Emerging Trends in Ocular Drug Delivery Special Reference to
In Situ
Ophthalmic
Gel
Ram Garg*, Vikas Kumar, Vandana Sharma
Arya College of Pharmacy, Kukas, Jaipur (RJ)- 302001, India
Article Information Received 30 January 2019
Received in revised form 21 May 2019 Accepted 22 May 2019
Abstract
Eye is the most complex and valuable organ of the body, because of its prompt pre-corneal elimination of dosage form. In order to overcome this, researchers developed a new system; in-situ gel forming system. This formulation undergoes phase transition in the eye to form gel, thus prolonging the precorneal contact time which will result in improved visual bioavailability. There are different novel ocular drug delivery systems such as In-situ gel, dendrimers, niosomes, nanoparticulate system, collagen shield, ocular iontophoresis suspension and ocusert etc. This framework comprises of polymer or mixture of polymers which display sol-gel transition due to physicochemical parameters (temperature, ion exchange & pH) of the body. This novel drug delivery system promotes the importantly ease and convenience of administration, deliverance of accurate dose as well as to prolong residence time of drug in contact with mucosa. This review incorporates different temperature, pH, and ion induced in situ-forming polymeric systems used to achieve prolonged contact time of drugs with the cornea and increment their bioavailability.
Keywords: In-situ gel,
Novel ocular delivery, Ion exchange triggered Corresponding Author: E-mail : [email protected] Mob.: xxxxxxxxxx
1 Introduction
Ophthalmic preparations are characterized in the USP as “sterile dosage forms, basically free from foreign particles, suitably compounded and stuffed for instillation into the eye.” In eye medicate is controlled at various site for example, cornea, conjunctiva and sclera for better achievement of bioavailability and required impacts related with the therapy. The drugs for allergies, glaucoma, bacterial infections, conjunctivitis, keratitis, local anaesthetics and viral infection can be administered at suitable sites in the eye1.
2 Ocular drug delivery system
Among the different courses of drug delivery, the field of ophthalmic drug delivery is one of the most interesting and challenging endeavours facing a pharmaceutical researcher.
The anatomy, physiology and biochemistry of the eye render this organ incredibly impermeable to foreign substances2. A
noteworthy issue of ocular drug delivery is not the lack of efficient drugs but the attainment of their optimal concentration at the required site of action3. The most significant and
well-acknowledged route of administration for the treatment of different eye disorders is the topical instillation of drugs through eye drops. Conventional pharmaceutical formulations, such as solutions, suspensions and ointments have many disadvantages –
Rapid precorneal elimination due to tear turnover
Frequent instillation
Enzymatic metabolism
Nasolacrimal drainage
Conjunctival absorption
Blurred vision
Absence of controlled release4
In spite of these impediments, noteworthy improvements have been made in ocular drug delivery. several new strategies for drug delivery are made which are equipped for controlling the rate of drug delivery, sustaining the duration of therapeutic activity or targeting the delivery of the drug to a tissue. These
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headways have prompted the improvement of a novel drug delivery systems that could upset the technique for medicine and give various remedial benefits 5.
The principle goal of the improvement is to keep up the medication in the eye cavity for a more extended period of time. Successful results have been acquired particularly in geriatric patients with collagen shields and inserts, inspite of disadvantages like poor patient compliance and losing the device without noticing it6.
Ophthalmic items are preparations intended for application to the eye either for the treatment of infection, for the alleviation of side effects, for symptomatic reason or an adjuvant to surgical procedure. The traditional ocular preparations are eye drops and ophthalmic ointments. As soon as the eye drop solution is instilled into cul-de-sac, it is rapidly drained away from the precorneal cavity by constant tear flow and lachrymal-nasal drainage. Just around 1-2% of instilled dose is ingested into the objective tissues and relatively concentrated solution is required for installation to achieve an adequate level of remedial impact. The frequent periodic instillation of eye drops becomes necessary to maintain a continuous sustained level of medication.
A fundamental idea in ophthalmic research and development is that the restorative adequacy of an ophthalmic medication can be enormously improved by prolonging its contact with the corneal surface. The viscosity enhancing agents for example, methylcellulose are added to eye drop preparations or ophthalmic drug is formulated in water-insoluble ointment formulation to sustain the duration of intimate drug-eye contact. But these dosage forms give only marginally more sustained drug-eye contact than eye drop solutions and do not yield a constant drug bioavailability as originally hoped. The ocusert system has prevailing in altogether decreasing dosing and furthermore in strikingly improving the remedial adequacy of ophthalmic medications.
