Biocompatible in-situ gelling polymer hydrogels for treating ocular infection

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Biocompatible in-situ gelling polymer hydrogels for treating ocular infection Manu Sharmaa,*, Ankita Deohraa, Kakarla Raghava Reddyc,*, Veera Sadhub a

Department of Pharmacy, Banasthali Vidyapith, Banasthali, India School of Physical Sciences, Banasthali Vidyapith, Banasthali, India c School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW, Australia *Corresponding authors: e-mail address: [email protected]; [email protected] b

1 Introduction Micro-organisms including both bacteria and fungi are the main agents of ocular infections worldwide. If left untreated, ocular infections can lead to harm to ocular tissues which can progress to blurring of vision and visual impairments. Infections are usually poly-microbial associated with use of contact lenses, trauma, surgery, age, drying of the eye, chronic nasolacrimal duct obstruction and earlier ocular infections. Until the middle of the twentieth century, bacterial infection was the leading cause of ocular infections. Bacterial eye infections range from mild to extremely serious, threatening normal vision. The occurrence of eye infections varies with age and geographic location of the patient (Bettiol et al., 2014). Bacterial eye infection is caused by common pyrogenic bacteria that include Escherichia coli, Salmonella and Streptococcus pneumonia. Ocular infections are perpetuated by endotoxins secreted by bacteria along with induced sensitivity to their antigenic properties. Various treatment options are available to treat ocular infections. Oral drug delivery systems are the effective way of ocular therapy but poor ocular bioavailability and corneal contact time delays the action of active pharmaceutical agents. Hence, direct instillation into the eye is required. An ideal ophthalmic delivery system must be capable of controlling drug release and proximity of the drug in the eye for a prolonged period of time. The design of ocular drug delivery systems is generally based on the drug’s physicochemical and pharmacokinetic properties. The complexity of the eye offers unique challenges to drug delivery strategies. The physiology of the eye offers several precorneal, dynamic and static ocular barriers for targeted delivery of drugs to ocular tissues. In the last few decades extensive advanced studies have been Methods in Microbiology, ISSN 0580-9517, https://doi.org/10.1016/bs.mim.2019.01.001 © 2019 Elsevier Ltd. All rights reserved.

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performed to develop novel, safe, patient compliant formulations with controlled drug release behaviour and improved penetration across barriers to maintain higher drug level in ocular tissues. However, designing potent and therapeutically efficient ophthalmic dosage forms is a challenging task for pharmaceutical scientists due to the complex anatomy, physiology and competent protective mechanisms of the eye (Almeida, Amaral, & Loba, 2014). The eye, is a vital organ of the human body that is divided into anterior and posterior segments. The anterior segment of the eye constitutes one-third of the eye including cornea, iris, ciliary body, aqueous humour and lens. The remaining two-thirds of the eye constitutes the posterior segment including sclera, choroid, optic nerve, vitreous humour and retina (Patel, Cholkar, Agrahari, & Mitra, 2013). Eye drops are commonly used topical formulations for treatment of diseases of the anterior segments. Less than 5% of drugs reach the cornea and intraocular tissues after instillation due to precorneal losses from drainage, high tear fluid turnover and dynamics. Suspensions, emulsions and ointments are commonly used to improve the bioavailability and retention time of drugs. However, poor stability and blurring of vision limits their effectiveness. Usually topically applied drugs do not reach the posterior segment of the eye, so systemic administration via intraocular injections of drugs is preferred for patients suffering with chronic disorders like glaucoma and refractory chorioretinal diseases (Kuno & Fujii, 2011).

1.1 Challenges in developing ocular drug delivery systems Development of ocular drug delivery systems has always been challenging due to induced lacrimation, lacrimal drainage, poor corneal permeability and the smaller size of the ocular cavity. Therefore, a dosage form should not cause any irritation or blurred vision on instillation, able to endure lachrymal fluid dilution after instillation and should preserve the drug for a longer period in the precorneal area (Qi et al., 2007). The most critical challenge is to attain an optimal drug concentration at the site of action in designing an ocular therapeutic with high therapeutic efficacy.

