|Year : 2015 | Volume
| Issue : 2 | Page : 75-86
Interpenetrating polymer network-based drug delivery systems: emerging applications and recent patents
Gupta Somya, Parvez Nayyar, Bhandari Akanksha, Sharma Pramod Kumar
Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
|Date of Submission||14-Nov-2014|
|Date of Acceptance||14-Jan-2015|
|Date of Web Publication||21-Jul-2015|
Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Gautam Buddh Nagar, Greater Noida - 203 201, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Interpenetrating polymer network (IPN) systems use novel polymers that are synthesized by the interlacing of two independent polymers in a cross-linked form. For successful preparation of such IPN systems, at least one of the participating polymers should be synthesized/cross-linked in the immediate presence of the other. The polymers used to fabricate an IPN system are independently cross-linked or cross-linked to each other. They can be prepared by selective combination of the starting polymers to tailor the final product based on the ultimately desired characteristics. The nontoxic nature and biodegradability of natural polymers can thus be combined with the robustness and strength offered by the synthetic polymers by fabricating their IPN systems. The present review aims to summarize the IPN systems in terms of their advantages, disadvantages, and different drug delivery systems based on these polymers and their numerous biomedical applications. This review includes a detailed study of the recent publications and patents describing the use of IPNs in different spheres/formulations.
Keywords: Hydrogel, interpenetrating polymer network, interpenetrating polymer network applications, interpenetrating polymer network patents, microspheres
|How to cite this article:|
Somya G, Nayyar P, Akanksha B, Kumar SP. Interpenetrating polymer network-based drug delivery systems: emerging applications and recent patents. Egypt Pharmaceut J 2015;14:75-86
|How to cite this URL:|
Somya G, Nayyar P, Akanksha B, Kumar SP. Interpenetrating polymer network-based drug delivery systems: emerging applications and recent patents. Egypt Pharmaceut J [serial online] 2015 [cited 2018 Mar 22];14:75-86. Available from: http://www.epj.eg.net/text.asp?2015/14/2/75/161266
| Introduction|| |
The recent advancements in polymeric science have led to the development of many novel drug delivery systems . An interpenetrating polymer network (IPN) is a category of such newly developed bioactive materials that are an emerging tool for the pharmaceutical industry . IPNs play an excellent role because of the improved biocompatibility and safety profiles they offer owing to their physical characteristics such as good swelling properties. They can be useful in various domains of drug delivery, such as improving the solubility of hydrophobic drugs, imparting stability to the formulations containing active drugs, drug targeting a specific tissue, improving bioavailability and biodegradability, etc. . The range of applications for IPNs has grown rapidly as they showcase much finer performance over conventional individual polymers. In the pharmaceutical field, mainly in the field of drug delivery systems, IPNs have attracted considerable attention because of their advanced properties as these novel bioactive polymer networks are biocompatible, nontoxic, and biodegradable in nature, thereby lending substantial advantages particularly in controlled and targeted drug delivery. Through various investigations using different drugs it was observed that IPN systems can be harnessed for safe and effective drug delivery . Synergistic effect can be produced using IPN technology by formulating an IPN between a natural and other synthetic polymer, hence gaining the properties of both polymers and consequently avoiding the drawbacks of both. For example, from many studies it can be concluded that, when a natural polymer is interpenetrated with a synthetic polymer, the IPN system thus obtained is expected to have better capability for the controlled release of drugs under physiological conditions. Thus, in recent times, interest has been focused on the advancement of IPN-based drug delivery systems ,. IPN systems can be simply stated to be a combination of two independent polymers . It is also a combination of at least two polymers, where at least one network is synthesized between two or more networks without any covalent bonds or in the presence of other cross-linked polymer networks leading to interlacing between the two at a molecular level and in turn leading to interlacing between the different features and performances of the individual components . In other words, an IPN is a combination of at least two polymers, exhibiting varied characteristics , in which at least one network is synthesized and/or cross-linked in the presence of the other polymer network without any covalent bonds between them or in the presence of two or more networks . When the polymer chains of the second system are cross-linked with or penetrated in the network formed by the first polymer, a physically cross-linked network is formed. Each network retains its individual properties so that synergistic improvements in properties like strength or toughness can be seen .
Three types of noncovalent physical cross-linking mechanisms are considered to be involved in the formation of IPN polymers:
- Block copolymers based on:
- Glassy blocks.
- Crystalline blocks.
- Hydrogen bonded blocks.
- Ionomeric sites.
- Entrapment of crystalline regions in semi crystalline homopolymers .
IPN systems are also termed as 'Hungary Network'. These intelligent polymers are a focus of considerable current scientific research because of their potential technological applications in various fields such as medicine, industry, biology, and environmental cleanup. Some of the important biomedical applications of IPNs are in artificial implants, dialysis membranes, drug delivery systems, burn dressing, etc. .
Basis of selection of polymers for formulating a successful interpenetrating polymer network system
- The kinetic profiles of the two polymers should be similar.
- One polymer is cross-linked and/or synthesized in the presence of the other polymer.
- The two polymers are not markedly phase separated.
IPNs that have only one cross-linked polymer (when the polymers are synthesized separately) or have polymers with vastly different kinetics are still considered IPNs.
IPNs in which the polymers have a vast difference in their kinetics or one polymer is cross-linked or both polymers are synthesized separately are also considered to be IPNs .
A pictorial representation of the basic structure of IPNs is given in [Figure 1].
| Advantages of interpenetrating polymer network|| |
IPN technology is gaining huge popularity because of its following inherent merits :
- An IPN can combine the synergistic properties of both polymers such that when one natural polymer is interpenetrated/cross-linked with the other synthetic polymer the resultant IPN can be better used for the controlled release of the drug ,, and the drug can be expected to be immobilized .
- Whenever an IPN hydrogel is formed from two polymers at a given temperature, the possibility of physical phase separation between the component polymers is almost negligible because of the infinite zero viscosity of the gel.