Medications that could be considered for delivery by log-acting inserts, in addition to anti glaucoma drugs, are antibiotics and anti-bacterials which require several applications daily in standard vehicles for treatment of Acanthamoeba Keratitis, trachoma etc. Different medications chose for topical administration with inserts are antiviral, antifungal, anti-filarial, anti-allergenic, anti-inflammatory (Steroidal and NSAID), fibrinolytes, immuno suppressant and growth factors7.
Significant advancement has been made in ophthalmic gel innovation in the development of in situ gelling systems which are solutions administered by simple conventional instillation into the eye, changes to the gel phase upon exposure to physiological conditions thereby increasing the pre-corneal residence time of the drug enhancing the ocular bioavailability.
As a result, sustained release and enhanced patient compliance is achieved.
Contingent upon the strategy utilized to make sol to gel phase transition on the ocular surface, the accompanying three systems are perceived
pH-triggered -Gelling of the solution is triggered by an adjustment in the pH by the tear fluid to 7.4. Polymer forms hydrogen bonds with mucin at higher pH which leads to formation of in-situ gel. The polymers utilized in this system arepseudo latex - Carbomer (Carbopol), Cellulose Acetate Phthalatelatex (CAP-latex).
Temperature-dependent -Sustained drug delivery accomplished by the utilization of a polymers like Poloxamers (Pluronic, Tetronics), cellulose derivatives (MC, HPMC), Xyloglucan that changes from solution to gel at the temperature of the eye i.e 32-34°C
Ion-activated - Alginates, Gelrite (Gellan gum). These polymers form a clear gel in the presence of mono or divalent cations present in the tear fluid.
Sodium alginate, the sodium salt of alginic acid, is a natural hydrophilic polysaccharide containing two kinds of monomers, β-d-mannuronic acid (M) and α-l-glucuronic acid. Alginate changes into stable gel upon exposure to divalent cations, which isn't effectively dissolved by tear liquid. Along these lines, it may be an attainable way to deal with improve patient compliance to diminish the measure of alginate required for gelation by incorporating HPMC in the formulation8.
3 In situ gels
This concern has been started by the focal points appeared in situ forming polymeric delivery systems for example, ease of administration and diminished recurrence of administration, improved patient compliance and comfort.
3.1 Advantages of in situ drug delivery system
The significant favorable circumstances of the in situ gel are the opportunity of administering precise and reproducible amounts of medication contrasted with an already formed gel. ifferent points of interest of in situ forming gel include:
low dose is required for treatment
minimum nearby and fundamental side effects
ease of application
reduced recurrence of medication administration
delivers accurate dose as well as prolongs residence time of drug in contact with mucosal membrane
achieved effective plasma drug concentration
increased residence time
improved bioavailability
It can also be administered to unconscious patient In situ gels can be designed to encourage drug focusing on, particularly through mucus membranes, for non-obtrusive medication administration9.
Any medicament when accomplish least therapeutic concentration at the proposed site of activity can inspire pharmacological response. A noteworthy issue being looked in ocular therapeutics is the achievement of an ideal concentration at the site of action. Tear production, transient residence time, and non-permeability of corneal epithelium make serious issue bringing about poor bioavailability and absorption of ocular dosage form. Binding to the lachrymal proteins, limited corneal surface, and metabolism are the other problems associated with the poor bioavailability of ocular dosage forms. Inability to accomplish least remedial concentration by conventional ophthalmic solutions is the aftereffect of quick rapid pre-corneal elimination of drug that can be limited and overwhelmed by the utilization of a sol-gel system 10,11.
In situ gel upon administration does not cause obscured vision or irritation. These are delivered as solution in cul-de-sac and relying upon the physiological stimuli, they experience sol to gel transition. Topical route of administration is favored in treatment of visual issues because a lesser fraction of the dose will effectively pass the blood–retinal hindrance. In this manner, the eye appears a perfect and effectively available target organ for topical treatment, however the assimilation of medication moiety from the corneal surface is additionally confined. In situ gelling system gives the expanded pre-corneal residence time of drugs and subsequently, their bioavailability by the utilization of polymeric solutions which change to a gel because of introduction to the physiological temperature, pH, or ionic composition of the lachrymal fluid. For in situ gels-based ocular drug delivery, natural polymers for example, gellan gum, alginic acid, and xyloglucan are most ordinarily utilized. Topical delivery of the formulation to the eye is a confounded issue on account of the various defensive systems that are available in the eye to keep the visual pathway from foreign particles12-16.
