INTRODUCTION:

Due to its properties for drug disposition, the eye is the most fascinating organ. In most cases, applying medication topically is the preferred technique. Due to the ease and safety using it for ophthalmic chemotherapy¹. It is a huge difficulty for the formulator to get around (bypass) the eye’s defences without enduring long-term tissue damage. Emergence of Ocular delivery systems with great therapeutic efficacy continue to be offered by better, more sensitive diagnostic procedures and innovative treatment substances. Traditional ophthalmic formulations, such as solution, suspension, and ointment, have a number of drawbacks that contribute to the drug’s poor ocular cavity bioavailability. To get the best medication concentration at the active site for the right amount of time is the specific goal while creating a therapeutic system².

A medicinal agent’s ocular disposition and removal depend on both its physicochemical characteristics and the pertinent ocular anatomy and physiology. So, in order to successfully develop a drug delivery system, it is necessary to have an integrated understanding of both the drug molecule and the limitations imposed by the ocular route of administration³. Two categories can be made out of the different methods that have been used to lengthen the therapeutic effect of ophthalmic medicines and boost their absorption. The first one relies on sustained drug delivery systems, which offer the continuous and regulated delivery of ophthalmic medications. The following Involves decreasing precorneal drug loss and increasing medication absorption through the cornea³. The best ophthalmic medication delivery system must be able to maintain drug release and stay close to the front of the eye for an extended period of time. Hence, it is essential to improve ocular drug delivery; one approach to do this is by adding polymers of different grades, developing in-vitro to increase the pre corneal medication retention, use an erodible or non-erodible insert, an in-situ gel, or a colloidal suspension⁴.

Forming Gels In Situ for Opthalmic Drug Delivery:

Modern pharmaceutical design has recently adopted regulated and sustained drug distribution as the norm, and extensive research has been done to achieve this. Considerably superior medication product in terms of reliability, safety, and effectiveness. Several polymers that undergo reversible sol to gel phase change in response to physiological cues are extremely helpful in this area⁵. In situ gels are easily injected as a solution into the conjunctival sac, where they undergo a transformation into a gel with its beneficial residence. The physiological environment causes a chemical/physical alteration that leads to the sol-gel transition. This particular form of gel combines the benefit of a patient-friendly solution with the favourable residence time of a gel to increase ocular bioavailability^6,7. A change in temperature, as with the thermogelling Poloxamer 188, a change in pH, as with cellulose acetate phthalate, or by one of these factors can cause the sol-gel transition. Presence of cations for alginates and deacetylated gellan gum. In situ gelling systems for ophthalmic usage can be divided into three categories: pH-sensitive, temperature-sensitive, and ion-activated systems. Since a weak gel or solution is more likely to be eliminated by the fluid mechanics of the eye when deposited in the eye before a strong gel has formed, the velocity of gel development in situ is crucial⁸. Being a naturally occurring hydrophilic polysaccharide with two sugars, sodium alginate, the sodium salt of alginic acid, can be used to create the ion activated in situ gelling system. Due to the presence of divalent calcium ions in the lacrimal fluid, two types of monomers, -D-mannuronic acid (M) and x-L- guluronic acid (G), gel in the cul-de-sac⁹. Hence, the residence period of the medication in the eye is lengthened by the use of these in situ gelling systems. Continuous regulated medicine delivery to the patient By eliminating the need for frequent medication administration and extending the duration of action, the anterior chamber of the eye will improve patient compliance and result in a lower overall dose, which will reduce any local and/or systemic side effects¹⁰.

THE ANATOMY OF THE EYE^11,12:

The human eye is a portal to the phenomenon known as vision because of its exquisite detail and design. The eyeball measures about an inch wide and is spherical in shape. It contains a number of buildings that cooperate to improve sight. The layers and internal structures that make up the human eye each serve a specific purpose. This is an explanation of each eye part in further depth.

