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 Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 4  |  Page : 224-230

pHEMA hydrogels: Devices for ocular drug delivery


Department of Pharmaceutics, BIT-School of Pharmacy, Partapur, Meerut, Uttar Pradesh, India

Date of Web Publication27-Feb-2013

Correspondence Address:
Neha Tomar
Department of Pharmaceutics, BIT-School of Pharmacy, By-Pass Road, Partapur, Meerut, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-344X.107844

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  Abstract 

Drug delivery to eye has become a demanding task because of various constraints of eye i.e., physiological and anatomical, which results in improper therapeutic concentration at the site of action. Due to this problem, frequent dosing was recommended causing patient incompliance and adding to the cost of therapy. To overcome these barriers, researchers have discovered novel ocular delivery systems like hydrogels, ocuserts, colloidal carriers, etc. However, every delivery system has its own advantages and disadvantages. Hydrogels are presently utilized as delivery system for actives because of their comparable physical properties to that of living tissue. A plethora of biodegradable polymers are used for hydrogel formulations like polyanhydrides, poly (orthoesters), polyesters and poly (2-hydroxyethyl methacrylate) (pHEMA), chitosan and sodium alginate out of which pHEMA hydrogels are becoming popular from a therapeutic point of view for the ocular drug delivery. The present paper broadly describes the recent advances on drug delivery using pHEMA hydrogels with exhaustive details of researches explored till date.

Keywords: Colloidal carriers, drug delivery, hydrogel, liposomes, microemulsions, nanoparticles, ocular, pHEMA


How to cite this article:
Tomar N, Tomar M, Gulati N, Nagaich U. pHEMA hydrogels: Devices for ocular drug delivery. Int J Health Allied Sci 2012;1:224-30

How to cite this URL:
Tomar N, Tomar M, Gulati N, Nagaich U. pHEMA hydrogels: Devices for ocular drug delivery. Int J Health Allied Sci [serial online] 2012 [cited 2020 Feb 28];1:224-30. Available from: http://www.ijhas.in/text.asp?2012/1/4/224/107844


  Introduction Top


Ophthalmic drug delivery is an interesting area of research with a huge potential for communal impact. The anatomy and physiology of the eye makes this organ highly impenetrable to foreign substances. The main challenge is to circumvent the protective barriers of the eye without causing permanent tissue damage. The goal of therapy is to treat a disease in a consistent and predictable fashion. Generally, an assumption is made that a correlation exists between the concentration of a drug at its intended site of action and the resulting pharmacological effects. The specific aim of designing a therapeutic system is to achieve an optimal concentration of a drug at the active site for the necessary period. Topical ocular administration is usually aimed for two purposes: To treat superficial eye diseases, such as infection (i.e., conjunctivitis, belpharitis, keratitis sicca, dry eye), and to treat intra-ocular diseases through corneal absorption such as glaucoma or uveitis. The tendency today in ophthalmic research is to develop systems that not only prolong the contact time of the vehicle with the ocular surface, but would at the same time reduce elimination of the drug. This approach is based on the supposition that the drug is retained in the vehicle by bonds, which are sufficiently labile not to remain trapped beyond the residence time of the vehicle in the precorneal region. Many non-invasive approaches have been proposed to increase ocular bioavailability of drugs including the use of bioadhesive hydrogels. [1]

Hydrogels are made up of polymeric materials, which may be of synthetic or natural origin, with the unique property of not dissolving in water at physiological temperature and pH. They can swell in an aqueous medium and demonstrate extraordinary capacity for imbibing water into the network structure. Hydrogels made from natural polymers may not provide appropriate mechanical strength, but they consist of several advantageous properties such as inherent biocompatibility, biodegradability and biologically recognizable moieties that support cellular activities. [2],[3],[4] In contrast, synthetic hydrogels do not contain such type of inherent bioactive properties. Fortunately, synthetic polymers usually have well-defined structures that can be modified to yield tailored degradability and functionality. "Stimuli-responsive" or "Smart" gels are those gels that exhibit a phase transition in response to change in external conditions such as pH, ionic strength, temperature and electric currents.