3.2 Ideal characteristics of polymers for preparation of in situ ophthalmic gels
1. Should be biocompatible.
2. It is capable of adhering to the mucus membrane.
3. Preferred pseudo plastic behavior of polymer.
4. Good tolerance and optical clarity is more preferred.
5. It should impact the tear behavior.
6. The polymer should be capable of decreasing the viscosity with increasing shear rate.
3.3 Production of in situ gelling17-19
There are 4 mechanisms for triggering the in situ gelling formation of biomaterials. These include:
3.3.1 Physiological stimuli
There are few polymers which experience enormous and unforeseen physical and chemical changes because of little external changes in their ecological conditions. Such polymers are called Stimuli-responsive polymers. They are additionally called as stimuli-sensitive, intelligent, smart or environmentally sensitive polymers. These polymers recognize a stimulus as a signal, judge the degree of the signal and then transform their chain confirmation in response.
3.3.1.1 Temperature triggered
Temperature sensitive polymers are most broadly considered class of environmentally responsive polymer systems in drug delivery. This is because temperature is generally simple to control and furthermore effectively relevant to both in vitro and in vivo. In this system, gelling of solution is triggered by alteration in temperature, thus sustaining the drug release. These hydrogels exists in liquid form at room temperature (20-25°C) and experience gelation when comes in contact with body fluid (35-37°C). The use biomaterial whose transition from sol-gel is triggered by increase in temperature is an attractive way to approach in situ formation. The best critical temperature range for such systems is ambient and physiologic temperature; such that clinical manipulation is facilitated and no external source of heat other than that of body is required to trigger gelation.
Three principle techniques are utilized in designing the thermosensitive sol-gel polymeric system. Thus they are classified into
Negatively thermosensible, which contract upon heating
Positively thermosensible, which contract upon cooling
Thermally reversible gel
Polymers which show temperature induced gelation are poloxamers/pluronics, cellulose derivatives [HPMC, ethyl (hydroxy ethyl) cellulose (EHEC), methyl cellulose], xyloglucan, tetronics, etc.
3.3.1.2 pH triggered
generally utilized for ocular drug delivery system. The increase in the precorneal residence time of drug and subsequently better bioavailability can be accomplished by utilizing in situ gelling frameworks. At pH 4.4, the formulation exists as a normal solution, but at pH 7.4, i.e. the pH of tear fluid, gelation occurs. The polymers having a enormous number of ionisable groups are called as polyelectrolyte. In case of weakly acidic groups (anionic), increment in swelling of hyrogel with increase in external pH is watched, while polymers containing fundamental (cationic) groups exhibit decreased swelling. Most of the pH sensitive polymers containing anionic group are based on PAA (Carbopol®, Carbomer) and its derivatives. Whereas at neutral pH conditions, polyvinylacetal diethylaminoacetate (AEA) solutions which have a low viscosity at pH 4, forms hydrogel. Other polymers which show pH prompted gelation are cellulose acetate phthalate (CAP) latex, polymethacrilic acid (PMMA), polyethylene glycol (PEG), pseudolatexes, and so on 20.
3.3.1.3 Ion activated system
Here, gelling of the imparted solution is initiated by the adjustment in ionic strength. It is trusted that the osmotic gradient across the surface of the gel determines the rate of gelation. In nearness of mono and divalent cations commonly present in the tear liquids, the aqueous polymer solution forms a clear gel. The electrolyte present in the tear fluid, Particularly Na+, Ca2+ and Mg2+ cations assume a significant job in inception of gelling when the solution is ingrained in the conjunctival cul-de-sac. Polymers that show osmotically instigated gelation incorporate gelrite or gellan gum, hyaluronic acid, alginates, etc.
3.3.2 In situ gel formation due to physical mechanism
3.3.2.1 Swelling
In this strategy gelling happens as the material retains water present in the encompassing condition and after that grows to consume wanted space. Case of such a substance is myverol (glycerol mono-oleate)
3.3.2.2 Diffusion
This strategy includes dissemination of dissolvable from polymer solution into encompassing tissue and results in precipitation of polymer matrix. N-methyl pyrrolidone (NMP) is one of the valuable solvent for such framework.
