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Pharmacokinetics and biological analysis of ophthalmic drugs

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Eyes are the most sensitive organs of human beings. Generally, their sophisticated functional structure prevents foreign bodies from intruding or removing foreign bodies. The importance of eyes is self-evident, but eye diseases are too numerous to mention. There are currently more than 500 eye diseases known, such as refractive errors (myopia, hyperopia, astigmatism), dry eye, cataracts, glaucoma (primary, secondary, congenital), macular degeneration, etc. The latter three are recognized as the three major blind eye diseases by the World Health Organization (WHO).

Eye diseases cover a wide range of people: from young people who are susceptible to dry eye and refractive errors to the elderly who are susceptible to glaucoma and cataracts. With the changes in the way people use eyes, and the further increase of aging, The incidence of ophthalmological diseases in middle-aged and elderly people is increasing continuously. Eye diseases not only seriously disrupt people’s lives, but also extremely affect people’s health. In the treatment of many eye diseases, drug therapy undoubtedly plays a pivotal role.

As we all know, there are two main aspects to study the interaction between drugs and the body. One is to study the beneficial/harmful effects of drugs on the body, that is, pharmacodynamics (PD)/toxicology (Tox); the other is to study the body’s effects on drugs. The treatment and effect of pharmacokinetics. These two constitute the two main aspects of pharmacological research or pharmacological evaluation of new drugs. Among them, pharmacokinetics is the application of kinetic principles and mathematical models to quantitatively describe the absorption of drugs by the body after drugs enter the body through various routes (such as intravenous injection, intravenous drip, oral administration, local administration, etc.) The dynamic law of “quantity and time” changes in the process of, distribution, metabolism and excretion. Pharmacokinetics plays an important role as a bridge in the development and evaluation of new drugs, such as: screening candidates with good metabolic properties; providing material basis for drug efficacy and toxicity studies; providing optimized solutions for pharmaceutical formulation research; designing clinical trials Provide basis, determine the clinical medication plan, predict the efficacy and toxicity of the drug, and guide the clinical rational use of the drug.

pharmacokinetic characteristics of ophthalmic drugs
pharmacokinetic characteristics of ophthalmic drugs

Due to the precise structure of the eye, the anatomical and physiological barriers and the protection of the systemic circulation, ophthalmic drugs show unique pharmacokinetic characteristics. Therefore, it is necessary to understand the pharmacokinetic characteristics of ophthalmic drugs.

This article will discuss the main anatomical structures and basic characteristics of the eye, therapeutic drugs for ocular diseases, the interaction characteristics of the main ocular structures and drugs, the effect of the ocular barrier on drugs, the intraocular processes of drugs, kinetic models, and biological analysis examples. A brief description of these aspects in order to clarify the pharmacokinetic characteristics of ophthalmic drugs.

Medicilon has established ocular diseases models, which contain Conjunctival tissue proliferation and NV model, Diabetic retinopathy (DR) model, Choroidal neovascularization (CNV) and subretinal fibrosis model, Corneal neovascularization (Corneal NV) model, Retinal neovascularization model, Acute ocular inflammation models, and dry eye models.

Eye anatomy and basic characteristics

To understand the pharmacokinetic characteristics of ophthalmic drugs, the basic anatomical structure of the eye must be clear. As shown in Figure 1, the eyeball wall is divided into three layers, the outer layer is the fibrous membrane; the media is the pigmented membrane, vascular membrane or uveal membrane; the inner membrane is the retina. The eyeball is bounded by the back of the lens and is divided into two parts, the anterior region and the posterior region.

The main structure of the eye and its barrier function
The main structure of the eye and its barrier function

Figure 1 The main structure of the eye and its barrier function [1-2,6]. I The cornea is an important route for drug delivery to the anterior area of the eye; II retinal pigment epithelial cells and retinal capillary endothelial cells are barriers for systemic administration; III vitreous administration methods. The drug enters the anterior area of the eye through venous blood and then spreads to the surface of the iris (2) or enters the aqueous circulation. (3) The drug can be cleared from the vitreous into the anterior chamber (4) or into the blood-retinal barrier.

Anterior area

The anterior area is composed of the cornea, conjunctiva, iris, ciliary body, and lens, and is filled with aqueous humor. Common lesions in the anterior area include cataract, glaucoma, and uveitis.

The anterior 1/6 transparent area of the outer layer of the eyeball wall is the cornea, the back 5/6 opaque area is the sclera, and the transition between the two is the limbus of the cornea. The cornea is slightly oval, with no blood vessels and a tear film on the surface. The cornea is composed of an epithelial layer, a pre-elastic membrane, a stromal layer and an endothelial layer. The epithelial layer is hydrophobic; the pre-elastic membrane is an acellular gel-like membrane (10 microns); the stromal layer is hydrophilic; the endothelial layer is a monolayer of loosely connected cells with hydrophobicity. The tear film is composed of a grease film that can reduce evaporation, an intermediate water layer containing enzymes and bactericidal substances, and a mucus layer that contains a variety of proteins that can provide lubrication and protect the cornea. The excretion of tears is through the lacrimal point to the lacrimal canaliculus to the lacrimal sac, and then through the nasolacrimal duct to the lower nasal passage.