- The phase stability of the final product is greatly enhanced and it has greater biological acceptability.
- Mechanical properties of the final product are profoundly enhanced  because of the combination of both natural and synthetic polymers.
- The separated phases remain together as when they are subjected to stress .
| Disadvantages of interpenetrating polymer network|| |
A disadvantage associated with the use of the IPN is that sometimes the polymers are interpenetrated to such an extent that it becomes difficult to release the active drug from the polymer matrix . Moreover, the quality of the final polymer obtained is highly susceptible to various in-process parameters like the reaction mechanism, reactor-type, and reactor operating conditions . One of the problems encountered may be the lack of effective interface stemming from various factors including the surface energy phenomenon and lack of molecular interaction between phases .
[Figure 2] shows the process of formation of an IPN system between chitosan, a natural polymer obtained from shrimp and other crustacean shells, and the synthetic polymer polyacrylamide often used as a thickener and suspending agent in pharmaceutical applications.
|Figure 2: Schematic representation of the formation of an interpenetrating polymer network (IPN) structure .|
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Interpenetrating polymer network-based drug delivery systems
IPN-based systems are mainly used for the controlled release of drugs. Various drug delivery systems have been developed that use IPNs.
Using the novel IPN technique, mucoadhesive microspheres of locust bean gum (LBG) and polyvinyl alcohol (PVA) were prepared by means of the water-in-oil (w/o) emulsion cross-linking method. These mucoadhesive microspheres were cross-linked with glutaraldehyde (GA) to deliver a model oral hypoglycemic drug for prolongation of gastric residence time. These microspheres were then evaluated through Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM), and the mean particle size of the microspheres was measured by optical microscopy. Percentage mucoadhesion of the microspheres showed a dependence on the LBG: PVA ratio and extent of cross-linking. In-vitro release studies were performed in 0.1 N HCl buffer solution at pH 1.2 to investigate the controlled release nature of the microspheres. The release of metformin HCl was sustained for up to 8 h .
Buflomedil hydrochloride, a vasodilator drug having high water solubility, has also been administered as a microsphere drug delivery agent by using IPN microspheres based on LBG and PVA fabricated by means of the emulsion cross-linking technique and GA as the cross-linker for oral controlled release. The effects of the gum-polymer ratio, concentration of cross-linker, and internal phase viscosity were then evaluated on the basis of various characteristics like the drug entrapment efficiency, particle size distribution, swelling property, and in-vitro characteristics, along with kinetic modeling of microspheres. The microspheres were also characterized by SEM, FTIR, solid-state 13 C-NMR, X-ray diffraction study, and differential scanning colorimetry (DSC). The prepared microspheres showed controlled release property without any incompatibility in the IPN device. Hence, IPN microspheres of LBG and PVA can be used successfully as a potential carrier for controlled oral delivery of highly water-soluble drugs .
IPN-based microspherical drug delivery systems have also been used for the delivery of antineoplastic drugs such as capecitabine to prolong the delivery of the drug by formation of a chitosan-polyethylene oxide-g-acrylamide intermolecular rigid network . [Table 1] summarizes the microsphere formulations developed using IPN systems.
|Table 1: Interpenetrating polymer network-based polymers for formulation of microspheres|
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Transdermal membranes or patches
IPN hydrogel membranes of sodium alginate and PVA embedding an antihypertensive drug, prazosin hydrochloride, were prepared by means of the solvent casting method for transdermal drug delivery. The prepared membranes were thin, flexible, and smooth. X-ray diffraction studies showed amorphous dispersion of drug in the membranes. DSC analysis was used to confirm the IPN formation. An interesting observation was recorded in that, on increasing the concentration of GA, membrane stiffness also increased. The membrane's permeability to water vapor was found to be dependent on the extent of cross-linking. In-vitro designing of hydrogels for site-specific oral delivery in the stomach and upper intestine is possible .
Semi-interpenetrating polymer network (SIPN) membranes were prepared for an antiasthmatic drug (salbutamol sulfate) using PVA, chitosan, and sodium alginate and GA as a cross-linker. Mechanical properties such as tensile strength and elongation of the membranes were determined, along with permeability properties and drug entrapment efficiency. Using Keshary-Chien diffusion cells, the in-vitro drug release profile was determined. In the PVA membranes (pure), the rate of swelling and water vapor transmission were high compared with their IPNs. The result indicated that blending of PVA with other polymers and cross-linking with GA led to higher entrapment efficiency. The drug release profiles showed that the drug permeated through the membranes for up to 20 h . Various examples of hydrogel membranes formulated using IPNs are given in [Table 2].
|Table 2: Hydrogels membrane synthesized using interpenetrating polymer networks|
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In studies examining the effect of polyethylene oxide (PEO) on the swelling behavior and enzyme-induced degradation in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.2) at 37°C of SIPN-based hydrogels, it was found that the surface degradation of the hydrogel decreases the diffusional path length of the drug for faster release as the gel degrades. By varying the PEO molecular weight and amount in gelatine-PEO SIPN, designing of hydrogels for site-specific oral delivery in the stomach and upper intestine is possible .
SIPNs of PVA and polymethacrylic acid were prepared by free radical polymerization of methacrylic acid in the presence of PVA using N,N-methylene-bis-acrylamide as the cross-linking agent. The effect of cross-linking agent and methacrylic acid concentrations on the swelling and release characteristics was evaluated. Insulin was incorporated by the active loading technique in the SIPN hydrogels. The formulations showed decreased insulin release in pH 2.0 buffer, whereas complete release was seen in pH 7.4 buffer. From the studies it can be concluded that SIPNs of PVA/PMMA can be explored for protein delivery, which can protect the protein against the harsh environment of acidic pH but releases the drug in the distal part of the intestine where the enzymatic activity is comparatively low .