3.3.3 In situ gel formation due to chemical reaction
3.3.3.1 Ionic cross-linking
There are some ion sensitive polysaccharides for example, gellan gum, pectin, sodium alginate which experience phase transition in nearness of different ions. An anionic polysaccharide, Gellan gum, undergoes in situ gelling in
occurrence of mono- and divalent cations, i.e. Ca2+, Mg2+, K+ and Na+.
3.3.3.2 Enzymatically cross linking
In situ development catalyzed by common enzymes has not been studied widely but it has some favorable circumstances over chemical and photochemical approaches.3 For example, under physiologic conditions, an enzymatic process operates efficiently without requirement for possibly hurtful synthetic compounds like monomers and initiators. Changing the measure of catalyst gives a helpful mechanism to controlling the rate of gelling, which enables the blend to be infused before gel formation.
3.3.3.3 Photo-polymerization
For in situ arrangement of biomaterials, photo- polymerization is generally utilized. An solution of monomer or responsive macromer and initiator is infused into a tissue site and electromagnetic radiation is connected to form gel. Acrylate and related polymerizable functional groups are normally utilized as the polymerizable gatherings on the individual monomers and macromers since they quickly experience photo-polymerization in presence of suitable photoinitiator. Especially long wavelength UV and obvious wavelengths are utilized. Short wavelength UV isn't frequently utilized a result of its restricted entrance into tissue and since it is naturally destructive.
Photo-polymerizable frameworks when acquainted with the ideal site by means of infusion get photocured in situ with assistance of fiber optic links and afterward release the medication for delayed timeframe. At physiological temperature, the reactions give fast polymerization rates. A photo-polymerizable, biodegradable hydrogel as a tissue contacting matter and controlled release carrier21.
4 Current researches on in situ ophthalmic gel
Kotreka et al., (2017) developed and described an ion-activated in situ gel-forming estradiol (E2) solution eye drops
proposed for the prevention of age-related cataracts. The formulations were tested for pH, clarity, osmolality, antimicrobial efficacy, rheological behavior, and in vitro drug release. Stability of the formulation was likewise checked for a half year. The solution eye drops resulted in an in-situ phase change to gel-state when blended with simulated tear fluid (STF). Drug release from the gel pursued non-fickian mechanism with 80% of drug released in 8 hr. The formulations were observed all things considered, isotonic with suitable pH and viscoelastic behavior and stable at accelerated and long-term storage conditions for 6 months22.
pH ranging from 6.2±0.2. As the concentration of each polymeric component was expanded, there was a reduction in phase change temperature. The in vitro drug release diminished with increment in polymeric concentrations. The antibacterial effectiveness of the chose formulation against staphylococcus aureus affirmed that structured formulation has drawn out impact and held its properties against bacterial infection23.
Prasanth et al., (2017) prepared 8 formulations of in situ gels of Levofloxacin hydrochloride by pH triggered in situ gelling framework utilizing various polymers like sodium alginate as gelling agent, Noveon AA-1 polycarbophil and HPMC E50LV as viscosity upgrading agent and benzalkonium chloride as preservative. The medication content varied between 96.84 ± 0.396 and 99.65±0.489 % which showed that the uniform dispersion of medication was found in all the prepared formulations. A4 and A8 Both formulations gave good fit to the Higuchi model. The selected formulations showed good anti-microbial action against the organisms and ocular irritation studies revealed that the selected formulations were great with non-disturbance and there were no visual harm or unusual clinical signs24.
Sheikh et al., (2017) formulated and evaluated in situ gelling system for sustained ocular delivery of moxifloxacin HCl. The prepared batches were assessed for clearness, visual appearance, pH, drug content, and in vitro drug release study. The developed formulations were clear, stable, and isotonic. The upgraded bunches CF1 and PF2 supported the medication up to 5 and 6 h, individually. The prepared formulations were passes the tests for example, antimicrobial, antibacterial, sterility, and Draize test25.
