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Application of Nanohydrogels in Drug Delivery Systems: Recent Patents. Review. Chintan Dalwadi and Gayatri Patel*. Department of Pharmaceutics and ...
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Application of Nanohydrogels in Drug Delivery Systems: Recent Patents Review Chintan Dalwadi and Gayatri Patel* Department of Pharmaceutics and Pharmaceutical Technology, Ramanbhai Patel College of Pharmacy, Charotar University of Science & Technology, CHARUSAT Campus, Changa–388 421, Gujarat, India Received: April 02, 2014

Revised: October 23, 2014

Accepted: October 24, 2014

Abstract: Nanohydrogel combines the advantages of hydrogel and nano particulate systems. Similar to the hydrogel and macrogel, nanohydrogel can protect the drug and control drug release by stimuli responsive conformation or biodegradable bond into the polymer networks. Nanohydrogel has drawn huge interest due to their potential applications, such as carrier in target-specific controlled drug delivery, absorbents, chemical/biological sensors, and bio-mimetic materials. Similar to the nanoparticles, stimuli responsive nanohydrogel can easily be delivered in the liquid form for parenteral drug delivery application. This review highlights the methods to prepare nanohydrogel based on natural and synthetic polymers for diverse applications in drug delivery. It also encompasses the drug loading and drug release mechanism of the nanohydrogel formulation and patents related to the composition and chemical methods for preparation of nanohydrogel formulation with current status in clinical trials.

Keywords: Biocompatibility, cross-linked, drug delivery, nanoparticle, nanocomposite, thermoresponsive. INTRODUCTION Hydrogels are three dimensional, cross-linked watersoluble polymer networks, that swell and expand in an aqueous environment. Hydrogels can absorb a large amount of water or biological fluid, ranging from 20% up to more than 10 times, and they swell up without dissolving [1]. Biocompatibility of hydrogels is due to its high water retention capacity and also the physio-chemical, compositional and mechanical similarity with the native extracellular membranes [2]. Polymer gels are classified by their diameter size, either as nano size or micro size gels, and this nano and micro size gel can be prepared by control of the gel forming crosslinking reactions used in the formulation of hydrogel [3]. Microsize gels, which is obtained by the inter-molecular cross-linking reactions has been studied extensively. However, polymer nanogels, which is prepared by the intramolecular cross-linking reaction, has been less diagnosed [4]. In the use of hydrogels, obstacles are their macroscopic dimensions and quick elution of drugs from the swollen hydrogel matrix. These challenges can be addressed through the use of nanohydrogels; hydrogel particles with nano scale dimensions [5]. Nanohydrogels simultaneously possess, features and characteristics of hydrogels and nano systems. Therefore, they benefit from the hydrophilicity, flexibility, versatility, high water absorptivity and biocompatibility of hydrogels along with all the merits of nanoparticles [6]. *Address correspondence to this author at the Department of Pharmaceutics and Pharmaceutical Technology, Ramanbhai Patel College of Pharmacy, Charotar University of Science & Technology, CHARUSAT Campus, Changa–388 421, Gujarat, India; Tel: +91-9925054142; Fax: +91 2697 247 100; E-mail: [email protected] 1872-2105/15 $100.00+.00

A polymeric nanohydrogel can be defined as a threedimensional polymer network composed of hydrophilic cross-linked macro-molecular chains possessing a diameter of 1-100 nanometers (nm) [7]. Because of excellent properties and performance with small size nanometer-sized structures are gaining more interest. There are a lots of hard nanomaterials, like metals and ceramics, which have been extensively diagnosed and evaluated. Soft materials, like polymer gels that possess mutability and responsiveness to their surroundings can also be used to form nanostructured products [8]. These characteristics of soft material have initiates a research for potential applications including targeting drug delivery systems, nanoreactors, and biomimetic mechanical devices [9]. Nano particulate systems have many advantages over micro- and macro- systems, such as longer circulation time in the blood stream without being captured by macrophages, ease of penetration into the tissues through the receptors, capillaries and biological membranes, and ability to be easily recognized by cells. Moreover, nanohydrogels demonstrate high therapeutic activity at the targeted site with sustained effects on the target area over a period of days or even weeks [10]. Nanohydrogels can carry a wide variety of drugs (of high and low molecular weights, and hydrophilic and hydrophobic molecules) and are also suitable for numerous delivery strategies [11]. Among the available nanosystems, selfassembled polymeric nanohydrogels are user-friendly, since the methods of preparation are effortless, affordable, and may effectively incorporate a variety of drugs, including biopharmaceuticals. Furthermore, they may be modified with different kind of molecules, improving their stability and targetability [9]. © 2015 Bentham Science Publishers

