the degradation of miniemulsion through coalescence, a bisacrylamide (BIS) to form semi-IPN nanogels, which were surfactant and a costablizer are added that are soluble in sequentially cross-linked using glutaraldehyde to form IPNs dispersed phase but insoluble in continuous phase. This [35]. process of IPN formation can be divided into three steps. In the first step, constituent polymers are obtained by sonication using specific initiator. In the second step, one of 4. Factors That Affect IPN Morphology the constituent polymers is polymerized and cross-linked using a cross-linking agent. As a result a semi-IPN is formed Most IPN materials that have been investigated show phase till the second stage. In the third step, a full IPN is formed separation. The phase however varies in amount, size, shape, polymerizing and cross-linking the second constituent and sharpness of their interfaces and degree of continuity. polymer by the addition of second cross-linker. Figure 4 These aspects together constitute the morphology of IPN Journal of Drug Delivery 5

Table 1: Delivery of variety of drugs via different IPN based novel carriers.

Therapeutic Drug Carrier system Inference Reference category 5-Fluorouracil and Antimetabolite and Hydrogels Localized drug delivery [14] diclofenac sodium anti-inflammatory Buflomedil Controlled oral delivery of highly water Microspheres [15] hydrochloride soluble drug 5-Fluorouracil Antimetabolite Hydrogels pH sensitivity to localize drug delivery [16] Intestine specific drug release with Diclofenac sodium Anti-inflammatory Microbead [17] minimum gastric side effects of drug Aspirin Anti-inflammatory Microparticles Intestinal specific drug delivery [18] Chlorpheniramine Antihistaminics Beads Controlled drug delivery [19] maleate Ofloxacin hydrochloride Antibacterial Beads Sustained drug release [20] Simvastatin Hypolipidemic IPN beads Controlled drug release [21] Anti-Helicobacter Clarithromycin Hydrogels Stomach-specific drug delivery [22] pylori Prolonged sustained release in simulated Cloxacillin Antibiotic Floating beads [23] gastric fluid Improved drug release in physiological Bovine serum albumin Serum albumin Hydrogel beads [24] saline solution Insulin Hypoglycaemic Microparticles Innovative carrier for oral insulin delivery [25] Cefadroxil Antimicrobial Microgels pH dependent extended drug release [26] Metformin Mucoadhesive Prolonged gastric residence with Hypoglycaemic [27] hydrochloride microspheres sustained release Extended drug release through Prazosin hydrochloride Antihypertensive Hydrogel [28] transdermal route Ciprofloxacin Antibacterial IPN scaffold For quick and regulated wound healing [29] hydrochloride which includes chemical compatibility of the polymers, inter- 5. Typical Pharmaceutical Factors facial tension, cross-linking densities of the networks, poly- 5.1. Mechanical Strength. Mechanical property of IPN is very merization methods, and IPN composition. Compatibility important for pharmaceutical applications. The integrity of between polymers is necessary for IPNs because monomers the drug delivery system during the lifetime of the appli- or prepolymers must be in solution or swollen networks cation is very important, unless the device is designed as during synthesis. Phase separation generally ensues in the a biodegradable system. A drug delivery system designed course of polymerization, but the resulting phase domain to protect a sensitive therapeutic agent must maintain its size is smaller for higher compatibility systems [13]. Increase integrity to be able to protect the therapeutic agent until it incross-linkingdensityofpolymernetworkIinanIPN is released out of the system. Changing the degree of cross- clearly decreases the domain size of polymer II. This effect is linking has been utilized to achieve the desired mechanical reasonable because the tighter initial network must restrict property of the IPN. Increasing the degree of cross-linking thesizeoftheregionsinwhichpolymerIIcanphase- of the system will result in a stronger polymer network [36]. separate. Polymer composition also plays an important role However, a higher degree of cross-linking can create a more in IPN morphology. The IPN composition determines the brittle structure. Hence, there is an optimum degree of cross- relative amounts of the two phases present after polymer- linkingtoachievearelativelystrongIPNbaseddrugdelivery ization. Increase in the amount of polymer II generally system. Copolymerization has also been utilized to achieve leads to increase in domain size, but effect depends upon the desired mechanical properties [37]. method of polymerization [7]. Ratio of viscosity between dispersed phase and the viscosity of matrix also plays an 5.2. Sterilization. Research in the field of IPNs for drug important role in affecting the morphology of IPN. If the delivery applications has been intense in the last decade. minor component of the blend has lower viscosity than a IPN represents a new class of materials with better thermal major component, that component will be homogenously stability than the individual polymer and it is very important dispersed. On the other hand the minor component will be during the processing of the materials and heat sterilization. coarsely dispersed if it has higher viscosity than the major Sterilization capability is a necessary requirement for these component. materialstobeusedindrugdeliveryormedicalapplication. 6 Journal of Drug Delivery