IPN-based hydrogel was prepared using soy protein and polysodium acrylate and was characterized by FTIR, SEM, DSC, and thermogravimetric analysis (TGA) and investigated for swelling and deswelling behavior. The swelling behavior, water retention, pore size, and pore wall thickness of the hydrogel were controlled by changing the content of soy protein or cross-linker. The swelling ratio was low at pH 1.2 and the fastest to reach equilibrium, whereas when the swelling ratio increased to above pH 4.0 it showed non-Fickian diffusion and below pH 4.0 it showed Fickian diffusion. Thus, the results reveal that novel IPN hydrogels can be of interest in IPN-based drug delivery systems .
Certain examples of hydrogels formulated using IPN polymers are summed up in [Table 3].
|Table 3: Hydrogels formulated using interpenetrating polymer network systems|
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By using the IPN system, alginate-gelatin microgels were prepared containing tramadol as an active drug by the chemical cross-linking technique with GA as the cross-linking agent. Microgels were then evaluated for various parameters using FTIR, DSC, etc. The mucoadhesive properties of microgels were evaluated in aqueous solutions by measuring the mucin adsorbed on microgels. The dependence of drug release on the extent of cross-linking and the amount of gelatin used in preparing IPNs were determined by the in-vitro release studies. The release rates were then fit to Higuchi's model to compute the various drug transport parameters, which suggest that the release may vary from Fickian to quasi-Fickian depending upon variation in the formulation composition  as summarized in [Table 4].
Novel IPN-based nanogels composed of polyacrylic acid (PAA) and gelatin were synthesized using the inverse miniemulsion technique. This concept was based on nanoreactors and cross-checked with the template polymerization technique. The gelatin macromolecules were stabilized by acrylic acid monomer in which each droplet was polymerized using ammonium persulfate and tetramethyl ethylene diamine in 1: 5 ratio and SIPN nanogels were formed when cross-linked with N, N-methylene bisacrylamide and when cross-linked sequentially with GA (Glu) to form IPNs. For the formation of homopolymer, SIPN and an FDA-approved surfactant were used to produce an IPN nanogel, acrylic acid stable gelatine. The droplets were observed in 2% surfactant concentration. Spherical IPN nanogels thus prepared were studied using dynamic light scattering and SEM to rule out any interactions and changes in crystal structure of the polymers. Similarly, SIPNs prepared by the same method, but in great shape, formed nanogels. The presence of interpenetrated polymer component on the surface of the nanogels can be detected by using methods like XPS measurement, infrared spectroscopy (FTIR) and zeta potential measurement etc. Thus, these nanogels were used in cancer targeting .
With the use of micron-sized colloidosomes of polymethyl methacryalate-co-divinylbenzene microgels as reaction vessels, we can prepare supracolloidal IPN-reinforced capsules. By using the technique of radical polymerization of the interior phase, an IPN as scaffold is generated, to produce hollow supracolloidal structures with a raspberry core-shell morphology .
Sponges prepared by SIPNs of the polymers. Poloxamer and chitosan (CS) are being increasingly used for wound dressing. Possible interactions between the CS and poloxamer in SIPNs and changes in crystalline structures of both polymers were evaluated by FTIR and X-ray diffraction, respectively. Formation of SIPNs with poloxamer remarkably increased the water content of CS because of the hydrophilicity of CS and the poloxamer. These studies suggest that CS/poloxamer sponges can be prepared by the SIPN method and may have potential in wound dressing application owing to the rapid water adsorption, high mechanical strength, and interconnected cross-sectional morphology of SIPNs .
In experimental studies it was found that SIPNs composed of silk fibroin (SF) and polyethylene glycol (PEG) can be prepared by photopolymerization of a PEG macromer in the presence of SF to improve the mechanical properties of the SF sponge, which can be used in wound dressing. The morphological structure of the SF/PEG SIPNs was observed to be composed of an interconnected microporous surface and a cross-sectional area. SF/PEG SIPNs showed noncytotoxicity evaluated by a cell proliferation method using L929 fibroblasts. Wound contraction treated with SF/PEG SIPN sponges was faster than that treated with vaseline gauze as a control. Histological observation confirmed that the deposition of collagen in the dermis was organized by covering the wound area with SF/PEG SIPNs. The above results showed that SF/PEG SIPNs could be used in wound dressing .
Cross-linked sponges have been prepared by freeze-drying amorphous alginate-oxidized nanocellulose in the presence of ionic Ca 2+ as a cross-linker. On the surface of nanocellulose a new carboxyl group was introduced by chemical oxidization, which played a role in the formation of an alginate-based sponge structure, providing the structural and mechanical stability of sponges. Further, mechanical strength was induced by oxidized cellulose nanocrystals. The improved compression strength of cross-linked sponges as a result of ultrahigh porosity, promising water absorption and retention, can extend the use of this soft material in various practical applications .
Using the technique of temperature-responsive IPN formation, thermally active metal nanoshells are produced in which therapeutic drugs are dispersed and released upon radiation-induced heating of the metal nanosphere. IPN devices that swell in response to increase in temperature can be successfully used to safely localize and release therapeutic levels of potent drugs. However, to be effective in vivo the heating source has to meet several requirements such as being small in size (300 nm in diameter) so as to fit within therapeutic agents and being able to heat through a safe noninvasive external trigger so that it is capable of reaching the nanoshell at high penetration depths in vivo. The first and outermost layer of composite nanoparticles is the PEG or surface PEG layer. This process is commonly referred to as PEGylation, and involves either the adsorbing or the grafting of PEG chains to a material's surface. PEGylation allows materials in the form of polymeric nanoparticles that filter out of the blood immediately after injection to remain in circulation for hours and even days. The more these nanoparticles remain in circulation, the more chances they have to interact with tissues and desirable components in the body. These nanoparticles can be used in the field of cancer treatment .