1.2 Barriers 1.2.1 Precorneal barrier Precorneal barrier constituted by tear film and conjunctiva are the preliminary barriers that slow down the penetration of active components into the cornea (Patel, Shastri, Shelat, & Shukla, 2010). The tear film appears as a layer of homogenous, fine network like structure, 2 to 6 μm in thickness on the corneal surface (Chen et al., 1997). There are three distinct layers that constitute tear film: (1) an outermost lipid layer containing lipids like triglycerides, phospholipids, sterols, fatty acids; (2) an aqueous layer in the middle that contains inorganic salts, retinol, ascorbic acid, glucose, lysozyme, urea, glycoprotein and constitutes up to 90% of the tear film

ARTICLE IN PRESS 1 Introduction

volume; and (3) an innermost mucin layer which coats the corneal layer and improves the stability and spreading of the tear film (Mishima, 1965). Precorneal factors that affect the bioavailability of topically applied ocular dosage form are corneal absorption, evaporation of tears, normal tear turnover, induced lacrimation, drainage, drug metabolism, evaporation of tears, conjunctival absorption and drug protein interaction (Patel et al., 2010).

1.2.2 Permeability barrier The corneal epithelium affirms the rate limiting permeability barrier for most foreign materials and acts as a protection mechanism for the eye (Kompella, Kadam, & Lee, 2010). The tight epithelium of the cornea limits trans-corneal drug permeation. However, to a great extent, permeability of the cornea is more for lipophilic drugs. Corneal absorption of drugs is governed by solute partition coefficient, molecular size, viscosity, tonicity modifiers, buffer and pH (Ahuja, Singh, & Majumdar, 2008; Edwards & Prausnitz, 2001). The conjunctiva is another barrier that limits drug permeation because of multicellular structures and tight junctions (Kompella et al., 2010). Compared to the corneal epithelium the conjunctival epithelium is twice as porous with 16 times higher pore density. Thus, the conjunctival epithelium is fairly permeable to hydrophilic and large molecules due to 15- to 20-fold higher permeability compared to the cornea (Andrew, Huang, Tseng, & Kenyon, 1989). Hence, it serves as a route of absorption for larger bio-organic compounds such as proteins and peptides (Candia, Shi, & Alvarez, 1998). The mechanism of permeation across the cornea and conjunctiva can be either passive, active or facilitated diffusion (Urtti, 2006).

1.2.3 Blood- ocular barrier The blood ocular barrier prevents the entry of lethal substances and maintains homeostasis to protect the eye. The blood-aqueous barrier (BAB) and the blood-retinal barrier (BRB) constitute the blood-ocular system. The blood-aqueous barrier (BAB) is the anterior barrier of the eye that is composed of endothelial cells of blood vessels in the iris and the non-pigmented cell layer of the ciliary epithelium (Hornof, Toropainen, & Urtti, 2005). The BAB gets altered during various eye conditions like ocular inflammation, intraocular surgery, trauma, or vascular diseases. Inflammatory cells may also disrupt the integrity of this barrier (Chen, Hou, Tai, & Lin, 2008). It also exhibits a high degree of selectivity and keeps the aqueous humour completely plasma protein free. The blood-retinal barrier (BRB) is the posterior barrier comprised of retinal pigment epithelium and endothelium cells of retinal blood vessels (inner barrier) with non-leaky tight junctions (Occhiutto, Freitas, Maranhao, & Costa, 2012) (Fig. 1). It limits the movement of substances after systemic and periocular application to the retina. Variations in BRB may lead to the development of retinal diseases e.g., outer barrier alteration leads to diabetic retinopathy and inner barrier alteration leads to age-related macular degeneration (Cunha-Vaz, Bernardes, & Lobo, 2011).

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Lens

Ciliary Body Subconjunctival Route Aqueous Humor Topical Route

Choroid Sclera Retina Optic Nerve

Cornea Epithelium Conjunctival Epithelium

Blood Retinal Barrier

Permeability Barrier Intravitreal Route Blood Aqueous Barrier

FIG. 1 Model of eye illustrating various routes and barrier.

2 Ocular pharmacokinetics 2.1 Transcorneal absorption Transcorneal absorption of topically instilled therapeutic ocular formulations depend upon the lipophilicity of the molecule. Usually small lipophilic molecules are absorbed through the cornea whereas large hydrophilic molecules like protein and peptide-based medicines are preferentially absorbed by conjunctiva and sclera. Lachrymal drainage and systemic absorption from conjunctiva sweep off instilled ocular formulations leading to absorption of only a small fraction of the drug (Fig. 2).

