INTRODUCTION:

Ocular inserts refer to sterile formulations consisting of thin, multi-layered devices infused with drugs, typically solid or semi-solid in consistency. These inserts are specifically crafted for ophthalmic use, tailored in size and shape to fit into the cul-de-sac or sac of the conjunctiva. While their primary placement is in the lower fornix, they can also be occasionally positioned in the upper fornix or on the cornea. Composed primarily of polymer-based materials, ocular inserts often contain drugs within their structure.

These drugs may either be dispersed throughout the polymeric support or dissolved within it. Ocular inserts are predominantly employed for topical therapy, offering controlled release and prolonged contact with the ocular surface to enhance drug absorption and therapeutic efficacy¹.

Developing effective ocular drug delivery systems necessitates a thorough understanding of ocular anatomy, physiology, and biochemistry to circumvent the eye's protective barriers without causing harm to its delicate tissues. Current research in ocular drug delivery systems is primarily directed towards various technologies aimed at extending the duration of vehicle contact with the ocular surface and delaying drug elimination. Among these advancements, ocular inserts represent a particularly innovative approach in this field².

An ocular drug delivery system encompasses various forms, vehicles, or mechanisms designed to administer medication to the eye, targeting ailments or disorders affecting vision. Common conditions requiring such systems include refractive errors, glaucoma, cataracts, ocular infections, inflammation, dry eye syndrome, diabetic retinopathy, and diabetic macular edema. Treatment aims to alleviate symptoms over short to moderate durations, ranging from a few days to a couple of months, and involves diverse medication categories like anticholinergics, antimicrobials, and endothelial growth factor inhibitors. Successful development of ocular drug delivery systems hinges upon a comprehensive understanding of ocular anatomy and physiology³.

The eye is a complex organ comprised of various structures that work together to facilitate vision. The sclera forms the outer protective layer, commonly known as the "white of the eye." Positioned at the front, the cornea is a transparent, curved structure with limited drug penetration capabilities. The iris, distinguished by its color, surrounds the pupil, the black center of the eye. Transparent discs known as lenses sit immediately behind the iris and pupil. Aqueous humor, a clear fluid, circulates between the cornea and the lenses. Filling the eyeball between the lens and the retina, the vitreous humor resembles transparent jelly. The retina, located at the back of the eyeball, consists of millions of light-sensitive nerve cells. Supporting these structures, the choroid comprises a network of blood vessels that supply oxygen and nutrients to the retinal pigment cells. Each component plays a crucial role in the eye's function, contributing to the complex process of vision⁴.

The cornea is pivotal in optimizing the duration of contact with medication. Viscosity enhancers offer a promising avenue for achieving this goal (Figure 1)⁵.

The manuscript provides a comprehensive overview of the eye's anatomy, various ophthalmic dosage forms, ocular drug delivery systems, and historical successes in this field.

Figure1: structure of eye

OPHTHALMIC PREPARATIONS:

The sterile preparation comprises one or more active pharmaceutical ingredients administered to the eye's surface in solution, suspension, ointment, or similar forms.

Ophthalmic solutions:

Eye solutions are among the most commonly utilized dosage forms for ocular administration. Active pharmaceutical ingredients in solution maintain their efficacy upon reaching the eye's surface, having traversed the cornea or conjunctiva. However, solutions exhibit drawbacks such as limited retention time in the eye, reduced bioavailability due to approximately 75% of the solution being drained through the nasolacrimal fluid, drug instability, and the necessity for preservatives. These limitations can be mitigated by incorporating viscosity-enhancing agents into the solution. These agents extend the drug's retention time in the eye and can modify the solution's pH, thereby addressing some of the shortcomings associated with traditional eye solution⁶.

Ophthalmic suspensions:

Suspensions are characterized as dosage forms comprising finely divided insoluble drug particles dispersed in an aqueous vehicle, typically containing a suspending and dispersing agent. Compared to solutions, suspensions offer prolonged retention time in the eye due to the ability of the particles to remain in the cul-de-sac. The dissolution rate of suspended particles is inversely related to their size. Therefore, for optimal drug delivery into the eye and enhanced dissolution, particle sizes of less than 10μm are typically preferred in suspensions⁷.

Ophthalmic ointments:

Ophthalmic ointments represent semi-solid dosage forms composed of mineral oil and white petroleum jelly as a base, with varying concentrations to achieve the desired consistency and melting temperature. Compared to solutions, ointments offer higher drug-loading capacities. However, their high viscosity and consistency can temporarily impair vision, limiting their application primarily to nighttime use before sleeping. Ointment bases, being anhydrous, are suitable for delivering moisture-sensitive drugs. They are particularly favored by pediatric patients. The main advantages of ophthalmic ointments include prolonged contact time and enhanced overall drug absorption. The Higuchi model describes the relationship between the presence of small drug particles dispersed in the ointment base. According to this model, the rate of drug release per unit of time is influenced by the drug's concentration, its solubility in the base, and the diffusivity of the base itself. This model provides valuable insights into the mechanisms underlying drug release from ophthalmic ointments, aiding in their formulation and optimization for effective ocular drug delivery⁸.