Nanoparticles are a recent focus of interest among scientists because of the innumerable benefits they offer over conventional dosage forms. Formulating IPN-based nanoparticles to combine the best of both worlds is a recent trend. A summary of such nanoparticle formulations is given in [Table 5].
|Table 5: Nanoparticles formulated using interpenetrated polymer network systems|
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Synthesized and characterized IPN-based natural polymer curcumin films for accelerating the rate of wound healing were prepared using natural polymers like chitosan, hypromellose, citric acid, and genipin. This helped in developing an effective, biodegradable, and biocompatible film and the physicochemical, biological and mechanical properties of the same SIPN film were evaluated by employing FTIR, DSC and Young's modulus studies. Further in-vitro and ex-vivo studies were also performed. Results showed that, when in contact with the dissolution medium, the release of drug occurred at the rate of 1.1 mg during the first hour because of burst release, followed by the release of 2.23 mg of the drug due to bioactive permeation through the skin. Thus, the lipophilic nature of the skin had a great impact on the release rate. Properties of the film were greatly influenced with the degree of cross-linking and concentration of polymeric material .
Full-IPN films of PAA/PVA were developed by radical solution polymerization and sequential IPN technology. The film was investigated for various physical and chemical properties. New hydrogen bonds between PVA and PAA were formed, which were shown by FTIR spectrum analysis. The swelling property of the film in distilled water and different pH buffer solution was studied and showed increased swelling ratio on increasing PAA content of the IPN film in all media; the swelling ratio decreased with increasing PVA cross-linking. The constitution of IPN and the swelling ratio of IPNs formed the basis of the tensile strength and elongation at break. The mechanical property of GA (0.5%) for PVA was better. The DSC of the IPN film depicted a single glass transition temperature (Tg) for each sample, and Tg data showed a linear relationship with the network composition. PAA and PVA showed good compatibility and miscibility. The potentiality of IPN films in controlled drug delivery was examined using crystal violet as a model drug. The increase in drug release rate was higher at 37°C than at 25°C for all IPNs and slightly increased with decreasing PAA .
Films designed for various therapeutic purposes based on the use of the novel interlacing polymer systems are given in tabular form in [Table 6].
Sustained release cross-linked SIPN xerogel matrix tablets were developed by chemical cross-linking of PEO and gellan gum and epichlorohydrin as cross-linker. To confirm the ideal combination of native polymer and cross-linking agent, a Box-Behnken design was used for the statistical optimization of the matrix system. Formulated matrix tablets showed zero-order release kinetics for 24 h. Swelling and surface erosion were the primary mechanisms for the drug release. A comparison was made of the cross-linked SIPN xerogel matrix tablet with the non-cross-linked polymer. Results showed that the physicochemical properties of the PEO and GG were modified for controlled release of sulpiride with 100% drug release at 24 h in a sustained manner compared with non-cross-linked formulations. Surface morphology of the cross-linked system revealed a porous structure formed by an IPN, which allowed a greater degree of controlled penetration into the system, ascertaining its ability to sustain the drug release. Therefore, from the study it was concluded that the release of sulpiride was sustained from the hydrophilic SIPN xerogel matrix system using PEO-GG as the cross-linker .
The IPN technique was used with xanthan gum, which was derivatized to carboxymethyl xanthan gum, which was then further cross-linked in situ with Ca 2+ ions during wet massing for preparing tablets of prednisolone. The study showed no drug-polymer interactions. In-vitro release depicted that increasing the amount of Ca 2+ ion decreased the drug release but that beyond a certain amount the drug release was increased; in contrast, increasing the exposure time in acid solution of pH 1.2 increased the overall release of the drug, which followed the non-Fickian mechanism of drug release. Therefore, it can be concluded that fluctuation in the amount of Ca 2+ ion modulates the drug release from carboxymethyl xanthan gum matrix tablets .
| Novel biomedical applications of the interpenetrating polymer network-based drug delivery system|| |
Repair and regeneration of living organs : Scientists have recently developed several novel systems based on the principle of double network (DN) hydrogels . Some tough hydrogels fabricated by DN techniques also exhibit good biocompatibility and low friction resistance with promise in industrial and pharmaceutical sectors, especially for load-bearing artificial soft tissues such as artificial cartilage . Specifically, cellulose-based DN gel and liquid crystalline DN gel exhibit anisotropic mechanical property, which is highly important for anisotropic functioning in the living organism . Poly (N,N0-dimethylacrylamide)[PDMAAm], when implanted in a living body (rabbit), was found to hardly degrade , and induced negligible inflammation  and spontaneously generated an excellent articular/hyaline cartilage repair without the use of exogenous cells and without fulfilling the osteochondral defect. Recent studies showed that DN gels have good biocompatibility and are a good scaffold for cells cultured on the surface. However, a tough scaffold for three-dimensional cell culture development is also required as it can mimic some cell growth in typical environments such as the chondrocyte in biological cartilage. Further, it would be beneficial to implant the artificial tissues cultured with cells in the body to help the repair and regeneration of living organs .
Protein delivery and tissue engineering: A novel class of hydrogels based on the interpenetration of two polysaccharide networks can be utilized for protein delivery. It is shown that SIPNs and IPNs-based Alg-Ca and hydroxyethyl-methacrylate-derivatized dextran (dex-HEMA) can be suitable for in-situ hydrogel-forming applications. IPN beads seeded with equine chondrocytes showed good cell survival and differentiation. They facilitate chondrogenic differentiation. IPNs based on Alg-Ca and dex-HEMA can be potentially applied in regenerative medicine and can be further optimized to enhance specific tissue formation by embedded cells. Thus, IPNs can be promising systems as injectables in situ forming hydrogels for protein delivery and tissue engineering .
Infectious diseases: The localized treatment of infections can be scientifically improved by site-specific antibiotic drug delivery systems, as due to the failure of conventional treatment pH-sensitive polymers have been frequently used to develop the controlled release formulations using the IPN technique. IPN hydrogels prepared by the cross-linking process showed greater swelling, mucoadhesion, and drug release at lower pH values and maintained antibiotic concentration for prolonged periods of time. Thus, hydrogels formed by using the IPN technique can be used as a drug delivery system for treatment of infections .