Makwana et al., (2016) formulated and evaluated pH responsive in-situ gel for Ciprofloxacin hydrochloride antibiotic. Sodium alginate, an ophthalmic gel forming mucoadhesive polymer was picked as polymer because of development of calcium alginate by virtue of its interaction with divalent cation (Ca2+) present in lachrymal fluid. The formulations were
evaluated for clarity, pH measurement, gelling capacity, drug content, rheological study, and in vitro drug release. Result uncovered that the in situ gel based systems containing gums can be a significant methodology for ophthalmic drug delivery when contrasted with conventional systems26.
Kaur et al., (2016) formulated and assessed in-situ ocular gel of Gatifloxacin utilizing HPMC, HPMC K15M, Carbopol 934 as polymers. In-situ ocular gel was prepared by different combination of drug and excipients. Results showed that HPMC K15M and carbopol 934 in blend increment the precorneal residence time and prolong the drug release27.
Namdeo et al., (2016) prepared and evaluated an ophthalmic in-situ gel formulation of gentamicin sulphate made with Pluronic F127 in combination with various polymers for example,
Carbopol 934 and HPMC, which acted as a viscosity‐enhancing agent. The developed formulations showed sustained release of drug from formulation over a period of 8 hours. The prepared formulations were tested for eye irritation on albino rabbit (male). The formulations were found to be non-irritating. Therefore, the in situ gelling frameworks might be utilized as an option to the conventional systems28.
Dol et al., (2014) developed pH-triggered an ophthalmic drug delivery system utilizing blend of gelling agents various systems for in situ gelation of Moxifloxacin hydrochloride, a fluoroquinolone antibiotic Among formulation batches F1- F9; optimized formulation F6 imparted sustained release property to the gel formed in situ and effective other assessment parameters. The developed formulations were restoratively effective, stable, non-irritant and provided sustained release of the drug defeating convential downsides prompting better patient acceptance29.
Khan et al., (2013) structured in situ gelling framework for Gatifloxacin, an antibacterial agent utilizing hydroxypropyl cellulose and sodium alginate as the polymers to increase the pre-corneal resident time andophthalmic bioavailability of the drug. Formulated gel was transparent, good spreadability, pH range of 6.8 to 7.1 and uniform in consistency. Increased in the concentration of the polymer sodium alginate, therefore sustained drug release from the formulation for up to 12 hours30.
Bhatia et al., (2013) developed in situ gels based on thermo-reversible poloxamer 407 polymer alongside various muco adhesive polymers for example, sodium carboxy methyl cellulose (Na CMC), HPMC K100Lvp, and polyvinyl pyrrolidone (PVP) K30. Cold strategy was utilized to figure the thermoreversible mucoadhesive gels of Azithromycin. Result uncovered that the in situ gel can be securely introduced into the eye with no antagonistic impacts; improve steadiness and great antibacterial action contrasted with the marketed formulation of Azithromycin31.
Rathod and Patel (2013) structured and testedi on sensitive in situ gelling system for antibacterial agent Norfloxacin, by using Sodium alginate in blend with Hydroxypropyl Methyl Cellulose (HPMC K4M) which acted as a viscosity enhancing agent and gelling agent. Result was acceptable and developed was observed to be remedially compelling, stable, non-irritant, and provided prolong drug release32.
Mandal et al., (2012) prepared and assessed in situ gel-forming ophthalmic drug delivery system of moxifloxacin hydrochloride. Hydroxy propyl methyl cellulose (HPMC) is a mucoadhesive polymer used as viscosity enhancer. Result demonstrated that the prepared formulations exhibited sustained release of drug from formulation over a period of 10 hours thus increasing residence time of the drug. The optimized formulations were tested for eye irritation on albino rabbit (male). The formulations were found to be non-irritating with no ocular damage or abnormal clinical signs to the cornea, iris or conjunctiva observed34.
Nagargoje et al., (2012) formulated and evaluated an ophthalmic delivery system of an antifungal agent, fluconazole, based on the concept of ion-activated in situ gelation. ocular in situ gels can increase the drug residence time thus increasing the bioavailability. Gelrite was utilized as the gelling agent in mix with HPMC E-50(Hydroxy Propyl methyl Cellulose) that acted as a viscosity-enhancing agent. the formulations were restoratively viable, stable and provide sustained release of drug over a time of 8 Hrs35.