18 Recent Patents on Nanotechnology, 2015, Vol. 9, No. 1

Now a days, there has been a great sign of research activity to produce stimulus responsive polymeric hydrogels. In the literature, they are also known as smart or intelligent hydrogels. It has been reported that some hydrogels can respond (e.g., shrink or swell) to the change of environments, such as temperature, pH, ionic strength, and magnetic/ electric field [12]. Further, stimuli responsive nanohydrogels have a great ability in pharmaceutical applications, especially in site-specific controlled drug-delivery systems. Nanohydrogels can respond to the external stimuli much faster than the macroscopic hydrogels due to the smaller relaxation time (e.g., fast diffusion process) derived from their smaller dimensions [13, 14]. POLYMERS USED FOR THE PREPARATION OF NANOHYDROGEL Nanohydrogel based on Natural Polymers Table 1 lists polymer used for the preparation of the conventional and stimuli sensitive nanohydrogel for pharmaceutical applications [15, 16]. Natural polymers such as polysaccharides and proteins are widely used for the preparation nanohydrogels. This is because of the attractive properties of natural polymers like biocompatibility, biodegradability, lower cost. Proteins such as collagen, gelatin, fibrin, silk, lysozyme and polysachharides like chitosan, cellulose, hyaluronic acid, agarose, dextran are reported for the preaparation of the hydrogel [17]. General method used for the preparation of natural polymer nanocomposite formulation is chemical cross-linking of polymer to change the interaction and form chemically and mechanically stable hydrogel [18]. However, the chemical modification of polymers for e.g. the grafting of functional groups or synthetic polymer onto the polymer may change the biocompatibility of the natural polymer because the toxic chemicals are not removed completely during the synthetic modification, which is a common argue for using unmodified natural polymers. Another method to produce gelation of natural polymers, stated by Shchipunov et al. involves mineralization of the polymer like chitosan, guar gum, carboxymethylcellulose, β-cyclodextrin, etc. with silica. In this study, the author reports that water soluble tetrakis (2-hydroxy ethyl) orthosilicate (THEOS) was disbanded along with the polymer. THEOS hydrolyzes insitu to form silica nanoparticles that are cross-links with the suitable polymer network. This will produce a gelation of diverse groups or non gelable polysaccharides [19]. Stimuli responsive nanohydrogels containing natural polymers have been extensively examined for their response to changes in pH and temperature. Ma et al. have prepared nanohydrogel of carboxymethyl chitosan–PNIPAM semi interpenetration polymeric network cross-linked by clay. Phase transition temperature of this hydrogel is ~33°C that is similar to the conventional PNIPA hydrogels. Authors concluded that the novel cross-linked hydrogel exhibit more swelling, absorbs higher amount of water and more response rate compare to the conventional PNIPA hydrogels when the pH is less than ~2.5 or greater than ~4 [20]. Chiara Di Meo et al. have developed and characterized self-assembling nanohydrogels based on sonicated gellan gum chains. Prednisolone, a not-so-good water soluble antiinflammatory drug, was chemically conjugated to the car-

Dalwadi and Patel

boxylic groups of gellan (Ge–Pred) and the hydrophobic moiety was responsible for the self-assembling process. This conjugated nanohydrogel Ge–Pred was characterized by proton nuclear magnetic resonance spectra and self-aggregation behavior in aqueous media of Ge–Pred was evaluated by the pyrene fluorescence technique. Author reports the average size of the nanohydrogels, prepared by bath sonication in water, was about 300 nm and their z-potential values were negative [21]. Liu et al. have checked the Drug release behavior following electrostimulation of chitosan–montmorillonite (MMT) nanocomposite hydrogels prepared by chemical cross-linking method. Here, the author defines the use of MMT as it overcomes the deterioration of the responsiveness and reversibility of chitosan upon repeated on-off electro-stimulation switching operations, and to enhance the anti-fatigue property and corresponding long-term stable release kinetics. Results demonstrate that the nanohydrogel with 2 wt % MMT gained a mechanically and practically preferable pulsatile release profile and unique anti-fatigue behavior, compared with that of the pure CS [22]. Lee et al. have reported nanohydrogel made from sodium alginate by emulsification-diffusion method using 1,2diacyl-sn-glycero-3-phosphocholin as the lipophilic surfactant and chloroform as an oil phase to obtain the steady solid nanohydrogel by lyophilisation. The authors report the effects of alginate and surfactant concentrations, agitation speed, and agitation time on the mean particle diameter, size distribution and swelling. Alginate to surfactant ratio had a significantly positive effect on mean particle diameters and swellability of nanohydrogel and agitation speed had a significantly negative effect on mean particle diameters [23]. Jun lim et al. have synthesized hydrogel nanoparticles via a cross-linking reaction between hyaluronic acid (HA) and polyethylene glycol for the transdermal delivery of hyaluronic acid nanohydrogel. Author report suggests that dispersion medium has more importance in transdermal or topical delivery systems. As dispersion medium changes, the hydrogel nanoparticle shows different penetration capacity into the skin and oil dispersion medium gives higher penetration compare to the aqueous dispersion medium [24]. Gelatin is a protein which is promptly use for nanohydrogel due to its biocompatibility and biodegradability, nontoxicity and high hydrophilicity. It is obtained by hydrolytic degradation of naturally occurring collagen. Due to its excellent gelling properties compared to other proteins, gelatin is mainly used for the preparing hydrogels. Hetti Mimi et al. have presents the polyethyleneamine based nanogels with a biodegradable gelatin core to deliver siRNA in the cytoplasm of HeLa cells. This nanogel was prepared by physical crosslinking method which has average diameter of 200 nm and +40 mV zeta potential. Using Confocal laser scanning microscopic images they have proved the intracellular uptake of siRNA into the cytoplasma of HeLa cells. They were concluded that the gelatin nanogel protects siRNA against enzymatic degradation with lower toxicity and enhance cellular uptake up to 84% [25]. Further gelatin is used in the magnetic hydrogel nanocomposites by Narayana Reddy et al. They have prepared