Wound healing management: In a study with the use of natural polymer cellulose pulp, a SIPN hydrogel cell/PEG/poly (sodium alginate) was formed by free radical polymerization when the cellulose pulp dissolved in PEG/NAOH solvent system was polymerized in the presence of monomer acrylic acid with N,N'-methylene bisacrylamide added as a cross-linker. Water uptake studies for the prepared hydrogels using a buffer of pH 7.4 at 37°C showed that the swelling property of hydrogels was governed by various parameters. The presence of salt in the swelling medium also affects the equilibrium percentage swelling of hydrogel. Thus, the hydrogel system has new possibilities in drug delivery and healing management .
Tissue scaffolds: PVA/GE hydrogels based on the IPN structure and prepared by the enzymatic and cyclic freeze-thawing method have shown promise as tissue scaffolds. The size and arrangement of the pores are the result of the number of freeze-thaw cycles and the presence of cross-linking agents. The IPN PVA/GE hydrogels showed excellent physical and mechanical properties, which met ideal medical applications. Because of the swelling property of hydrogels, they exhibited high capability in absorbing fluids and thus can be used for exudative wounds. Appropriate morphology and good proliferation is displayed when fibroblasts are grown over cells treated with extract solutions. Thus, the gels with a cross-linked network structure were stable enough, suggesting that developer scaffolds might be used in tissue engineering .
Medical implant: Researchers have focused attention on the development of methods for repairing an orthopedic joint, including replacing natural cartilage with water-swellable IPN or SIPN having a hydrophobic thermoset or thermoplastic polymer and an ionic polymer and engaging the IPN or SIPN with a bone surface defining the joint. The method may also include the step of inserting bone a stem portion into the bone surface. Thus, the shape of an IPN or SIPN was selected from a group consisting of a hat, a cup, a plug, a mushroom, a stem, and a patch, and it could be customized to fit a condyle, tibial plateau, meniscus, labrum, or glenoid .
Ophthalmic application: An IPN-based PEG/PAA hydrogel sufficiently permeable to glucose is used in ophthalmic applications - for example, in implant material such as keratoprostheses and intracorneal lens for corneal transplants. Thus, IPN-based hydrogels allow the passage of glucose from the aqueous humor to the epithelium in vivo. The results indicated that permeable substrates for ophthalmic and other biomedical purposes created using the PEG/PAA IPN system can be a promising candidate for ophthalmic applications .
Cancer therapy: IPN nanoparticles as a novel temperature-responsive agent can be used in formulating an intelligent therapeutic system capable of loading and releasing the therapeutic agent in response to controlled temperature fluctuations. More, specifically PEGylation is advantageous for the polymeric material in the case of treatment of neoplasms due to the inherent nature cancerous tissues to have leaky vasculature. 'Stealth' nanoparticles or long circulating PEGylated nanoparticles accumulate in tumors because of their preferential extravasations through this leaky vasculature. Thus, surface PEG chains could be functional with antibodies, peptides, or other ligands to achieve active targeting of integrins, growth factors, and receptors that are upregulated in tumors. Thus, IPN-based nanoshells can be used for the leaky vasculature of cancer .
Control of obesity: Obesity could be controlled by an IPN-based phase-transition gel of PAA by absorption of fat from the intestinal tract. As they enter the gastrointestinal tract, they can absorb cholesterol from the digested food. Because of the high level of cholesterol, the interaction of cholesterol and the phase-transition gel results in expansion of the gel and thereby the gel absorbs the cholesterol and inhibits absorption through the gut wall. By incorporation of bile salts, cholesterol and dietary fat can be removed from the system . Some of the other interesting applications of IPN systems are summarized in [Table 7].
|Table 7: Miscellaneous applications of interpenetrating polymer network systems|
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A study was conducted on the recent patents based on application of IPN systems for biomedical and therapeutic purposes. A detailed description of the recent patents based on application of IPN systems is given in [Table 8].
| Conclusion|| |
In this review article efforts were made to summarize different IPN-based drug delivery systems as they have been employed in the development of various dosage forms such as tablets, capsules, microspheres, transdermal films, wound dressings, hydrogels, etc. The review also focuses on the multidimensional applications of interpenetrating systems in diverse fields like tissue scaffolds, protein delivery to controlling hypercholesterolemia, and regeneration of living organs. The basic benefit of IPN systems is that there is freedom to engineer the desired qualities by selecting the polymers carefully by the IPN approach. The use of these systems in chemotherapy, protein delivery, and tissue regeneration requires further research and may prove to be of strategic importance in the future. Moreover, it can be concluded that IPN systems can be used as a carrier system providing better treatment options, eradicating various pathological diseases, and can serve as a better candidate for the treatment of various diseases.
| Acknowledgements|| |
The authors thank the Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, and NISCAIR (National Institute of Science Communication and Information Resources), New Delhi, India, for providing library facilities for the completion of this paper.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lohani A, G Singh, SS Bhattacharya, A Verma. Interpenetrating polymer networks as innovative drug delivery system. J Drug Deliv 2014; 2014:583612.
Shidhaye S, Surve C, Dhone A, Budhkar T. Interpenetrating polymer network - an overview. Int J Res Rev Pharm Appl Sci 2010; 2:637-650.
Patel JM, Savani HD, Turakhiya JM, Akbari BV, Goyani M, Raj HA. Interpenetrating polymer network (IPN): a novel approach for controlled drug delivery. Univers J Pharm 2012; 01:1-11.
Murugesh S, Mandal BK. A review on interpenetrating polymer network. Int J Pharm Pharm Sci 2012; 4:1-7.
Itokazu M, Yamamoto K, Yang WY, Aoki T, Kato N, Watanabe K. The sustained release of antibiotic from freeze-dried fibrin-antibiotic compound and efficacies in a rat model of osteomyelitis. Infection 1997; 25:359-363.
Kawaguchi H. Functional polymer microspheres. Prog Polym Sci 2000; 25:1171-1210.
Naught AD Mc, Wilkinson A. IUPAC compendium of chemical terminology
. 2 nd ed. Oxford, UK: The Gold Book, Blackwell; 1977.