Ophthalmic emulsions:

Ophthalmic dosage forms offer a distinct advantage in delivering poorly water-soluble drugs. Emulsions, a common type of ophthalmic formulation, typically comprise an oil phase or non-aqueous phase, wherein the drug is dissolved, or an aqueous phase rendered miscible using an emulsifying agent. Emulsions are categorized into two types: oil-in-water (o/w) and water-in-oil (w/o). Of these, w/o emulsions, where water is present in the external phase, are generally less irritating to the eye and are more tolerable for patients compared to o/w emulsions. This characteristic makes w/o emulsions preferable for ophthalmic applications⁹.

BACKGROUND:

The history of ocular inserts dates back to the 19^th century when solid medications which consisted of squares of dry filter paper, previously impregnated with dry solutions (e.g., atropine sulfate, pilocarpine hydrochloride) were used as ocular inserts. Small sections were cut and applied under the eyelid. Later, the precursors of the present soluble inserts called lamellae were developed which consisted of glycerinated gelatin containing different ophthalmic drugs. Glycerinated gelatin ‘lamellae’ were present until the first half of the present century in official compendia. However, the use of lamellae ended when more stringent requirements for sterility of ophthalmic preparations were enforced. Nowadays, growing interest is observed for ophthalmic inserts as demonstrated by the increasing number of publications in this field in recent years^10,11.

MECHANISM OF OCULAR DRUG ABSORPTION:

Maximum absorption takes place through the cornea, which leads the drug into aqueous humor. The non-corneal route involves absorption across the sclera and conjunctiva, this route is not productive as it restrains the entry of drug into the intraocular tissues^12,13.

The drug release from the ocular inserts takes place by follows mechanisms:

Diffusion:

In this mechanism, drug release into the tear fluid occurs steadily and in a controlled manner through a membrane. When the insert comprises a non-erodible solid body with pores and the drug is dispersed within, release occurs through these pores via diffusion. Optimal controlled release can also be attained through the dissolution of the solid dispersed drug within a matrix, facilitated by diffusion of an aqueous solution. In soluble systems, as the polymer swells, true dissolution of the drug takes place, contributing to controlled release^13-15.

In swelling-controlled devices, the active form of the drug is uniformly dispersed within a glassy polymer matrix. Initially, diffusion is impeded as the dry matrix is impermeable to the drug. Upon insertion into the eye, water from tear fluid penetrates the matrix, initiating polymer swelling and chain relaxation. Subsequently, drug diffusion occurs as the swollen polymer facilitates movement. Matrix dissolution, following the swelling process, is influenced by the polymer's structure. Linear and amorphous polymers dissolve more rapidly compared to cross-linked or partially crystalline polymers^15,16.

Osmosis:

In the Osmosis mechanism, the insert comprises a transverse impermeable elastic membrane dividing the interior of the insert into a first compartment and a second compartment; the first compartment is bounded by a semi-permeable membrane and the impermeable elastic membrane, and the second compartment is bounded by an impermeable material and the elastic membrane. There is a drug-release aperture in the impermeable wall of the insert. The first compartment contains a solute that cannot pass through the semi-permeable membrane and the second compartment provides a reservoir for the drug which again is in liquid or gel form. When the insert is placed in the aqueous environment of the eye, water diffuses into the first compartment and stretches the elastic membrane to expand the first compartment and contract the second compartment so that the drug is forced through the drug-release aperture^17,18.

Bio-erosion:

In the Bio-erosion mechanism, the insert's body consists of a matrix made of bio-erodible material with the drug dispersed within. When the insert comes into contact with tear fluid, the drug is released gradually and in a controlled manner through the bio-erosion of the matrix. While the drug can be uniformly dispersed throughout the matrix, it's believed that a more controlled release is achieved when the drug is concentrated superficially within the matrix. Truly erodible devices control the rate of drug release through chemical or enzymatic hydrolytic reactions, leading to the solubilization of the polymer or degradation into smaller, water-soluble molecules. These polymers may undergo either bulk or surface hydrolysis. Erodible inserts undergoing surface hydrolysis can exhibit zero-order release kinetics, provided that the devices maintain a constant surface geometry and the drug is poorly water-soluble^19,20.

Advantages of ocular inserts:

The merits of ocular inserts as described below^21,22.

· Exclusion of preservatives, thus reducing the risk of sensitivity reactions;

· Increased shelf life concerning aqueous solutions;

· Possibility of incorporating various novel chemical/ technological approaches like pro-drugs, mucus adhesives, permeation enhancers, micro-particulates, salts acting as buffers, etc.

· Possibility of targeting internal ocular tissues through non-corneal (conjunctival scleral) routes;

· Reproducibility of release kinetics.