2.2 Ocular drug distribution and elimination Topically instilled drugs in the ocular cavity penetrate across the cornea to reach the aqueous humour followed by distribution to the surrounding tissue. The preferable routes for ocular absorption of drugs are conjunctival and scleral via the aqueous humour. The ocular volume of distribution is usually significantly higher than the aqueous humour volume (0.3 mL) due to multicomponent kinetics. However, a smaller volume of distribution results from protein binding in the aqueous humour (Watsky, Jablonski, & Edelhauser, 1988). During ocular clearance, drugs are eliminated from the aqueous humour by chamber angle and Sclemm’s canal along with blood flow in anterior uvea. A variety of drugs are eliminated through uveal blood flow. However, vitreous cavity drugs can be eliminated through anterior and/or posterior routes. Ocular clearance of most of drugs varies from 4.7 to 1.5μL min 1 (Rojanasakul et al., 1992).

2.3 Factors affecting ocular bioavailability Ocular bioavailability of drugs is affected by various factors including: A. Biological factors • Lacrimation and tear turnover

ARTICLE IN PRESS 2 Ocular pharmacokinetics

Diffusion

Absorption (Corneal or Non-Corneal)

Dissolution

Erosion

Drug in tear film

Lacrimal Drainage Metabolism Drug in Aqueous Humor and Interior ocular Structure

Elimination

(Non Productive Absorption)

Loss

FIG. 2 Model depicting ocular pharmacokinetics.

• pH and ionic strength of tear fluid • Lacrimal protein binding • Impermeability of corneal epithelium • Tear evaporation and permeability B. Physicochemical factors • Molecular weight and particle size • Partition coefficient • Isotonicity of preparation

2.4 Approaches to enhance the ocular bioavailability Attempts to treat ocular infections and injuries include the use of eye drops, ointment and suspensions. General considerations which are taken care of during the development of ocular formulations include the nature of the drug molecule which can be lipophillic or hydrophilic; the degree of ionization of the drug since unionized

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compounds are able to cross the corneal epithelium; molecular size (should be less than 10A0); pH of the formulation to avoid ocular irritation and lacrimation; viscosity between 15 and 50 cps to increase contact time and lowest buffer concentration (<0.1 M) to optimize ocular bioavailability and efficacy of the drug (Lang, Roehrs, & Jani, 2005). Eye drops are convenient and stable but cause the loss of drugs through rapid drainage or because of the short contact time between drug and absorption surface area. Suspensions and ointments have been considered to solve the issues leading to rapid drainage of the instilled dose from the site of application. Suspension prolongs retentivity but sedimentation of suspended solids on storage affects stability. Ointments are formulated and used due to high viscosity with the aim of increasing retention time by limiting rapid drainage. However, blurring of vision using ointments ultimately affects patient compliance (Lang, 1995). Thus, the most suitable dosage form would be the one that delivers the drug in solution form, does not interfere with vision, does not have side effects and can be administered with fewer doses i.e., once or twice a day (Mali & Hajare, 2010). Thus, it becomes imperative to develop formulations which can improve the contact time of the drug to the ocular surface and slow down drug elimination. Different approaches have been used to enhance the bioavailability and therapeutic action of drugs. Alternative strategies used by pharmaceutical scientists to overcome poor ocular bioavailability issues include development of novel drug delivery systems to maximize corneal drug absorption and minimize precorneal drug loss. Novel delivery systems facilitate continuous, controlled and sustained release to attain sufficient therapeutic action with smaller doses and fewer side effects. These systems include particulate system (Park & Robinson, 1984), vesicular system (Bourlais et al., 1998), advanced systems and control release systems (Zimmer & Kreuter, 1991) (Fig. 3). During the development phase of novel formulations, properties like solubility, stability and permeability are the prime considerations taken into account. However, particulate delivery systems also have some limitations such as hindrance in vision, uneasiness due to their movement in the region of the eye, particularly in children and elderly patients, complexity in placement, particle contamination and surgical problems (Kushwaha, Saxena, & Rai, 2012). In situ gel systems offer the promising benefits of ideal formulations. These systems undergo sol-to-gel phase transition upon exposure to physiological conditions of the eye. Various natural, semi-synthetic and synthetic polymers are used to prepare in situ gel forming drug delivery systems. However, successful development of in situ gel systems require a strategic approach to overcome the challenges in ocular drug delivery.