Sperling LH. Interpenetrating polymer networks and related materials. J Polym Sci Macromol Rev 1977; 12:141-180.
Siegfried David L, Thomas David A, Sperling Leslie H. Thermoplastic interpenetrating polymer network composition and process. 1984; US 4468499 A.
Ignat L, Stanciu A??. Advanced polymers: interpenetrating polymer networks. In handbook of polymer blends and composites 2011; AK Kulshreshtha, C Vasile, Eds., 2011; 3:275-280.
Singh P, Kumar S, Keerthi TS, Tamizh M, Getyala A. Interpenetrating polymer network (IPN) microparticles, an advancement in novel drug delivery system: a review. Int J Pharm Sci 2012; 3:1826-1837.
Crouch RD, Clay SB, Oskay C. A review on interpenetrating polymer network. Int J Pharm Pharm Sci 2012; 5:1-7.
Pater, Ruth H. Interpenetrating polymer networks high performance
. New York: VCH Pub; 1990. 377-401.
Klempner D, Sperling LH, Utracki LA. Interpenetrating polymer networks advances in chemistry
. Washington, DC: American Chemical Society; 1994.
Jain N, Banik A, Gupta B. Novel interpenetrating polymer network microspheres of Lepidium sativum
and poly (vinyl alcohol) for the controlled release of simvastatin. Int J Pharm Pharm Sci 2013; 5:125-130.
Margaret Mercy T, Brahmaiah B, VamsiKrishna P, Revathi B, Nama S. Interpenetrating polymer network (IPN) microparticles. An advancement in novel drug delivery system: a review. Int J Pharm Res Biosci 2013; 2:215-224.
Kiparissides C. Polymerization reactor modelling: a review of recent development and future directions. Chem Eng Sci 1996; 51:1637-1659.
Lakshman Kumar P, Siva Prasad SNV, Srinivas M, Brahmaiah B, Nama S. Interpenetrating polymer network (IPN) microparticles. An advancement in novel drug delivery system: a review. J Pharm Biol 2013; 3:53-57.
Bhardwaj V, Kumar S. Design and characterization of novel interpenetrating polymer network mucoadhesive microspheres of locust bean gum and PVA for controlled release of metformin HCl. Int Pharm Sci 2012; 2:115-121.
Kaity S, J Issac, Ghosh A. Interpenetrating polymer network of locust bean gum-poly (vinyl alcohol) for controlled release drug delivery. Carbohydr Polym 2013; 94:456-467.
Agnihotri SA, Aminabhavi TM. Novel interpenetrating network chitosan-poly(ethylene oxide-g-acrylamide) hydrogel microspheres for the controlled release of capecitabine. Int J Pharm 2006; 324:103-115.
Banerjee S, Chaurasia G, Pal D, Ghosh AK, Ghosh A, Kaity S. Investigation on crosslinking density for development of novel interpenetrating polymer network (IPN) based formulation. J SciInd Res 2010; 69:777-784.
Rokhade AP, Kulkarni PV, Mallikarjuna NN, Aminabhavi TM. Preparation and characterization of novel semi-interpenetrating polymer network hydrogel microspheres of chitosan and hydroxypropyl cellulose for controlled release of chlorothiazide. J Microencapsul 2009; 26:27-36.
Risbud MV, Hardikar AA, Bhat SV, Bhonde RR. pH-sensitive freeze-dried chitosan-polyvinyl pyrrolidone hydrogels as controlled release system for antibiotic delivery. J Control Release 2000; 68:23-30.
Angadi SC, Manjeshwar LS, Aminabhavi TM. Interpenetrating polymer network blend microspheres of chitosan and hydroxyethyl cellulose for controlled release of isoniazid. Int J Biol Macromol 2010; 47:171-179.
Dandagi P, Mastiholimath V, Gadad A, Lliger S. Mucoadhesive microspheres of propanolol hydrochloride for nasal delivery. Indian J Pharm Sci 2007; 69:402.
Al-Kahtani AA, Sherigara BS. Controlled release of theophylline through semi-interpenetrating network microspheres of chitosan-(dextran-g-acrylamide). J Mater Sci Mater Med 2009; 20:1437-1445.
Kajjaria Praveen B, ManjeshwarLata S, Aminabhavi TM. Novel interpenetrating polymer network hydrogel microspheres of chitosan and poly (acrylamide)-grafted-guar gum for controlled release of ciprofloxacin. Ind Eng Chem Res 2011; 50:13280-13287.
Ramakrishna P, Rao Madhusudana K, Sekharnath KV, Kumarbabu P, Veeraprathap S, Rao Chowdoji K, et al.
Synthesis and characterization of interpenetrating polymer network microspheres of acryl amide grafted carboxymethylcellulose and sodium alginate for controlled release of triprolidine hydrochloride monohydrate. J Appl Pharm Sci 2013; 3:101-108.
Jain N, Sharma P, Banik A, Gupta A, Bharadwaj V. Pharmaceutical and biomedical applications of interpenetrating polymer network. Curr Drug Ther 2011; 6:263-270.
Kulkarni Preeti V, Keshavay AJ. Preparation and evaluation of polyvinyl alcohol transdermal membranes of salbutamol sulphate. Int J Current Pharm Res 2010; 2:13-15.
Kulkarni RV, Sreedhar V, Mutalik S, Setty CM, Sa B. Interpenetrating network hydrogel membranes of sodium alginate and poly (vinyl alcohol) for controlled release of prazosin hydrochloride through skin. Int J Biol Macromol 2010; 47:520-527.
Amiji M, Tailor R, MK Ly, G Joseph. Gelatin-poly (ethylene oxide) semi-interpenetrating polymer network with pH-sensitive swelling and enzyme-degradable properties for oral drug delivery. Drug Dev Ind Pharm1997; 23:575-582.
CS Satish, HG Shivakumar. Dynamic swelling and in vitro
release of insulin from semi-interpenetrating polymer networks of poly (vinyl alcohol) and poly (methacrylic acid). Indian J Pharm Sci 2007; 69:58-63.