Sathyavathi et al., (2012) developed brimonidine tartrate niosomal in situ gels for glaucoma treatment by utilizing various proportions of span series and cholesterol. Span 60 (S/C 2:1) niosomes had highest entrapment efficiency and demonstrated prolonged drug release. Small unilamellar vesicles were observed and had the size of about 50-100 nm. In situ gelling of niosomal drops was formulated by using HPMC K 15 M and carbopol 940 to maintain the drug localization for extended period of time. All the gel formulations showed pseudo plasticrheological behavior and slow drug release pattern. Antiglaucoma activity of the prepared gel formulations demonstrated increasingly huge and sustained impact in decreasing intra ocular pressure than marketed and niosomal drops36.
Abashzadeh et al., (2011) Formulated and assessed an in situ gel framing framework for controlled delivery of triptorelin acetate. The gel development and medication release from the framework was assessed both in vitro and in vivo. outcomes were contrasted with Diphereline SR 3.75 mg, an industrially accessible controlled delivery system of triptorelin. In vitro
release studies demonstrated a sustained release profile for about 192 h with first order kinetics. In vivo investigations on male rodents by assurance of serum testosterone were affirmed the satisfactory presentation of in situ gel framing framework contrasted with Diphereline SR in diminishing the serum testosterone level for 35 days, showing the capability of the novel in situ gel forming system for controlled delivery of peptides37.
Eaga et al., (2011) formulated and assessed in situ gels for ciprofloxacin dependent on the ideas of pH‐triggered in situ gelation, thermo reversible gelation and Ion activated
system. Pluronic F‐127 (14%) was used as the thermal reversible gelation in combination of HPMC (1.5%) incorporation of HPMC was to reduce the concentration of pluronic required for in-situ gelling property, with 25% w/w pluronic F‐127 reported to form good gels. The developed formulation was restoratively viable, stable, non irritant and provided sustained release of the drug more than six hours time frame, yet Gelrite formulation indicating long duration of release pursued by blend of carbopol, HPMC and pluronic F‐
127 and HPMC. The developed system is therefore a suitable option in contrast to traditional eye drops 38.
Giuseppina et al., (2011) developed thermosensitive and mucoadhesive eye drops to keep up and drag out the contact of platelet lysate (PL) with corneal ulcers. A sterile vehicle based on chondroitin sulphate sodium (CS) and hydroxypropylmethyl cellulose (HPMC) was developed. An extemporaneous loading of the vehicle with PL was performed by them and the obtained formulation was able to quickly thermogelify at about 32°C and was portrayed by great mucoadhesive properties39.
Manas et al., (2011) assessed in-vitro ophthalmic thermo-sensitive in-situ gels of ketorolac, based on methylcellulose (MC) in blend with hydroxypropylmethyl cellulose (HPMC). The gel temperature of 1% MC solution was seen at 60°C. It was discovered that 6% oral rehydration salt without dextrose (ORS) was able to decrease the gel temperature beneath physiological temperature. HPMC was added to expand viscosity and drug release time. The outcomes showed a huge increment in viscosity at 37°C with addition of HPMC which provided sustained release of the drug over a 4 hour period. From in-vitro release studies, it has inferred that the developed systems were hence a superior option in contrast to traditional eye drops
40.
Rathapon et al., (2011) investigated Pluronic F127-based thermoresponsive diclofenac sodium ophthalmic in-situ gels by cold method in rabbits. It was discovered that physicochemical properties of diclofenac sodium in-situ gels were influenced by formulation compositions. Augmentation of Pluronic-F127 substance diminished sol–gel change temperature of the products while increment in Pluronic-F68 concentration tended to increase sol–gel transition temperature. Carbopol 940 did not affect sol–gel transition temperature but it affected transparency, pH, and gelling capacity of the products. The optimized formulation displayed sol–gel transition at 32.6±1.1°C with pseudoplastic flow behavior41.
the drug over a long period and shelf-life determined by Arrhenius equation was 1.6 years42.
Lekhraj et al., (2010) developed an in-situ gel forming systems of flurbiprofen, based on the ion-activated and pH-induced in-situ gelation. In-situ gels of flurbiprofen were prepared by simple dispersion method using sodium alginate and carbopol along with HPMC and after that assessed for for pH, gelling capacity, rheological, isotonicity, in vitro and in vivo investigations. The developed formulations demonstrated sustained release of drug for upto 5 hours43.