A. Aqueous Humour: A jelly-like material called aqueous humour fills the outer/front chamber of the eye. The "anterior chamber of the eye" is filled with a watery fluid that is positioned directly in front of and behind the lens. The aqueous humour is a salt solution that is only very mildly alkaline and contains extremely small amounts of sodium and chloride ions. It is continuously created, primarily by the ciliary processes, flows via the pupil from the posterior chamber into the anterior chamber, and then leaves through the trabecular route at the angle and the uveoscleral route. The scleral venous sinus, also known as Schlemm’s canal, is a circular duct that absorbs aqueous humour from the Through the anterior ciliary veins, it exits the anterior chamber and enters the bloodstream. It is situated where the sclera and cornea meet. Aqueous humour turnover in humans occurs at a rate of 1% to 1.5% of anterior chamber volume per minute. Aqueous formation occurs at a rate of around 2.5 l/min. There are pressure-dependent and pressure-independent routes in aqueous humour. The trabecular meshwork-canal-venous Schlemm’s system is known as the pressure-dependent outflow, whereas the pressure-independent outflow is known as the uveoscleral outflow and refers to any non-trabecular outflow.

B. Cornea: At the front of the eye, there is a prominent, transparent bulge called the cornea. The adult cornea's surface has a radius of about 8mm. It performs a crucial optical function as it refracts light as it enters the eye, directing it onto the lens where it is focused on the retina after passing through the pupil. The capillaries that terminate in loops at the cornea's periphery provide the required nutrition to the non-vascular (blood vessel-free) cornea. Several nerves that are descended from the ciliary nerves supply it. They seep into the cornea's layered tissue. Thus, it is very sensitive.

C. Conjunctiva: The anterior portion of the eyeball is protected by the conjunctiva, a thin, transparent mucous epithelial membrane that borders the inside of the eyelids. The appropriate portion The palpebral and bulbar conjunctiva are the two types of conjunctiva. The conjunctiva is made up of two layers: the stroma (substantia propria), which lies beneath the outer epithelium. Conjunctiva and cornea, which are on the eye's exposed surface, are shielded by the tear film. The conjunctiva contributes to the development of the tear film by secreting significant amounts of fluid, mucins, and electrolytes.

D. Sclera: The strong white sheath that makes up the ball’s outer layer is known as the sclera (the white part of the eye). It is a strong fibrous membrane that keeps the eye’s form. As a roughly sphere-shaped object. When compared to the front/anterior of the eye, it is significantly thicker towards the back/posterior of the eye.

E. Optic nerve: The nearly 1 million nerve fibres that make up the optic nerve are in charge of carrying nerve signals from the eye to the brain. These nerve signals include data on a visual that the brain can process. The optic disc refers to the front surface of the optic nerve, which is visible on the retina.

F. Underneath the retina, the choroid layer absorbs unneeded radiation and nourishes the outer parts of the eye. Eye’s retina. It is a dark brown membrane that is thin, extremely vascular (i.e., has blood vessels), and contains a pigment that absorbs extra light to prevent vision blur (due to too much light on the retina). One of the highest blood flows occurs in the choroid. The lamina fusa loosely fastens the choroid to the sclera’s inner surface.

G. Macula: The macula is the name for the retina’s central region. Photoreceptor cells are concentrated in the macula. In which light is converted into nerve messages. We can perceive small details, like newsprint, with the macula thanks to the great density of photoreceptors. The fovea, where our sharpest vision is located, is located right in the middle of the macula.

H. Vitreous Humour: The vast region that encompasses the vitreous humour, also known as the vitreous body, Each human eye accounts for about 80% of the body. The vitreous humour covers the space behind the eye’s lens and is a completely transparent, thin, jelly-like fluid. The hyaloid membrane, a fragile translucent membrane, encloses an albuminous fluid.