3 In situ gelling system Ocular in situ gels are polymer based viscous liquids capable of undergoing phase transition in the ocular cavity to form viscoelastic gels under physiological conditions to enhance contact time of drug with ocular tissues. Increased contact time

ARTICLE IN PRESS 3 In situ gelling system

Liposomes Vesicular System

Niosomes Pharmacosomes Nanoparticle

Particulate System Microparticle Recent Advances Implants Control Release System

Contact Lens Nanosuspension Scleral Plugs

Advanced System

Gene Delivery Stem Cells

FIG. 3 Recent advances to improve bioavailability.

prolonged the residence time of gel formed in situ along with its ability to sustain the continuous release of drugs to enhance the bioavailability, minimize interference with blinking, reduce systemic absorption and improve patient compliance by reducing frequency of administration. (Kaur, Singh, & Kanwar, 2000). In situ gelling systems are smart carrier, compatible and responsive to different stimuli. These are formulated to undergo transformation in response to small change in environmental stimuli like temperature, pH, ionic strength, light and electric field (Vashist, Vashist, Gupta, & Ahmad, 2014). These gelling systems are a network of hydrophilic polymers formed by the crosslinking of polymers through covalent bonds, Van der Waal interactions and hydrogen bonding with swelling and water holding capacity to maintain the gel structure. Thus, the physicochemical properties of gelling polymers govern the strength, quality and performance of in situ gelling systems. Thus, the characteristic features of gel establish the relationship between therapeutic efficacy and rate of drug delivery. Advantages of in situ gelling system • It possesses good corneal penetration and prolongs contact time. • It gives comfort and simplicity of installation for patient. • It possesses considerable rheological properties and concentration of viscous system. • In situ polymeric delivery system gives accurate dosing and reduces the frequency of administration. • It gives sustained drug release due to the gel network formed after being influenced by physiological stimulation. • Reduces nasolacrimal drainage of drug.

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3.1 Various approaches for the preparation of In Situ gelling system 3.1.1 Temperature sensitive in situ gelling system Temperature sensitive in situ gels are composed of thermosensitive polymers characterized by their critical solution temperature (CST) at which abrupt transition in phase occurs from sol to gel (Jeong, Kim, & Bae, 2012). It possesses fluid characteristics at low or room temperature (20–25 °C) and gel characteristics at high or under physiological conditions (35–37 °C). Temperature sensitive in situ gels exhibit low viscosity and high flowability before they are dropped into the eyes at a temperature lower than the body temperature. This improves the ease of administration (Lihong, Xin, Yongxue, Yiying, & Gang, 2013) (Table 1). The changes occurring above CST are contributed by hydrophobic interaction, micellar growth, entanglements and coil to helix transition (Matanovic, Krist, & Grabnar, 2014) (Fig. 4). These polymers based on their origin can be divided into two major categories- natural polymers and synthetic polymers. Cellulose derivatives (methylcellulose, hydroxy propyl methylcellulose) and xyloglucan are the naturally occurring polymers and N-isopropylacrylamide, poloxamer (PEO/PPO based systems), PLGA-PEG-PLGA based systems are synthetic polymers.

3.1.2 pH sensitive The pH responsive gelling system shows phase transition triggered by change in hydrogen ion concentration in surrounding media (Fig. 5). These systems are formulated using polymers having acidic or basic functional group which exist in free running solution form at pH 4.5 but coagulate when the pH is raised by tear fluid to pH 7.4. Tear film facilitates prompt transition of highly fluid latex into viscous gel after ocular instillation of the formulation (Wu et al., 2011). All pH sensitive polymers contain acidic (carboxylic or sulfonic) or basic groups (ammonium salts) which either accept or donate protons in reply to changes in surrounding pH. pH is an important environmental factor governing the degree of ionization of polymeric systems and their water solubility. Electrostatic repulsive forces and osmotic forces due to the presence of ions are responsible for pH dependent swelling or deswelling of the gel in situ (Table 2). The pH sensitive anionic gel swells at pH above the polymer pKa while cationic gel swells at pH below the polymer pKa (Gupta, Vermani, & Garg, 2002). Cellulose acetate phthalate, carbopol, polycarbophill, polyacrylic acid and chitosan represent pH sensitive polymers (Gratieri et al., 2011; Pathak et al., 2013; Sharma, Gupta, & Gupta, 2014).

3.1.3 Ion activated Similar to hydrogen ions, different ions, mainly sodium, calcium and various other cations present in tear fluid affect the rheological behaviour of various polyampholytes depending upon the magnitude of inherent ionizable functional groups (Thakur & Sharma, 2012) (Table 3). Basically, the sol-gel transition occurs when the anionic polymers interact with cations (Fig. 6). Gelation of polyampholytes is contributed by their ionic interaction with tear fluid ions while gelation rate depends on the osmotic gradient stimulated by changes in the ionic strength

Table 1 Temperature responsive in situ gelling system in ocular drug delivery. Gelation mechanism

Polymers

Drug

1.

