Types of Topical Ophthalmic Preparations and Development of New Ophthalmic Formulations

Topical administration is a conventional treatment for ophthalmic diseases. Common types of topical ophthalmic formulations include solutions, suspensions, emulsions, gels, and ointments, and others. However, due to the relatively precise structure of the eye, unique anatomical and biological characteristics, etc., only a small part of the drug administered locally can reach the target tissue and cannot be effectively delivered in the eye, resulting in low bioavailability of ocular drugs.

Recent advances in the fields of pharmacy, biotechnology, and materials science have facilitated the development of novel ophthalmic dosage forms that can provide sustained drug delivery, reduce dosing frequency, and improve the ocular bioavailability of drugs. [2]

The eye is divided into an anterior segment and a posterior segment. The anterior segment includes the cornea, conjunctiva, iris, aqueous humor, and ciliary body, and the posterior segment includes the vitreous, retina, choroid, and sclera. The physiological barriers of the eye include the cornea and conjunctiva barrier, the blood-aqueous humor barrier, and the blood-retinal barrier, among which the cornea and retina are barriers that are difficult for drugs to penetrate. [4]

The eye is a complex organ with unique anatomical and physiological properties that limit drug delivery to target ocular tissues/sites.

Medicilon’s ophthalmic drug preparation services cover four types: eye drops, injections, gels, and eye ointments. It has completed safety research on the preparations of various eye drops and vitreous injection new drugs and helped to obtain clinical approval.

Background on Ophthalmic Preparations

From 2016 to 2020, the global ophthalmic drug market size will grow from US$27.7 billion to US$32.7 billion at a CAGR of 4.2%. With the development and marketing of more innovative ophthalmic drugs in the future, it is expected to reach US$46.4 billion in 2025 and US$73.9 billion in 2030.

From 2016 to 2020, the size of China’s ophthalmic drug market has grown from RMB 15.1 billion to RMB 18.8 billion, with a compound annual growth rate of 5.7%. It is expected to reach RMB 44 billion in 2025 and RMB 108.4 billion in 2030.

From the comparison of the two figures, it can be seen that the Chinese growth expectation is greater than the global growth expectation, and the domestic ophthalmology market has huge potential. In order to fill the market demand for ophthalmic drugs as soon as possible, ophthalmic drugs have been continuously approved in recent years, and more and more pharmaceutical companies have joined the research and development, and production of ophthalmic drugs. According to the Yaorong Cloud database, since 2014, there have been 234 new ophthalmic drugs in China, of which 15 are in the drug discovery stage, and 61 are in the preclinical stage. In terms of the clinical stage, the number of products in phase II clinical trials is the largest, reaching 47.

Classification of Eye Diseases

From the perspective of the prevalence of ophthalmic diseases, the prevalence of allergic conjunctivitis, dry eye, cataract and myopia is relatively high. On average, more than 10 out of every 100 people are suffering from one of these eye diseases.

Among them, dry eye syndrome and allergic conjunctivitis account for a large proportion, and most eye diseases, including cataracts, glaucoma, retinal diseases, refractive eye diseases and other more harmful blinding eye diseases, are positively correlated with population aging.

Eye diseases that may damage vision or even cause blindness include retinopathy, wet age-related macular degeneration, cataract, glaucoma, etc. Among them, the blindness of wet age-related macular degeneration and glaucoma is irreversible.

 At present, the current situation of eye health in China is severe, and China is the country with the largest number of eye disease patients in the world. With the development of China’s aging trend, the number of patients with cataracts, glaucoma, and dry eye is on the rise, and the age of patients with retinopathy caused by high blood pressure and high blood sugar is gradually getting younger. Myopia is the most common eye disease. At present, the number of myopia patients in my country has exceeded 600 million. The myopia rate is as high as 48.5%, and the myopia rate among teenagers is even more than half.

Common Types of Topical Ophthalmic Preparations

Due to the slow progress in basic research related to ophthalmic diseases, with regard to drug research and development, China mainly focuses on the development of improved processes or dosage forms of approved drugs. Solutions, suspensions, emulsions, gels, and ointments are common topical ophthalmic formulations. Among them, eye drops have dominated the ophthalmology market for a long time, with various categories. Generally speaking, water-soluble drugs are generally formulated into aqueous solutions, and water-insoluble drugs are developed into aqueous suspensions, emulsions, gels or ointments.

Eye drops:

Most ophthalmic preparations are eye drops. Solution dosage forms are easier to handle and scale up and are well tolerated. However, an appropriate salt form with appropriate solubility, buffer capacity, and tolerability needs to be selected.