I. Lens: A thin clear capsule surrounds the transparent lens, which is a transparent structure. It is situated beneath the eye's pupil and is surrounded by the ciliary muscles. Refracting is beneficial. Travelling via the cornea-first refracted light of the eye. The retina receives an image from the lens's focus of light. This is made possible by the lens' ability to alter form in response to an object's proximity to the observer's eye. This lens shape shift, known as accommodation, is made possible by the ciliary muscles contracting and relaxing.

J. Ciliary muscle: The middle layer of the eye’s ciliary muscle is a ring of striated smooth muscles that regulates accommodation for viewing things at various distances and Controls the aqueous humour’s flow into Schlemm’s canal. Both sympathetic and parasympathetic nerves innervate the muscle. The lens’s curvature changes as a result of ciliary muscle contraction and relaxation. The balance between two states—Ciliary Muscle tightened (which helps the eye focus on distant things) and Ciliary Muscle relaxed—can be used to characterise this process (This enables the eye to focus on near objects).

K. Iris: The iris is a tiny, round, contractile veil that hangs behind the cornea and in front of the lens. The purpose of the iris, a diaphragm of changeable size, is to regulate the size of the pupil to control how much light is let into the eye. It is the coloured portion of the eye, which can be blue, green, brown, hazel, or grey in different shades.

L. Pupils: Although the pupil sometimes appears to be the dark "centre" of the eye, it is actually the light-passing circular opening in the centre of the iris. Into the pupil. The pupillary reflex controls the size of the pupil (and subsequently the amount of light admitted into the eye) (also known as the "light reflex").

Accessory organs of the eye¹³.

There are various structures that guard the eye.

· The eyebrows

· Eyelashes and lids

· Lacrimal mechanism

The front of the eyeball is shielded by the brows from sweat, debris, and foreign objects. The sensitive cornea and front of the eye are protected by the conjunctiva, one of the many layers of tissue that make up the eyelids. Drops for the eyes are delivered into the lower conjunctival sac. Tears made of water, ions from minerals, antibodies, and the bactericidal enzyme lysozyme are secreted by the lacrimal glands. On instillation, the eye drops begin to instantly drain down the nasolacrimal system into the digestive tract. This happens when the amount of fluid in peripheral tissue exceeds the typical lacrimal volume of 7–10 l due to reflex tearing or the dose type. The lacrimal puncta in the superior and inferior eyelids are filled with extra fluid travels into the lacrimal sac and continues into the gastrointestinal tract after descending the canalicula.

Routes of the Ocular Drug Delivery:

There are numerous ways to deliver drugs to the tissues of the eye. The target tissue is the main factor in choosing the administration route.

Topical route:

Eye drops are typically used to administer topical ocular medications, although they only have a brief contact period with the eye surface. The interaction and resulting By using formulation design, such as viscoelastic gels, gelifying formulations, ointments, and inserts, the duration of a drug’s action can be extended.

Subconjunctival administration:

Drugs have traditionally been administered to the uvea through subconjunctival injections at higher concentrations. This method of medicine delivery is currently gaining new momentum for a variety of causes. New and interesting opportunities to create controlled release formulations to distribute medications to the posterior segment and direct the healing process following surgery have been made possible by advancements in pharmaceutical formulation and materials science.

Intravitreal administration:

Access to the medicine is made much easier with direct drug injection into the vitreous.Retina and vitreous. However, it should be emphasised that the RPE (Retinal Pigment Epithelium) barrier makes distribution from the vitreous to the choroid more difficult. Tiny molecules can diffuse quickly in the vitreous, while bigger molecules, especially ones that are positively charged, have limited mobility.

Mechanism of Ocular Drug Absorption^14-16:

Medicines injected into the eye must enter the eye, first through the cornea and then by non-corneal pathways. Several other pathways to the cornea medicines that are poorly absorbed across the cornea tend to be especially dependent on drug diffusion across the conjunctiva and sclera.

Corneal permeation:

Drugs enter the precorneal space and then permeate across the corneal membrane.