Chitosan, Poly (N-isoproplyacrylamide

Timolol maleate

Hydrophobic interactions, coil to globule transition

2.

Pluronic F127

Gatifloxacin

Micelle packing and entanglements

3.

Aqueous solutions of drug in chitosan/Pluronic (poloxamer)

Ciprofloxacin

Micelle packing and entanglements

4.

Pluronic F-127, xylocaine (4%)

Forskolin

3D-membrane network

5.

Poloxamer (407, 188), triacetin (glycerol triacetate), Isopropyl myristate, Propylene glycol

Dorzolamide HCL

Micelle packing and entanglements

Conclusion benefits

References

In situ gelling system for timolol maleate showed improvement in the pharmacokinetic profile of drug by increasing residence time of drug as compared to conventional eye drop. In vivo studies depicted higher total resident time (fivefold) and concentration (2.6-fold) of drug in rabbit’s conjunctival sac in comparison to conventional eye drops. In vitro release study showed diffusion and dissolution development release behaviour of in situ formed gel. Formulation was liquid in non-physiologic conditions (pH 4 and 25 ° C) whereas transformed to gel under physiologic conditions (pH 7.4 and 37 °C) The prepared formulation showed the sustained drug release, good rheological property, gelation temperature at the optimum concentration of 22% with good stability. Nano-emulsion formed using these polymers exhibited Newtonian flow behaviour at 25 °C whereas gelling occurred at body temperature with sustained drug release behaviour. Pharmacokinetic profile of dorzolamide HCL nano-emulsion in situ gel showed increased residence time, amount of drug absorbed and bioavailability.

Cao et al. (2007)

Ma, Xu, Nie, and Pan (2008)

Varshosaz, Tabbakhian, and Salmani (2008)

Gupta and Samanta (2010)

Ammar, Salama, Ghorab, and Mahmoud (2010)

Continued

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Table 1 Temperature responsive in situ gelling system in ocular drug delivery.—cont’d Gelation mechanism

Polymers

Drug

6.

Pluronic F127, Pluronic F68, Bovine serum albumin

Curcumin

3D-membrane network

7.

Sodium salts of HA, poloxamer 407

Ciprofloxacin

8.

Poloxamers (P407 and P188)

Methazolamide

Micelle packing and entanglements Micelle packing and entanglements

9.

Chitosan, Poloxamer 407

Fluconazole

Hydrophobic forces

10.

Metolose SM 4000, HPMC K 15 M, Sodium chloride

Ketorolac tromethamine

Hydrophobic interactions

11.

Glycerin monostearate, Gelucire 44/14, Miglyol 812, Myri 52, Poloxamer 188 and Poloxamer 407

Curcumin

Micelle packing and entanglements

Conclusion benefits

References

Curcumin loaded nanoparticles in situ gel achieved sustained release effect with good ocular safety and significantly increased curcumin bio-availability in aqueous humour. Bio-adhesive, thermo responsive and tissue regenerating properties of graft copolymers prolonged drug delivery to surface of eye. This study demonstrated that poloxamer formulation exhibited better retainability and rheological behaviour in comparison to aqueous solution. In situ gel exhibited 1.27fold Cmax and 1.55-fold Tmax 1.61-fold AUC0–24 and 1.58 fold AUC0–∞ with respect to aqueous solution confirming higher mean residence time and bioavailability. In vitro drug release study followed the Higuchi diffusion model. The pharmacokinetic parameters of in situ gel confirmed achievement of higher amount of drug in aqueous humour. Metolose SM 4000 (MC) in combination with HPMC K 15 M showed significant improvement in prolonging the drug release compared to salted MC solutions depending on concentration and type of salt. Thermosensitive ophthalmic in situ nanogel loaded with curcumin significantly improved bioavailability of curcumin in aqueous humour contributed by enhanced corneal permeation and retention time of drug in eye.

Lou et al. (2014)

Cho et al. (2003)

Qian, Wang, Li, Zhang, and Xu (2010)

Gratieri, Gelfuso, de Freitas, Rocha, and Lopez (2011) Bhowmik, Das, Chattopadhyay, and Ghosh (2011) Liu et al. (2016)

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ARTICLE IN PRESS 3 In situ gelling system

Incorporation of drug Hydrophobic block

(Protein and peptides) (Hydrophobic/hydrophilic)

Temperature increase

Hydrophilic block Thermoresponsive polymer

Transition state

Gel formation

FIG. 4 Temperature responsive in situ gelling system showing sol to gel transition.