Sirishet al.,(2010)prepared novel in-situ ocular gelling system (Thermo-reversible gelling systems) of Ketorolac tromethamine. These gelling frameworks include the utilization of Poloxamer as thermo reversible polymer and Methyl cellulose as release retardant. They assessed the formulations for clearness, pH estimation, gelling capacity, drug content estimation, rheological investigation, in vitro drug release, ocular irritation studies (as per Draize test) and ex-vivo corneal permeation studies utilizing isolated goats cornea. The developed formulations indicated sustained release of drug for upto 5 hr44.
Tais et al.,(2010)formulated an ophthalmic delivery system with improved mechanical and mucoadhesive properties. Diverse polymer proportions were assessed by oscillatory rheology, texture and mucoadhesive profiles. The outcomes demonstrated that chitosan (0.25% and 0.5% w/v) improves the mechanical strength and texture properties of poloxamer (from 7% to 14% w/v) formulations and furthermore presents mucoadhesive properties in a concentration-dependent manner. Poloxamer/chitosan formulation in a concentration of 16/1.0% w/w showed an optimal gelation temperature (32 °C) and was able to withstand low shearing forces at 35 °C. The mechanical properties demonstrated that the formulation has a high hardness value (particularly at 35°C). Gamma scintigraphy in humans confirmed a prolonged retention time of the poloxamer/chitosan 16:1 formulation in human eyes, 50–60% of the gel was still in contact with the cornea surface, which speaks to a fourfold expanded retention in correlation with an conventional solution 45.
Gupta et al.,(2010) formulated chitosan and gellan gum based novel in-situ gel system activated by dual physiological mechanisms. Chitosan (a pH-sensitive polymer) in combination with gellan gum (an ion-activated polymer) were used as gelling agent. Timolol maleate, the drag which is frequently used for glaucoma therapy was used as model drag to check the efficacy of the formulation46.
Indrajeet et al., (2010) evaluated various in-situ gels of gatifloxacin prepared through use of sodium alginate and mucoadhesive polymers such as poloxamer 407, Carbopol 974P, and hydroxyethyl cellulose (HEC). They investigated the combined effect of two independent formulation variables in the
preparation of in-situ gels by using a 32 factorial design. A
surface plot was also created to graphically represent the effect of independent variables on the evaluation parameters. The developed formulations showed sustained release of drug for upto 6 hrs47.
Liu et al., (2010) developed an ion-activated in situ gelling vehicle for ophthalmic delivery of matrine. The effect of formulation characteristics on in vitro release and in vivo
precorneal drug kinetic of matrine was investigated. The Gelrite formulations of matrine-containing alginate released the drug most slowly. Both the in vitro release and in vivo pharmacological studies indicated that the Gelrite/alginate solution had the better ability to retain drug than the Gelrite or alginate solutions alone. Results revealed that the Gelrite/alginate mixture can be used as an in situ gelling vehicle to enhance ocular retention48.
Abraham et al., (2009) prepared and characterized ion-activated in situ gel with antibacterial agent, Ofloxacin. In vitro drug release, studies showed that Alginate or HPC solution alone was poor in retaining the drug compared to the alginate/HPC solution which showed theoptimum result. The formulated in situ gel achieved prolong drug release over a period of 8 hours, reduced frequency of drug administration, improved patient compliance and can be served as analternative to the conventional ophthalmic drops, economically and industrially orientated49.
Wenet al., (2008) studied the precorneal resident time and improves ocular bioavailability of the drug; Pluronic F127‐
gpoly(acrylic acid) copolymers in-situ gelling vehicle for ophthalmic drug delivery system. The rheogram and in vitro drug release studies indicated that the drug release rates decreased as acrylicacid/Pluronic molar ratio and co-polymer solution concentration increased. But the drug concentration had no obvious effect on drug release. In vivo resident experiments showed the drug resident time and the total resident amount in rabbit’s conjunctiveal sac increased by 5.0 and 2.6 folds for in-situ gel, compared with eye drops. The decreased loss angle at body temperature and prolonged precorneal resident time also indicated that the copolymer gels had bioadhesive properties50.
5 Conclusion
necessity of a fruitful controlled release product. Utilization of biodegradable and water soluble polymers for the in situ gel formulations can make them progressively adequate and brilliant drug delivery systems with least chances of irritation, and consequently improved patient compliance.
6 Conflict of interests
The authors have no conflict of interests.
7 Author’s contributions
RG, VK and VS were equally participated in the preparation of manuscript. All authors read and approved the final manuscript.
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