Various barriers to the drug absorption:

The effectiveness of medicine absorption into the inner eye is directly impacted by tears. The efficient ingestion of the majority of eye medications work by diffusing through the corneal membrane. The speed and volume of the eye’s transport processes determine how well the absorption process works. The physicochemical characteristics of the permeating molecule and its interaction with the membrane determine the flow of any medicinal molecule over the biological membrane. The physiological mechanism of precorneal fluid drainage or turnover also affects how much the transport or absorption process happens. The cornea can be viewed as having three primary layers when considering transcorneal drug penetration (epithelium, stroma and endothelium).

Non corneal permeation:

In the case of structurally comparable corneal surfaces, the primary route of drug absorption is anticipated to be diffusion across the intercellular aqueous media. Hence, it is impossible to rule out the existence of a partitioning mechanism. The conjunctival epithelium provides significantly less resistance than the corneal epithelium, despite the fact that both are made up of an epithelial layer covering an underlying stroma.

There are various factors that are responsible for disposition of ocular drugs:

The bioavailability of medications given orally to the eye is a crucial factor. The bioavailability of a medicine can be impacted by physiological factors, such as Lachrymal drainage, drug metabolism, and protein binding.

Drugs that are protein-bound are unable to penetrate the corneal epithelium because of the size of the drug-protein combination. Ophthalmic solutions may only stay in the eye for a short period of time (due to lachrymal drainage), therefore protein binding of a pharmacological ingredient could quickly nullify its therapeutic efficacy by making it inaccessible for absorption. The quick and thorough removal of medications from the precorneal lachrymal fluid is one of the main issues with conventional ophthalmic treatments.

System of nasolacrymal drainage:

The secretory system, the distributive system, and the nasolachrymal drainage system are the digestive system. The secretory system consists of reflex secretors, which have an efferent parasympathetic nerve supply and secrete in response to physical or emotional stimuli, and fundamental secretors, which are triggered by blinking and temperature change brought on by tear evaporation.

The eyelids and tear meniscus around the lid borders of the open eye make up the distributive system, which spreads tears over the ocular surface via blinking. Preventing the emergence of dry patches. The lachrymal puncta, superior, inferior, and common canaliculi, the lachrymal sac, and the nasolachrymal duct make up the excretory portion of the nasolachrymal drainage system. The two puncta, which are located on an elevated region called the lachrymal papilla in humans, are the apertures of the lachrymal canaliculi. It is believed that most tears are absorbed by the mucous membrane lining the ducts, and only a tiny amount makes it to the nasal tube through the lachrymal sac¹⁵.

Novel ophthalmic drug delivery interests:

One of the most fascinating and difficult tasks facing pharmaceutical scientists is ophthalmic medication delivery. The ophthalmic medication market Delivery is extremely competitive and changing quickly. The demand for innovative medication delivery is being driven by new kinds of medicines and biologics. Pharmacotherapeutics’ primary goal is to achieve an effective medication concentration at the site of action for long enough to trigger a reaction. Creating a system with increased ocular medication absorption and longer duration of action while maintaining a low risk of ocular problems is difficult. Not the absence of effective medications, but rather achieving their ideal concentration at the location attaining their optimal concentration at the site of action, is a significant issue with ocular drug delivery^14,15. The development of novel and creative techniques for enhancing therapeutic efficacy predicts that a wider variety of dose forms will be offered to doctors and patients. In the upcoming ten years. The majority of formulation efforts try to limit drug release from the delivery system, reduce precorneal drug loss, and maximise ocular drug absorption by extending the drug’s residence time in the cornea and conjunctival sac. Here is a list of several ophthalmic formulations and how long they stay in the eye cavity for¹⁶.

Ophthalmic drug formulation:

Ophthalmic medications are designed to bring the active ingredients into contact with the eye’s surface so that they can be absorbed. Increased corneal contact time could lead to Improved medication administration and penetration into the eye. Ophthalmic formulations should also include other substances to regulate the formulation’s varied properties, including buffering, pH, osmolality and tonicity, viscosity, and antimicrobial preservatives. Despite being classified as inactive components, these substances can change the drug’s capacity to pass through ocular surface barriers and modify its therapeutic effectiveness.