Disadvantages of ocular inserts:

The demerits of ocular inserts as described below^23-25.

· A leakage may occur.

· Dislocation of the device in front of the pupil.

· Sometimes the insert twists to form a figure eight’, which diminishes the delivery rate.

· The insert may be lost immediately.

EVALUATION OF OCULAR INSERTS:

Identification:

The purpose of this test is to verify the identity of the active pharmaceutical ingredient (API) in ophthalmic pharmaceuticals. This test should be able to discriminate between compounds of closely related structures that are likely to be present^10,26.

Impurities:

This test determines the presence of any component that is not the API or an excipient of ophthalmic pharmaceuticals. The most common type of impurities that are measured are related substances, which are processed impurities from the new drug substance synthesis, degradation products of the API, or both^27,28.

Swelling index:

A small amount of film is cut and weighed initially and then it is soaked in pH 7.4 tear fluid for 1 hour. After 1 hour, the film is reweighed. The swelling index is calculated by following the formula²⁹.

Intial weight

Swelling index = ---------------------

Final weight

Content uniformity:

Select not less than 30 units, and proceed as follows for the dosage form designated. For solid dosage forms like powders assay 10 units individually using an appropriate analytical method. Calculate the acceptance value (AV) using equation^30-32.

Single-dose powders for eye drops and eye lotions comply with the test or, where justified and authorized, with the tests for uniformity of content and/or uniformity of mass^33-35. Herbal drugs and herbal drug preparations present in the dosage form are not subject to the provisions of this paragraph. The successful attempts in making ocular inserts and the polymers adopted are illustrated in Table 1.

Table 1: The polymers that were used in the making of ocular inserts

Drug name	Polymer used	Reference
Moxifloxacin HCl	Eudragit S-100, RL-100, RS-100, E-100 or E- L-100	36
Ciprofloxacin HCl	Polyethylene oxide	37
Sparfloxacin	Sodium alginate (SA) and methylcellulose (MC)	38
Azithromycin	Hydroxypropyl methylcellulose (HPMC) and hydroxyethyl cellulose (HEC)	39
Chloramphenicol	E-L100, E-S100, and E-RL100.	40
Voriconazole	E-RLPO and ethyl cellulose (EC)	41
Cyclosporine	Sodium hyaluronate (HA) and hydroxypropyl-β-cyclodextrin (HPβCD)	42
Valacyclovir HCl	EC	43
Brimonidine tartarate	Polyvinylpyrrolidone K-90 (PVP K-90)	44
Brinzolamide	HPMC and Kolliphor P 407 (Poloxamer 407, P407)	45
Bimatoprost	Chitosan	46
Glycerogelatin	Glycerol-gelatin	47
Gatifloxacin	E-RL-100 and E-RS-100	48
Ofloxacin	chitosan oligosaccharide lactate and PEG 400	49
Timolol maleate	EC, HPMC, and E-RS 100	50
Besifloxacin HCl	SA and thiolate sodium alginate (TSA)	51
Lidocaine HCl	HPMC, PVA, and β-cyclodextrin	52
Erythromycin	E-L100 and PVA	53
Azithromycin	HPMC, HEC, E-L100, and PVA	54
Acetazolamide	E-NPs	55
Dexamethasone	poly (acrylic acid) derivatives (polyalquilcyanocrylates), albumin, poly-ε-caprolactone, and chitosan	56
Pefloxacin mesylate	E-RS 100 and E-RL 100	57
Dorzolamide	Carboxymethyl cellulose (CMC), chitosan, and PEG 6000	58
Norfloxacin	HPMC, EC, and PVP K30	59
Triamcinolone acetonide	PEG, E-S100 and Zein	60
Fluconazole	HPMC, PVP, PVA and PEG-400	61
Acyclovir	HPMC, PVA and eudragit	62
Ketorolac tromethamine	SA and chitosan	63
Sodium Alginate	Lipophilic alginate copolymer	64
Levobunolol HCl	MC, PVP, and HPMC	65
Piroxicam	PVP, HPMC, CMC, and Carbopol	66
Atorvastatin	MC and PVA	67

CONCLUSION:

The study concludes that ocular inserts offer improved compliance and effectiveness compared to traditional eye drop therapy, enhancing drug dosing accuracy and reducing the risk of cross-contamination. Furthermore, the technological process involved in producing ocular inserts is noted for its simplicity, allowing for validation in accordance with current legislative requirements. This applies to both small-scale production and large-scale industrial manufacturing, facilitating the journey of medicinal drugs to the market.

ACKNOWLEDGMENTS:

The authors are thankful to the college management for the support and encouragement

CONFLICTS OF INTEREST:

All authors declare they have no conflicts of interest.

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Received on 13.02.2024 Modified on 18.04.2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(3):245-250.

DOI: 10.52711/0975-4377.2024.00039