Insoluble polymer particles Drug particles

Phase transition

Viscous gel

Aqueous phase Lacrimal pH7 pH<5

FIG. 5 pH responsive in situ gelling system showing pH dependent phase transition.

(Gambhire, Bhalerao, & Singh, 2013). Commonly used ion sensitive polymers in preparation of in situ gelation are alginates (Cohen et al., 1997) and gellan gum (Balasubramaniam & Pandit, 2003).

3.1.4 Photo responsive in situ gelling system Photo responsive gelling systems undergo gelation by the continuous imposition of light stimulus. These gelling systems have the advantage of triggering reversible control of physical and chemical properties of gel continuously. Thermal diffusion and hydrogen ion diffusion has limiting effect on the reversibility of gels (Peppas & Khare, 1993). The designing of photo-responsive systems involves the selection of polymer with a photochromic chromophore and a functional part. Photochromic molecules capture the optical signal and facilitate the conversion of signal to chemical signal through isomerisation which is conveyed to the functional part that manages the polymer properties (Irie, 1990). Optical signal can be UV or visible

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Table 2 pH responsive in situ gelling system in ocular drug delivery. Polymers

Drug

1.

Carbopol 940, HPMC E50 LV

Ofloxacin

2.

Carbopol 980NF, HPMC (E4M, PVP K30)

Puerarin

3.

Carbopol 980NF, Methocel K100LV, Disodium edetate

Ciprofloxacin HCL

4.

Carbopol (934, 971), Sodium alginate Carbopol, HPMC (K4M, E50LV and E15LV) Carbopol 974P NF, Methocel E4M

Ciprofloxacin

7.

Carbopol 934 P

Acetazolamide

8.

Carbopol 934

Fluconazole

9.

Carbopol 940, HPMC

Norfloxacin

5.

6.

Levofloxacin

Baicalin

Gelation mechanism pH triggered transition/gelation, Mucoadhesion due to hydrogen bonding. pH triggered transition with increased viscosity.

pH induced gelation, Mucoadhesion due to hydrogen bonding. pH induced gelation with electrostatic interaction. pH induced gelation

pH triggered transition with electrostatic interaction. pH induced gelation with bio-adhesive property. pH triggered transition with increased viscosity pH triggered transition with increased viscosity.

Inference

References

Developed formulation showed pH dependent increase in viscosity with sustained drug release up to 8 h with good stability.

Srividya, Cardoza, and Amin (2001)

Lower concentration of carbopol and higher concentration of HPMC showed strong gel strength compared to aqueous solution. The pseudoplastic property of formulations favoured sustained drainage of drug. In situ gel exhibited 1.76-fold tmax and 2.17-fold AUC0–24h with no significant change in Cmax. HPMC showed drug release rate retardant effect and increased the gel strength in a concentration dependent manner. Formulation showed sustained drug release up to 24 h and shelf life was found to be over 2 years.

Wu et al. (2007)

Formulation followed zero order release kinetics independent of drug load in surrounding environment depending upon permeability coefficient of drug across polymer matrix. The formulation followed the pseudo plastic behaviour which favours the sustained release (8 h).

Al-Kassas and El-Khatib (2009) Mohanambal, Arun, and Abdul (2011) Wu et al. (2011)

Formulation at low concentration of carbopol and high concentration of HPMC showed sustained drug release up to 8 h with good rheological behaviour. Pharmacokinetic profile showed increase in Cmax (3.6-fold) and bio-availability (6.1-fold) higher than those of the control solution. Higher permeation with prolonged precorneal residence time.

Increased drug residence time more than 6 h.

Formulation showed characteristics pseudo plastic behaviour, good gelling property, stability, safety and sustained release for 8 h.

Jain, Shah, Rajadhyaksha, Singh, and Amin (2008)

Singh, Chhabra, and Pathak (2014) Pathak, Chhabra, and Pathak (2013) Patil, Kadam, Bandgar, and Patil (2015)

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Pluronic, Carbopol

Pilocarpine

11.

Poloxamers (P407, P188), Carbopol (971P NF,980NF,1342P NF) Pluronic F-127, Chitosan

Puerarin

13.

Carbopol 940, HPMC, Pluronic F127, gellan gum

Ciprofloxacin

14.

Poloxamers (P407, P188), Carbopol 974P

Azithromycin

Combination of pH and temperature activated gelation

15.

Chitosan, Carbopol 940

Ketorolac tromethamine

Combination of pH and temperature activated gelation

16.

Poloxamer 407, HPMC K4M, Carbopol 974P, 940

Moxifloxacin Hydrochloride

Combination of pH and temperature activated gelation

12.