Hydrogel polymers based on hydroxyalkyl methacrylates, polyethylene glycol and its derivatives have found extensive application areas over the few decades primarily in medicine. Poly 2-hydroxyethyl methacrylate (pHEMA) has become the most used since its first preparation and description for biological use by Wichterle and Lim. [5],[6]

Structure of pHEMA and its properties

pHEMA is a non-toxic polymer of the toxic monomer HEMA (hydroxyethyl methacrylate). It forms hydrogel in water [Figure 1]. Stereochemistry behind hydrogel formation is rotation around its central carbon. When present in air, non-polar methyl side turns outward, which imparts pHEMA brittleness and easy-to-grind feature to mould it in correct lens shape. While in water, the polar hydroxyethyl side turns outward and the polymer becomes flexible. pHEMA is a three-dimensional hydrophobic polymer capable of swelling in water or biological fluids, and retaining a large amount of fluids in the swollen state. [7] Their capability to absorb water is due to the presence of hydrophilic groups such as -OH, -CONH-, -CONH 2 , -COOH and -SO 3 H. [8] The main hydrophilic groups present in pHEMA are -OH and -COOH. The water content in pHEMA affects different properties like permeability, mechanical properties, surface properties and biocompatibility. The ability of molecules of different size to diffuse into (drug loading), and out (release drug) of hydrogels, permits the use of pHEMA as delivery system.
Figure 1: Structure of pHEMA

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The material properties of pHEMA hydrogels have been extensively investigated in many aspects including swelling characteristics in aqueous solutions, [7],[8],[9],[10],[11] gas permeation characteristics [12],[13],[14],[15],[16] and mechanical properties. [17],[18],[19] The polymer is hydrophobic; however, when the polymer is subjected to water it will swell due to the molecule's hydrophilic pendant group. [20] In its dehydrated state, pHEMA is hard and brittle. When swollen in water, however, it becomes soft and rubber-like with a very low tensile strength. Although the water content has a marked effect on mechanical strength, the chemical structure of the polymer can also play a big role in determining its value. The elastic behavior and rigidity of hydrogels are closely governed by monomer molecular structure and effective cross-link density.

Since hydrogels have high permeability for water-soluble drugs and proteins, the most common mechanism of drug release in the hydrogel system, is diffusion. Factors like polymer composition, water content, cross-linking density and crystallinity, can be used to control the release rate and release mechanism from hydrogels. [21] pHEMA is a pH sensitive hydrogel, which is an anionic copolymer, swells high in neutral or high pH but does not swell in acidic medium. It was also observed that pH and ionic strength determine kinetics of swelling of pHEMA and guar gum. [22] pHEMA is a synthetic hydrogel, and it possesses a high mechanical strength, resistance to many chemicals and relatively high water content in swollen state. pHEMA hydrogel has a high water content similar to body tissues and is currently used in medical applications such as corneal implants, ureters, cardiovascular implants, contact lenses, tissue repair surgery and many dental applications. [13],[14] pHEMA has been used to enhance mechanical properties of thermosensitive hydrogels based on poly (N-isopropylacrylamide). [23] pHEMA are thermoplastic materials. They exhibit excellent properties for the specific experiment. Their glass transition temperature is low, 87°C and 53°C correspondingly and they present a very small value of thermal (<1%) and pressure shrinkage (<0.1%) for the experimental conditions range. [24] Drahoslav Lim invented pHEMA hydrogels for use in soft contact lenses. These hydrogels are highly biocompatible, transparent, soft materials, with a high thermal stability, resistance to acid and alkaline hydrolysis, and tunable mechanical properties. These properties make pHEMA hydrogels particularly useful for application in biomedical devices such as catheters, intrauterine inserts, prosthesis, or intraocular and soft contact lenses, as well as a basis for drug delivery systems. [25],[26]

Drug delivery via pHEMA

Various drugs have been delivered via pHEMA hydrogels. These are shown in [Table 1]. Several researches carried out have also been discussed in detail as given below.
Table 1: Overview of pHEMA hydrogels

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Via contact lenses

Several researchers find the enormous potential for the drug delivery via contact lenses made up of pHEMA. Hiratani and Alvarez-Lorenzo made contact lenses of HEMA or N, N-diethyl acrylamide (DEAA) and a small proportion of monomer (methacrylic acid, MAA). MAA has capacity to form ionic and hydrogen bonds with drug (timolol maleate). The result of timolol uptake was more in imprinted HEMA-based and DEAA-based contact lenses as compared to non-imprinted systems. It sustained the drug released from loaded lenses in lacrimal fluid for more than 12 hours and the empty lenses can be reloaded again with drug for use the next day. [34],[35] Furthermore, drug loading capacity, release behaviors, and properties such as the hydrophilic character and swelling degree were investigated due to the effects of backbone monomers and functional/template monomer. On conducting in vivo studies, it was seen that the imprinted contact lenses are capable of extending the retention time of drug in the precorneal area as compared to conventional contact lenses and eye drops. Afterward, by using acrylic acid (AA) as functional monomer to load on imprinted HEMA-based hydrogel contact lens to release norfloxacin in a sustained way for several hours or even days was designed. [36]