Liu Y, Cui Y, Yin G, Luo L. Preparation and properties of novel pH-sensitive soy protein/poly (sodium acrylate) interpenetrating polymer network hydrogels. J Biobased Mater Bioenerg 2009; 3:437-442.
Vaghani SS, Patel MM. pH-sensitive hydrogels based on semi-interpenetrating network (semi-IPN) of chitosan and polyvinyl pyrrolidone for clarithromycin release. Drug Dev Ind Pharm 2011; 37:1160-1169.
Pillai JJ, Thulasidasan AK, Anto RJ, Chithralekha DN, Narayanan A, Kumar GS. Folic acid conjugated cross-linked acrylic polymer (FA-CLAP) hydrogel for site specific delivery of hydrophobic drugs to cancer cells. J Nanobiotechnol 2014; 1:12-25.
Yin L, Ding J, Fei L, He M, Cui F, Tang C, Yin C. Beneficial properties for insulin absorption using superporous hydrogel containing interpenetrating polymer network as oral delivery vehicles. Int J Pharm 2008; 350:220-229.
Gupta AK, Maurya SD, Dhakar RC, Singh RD. pH-sensitive interpenetrating hydrogel for eradication of Helicobacter pylori
. Int J Pharm Sci Nanotechnol 2010; 3:924-932.
H Eltanji-Eltahir, Li X. Interpenetrating polymer network Hydrogels based on gelatin and PVA by biocompatible approaches: synthesis and characterization. Adv Mater Sci Eng 2013; 328763:1-9.
Bajpai SK, Swarnkar MP. New semi-IPN hydrogels based on cellulose for biomedical applications. J Polym 2014; 376754:1-12.
Maiti S, Chowdhury M, Chakraborty A, Ray S, B Sa. Sulfated locust bean gum hydrogel beads for immediate analgesic effect of tramadol hydrochloride. J Sci Ind Res 2014; 73:21-28.
Kumar P, Singh I. Formulation and characterization of tramadol-loaded IPN microgels of alginate and gelatin: optimization using response surface methodology. Acta Pharm 2010; 60:295-310.
Koul V, Mohamed R, Kuckling D, Adler HJ, Choudhary V Interpenetrating polymer network (IPN) nanogels based on gelatin and poly(acrylic acid) by inverse miniemulsion technique: synthesis and characterization. Colloids Surf B Biointerfaces 2011; 83:204-213.
Bon SAF, Cauvin S, Colver PJ. Colloidosomes as micron-sized polymerisation vessels to create supracolloidal interpenetrating polymer network reinforced capsules. Soft Matter 2007; 3:194-199.
Kim IY, Yoo MK, Kim BC, Kim SK, Lee HC, Cho CS. Preparation of semi-interpenetrating polymer networks composed of chitosan and poloxamer. Int J Biol Macromol 2006; 38:51-58.
Kweon H, Yeo JH, Lee KG, Lee HC, Na HS, Won YH, Cho CS. Semi-interpenetrating polymer networks composed of silk fibroin and poly(ethylene glycol) for wound dressing. Biomed Mater 2008; 3:034115.
Lin N, Bruzzese C, Dufresne A. TEMPO-oxidized nanocellulose participating as crosslinking aid for alginate-based sponges. ACS Appl Mater Interfaces 2012; 4:4948-4959.
Owens Donald E, Peppas Nicholas A. Gold sulphide core, gold shell, interpenetrating polymer network of polyacrylamide; irradiate paricles with NdYag lase to effect temperature induced swelling; near infrared light passes easily and harmlessly through the body. 2008; US 20080138430 A1.
Babu Chandra A, Prabhakar MN, Babu Suresh A, Mallikarjuna B, Subha MCS, Rao Chowdoji K. Development and characterization of semi-IPN silver nanocomposite hydrogels for antibacterial applications. Int J Carbohydr Chem 2013; 243695:1-8.
Mayet N, Kumar P, Choonara YE, Tomar LK, Tyagi C, du Toit LC, Pillay V. Synthesis of a semi-interpenetrating polymer network as a bioactive curcumin film. AAPS Pharm Sci Tech 2014; 15:1476-1489.
YM Yue, K Xu, XG Liu, Q Chen, X Sheng. et al.
Preparation and characterization of interpenetrating polymer network films based on poly (vinyl alcohol) and poly(acrylic acid) for drug delivery. J Appl Polym Scis 2008; 108:3836-3842.
Rodkate N, Wichai U, Boontha B, Rutnakornpituk M. Semi-interpenetrating polymer network hydrogels between polydimethylsiloxane/polyethylene glycol and chitosan. Carbohydr Polym 2010; 81:617-625.
MD Lynda, Sivasankar B. Synthesis and characterization of semi-interpenetrating polymer networks using biocompatible polyurethane and acrylamide monomer. Eur Polym J 2009; 45:165-170.
Rezaei SM, IZA Mohd. Grafting of collagen onto interpenetrating polymer networks of poly (2-hydroxyethyl methacrylate) and poly (dimethyl siloxane) polymer films for biomedical applications. Expr Polym Lett 2014; 8:39-49.
Hoosain FG, Choonara YE, Kumar P, Tomar LK, Tyagi C, du Toit LC, Pillay V. An epichlorohydrin-crosslinked semi-interpenetrating GG-PEO network as a xerogel matrix for sustained release of sulpiride. AAPS Pharm Sci Tech 2014; 15:1292-1306.
Maity S, Sa B. Development and evaluation of Ca (+2) ion cross-linked carboxymethyl xanthan gum tablet prepared by wet granulation technique. AAPS Pharm Sci Tech 2014; 15:920-927.
HM Anamul, Kurokawa T, Gong JP. Super tough double network hydrogels and their application as biomaterials. Polymer 2012; 53:1805-1822.