Timolol maleate

Combination of pHand temperatureinduced gelation Temperature- and pH induced gelation with mucoadhesive property

Pluronic solution shows better hysteresis. However, both carbopol and pluronic solution showed the better retention of drug as compared to individual solution. In vivo evaluation of individual polymer formulations depicted that combined polymer solutions exhibited better ability to retain drug than individual polymer solution.

Lin and Sung (2000)

Combination of pHand Temperature activated gelation pH and temperature triggered transition

Formulation was clear, isotonic, readily converted from solution into gel at temperatures above 35 °C and pH 6.9–7.0. Formulation showed a sustained release profile. Formulation was stable and efficacious with sustained drug release behaviour. Duration of drug release from different polymer combination followed order: Gelrite > Carbopol + HPMC > pluronic F-127 + HPMC, respectively. Muco-adhesion of system containing P407/P188/CP 974P (21/5/0.3%, w/v) was 2.3-fold higher then combination without carbopol 974P. In vivo experiments indicated 1.78-fold higher bio-availability from in situ gels compared to eye drop. Formulations exhibited pseudo plastic flow with thixotropic behaviour, prolonged residence time and enhanced healing rate.

Gupta et al. (2007)

Improved precorneal residence time, ocular bioavailability and decreased dosing frequency.

Qi et al. (2007)

Mohan, Kandukuri, and Allenki (2009) Cao, Zhang, and Ping (2010)

Zaki, Hosny, Khames, and Abd-elbary (2011) Sheikh, Sheikh, and Admane (2017)

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Table 3 Ion activated in situ gelling drug delivery systems in ocular drug delivery. Polymers

Drug

Gelation mechanism

1.

Sodium alginates

Pilocarpine

Ionic gelation

2.

Gellan gum, sodium alginate

Ciprofloxacin HCL

Ion induced gelation

4.

Gellan gum (gelrite)

Pefloxacin Mesylate

Ion induced gelation

5

Sodium alginate, Methocel (E15LV & E50LV),

Gatifloxacin

Ion induced gelation

5.

Gatifloxacin

Ion induced gelation

6.

Gellan, sodium carboxymethylcellulose (NaCMC) or sodium alginate Gellan gum

Flurbiprofen axetil

Ion induced gelation

7.

Gellan gum

Terbinafine HCL

Ion induced gelation

8.

Chitosan, Gellan gum

Timolol maleate

9.

Carbopol 934P, Xanthan gum

Ofloxacin hydrochloride

Combination of pHand ion activated gelation Combination of pHand ion activated gelation

Conclusion

References

Alginate served as excellent drug carrier with good ocular tolerance. Alginate exhibited concentration dependent effect on drug release profile. Formulation showed pseudo plastic rheological behaviour along with sustained release (8 h). In situ gelation increased therapeutic efficacy by inhibiting the microbial growth. In situ ionic gelation of formulation sustained drug release for 12 h in in vitro release studies.

Cohen, Lobelb, Trevgodaa, and Peled (1997) Balasubramaniam and Pandit (2003)

Gel formed in vitro produced sustained drug release over 8 h. Comparative in vivo pre-corneal retention studies indicated that the alginate/HPMC solution retained drug better than the alginate or HPMC E50LV solutions alone. Enhanced precorneal residence time along with prolonged sustained drug release.

Sultana, Aqil, and Ali (2006) and Sultana, Aqil, Ali, and Zafar (2006) Liu et al. (2006)

Kesavan, Nath, and Pandit (2010)

Nanogel containing emulsified flubiprofen axetil enhanced MRT and AUC (0 12 h) to 2.7- and 2.9-fold higher compared to eye drops, respectively. Gels were transparent showing mucoadhesive pseudo plastic behaviour, with prolonged mean residence time and increased bioavailability. Viscosity of formulation increased with increase of pH (>7) upon instillation into eye.

Shen, Gan, Gan, Zhu, and Zhu (2010)

Increased concentration of xanthan gum and carbopol enhanced the duration of action of drug by sustaining drug release.

Deshmukh and Gattani (2011)

Tayel, El-Nabarawi, Tadros, and AbdElsalam (2013) Gupta, Velpandian, and Jain (2010)

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Sodium alginate, Methylcellulose

Sparfloxacin

11.

Sodium alginate, HPMC E50 LV, K4M

Ciprofloxacin hydrochloride

12.

HPMC, Sodium alginate

Moxifloxacin HCL

13.