Nanohydrogel Drug Delivery System

Table 1. Origin

Natural

Synthetic

Recent Patents on Nanotechnology, 2015, Vol. 9, No. 1

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Polymers reported for the preparation of the nanohydrogel in drug delivery. Polymer

Type of Stimuli

Method of Preparation

References

Chitosan- N-isopropylacrylamide

pH and thermosensitive

Chemical crosslinking

[20]

Chitosan-montmorillonite

Electric responsive

Chemical crosslinking

[22]

Gellan gum

Ion sensitive

Bath sonication

[21]

Sodium alginate

Thermosensitive

Emulsification diffusion

[23]

Hyaluronic acid

------

Chemical crosslinking

[24]

Cellulose derivative

Thermosensitive

Chemical crosslinking

[19]

Gelatin-Polyacrylamide

Magnetic responsive

Free radical polymerisation

[26]

Chitosan-Gelatin

------

Emulsion-double crosslinking

[27]

Gelatin-Polyethyleneimine

------

Physical crosslinking

[25]

N-isopropylacrylamide

Thermosensitive

Free radical polymerisation

[28, 29, 32]

Polyvinyl alcohol

pH and temperature sensitive

Chemical crosslinking

[30, 31]

Poly(vinyl pyrrolidone)

-------

Free radical polymerisation

[15]

p-nitro phenol acrylate (NPA)

pH sensitive

Inverse microemulsion polymerisation

[33]

Poly(acrylonitrile-co-1-vinylimidazole)

Multi responsive

Microemulsion polymerisation

[16]

Poly(methacrylic acid) (PMAA)

Redox/pH dual responsive

Distillation precipitation polymerization

[35]

Acrylonitrile (AN), Methacrylic acid (MA) and acrylic acid (AAc)

pH sensitive

Microemulsion polymerisation

[34]

Acrylamide (AAm)

--------

Free radical polymerisation

[36]

Poly(acrylamide–gelatin) hydrogel via free radical polymerization using N,N-methylenebisacrylamide (MBA) as a crosslinker. This hydrogel was transferred to the ferrous and ferric chloride tetrahydrous solution to entrap the iron salts throughout the hydrogel core it forms a brown color hydrogel magnetic nanocomposites. Then drug was loaded in the hydrogel samples by immersing the hydrogel in the drug solution. It shows good biocompatibility, swelling property with magnetically controlled release of doxorubicin [26]. In the same way Mihaela Holban et al. have prepared chitosangelatin nanoparticles by both ionic and covalent crosslinking in reverse emulsion with size ranging from 527nm to 897nm. They were loaded chloramphenicol as a model drug in to the nanoparticle by diffusion mechanism which gives slower release up to 24 hr and this nanoparticle has a great swelling capacity due to highly hydrophilicity of gelatin [27]. Nanohydrogel based on N-Isopropylacrylamide Ali et al. have proposed a cross-linker free route to synthesize thermosensitive self cross-linked Nisopropylacrylamide-vinylpyrrolidone-acrylamide polymer by free radical polymerization using H2O2 as a safe initiator. Here, self cross-linking occurs by NIPAAm chain transfer reactions in high dilute solution and at elevated temperature and cross-linked polymer chains associate into nano aggregates. The average size of nanohydrogels was found to be