Hagiwara A, Putra A, Kakugo A, Furukawa H, Gong JP. Ligament-like tough double-network hydrogel based on bacterial cellulose. Cellulose 2010; 17:93-101.
Yasuda K, Gong JP, Katsuyama Y, Nakayama A, Yoshie Tanabe Y, Kondo E, et al.
Biomechanical properties of high-toughness double network hydrogels. Biomaterials 2005; 26:4468-4475.
Azuma C, Yasuda K, Tanabe Y, Taniguro H, Kanaya F, Nakayama A, et al.
Biodegradation of high-toughness double network hydrogels as potential materials for artificial cartilage. J Biomed Mater Res A 2007; 81:373-380.
Imabuchi R, Ohmiya Y, Kwon HJ, Onodera S, Kitamura N, Kurokawa T, et al
. Gene expression profile of the cartilage tissue spontaneously regenerated in vivo by using a novel double-network gel: comparisons with the normal articular cartilage. BMC Musculoskelet Disord 2011; 12: 200-213.
Pescosolido L, Vermonden T, Malda J, Censi R, Dhert WJ, Alhaique F, et al
. In situ
forming IPN hydrogels of calcium alginate and dextran-HEMA for biomedical applications. Acta Biomater 2011; 7:1627-1633.
EE Hago, X Li. Interpenetrating polymer network hydrogels based on gelatin and PVA by biocompatible approaches: synthesis and characterization. Adv Mater Sci Eng 2013; 328763:1-9.
Myung D, Jaasma Michael J, Kourtis L, Chang D, Frank Curtis W. Hydrophobic and hydrophilic interpenetrating polymer networks derived from hydrophobic polymers and methods of preparing the same. 2012; US 20120045651 A1
Myung D, Farooqui N, Waters D, Schaber S, Koh W, Carrasco M, et al
. Glucose-permeable interpenetrating polymer network hydrogels for corneal implant applications: a pilot study. Curr Eye Res 2008; 33:29-43.
Annaka M, IIlmain F, Etsuo K, Toyoichi T. Interpenetrating-polymer network phase-transition gels. 1992; WO 1992013566 A1.
Rani M, Agarwal A, Maharana T, Negi TS. A comparative study for interpenetrating polymeric network (IPN) of chitosan-amino acid beads for controlled drug release. Afr J Pharm Pharmacol 2010; 4:35-54.
Gupta KC, Ravi-Kumar MNV. Semi-interpenetrating polymer network beads of chitosan-glycine for controlled release of chlorpheniramine maleate. J Appl Polym Sci 2000; 76:672-683.
Kulkarni AR, Soppimath KS, Aminabhavi TM, Rudzinski WE. In-vitro
release kinetics of cefadroxil-loaded sodium alginate interpenetrating network beads. Eur J Pharm Biopharm 2001; 51:127-133.
Ray R, Maity S, Mandal S, Chatterjee TK, Sa B. Development and evaluation of a new interpenetrating network bead of sodium carboxymethyl xanthan and sodium alginate for ibuprofen release. Pharmacol Pharm 2010; 1:9-17.
Ward R, McCrea K. Hydrophilic interpenetrating polymer networks derived from hydrophobic polymers. 2014; US 20140120177.
Lawson Del R. Semi-interpenetrating polymer network. 2013; EP 2585541 A1.
Krishna Rao KSPV, Naidu BVK, Subha MCS, Sairam M, Aminabhavi TM. Novel chitosan-based pH-sensitive interpenetrating network microgels for the controlled release of cefadroxil. Carbohydr Polym 2006; 66:333-344.
Shea Lonnie D, Woodruff Teresa K, Shikanov A. Interpenetrating biomaterial matrices and uses thereof.2012; US 20120142069 A1.
Bonner AG, Udell L, Andrews DW, Tsai Fu-Jya D, RG de los. Porous interpenetrating polymer network 2012; US 8298657 B2.
Zhao L, Zhou ZL, Brug J, Lam S, Gibson G. Emissive semi-interpenetrating polymer networks.2012; EP 2459620 A1.
Weber Gary Robert. Composite structures using interpenetrating polymer network adhesives. 2012; US 20120052305 A1.
Myung D, Ta C, Frank Curtis W, Koh WG, Noolandi J. Interpenetrating polymer network hydrogel corneal prosthesis.2011; US 7909867 B2.
Dillon ME. Novel wound dressing, process of manufacture and useful articles thereof. 2009; CA 2396218 C.
Robert LS, Jennifer EH, Kristi AS. Semi-interpenetrating or interpenetrating polymer networks for drug delivery and tissue engineering. 2009; CA 2290743 A1.
Griffith M, Li F, Liu W, Rafat M. Interpenetrating networks, and related methods and compositions.2007; WO 2007028258 A3.
Dillon ME. Process for the manufacture of interpenetrating polymer network sheeting and useful articles thereof. 2006; US 7087135 B2.
Wang Y, Boxtel RV, Zhou Stephen Q. Process for the modification of elastomers with surface interpenetrating polymer networks and elastomers formed therefrom. 2005; US 6943204 B2.
Healy K, Stile R. Tunable semi- interpenetrating polymer networks (sIPNS) for medicine and biotechnology. 2004; US 20040001892 A1.
Barrera Denise A, HareIstad Roberta E, Joseph William D, Pavelka Lee A. Interpenetrating polymer network. 2002; US 6498218 B2.
Langer Robert S, Elisseeff Jennifer H, Anseth K, Derek S. Semi-interpenetrating or interpenetrating polymer networks for drug delivery and tissue engineering. 2001; US 6224893 B1.
DeCrosta Mark T, Jain Nemichand B, Rudnic Edward M. Drug delivery systems including novel interpenetrating polymer networks and method. 1986; US 4575539A.
Amiji Mansoor M. Drug delivery using pH sensitive semi-interpenetrating network hydrogels. 1999; US 5904927A.
Shah Navinchandra B, Rizk Sidky D. Thermosetting composition for an interpenetrating polymer network system. 1992; CA 1301981.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]