The conjunctiva belongs to the eye appendage, which is a thin and transparent mucosal tissue. The cystic space formed by the conjunctiva is the conjunctival sac. There are accessory lacrimal glands in the conjunctiva of the fornix. Histologically, the conjunctiva can be divided into epithelial layer and lamina propria. The lamina propria is rich in lymphocytes. The conjunctiva is also rich in small blood vessels.

The iris is a brown disc-shaped membranous tissue. The iris is divided into five layers from front to back: the endothelial cell layer continues with the corneal endothelial cells; the front limiting membrane is composed of fibroblasts and melanocytes, without blood vessels; the stromal layer is It is composed of loose connective tissue, composed of blood vessels, nerves, pigment cells and pupil sphincter; the pigment epithelium contains melanin; the inner limiting membrane is continuous with the inner limiting membrane of the ciliary body and the retina.

The ciliary body is the middle part connecting the iris and choroid. The front end is attached to the root of the iris, and the back end is connected to the choroid. This structure of tight junctions between ciliary body epithelial cells is an important part of the blood-aqueous barrier.

The lens is a flexible, transparent, biconvex structure located behind the iris and in front of the vitreous body. The lens suspensory ligament connects it with the ciliary body to maintain the position of the lens. The lens becomes larger and thicker with age, and its elasticity decreases.

The space between the back of the cornea and the front of the iris and lens is called the anterior chamber. The circular space behind the iris, the front of the ciliary body, the suspensory ligament of the lens, and the side of the lens is called the posterior chamber. The anterior chamber angle is located in the gap between the cornea, sclera, and iris root, and is one of the important structures in the aqueous circulation. The anterior and posterior chambers are filled with aqueous humor. The aqueous humor is a colorless and transparent liquid produced by non-pigmented ciliary epithelial cells in the ciliary body. The circulation route is: after ciliary epithelial cells are produced, they enter the posterior chamber, enter the anterior chamber and the trabecular meshwork through the pupil, enter the Schlemm’s tube and then reach the collecting tube, and finally reach the anterior ciliary vein through the aqueous vein. The biggest difference between aqueous humor and plasma is the low protein level and high ascorbate concentration in aqueous humor.

Back of the eye

The posterior area occupies 2/3 of the eye, including the vitreous membrane and all the structures behind it, including: sclera, choroid, retina, vitreous, and optic nerve. The vitreous cavity is filled with vitreous humor. Common pathological changes in the posterior area include age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and optic neuropathy caused by glaucoma. Diseases involving visual impairment and irreversible blindness are all related to the posterior area of the eye. Symptoms such as inflammation and fibrosis are also related to the dysfunction of the posterior area of the eye and ocular tissue damage.

The sclera is composed of dense collagen fibers and elastic fibers. The texture is tough, opaque, and milky white. It consists of the upper layer of the sclera, the parenchyma of the sclera and the brown blackboard of the sclera. The upper sclera contains many small blood vessels. The parenchymal layer is composed of collagen fiber bundles, fiber cells and matrix. The brown sclera is the innermost layer of the sclera and the outer wall of the suprachoroidal space. This layer is composed of more pigment cells and fine collagen fiber bundles containing pigmented macrophages. Due to the effect of intraocular pressure, the fluid passing through the sclera has the characteristic of continuous outflow.

The vitreous body is a colorless and transparent colloid. The vitreous body has no blood vessels and nerves, and cannot be regenerated. The nutrition comes from the choroid and aqueous humor.

The choroid starts from the serrated edge of the front end of the retina and reaches around the optic nerve. It is rich in blood vessels that supply nutrients and oxygen to the retina.

The retina is a transparent film, which is closely attached to the inner surface of the choroid. It is mainly composed of retinal pigment epithelial cells, optic cells, bipolar cells, ganglion cells, horizontal cells, amacrine cells, interreticular cells and Muller cells. The central retinal artery supplies the five layers of the retina and the nerve fibers on the surface of the optic disc. The retina is the most metabolically active tissue in the human body.

Eye disease treatment drugs

The United States is the world’s largest market for ophthalmic drugs, followed by Europe, followed by the Asia-Pacific region, and developing countries have great market potential for ophthalmic drugs. At the same time, ophthalmic drug products have gradually shown the characteristics of segmentation and diversification. The market segmentation of ophthalmic drugs can be divided into: ophthalmic anti-infection, ophthalmic corticosteroids, ophthalmic antiviral, anti-glaucoma, anti-allergic, ophthalmic anesthetics, lubricants, diagnostic agents, cataracts, ocular anti-neovascularization, etc. More than a decade ago, the treatment of related diseases in the posterior area of the eye only relied on traditional treatment methods such as vitrectomy, laser and photodynamic therapy. With the emergence of anti-VEGF drug therapy, a new direction has been opened up for the treatment of neovascular ophthalmopathy. The drugs approved by the FDA for the treatment of ophthalmic diseases and still in clinical application are shown in Table 1. In addition, most of the retinopathy has no cure, especially the lack of drugs related to neuron and glial degeneration.

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