Poloxamer (407 and 188), Xanthan gum, Sodium alginate

Moxifloxacin HCL

14.

Sodium alginate, Poloxamer

Pilocarpine Hydrochloride

Combination of pHand ion induced gelation Combination of pHand ion activated gelation Ion and temperature triggered gelation Ion and temperature activated gelation Combination of temperature and ion-activated gelation

Formulation showed prolonged controlled release of the drug for 24 h with no ocular damage or irritation.

Khan, Aqil, Imam, and Ali (2014)

Formulation showed sustained effect with enhanced ocular bioavailability.

Makwana, Patel, and Parmar (2015)

Improved precorneal residence time of the drug

Mandal, Thimmasetty, Prabhushankar, and Geetha (2012) Shastri, Prajapati, and Patel (2010)

Increased concentration of mucoadhesive polymers in the formulation prolonged the drug release. However, combination of polymers depicted higher bio-adhesive forces and gel strength compared to polymers alone. Total mitotic response increased to 4.38-fold in comparison to drug in simulated tear fluid.

Lin and Sung (2000)

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Cations present in lacrimal fluid

Cross link of polymers

Polymer of opposite charge

FIG. 6 Behaviour of ion responsive in situ gelling system in eye.

light. UV sensitive in situ gels were produced by bringing the leuco derivative molecule into the polymer matrix (Mamada, Tanaka, Kungwachakun, & Irie, 1990) whereas visible sensitive in situ gels were prepared by introducing a light sensitive chromophore (e.g. trisodium salt of copper chlorophyllin) to poly (N- isoproplyacrylamide) gels (Suzuki & Tanaka, 1990).

3.1.5 Electric signal sensitive in situ gelling system Electric signals are also used as activation stimuli to induce gelation in the presence of an electric field. These systems are very efficient in the development of controlled drug delivery systems by adjusting the electric field (Sawahata, Hara, Yasunaga, & Osada, 1990). The sol to gel transition of the system depends on the concentration of the electrolyte. For example, low concentrations of the electrolyte causes shrinkage of sodium acrylic acid and acryl amide copolymer in aqueous solution whereas high concentration causes the system to swell on applying the electric field. Shrinkage occurs due the movement of Na+ ions to the cathode which results in a change in carboxyl group of the polymer chain and swelling occurs because more Na+ enters the system (Shinga, Hirose, Okada, & Kurauchi, 1992).

3.1.6 Glucose sensitive in situ gelling system Glucose sensitive in situ gelling system undergoes transformation by glucose responsive crosslinking. An interaction occurs between the glucose and Con A (Concanavalin A, glucose binding protein, also helps in insulin delivery) to form the cross links between glucose containing polymer chains (Lee & Park, 1996).

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The concentration of Con A and glucose containing polymers can be adjusted to make this gelling system. The release of insulin is faster from the solution phase as compared to gel phase, hence insulin release can be controlled with the help of this system (Taylor, Tanna, Taylor, & Adams, 1995). Poly [3-(acrylamido) phenylboronic acid] and polymers having polyol groups like PVA forms the glucose sensitive gelling system by complex formation. Glucose hydroxyl group and polyol polymer competes for the crosslinking with borate. Glucose has only one binding site for borate group hence it cannot act as crosslinking agent but polyol polymers are better binders. As the glucose concentration increases, the cross linking density of the gel retards and the gel facilitates more insulin release. On the other hand, in the presence of lower glucose concentration, cross linking is reformed with retardation of insulin release (Hisamitsu, Kataoka, Okano, & Sakurai, 1997).

4 Conclusion Ocular drug delivery is always complicated because of the various barriers imposed by the eye and also the complexity of routes against the entry of xenobiotics. Improvement in drug delivery systems can only help to conquer these barriers. Over the past few years, efforts have been made to enhance ocular bioavailability through modification of formulations by altering viscosity, polymers and also using various approaches. A remarkable number of studies on in situ gelling systems have been illustrated in this chapter which confirms that preparation of ophthalmic formulations with different polymers works with different mechanisms. The combination of two or more polymers in similar formulations gives the assurance of increased compliance, residence time and therapeutic efficacy. Use of different combinations helps in reducing the concentration needed for the individual polymer and strengthens the response.

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Further reading Liu, Z., Yang, X. G., Li, X., Pan, W., & Li, J. (2007). Study on the ocular pharmacokinetics of ion-activated in situ gelling ophthalmic delivery system for gatifloxacin by microdialysis. Drug Development and Industrial Pharmacy, 33(12), 1327–1331.