Venkatesh et al., for the delivery of ocular medication such as H 1 -antihistamines synthesized imprinted HEMA-co-polyethylene glycol (200) dimethacrylate- (PEG200DMA-) based contact lenses containing multiple functional monomers of AA, acrylamide (AM), and N-vinyl 2-pyrrolidinone (NVP). It was shown that these contact lenses had the potential to load significant amounts of drug, and also released a therapeutic dosage of drug in vitro in a controlled way for 5 days with further extension in the presence of protein. It was also found that hydrogels of multiple complexation points with varying functionalities outperformed hydrogels formed with less diverse functional monomers, mechanical and optical properties of these hydrogels agreed with conventional lenses, and increased loading was reflected in a reduced propagation of polymer chains. [37]

In 2007, Li and Chauhan combined in vitro experiments with modeling to deliver the timolol maleate. A transport model for releasing the drug from pHEMA contact lenses was created after conducting these in vitro experiments. This transport model includes drug adsorption on the polymer and drug diffusion in bulk water. Various parameters were determined from the experiments, which were conducted at three different cross-linker levels, and the transport models for each case. [38] The transport model was then incorporated into a model for the release of the drug from the contact lens into the pre- and post-contact lens tear films and the subsequent corneal uptake. Results showed that at least 20% of the drug timolol entrapped in the lens afterward will enter the cornea, which is much greater than the uptake from various delivery systems i.e., eye drops.

Paula Andrade, tested the efficacy of NSAIDs like diclofenac and ibuprofen by incorporating 4-vinyl-pyridine (VP) and N-(3-aminopropyl) methacrylamide (APMA) in to the network (25-150 mM). The incorporated monomers did not change either the viscoelastic properties or the state of water, but there was a remarkable increase in the amount of ibuprofen (up to 10-fold) and diclofenac (up to 20-fold). Dried loaded pHEMA-APMA and pHEMA-VP hydrogels rapidly swelled in water but ionic/hydrophobic interactions checked the amount of drug released to be above 10%. On the other hand, once the water-swollen hydrogels were transferred to pH 5.8 or 8.0 phosphate buffers or NaCl solutions, the release was quicker by competition with ions of the medium. The remaining of hydrophobic interactions and the high polymeric density of the pHEMA hydrogels contribute to be sustained release of process for at least 24 hours for ibuprofen and almost 1 week for diclofenac. [31]

Kim and Chauhan (2008) explored three derivatives of dexamethasone (dexamethasone 21-disodium phosphate (DXP), dexamethasone (DX) and dexamethasone 21-acetate (DXA). These drugs are loaded in the gels by soaking in aqueous or ethanol solutions, and also by direct addition of the drug to the polymerizing mixture. Active drug concentrations in the aqueous phase are monitored in loading and release experiments. For determining the partition coefficients and the mean diffusivity, the data was useful which includes contributions from both bulk and surface diffusion. Finally for predicting the bioavailability, they utilized the transport model of the three forms of dexamethasone for drug delivery through contact lenses, which is diffusion limited in the transport model of each drug with diffusivities of 1.08 × 10 -11 and 1.16 × 10 -11 m 2 /s for DX and DXA, respectively. The diffusivities of DXP depend on concentration and on ionic strength, which are much smaller than those for DX and DXP. The bioavailability of these drugs through the contact lenses was much greater than that for drops, and the highest bioavailability is for DXA. [27]