Management of Ocular Injection¹⁷:

Many types of bacteria, viruses, and fungi can cause ocular infections, both superficial and deep, such as conjunctivitis, corneal ulcers, and endophthalmitis. Pathogens. Antivirals, antifungals, and antibacterials are thus included in the arsenal of antimicrobials that are currently on the market and employed in the prevention and treatment of various illnesses. Sulfonamides, aminoglycosides, polymyxin-based combinations, and fluoroquinolones are typical topical antibacterials used in the treatment of ocular infectious disorders. These fluoroquinolones are prescribed for conditions such as chronic post-filtration hypotonia, corneal ulcers, severe bacterial keratitis, endophthalmitis, blepharo-conjunctivitis, etc. The fluoroquinolones are a growing class of broad spectrum antibiotics that are effective against a variety of Gram negative and Infections of the eyes are caused by anaerobic organisms. These antibacterials have grown in favour in the field of ophthalmology since studies have shown that they are just as effective as combination therapy in treating a variety of ocular infections. Streptococcal and Staphylococcal species are just a couple of the Gram positive pathogens that fluoroquinolones are effective against.

Mechanism of Action^18,19:

Two DNA topoisomerases that are absent from human cells and that are involved in bacterial DNA synthesis are inhibited by fluoroquinolones. Needed for bacterial DNA replication, making these substances both bactericidal and specific. DNA topoisomerases are in charge of dividing the duplex strands of bacterial DNA, putting another strand of DNA through the break, and then re-sealing the initially split strands. Before the replication fork, DNA gyrase adds negative superhelical twists to the bacterial DNA doublehelix, which helps to catalyse the division of Children’s chromosomes. This process enables the binding of initiation proteins and is crucial for the start of DNA replication. Topoisomerase IV is in charge of decantation, or the removal of daughter chromosomal interlinking, which enables segregation into two daughter cells at the conclusion of a round of replication. Fluoroquinolones alter the shape of the enzyme-bound DNA complex (such as DNA gyrase with bacterial DNA or topoisomerase IV with bacterial DNA), which inhibits the enzyme’s usual activity.

The new drug-enzyme-DNA complex prevents the replication fork from progressing as a result, which prevents regular bacterial DNA synthesis and ultimately leads to Sudden bacterial cell death When it comes to the specificity of enzyme inhibition in various types of bacteria, older fluoroquinolones show a rather consistent trend. The more recent fourth generation fluoroquinolones, such as moxifloxacin and gatifloxacin, block both DNA gyrase and topoisomerase IV in Gram-positive species by a dual-binding mechanism of action.

Benefits of polymeric medication administration include:

· Reducing harmful effects on healthy tissue and reaching areas that are inaccessible to people traditionallyA variety of obstacles to focused medicine delivery are present.

· Extend the half-life of medications to stop them from degrading quickly and slow down their rate of elimination to keep drug concentrations within a therapeutically useful range.

· Lower the dosage necessary to achieve therapeutic effectiveness.

· Reduce the amount of repeated intrusive dosages needed for some illnesses, which helps to increase patient compliance and provides improved quality of life^20,21.

Fig. 1: Anatomy of eye Fig. 2: Pathways of aqueous humour

Fig. 3: Different route for ocular administration

Fig4: Ocular drug absorption

Fig 5: Nasaolachrymal Drainage Apparatus

CONCLUSION:

Included in the new ophthalmic delivery system are hiosomes, collagen shields, ocular films, disposable contact lenses, and ocular inserts.As well as nanoparticles. Combining drug delivery systems is a more recent approach for enhancing the therapeutic response of a medicine that is not effective. For topical ophthalmic use, this may provide better dose forms. Only a small number of these medication delivery methods have had products that have reached the market.An ideal system would have minimal systemic effects and prolonged effective medication concentration at the target tissue.