IPN based devices (such as drug delivery vehicles, implants, acid)andgelatinwereevaluatedforinvivobiodegradation etc.) must be prepared under good manufacturing practice and release of gentamicin sulphate by Changez et al. [41]In conditions and sterilized or disinfected (depending upon vivo degradation studies demonstrated that the degradation necessity) before medical use. The sterilization method (wet and drug release depend on the composition of hydrogels. or dry heat, chemical treatment or radiation) should not It was observed that the rate of in vivo degradation of cause structural changes or lead to chain scission, cross- hydrogels was much lower than in vitro degradation. In linking, or a significant alteration in mechanical properties vivo drug release profile showed a burst effect, followed of IPN [38]. The traditional methods of sterilization include by controlled release. Drug concentration was measured the use of dry or moist heat, chemicals (ethylene oxide), or in the local skin tissue, blood serum, kidney, liver, and ∘ radiation. Steam sterilization by autoclaving at 121 Cisthe spleen of male Wistar rats. The concentration of drug in most widely employed method but might induce melting localskintissuewasfoundtobehigherthantheminimum and/or hydrolysis of the polymer matrix, which limits its bactericidal concentration for a study time of 60 days. It use for most of the polymeric materials [39]. Chemical was concluded that these delivery systems may have a good sterilization with ethylene oxide gas offers the advantage of therapeutic potential for the treatment of localized infection effective treatment at ambient temperature and is useful for like osteomyelitis. In another study Changez et al. evaluated hydrolytically unstable polymers. Nevertheless, its popularity theinvivosafetyandefficacyofgentamycinsulphate(GS) is decreasing due to the well-known toxicity and flammability or vancomycin hydrochloride (VCl) loaded IPN device [42]. of ethylene oxide. The placebo and drug-loaded device (acrylic acid: gelatin: High-energy radiation sterilization method has the 1 : 1 w/w) were employed for the treatment of experimental advantage of high efficiency, negligible thermal effects. Poly- osteomyelitis in rabbit. Rabbits were categorized into four mers exhibiting high heats of polymerization tend to cross- groups and were treated with IPN device loaded with varying link upon radiation, indicating an apparent increase in drug concentrations. After implantation of IPN device in mechanical stability with increasing radiation doses [39, 40]. the adjacent tissue of femoral cavity and serum the drug Radiation cross-linking does not involve the use of chemical concentration was measured. On the 7th day maximum additives and therefore retaining the biocompatibility of the drug concentration was found in femoral cavity with all the biopolymer. Also, the modification and sterilization can be devices. No drug was found after 21 days at the local site achievedinasinglestepandhenceitisacost-effectiveprocess with devices containing 12 ± 1mgof22%w/wGSand44% to modify biopolymers having their end use specifically in w/w GS whereas with 16 ± 1 mg device (44% w/w GS or biomedical application. VCl) drug was detected even after 6 weeks. Macroscopic evaluation after treatment revealed that swelling, redness, local warmth, and drainage decreased depending upon the 5.3. Large Scale Production. The major challenge of research drug loading of the implants. Sequential radiographs, histol- and development of IPNs for drug delivery is large scale ogy, microbiologic assay, and scanning electron micrograph production. There is always a need to scale up laboratory or demonstrated that devices containing 16 ± 1mgof44%w/w pilot technologies for eventual commercialization. It is easier GS or 44% w/w GS VCl are the most suitable devices, which to modify IPNs at laboratory scale for improved performance heal the infection after 6 weeks of treatment. None of the than at large scale. Maintaining concentration and compo- IPN devices showed toxic level of drug in serum at any given sition of polymers at large scale is also a challenge. Despite time. the number of researches and patents for IPN drug delivery Kulkarni et al. synthesized pH responsive IPN hydrogel technologies, commercialization is still at its early stage. This beads of polyacrylamide grafted 𝜅-carrageenan and sodium ispartiallyduetothefactthatmostoftheresearchstudiesare alginate for targeting ketoprofen to the intestine and studied carried out by researchers in academia. Nevertheless, greater their in vivo performance for the release of drug to the target effort is needed to bring IPN based drug delivery systems site (intestine) [43]. Stomach histopathology of albino rats from the experimental level to the pilot scale production indicated that the prepared IPN beads were able to retard the and extend their practical applications. This can be achieved drug release in stomach leading to the reduced ulceration, by addressing several aspects, which include boosting the hemorrhage, and erosion of gastric mucosa without any selectivity without compromising biocompatibility and sta- toxicity. bility, optimizing polymer modification techniques, using the proper engineering configurations, understanding the mechanism of transport, and using cost-effective materials and methods. 