Carmen et al. developed the lenses i.e., poly (hydroxyethyl methacrylate), pHEMA lenses that has the ability of loading the norfloxacin (NRF) and also controlling their release. By carefully choosing the functional monomers and then spatially ordering helps in applying the molecular imprinting technology. Isothermal titration calorimetry (ITC) studies showed that maximum binding interaction between NRF and acrylic acid (AA) occurs at a ratio of 1:1, and saturation of process at 1:4 molar ratio. By using different NRF: AA molar ratios (1:2 to 1:16), at two fixed AA total concentrations (100 and 200 mM), and also by using moulds of different thicknesses (0.4 and 0.9 mm), hydrogels were synthesized. The 1.6 times of cross-linker molar concentration was that of AA. Similarly the control (non-imprinted) hydrogels were prepared but with the omission of NRF. Results confirmed by all hydrogels showed a similar degree of swelling (55%) and, after hydration, showing the adequate optical and viscoelastic properties. The imprinted hydrogels showed loaded greater amounts of NRF after immersion in 0.025, 0.050 and 0.10 mM drug solutions than the non-imprinted ones. After synthesizing the imprinted hydrogels by using NRF: AA 1:3 and 1:4 molar ratios capable of controlling the release process, it sustained for more than 24 hours. For the optimization of the structure of the imprinted cavities, ITC was a useful tool that has proved from the above results for obtaining the efficient therapeutic soft contact lenses. [36] Recently, Ribeiro et al. designed bio-inspired imprinted hydrogels using HEMA. Zinc methacrylate, 1- or 4-vinylimidazole (1VI or 4VI), and N-hydroxyethyl acrylamide (HEAA) were added to reproduce the cone-shaped cavity of the CA in the hydrogels, which contains a Zn 2+ ion coordinated to three histidine residues. Therefore, more drugs can be loaded in biomimetic networks, which can be capable of controlling the better drug release as compared to the conventionally synthesized pHEMA hydrogels. [39]

Reiuchida et al. changed the era by making the contact lens equipped with drug delivery system. The hydrogels consisting of cationic functional group in its side chain was prepared with 2-hydroxyethyl methacrylate (HEMA) and methacrylamide propyl trimethyl ammonium chloride (MAPTAC) capable of storing the anionic drug such as azulene based on ion-exchange reaction. In physiological condition the incorporated anionic drug would be released. The change in size of the hydrogel may occur before and after drug release, but it was discovered that the addition of anionic monomer such as methacrylic acid (MAA) and 2-methacryloxyethyl acid phosphate (MOEP) to the above composition was effective in preventing the size change. So, this hydrogel can prove to be a significant drug delivery system device. [40]

Colloidal carriers loaded pHEMA hydrogels

Colloidal dosage forms like micro/nanoparticles, micro/nanoemulsions and liposomes are exploited for the ocular drug delivery. These are tabulated in [Table 2]. Colloidal drug carriers are known for their enhanced drug permeation, controlled release and targeting. Apart from this, encapsulating the drug in these carriers protects it from degradation in ocular environment like presence of enzymes. Furthermore, micro and nano sizes of drug does not affect the visibility of individual. For this reason, these carriers can easily be loaded in hydrogels so as to extend the sustained release time of active pharmaceutical ingredients and also their bioavailability. [45]
Table 2: Novel dosage form incorporated pHEMA hydrogels

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Nanoparticles

Nanoparticles are those particles varying in size from 10 to 100 nm. The drug may be attached to a nanoparticle matrix, or dissolved, and encapsulated, and these are entrapped, giving rise to different terminologies as nanoparticles, nanospheres or nanocapsules. [46] All these terms signify their most general characteristic, i.e., they are nanosized particles. Nanoparticles have been used as ophthalmic delivery systems because they are able to penetrate into the corneal or conjunctival tissue by an endocytotic mechanism. In order to achieve a sustained drug release and a prolonged therapeutic activity, nanoparticles must be retained in the cul-de-sac and the entrapped drug must be released from the particles at a certain rate. If the release is too fast, there is no sustained release effect. If it is too slow, the concentration of the drug in the tears might be too low to achieve penetration into the ocular tissues. [47] Now a days, nanoparticles have been loaded into pHEMA hydrogels for better efficacy. Gulsen and Chauhan have encapsulated the ophthalmic drug formulations in nanoparticles and dispersed these drug-laden particles in the lens material, such as poly-2-hydroxyethylmethacrylate (pHEMA) hydrogels. The drug-laden pHEMA hydrogels were synthesized by free radical solution polymerization of the monomers in presence of nanoparticles of lidocaine. [44] Upon insertion into the eye, the lens will slowly release the drug into the pre-lens (the film between the air and the lens) and the post-lens (the film between the cornea and the lens) tear films, and thus provide drug delivery for extended periods of time. This work mainly focused on dispersing stabilized microemulsion drops in poly-2-hydroxyethyl methacrylate (pHEMA) hydrogels. The results of this study showed that the pHEMA gels loaded with a microemulsion that is stabilized with a silica shell are transparent and that these gels release drugs for a period of over eight days.