Being accepted by patients necessary for the creation of any convenient drug delivery system for the eyes. Each system needs major improvements, such as more sustained drug release, large-scale manufacturing, and stability. Combining medication delivery methods could provide a new direction for enhancing a system’s ineffective therapeutic response. They can work around restrictions and combine the benefits of many systems.

REFERENCES:

1. Sasaki H, Yamamura K, Nishida K, Nakamurat J, Ichikawa M. Delivery of drugs to the eye by topical application. Progress In Retinal and Eye Research. 1996; 15 (2): 553-620.

2. Macha S, Mitra AK. Ophthalmic drug delivery systems; second edition revised and expanded. Chapter 1, Overview of Ocular Drug Delivery. P 1-3.

3. Mundada AS, Avari JG, Mehta SP, Pandit SS, Patil AT. Recent advances in ophthalmic drug delivery system. Pharm Rev. 2008; 6(1): 481-489.

4. Wagh VD, Inamdar B, Samanta MK. Polymers used in ocular dosage form & drug delivery system. Asian J Pharm. 2008; 2(1): 12-7.

5. Khurana AK, Khurana I. Anatomy & Physiology of Eye; 2nd ed. CBS Publishers & Dist. 2007.

6. Khurana AK. Comprehensive Ophthalmology; 4th ed. Age International (P) Ltd Pub. 2007.

7. Snell RS, Michel A. Clinical Anatomy of the Eye; 2nd ed. Cemp. Blackwell Science.

8. http://www.ivy-rose.co.uk/HumanBody/Eye/Anatomy_Eye.php. (Access on date 08/08/2009; 4.30 pm.)

9. Hosoyaa K, Vincent HL, Kim KJ. Roles of the conjunctiva in ocular drug delivery: a review of conjunctival transport Mechanisms and their regulation. Eur J Pharm Biopharm. 2005; 60: 227–40.

10. Cross JT. Fluoroquinolones Seminars in Pediatric Infectious Diseases. 2001; 12: 211-23.

11. Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev. 2006; 58: 1131–35.

12. Jtirvinena K, Tomi J, Urttia SA. Ocular absorption following topical delivery. Adv Drug Deliv Rev. 1995; 16: 3-19.

13. Nanjawade BK, Manvi FV, Manjappa AS. In situ-forming hydrogels for sustained ophthalmic drug delivery. J Control Release. 2007; 122: 119–34.

14. Meqi SA, Deshpande SG. Ocular drug delivery: Controlled and Novel Drug Delivery. New Delhi: CBS Publishers; 2002, p 82-84.

15. Eva M, Amo D, Urtti A. Current and future ophthalmic drug delivery systems. A shift to the posterior segment. Drug Discov Today. 2004; 13: 135-143.

16. Blondeau JM. Fluoroquinolones: Mechanism of Action, Classification, and Development of Resistance. Surv Ophthalmol. 2004; 49: S73-S78.

17. Gupta P, Vermani K and Garg S. Hydrogels: from controlled release to pHresponsive drug delivery. Drug Discov Today. 2002; 7: 569-79.

18. Desai PN. Synthesis and characterization of polyionic hydrogels, Bachelors of Homoeopathic Medicine and Surgery, LMF’s Homoeopathic Medical College, India, 2005.

19. He C, Kim SW, Lee DS. In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. J Control Release, 127, 2008, 189–207.

20. Satish CS, Satish KP, Shivkumar SG. Hydrogels as a controlled drug delivery system: Synthesis, cross linking, water and Drug transport mechanism. Indian J Pharm Sci. 2006; 3: 133-41.

21. Bourlais CL, Acar L, Zia H, Sado PA, Needham T, Levergc R. Ophthalmic drug delivery systems recent advances. Progress In Retinal and Eye Research. 1998; 17(1): 33-58.

Received on 06.11.2023 Modified on 14.12.2023

Research J. Science and Tech. 2024; 16(1):79-86.

DOI: 10.52711/2349-2988.2024.00013