7. IPN Based Drug Delivery Systems Development of suitable carrier systems for delivery of 6. Preclinical Studies with IPNs active pharmaceuticals always remains a major challenge. New technological advances have brought many innovative A preclinical study is a stage of research that begins before drug delivery systems. A variety of approaches have been clinical trials (testing in humans) and during which impor- investigated for the controlled release of drugs and their tant feasibility, iterative testing, and drug safety data is col- targeting to selective sites including hydrogel, microspheres, lected. The main goals of preclinical studies are to determine nanoparticles, tablet, capsule, and films. Some widely studied a product’s ultimate safety profile. IPNs based on poly(acrylic IPN based drug delivery systems are discussed here. Journal of Drug Delivery 7

7.1. Hydrogel. In recent decades hydrogels have been exten- sustained release characteristics. Xanthan gum facilitated sively used as a smart biomaterial in many biomedical appli- superabsorbent polymeric microspheres by w/o emulsion cationssuchasdrugdeliveryandtissueengineeringbecause cross-linking method which was successfully prepared and of their excellent physical and chemical properties. Hydrogels evaluated for sustained release of ciprofloxacin hydrochlo- are hydrophilic three-dimensional polymeric networks that ride. IPN formation was confirmed by Fourier transform are chemically cross-linked or physically entangled having infrared spectroscopy (FTIR) and X-ray diffraction (XRD) excellent swelling capacity [44]. To improve the properties of analysis. Differential scanning calorimetry (DSC) study was the hydrogel networks, a new class of hydrogels based on the performed to understand the dispersion nature of drug after interpenetration of two-polymer network has been recently encapsulation. In vitro drug release study was extensively developed. IPN hydrogels are a subset of the general class evaluated to observe the sustained drug delivery from IPN of IPNs. IPN hydrogel offers a variety in the formulation of microspheres [48]. In another study an anticancer drug (5 physical forms including microspheres, nanoparticles, and fluorouracil) was successfully encapsulated in carbohydrate films. One of the most outstanding achievements of IPN grafted IPN microspheres to increase the bioavailability. The hydrogels in drug delivery is the development of smart drug resulting IPN microspheres were found to have an ability to delivery systems (SDDS), also called stimuli-sensitive deliv- releasethedrugformorethan12hours[49]. ery systems. The concept of SDDS is based on conversation of physicochemical property of polymer systems upon an environmental stimulus, which includes physical (tempera- ture, electricity, light, and mechanical stress) chemical (pH, 7.3. Nanopar ticles. Polymer based nanoparticles have been ionic strength), or biological (enzymes) signals. Such stimuli developed since the early 1980s, when progress in polymer can be either internal signals (as a result of changes in the chemistry allowed the design of biodegradable and biocom- physiological condition of a living subject) or external signals patible materials for targeting the drug into the desired site (artificially induced). This sensitive behavior of hydrogels [50]. Nanoparticles as a carrier in drug delivery have attracted has sparked particular interest in their use as drug delivery much attention in the last few years and have undergone the vehiclecapableofcontrollingdrugreleaseanddrugtargeting. most investigation in recent years for biomedical applications In a study pH-sensitive IPN hydrogel beads of ibuprofen duetotheirwiderangeofapplicationsincludingtheirsize, were formulated to minimize the release of drug in acidic surface area, magnetic and optical properties, and biological medium and to control the drug release in alkaline medium transportthatarebroughtintotheperspectiveofdrug (phosphate buffer) depending on the need [45]. IPN beads delivery. Recently, there has been increased interest in IPN were prepared by ionotropic gelation process using AlCl3 as nanoparticles for utilization as the smart drug delivery system a cross-linking agent. It was observed that the drug release in in the field of controlled drug release, to meet the demand acidic medium (pH 1.2) was considerably slow and complete for better control of drug administration. The idea of IPN drug release was achieved in phosphate buffer (pH 6.8) within nanoparticles as drug carriers may be employed to modify or 210 to 330 min depending upon the formulation variables. It to control the drug distribution at the tissue, cellular, or sub- can be concluded that pH-sensitive IPN hydrogels could be cellular levels. IPN nanoparticles can be either nanospheres used to target the drug in the desired region. Pescosolido or nanocapsules depending on the method of preparation. et al. reported a novel class of hydrogels based on the Nanospheres are polymeric matrix systems in which the drug interpenetration of two polysaccharide networks. In situ is dispersed within the polymer throughout the particle. forming IPN hydrogels of calcium alginate and dextran On the contrary, nanocapsules are vesicular systems, which hydroxyethyl-methacrylate were developed and evaluated for are formed by a drug-containing liquid core (aqueous or protein release as well as for the behavior of embedded cells. It lipophilic) surrounded by polymeric; thus nanocapsules may wasobservedthatafteraninitialburstreleasebovineserum be considered a reservoir system. albumin was gradually released from the IPN hydrogels for Nanocomposites having antibacterial activity towards up to 15 days. Encapsulation of expanded chondrocytes in Escherichia coli weredevelopedbyKrishnaRaoetal.The theIPNsrevealedthatcellsremainedviableandwereableto chitosan particles were prepared by desolvation followed by redifferentiate. IPN was described as a promising system as cross-linking with poly(ethylene glycol-dialdehyde), which injectable in situ forming hydrogels for protein delivery and was prepared with poly(ethylene glycol) in the presence tissue engineering applications [46]. of a silver nitrate solution. The developed nanocomposites were characterized using UV-visible, FTIR, XRD, SEM, and TEM to understand their physicochemical properties. It 7.2. Microspheres. Microspheres are another promising class was observed that prepared nanocomposites showed good of IPN based drug delivery systems. Microspheres are free antibacterial activity towards E. coli [51]. In a recent study flowing small spherical powder particles made up of natural it was observed that the novel IPN nanoparticles can be or synthetic polymers having diameter in the range of used to form in situ thermogelling devices for controlled 1 𝜇m to 1000 𝜇m[47]. IPN microspheres are considered a protein release. IPN nanoparticles were synthesized by using versatile carrier for controlled release and drug targeting poly(oligo(ethylene glycol) methyl ether methacrylate-co- applications due to their capability to encapsulate a wide oligo(ethylene glycol) ethyl ether methacrylate)-poly(acrylic varietyofdrugs,protectionofdrugs,increasedbioavailability, acid). Atomic force microscopic images confirmed the biocompatibility, patience compliance, biodegradability, and homogenous and monodisperse morphology of the IPN 8 Journal of Drug Delivery nanoparticles. The study demonstrated that the IPN nanopar- and 3,6-anhydrogalactose (3,6 AG), both sulfated and non- ticles exhibit thermogelling properties at body temperature sulfated, joined by alternating 𝛼-(1,3) and 𝛽-(1,4) glycosidic and these IPN nanoparticles allow their ease of injection and links [58]. It is obtained from edible red seaweeds. The then slow release of protein. Histological analysis showed that name carrageenan has been originated from the Chondrus following subcutaneous implantation IPN implants exerted crispus species of seaweed known as carrageen moss or minimal inflammation [52]. Irish moss. There are three basic types of carrageenan— kappa (𝜅), iota (𝜄), and lambda (𝜆). The 𝜆-type carrageenan results in viscous solutions but is nongelling, while the 𝜅- 7.4.Tablets. Mandal et al. developed calcium ion cross-linked type carrageenan forms a brittle gel. The 𝜄-type carrageenan IPN matrix tablets of polyacrylamide-grafted-sodium algi- produces elastic gels [59]. Mohamadnia et al. developed pH- nate and sodium alginate for sustained release of diltiazem sensitive IPN hydrogel beads of carrageenan-alginate for hydrochloride. Formulation of IPN structure was confirmed controlled drug delivery of betamethasone acetate. The effect using FTIR spectroscopy. It was found that the relative of temperature and pH of the preparative media on the magnitude of swelling capacity of IPN matrix and viscosity of drug loading efficiency was investigated. Maximum loading ∘ the gel formed following dissolution of the polymers governs efficiency was observed at pH 4.8 and 55 C. The chemical the drug release from IPN matrix [53]. The application of structure and morphology of the carrageenan IPN hydrogel IPNtabletsforcontrolledreleaseofawatersolubleantihyper- with and without drug was studied using FTIR and SEM tensive drug (propranolol hydrochloride) was investigated analyses [60]. by Kulkarni et al. The IPN tablets were prepared by a wet granulation/covalent