Liposomes

Liposomes are usually within the size range of 10 nm to 1 μm or greater. Liposomes have been investigated for ophthalmic drug delivery since it offers advantages as a carrier system. It is a biodegradable and biocompatible nanocarrier. It can enhance the permeation of poorly absorbed drug molecules by binding to the corneal surface and improving residence time. It can encapsulate both the hydrophilic and hydrophobic drug molecules. Derya et al. encapsulated the ophthalmic drug formulations in dimyristoyl phosphatidylcholine (DMPC) liposomes to disperse the drug-laden liposomes in the lens material. Drug-laden liposomal gel was found to be transparent and release drugs for a period of about eight days. [48]

Microemulsions

Microemulsions have unique physical properties. They are composed of water, oil and a mixture of surfactants making a homogeneous, optically isotropic and thermodynamically stable solution. Microemulsions can be sterilized by filtration and their production is relatively simple and inexpensive. Because of these properties, they have attracted a great interest as drug delivery vehicles. [4],[43] Although microemulsions have been known for a long period, their potential as vehicles for topical ocular drug delivery has been investigated only within the last decade. [49]

Another research work was carried out that basically focused on dispersing stabilized microemulsion drops in poly-2-hydroxyethyl methacrylate (pHEMA) hydrogels. The results of this study show that the pHEMA gels loaded with a microemulsion that is stabilized with a silica shell are transparent and that these gels release drugs for a period of over eight days. 50 Contact lenses made of microemulsion-laden gels are expected to deliver drugs at the therapeutic levels for a few days. The delivery rates can be tailored by controlling the particle size and the drug loading. It may be possible to use this system for both therapeutic drug delivery to eyes and the provision of lubricants to alleviate eye problems prevalent in extended lens wear. Li et al. focused on trapping ethyl butyrate in water microemulsions, which are stabilized by pluronic F127 surfactant in 2-hydroxyethyl methacrylate (HEMA) gels. They measured the transport rates of timolol, which is a beta-blocker drug and used for treating glaucoma. Their results showed that microemulsion-laden gels could have high drug loadings, particularly for drugs such as timolol base, which can either be dissolved in the oil phase or form the oil phase of the microemulsions. However, the surfactant covered interface of the pluronic microemulsions does not provide sufficient barrier to impede the transport of timolol, perhaps due to the small size of this drug. [4]

Gulsen and Chauhan encapsulated the ophthalmic drug formulations in microemulsion drops, and the drug-laden microemulsion drops were dispersed in the pHEMA hydrogels. The results of their study showed that the pHEMA gels loaded with microemulsions were transparent; these gels released drugs for a period of over eight days, and the delivery rates could be tailored by controlling the particle and the drug loading. They also found that this system might provide lubricants to alleviate eye problems prevalent in extended lens wear as well as cure the ailments of eyes. However, the fabrication processes of microemulsion-loaded hydrogels require a two-step process: preparation of microemulsion drops, followed by entrapment in the hydrogels.

It has also been proposed to create colloid-laden hydrogel in situ in one step. Surfactant-laden hydrogels can be prepared by addition of surfactants to the polymerizing mixture. A schematic of the microstructure of the surfactant-laden gels is shown in [Figure 2]. During the process of fabrication, the surfactants interact with polymer chains and form micelles creating hydrophobic cores, where the hydrophobic drugs will preferentially enter into. The drug transport is inhibited due to the presence of surfactant micelles. [20] Kapoor et al. prepared Brij surfactant-laden pHEMA hydrogels that can release Cyclosporine A (CyA) at a controlled rate for extended periods of time (20 days). Their results show that Brij surfactant-laden pHEMA gels provide extended release of CyA and possess suitable mechanical and optical properties for contact lens applications. However, the hydrogels are not as effective for extended release of two other hydrophobic ophthalmic drugs, that is, dexamethasone (DMS) and dexamethasone 21 acetate (DMSA), because of insufficient partitioning inside the surfactant aggregates. [28]
Figure 2: Drug delivery through conventional and novel delivery system

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  Conclusion Top


Advancements in the area of pHEMA hydrogels-based drug delivery system have been established recently. In conclusion, it can be noted that pHEMA-based ophthalmic drug delivery system have shown great versatility as variety of drugs can be loaded by employing different techniques, which can result in high loading with sustained release. In comparison with topical alternatives, pHEMA-based contact lenses reveal an excellent performance since it can provide an increased residence time at the surface of the eye for efficacious therapy. Moreover, pHEMA-based hydrogels also have no apparent cytotoxicity or stimulatory effects, and thus having potential applications in biomedical and pharmaceutical areas.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]


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