cross-linking method. FTIR confirmed the cross-linking reaction and IPN formation, while XRD and 8.3. Alginates. Alginicacidalsocalledalginoralginateisan SEM studies confirmed the amorphous dispersion of the drug anionic polysaccharide found in brown seaweed and marine within the IPN tablets. It was observed that the plain drug algae such as Laminaria hyperborea, Ascophyllum nodosum, was released within 1 hr, while drug release from the resinate and Macrocystis pyrifera [61]. Alginic acid is converted to was prolonged for 2.5 hrs and the IPN matrices showed drug its salt like sodium alginate and potassium alginate. Sodium release up to 24 hrs [54]. alginate has been studied a lot for IPN drug delivery systems. Swamyetal.studiedonthermoresponsivesodiumalginate-g- poly(vinyl carpolactam) IPN beads as drug delivery matrices 8. Some Natural Polymers Used for IPN of an anticancer of an anticancer drug. They reported that the thermoresponsive IPN beads had higher drug release at ∘ ∘ 8.1. Chitin. Chitin is the natural polysaccharide composed 25 C than that at 37 C[62]. In a study pH-sensitive IPN of 𝛽 (1 → 4)-linked 2-acetamido-2-deoxy-𝛽-D-glucose (N- hydrogel composed of a water soluble chitosan derivative acetylglucosamine) [55]. The principle derivative of chitin is (N,O-carboxymethyl chitosan) and alginate was synthesized chitosan. Chitin and chitosan are naturally available polymers by Chen et al. for controlling protein drug delivery. Genipin having excellent properties such as biodegradability, biocom- was used as a cross-linker to form a semi-interpenetrating patibility, nontoxicity, and adsorption. Chitosan based IPN polymeric network within the developed hydrogel system. systems have gained considerable attention as a vehicle for The results clearly suggested that the synthesized IPN hydro- drug delivery systems. A number of chitosan based IPN gel could be a suitable polymeric carrier for site-specific delivery systems have been developed to explore the useful protein drug delivery in the intestine [63]. features of chitosan. Rani et al. reported use of pH-sensitive IPN beads com- 8.4. Xanthum Gum. Xanthan gum is a high molecular posed of chitosan-glycine-glutamic acid cross-linked with weight, anionic extracellular polysaccharide that is produced glutaraldehyde for controlled drug release. It was observed by the gram-negative bacterium Xanthomonas campestris. that the swelling behavior and release of drug depend on It is widely used in food, cosmetics, and pharmaceuticals pH,degreeofcross-linking,andtheircomposition.The because of its encouraging reports on safety. In pharma- results of this study indicated that the IPN beads of chitosan- ceuticalsxanthumgumisusedasthickening,suspending, glycine-glutamic acid might be useful for controlled release and emulsifying agent [64, 65]. Bhattacharya et al. synthe- of drug [56]. In a study Reddy et al. synthesized ghatti sized IPN hydrogel microspheres of xanthan gum based gum and chitosan IPN microparticles by emulsion-cross- superabsorbent polymer and poly(vinyl alcohol) by water- linking method using glutaraldehyde as a cross-linker. IPN in-oil emulsion cross-linking method for sustained release of microparticles were used to deliver diclofenac sodium to the ciprofloxacin hydrochloride. IPN formation was confirmed intestine. Characterization of IPN microparticles was done by FTIR and XRD analysis. It was reported that drug-loaded by SEM, DSC, and FTIR and was evaluated for in vitro drug IPN microspheres were suitable for sustained drug release release. FTIR studies assessed the formation of IPN structure. application [32]. It was found that the drug release from IPN microparticles was extended up to 12 hrs [57]. 8.5. Guar Gum. Guar gum is the powder of the endosperm of the seeds of Cyamopsis tetragonolobus Linn. (Leguminosae) 8.2. Carrageenan. Carrageenan is a high molecular weight [66]. Guar gum has recently been reported as an inexpensive linear polysaccharide comprising repeating galactose units and flexible carrier for oral extended release drug delivery Journal of Drug Delivery 9

[67]. In pharmaceuticals, it is used as tablet binder, sus- [3]W.B.Liechty,D.R.Kryscio,B.V.Slaughter,andN.A. pending, disintegranting, stabilizing, and thickening agent Peppas, “Polymers for drug delivery systems,” Annual Review and also as a controlled release drug carrier. Reddy et al. of Chemical and Biomolecular Engineering,vol.1,pp.149–173, reported chitosan-guar gum based semi-IPN microspheres 2010. for controlled release of cefadroxil. Drug was loaded into the [4] P.Giusti, L. Lazzeri, and M. G. Cascone, “Bioartificial materials,” microspheres and cross-linked with glutaraldehyde, leading in The Polymeric Materials Encyclopedia,J.C.Salomone,Ed.,pp. to the formation of a semi-IPN structure. XRD and DSC 538–549, CRC Press, Boca Raton, Fla, USA, 1996. studies indicated that drug is dispersed at the molecular level [5] M. G. Cascone, “Dynamic-mechanical properties of bioartifi- in the semi-IPN matrix. 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