Suspension eye drops:

About 20% of topical ophthalmic formulations are suspension eye drops. Lipophilic and slightly soluble drugs can be formulated as suspension eye drops. Drug particle size, morphology, shape, and crystallinity must be considered in the preparation of ophthalmic suspensions.

The average particle size of the ophthalmic suspension is about ten μm. The larger the particle size, the longer the contact time of the prescription, which can prolong the bioavailability, but it may cause irritation. Therefore, ophthalmic suspensions with smaller particle sizes are generally accepted but are quickly absorbed by eye tissues and are less irritating to patients’ eyes.

Eye Gels:

Gels are topical ophthalmic formulations formulated with polymers that swell in an aqueous environment. The unique ability of the gel is to improve the bioavailability of the drug by prolonging the release, which in turn reduces the rate of elimination. Dosing frequency can be reduced, toxicity is low, and patient acceptance can be improved. In addition, the use of hydrophilic gel is transparent, and the patient’s field of vision will not be affected.

Eye Creams:

An emulsion is a dispersion of two immiscible liquids, one of which (the dispersed phase) is dispersed in the other (the dispersion medium) as fine droplets by an emulsifier. Drugs with poor water solubility are dissolved in a suitable oil, and the oily phase is dispersed in water. The transcorneal penetration and bioavailability of ophthalmic emulsion drugs can be improved by adjusting the drug content in the oil phase of the emulsion.

Eye ointment:

Ointments are usually prepared with mineral oil or petrolatum. The contact time of the ointment with the cornea was significantly longer compared to other formulations. However, topical ophthalmic ointments have limited patient compliance due to blurred vision. In addition, patient variability in ophthalmic ointments is greater because ointments cannot be quantified.

Medicilon’s ophthalmic drug preparation services cover four types: eye drops, injections, gels, and eye ointments. It has completed safety research on the preparations of various eye drops and vitreous injection new drugs and assisted in clinical approval.

 

Injectable ophthalmic drugs encounter greater obstacles in the research and development stage than other dosage forms due to the difficulty of administration. Realize unique fine drug delivery, including subretinal injection, suprachoroidal injection, vitreous injection, etc., Medicilon uses years of rich practical experience and advanced equipment to solve various complex problems of customers about ophthalmology research, focus on details and control quality to provide customers with stable and high-quality research services.

Development of Nanotechnology Ophthalmic Preparations

How to improve the bioavailability of preparations in the eye is still a challenge for pharmaceutical workers. Most eye diseases are treated with topical medications. Because eye drops are cheap and easy to prepare, they have been the most commonly used dosage form for ocular administration. Due to the special physiological structure of the eye, there are corneal barrier, conjunctival barrier, blood-aqueous barrier, and blood-retinal barrier, etc. The drug drops into the conjunctival sac are continuously diluted by tears and rapidly lost through the nasollacrimal duct, resulting in poor bioavailability. [3]

At present, eye drug administration is faced with the application of non-physiological concentrations of substances into the eye, and blinking and tearing will quickly eliminate the drug. At the same time, the drug is bound to the tear protein, and the drug may be metabolized by the enzymes present in the tear, and the corneal permeability is poor. These challenges are faced by most commercial ophthalmic formulations in the form of eye drops and suspensions.

Recent advances in ophthalmic formulations allow prescribers to select the appropriate dosage form for the ocular disease of interest. Advanced ophthalmic drug delivery systems are specifically designed and tailored to enable sustained or extended drug delivery to reduce dosing frequency and increase ocular bioavailability. Improving or extending the ocular residence time of drugs is challenging. Currently, dwell times range from seconds with eye drops to months with implants/intraocular devices [2]

The advantages of drug delivery system based on nanotechnology in ocular targeting show unique advantages, mainly in the following aspects: ① Making insoluble drugs such as dexamethasone and ganciclovir into solid lipid nanoparticles Nanoparticles and nanoliposomes can solve the problem of low drug solubility; ②Due to the charge, surface characteristics and relative hydrophobicity on the surface of nanocarrier particles, they can effectively overcome the blood-retinal barrier; ③Encapsulating drugs in nanocarriers can Avoid the degradation of the drug, delay the release of the drug, and further improve the targeting efficiency of the drug in the eye. [4]

In addition to traditional ophthalmic solutions, emulsions, suspensions, gels, and ointments, increasing interest has shifted to developing new, advanced ophthalmic vehicles, including nano micelles, nanoemulsions, liposomes, nano Suspensions, in situ gels, and more. Lipid nano-preparations include nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and liposomes, and their application in ophthalmology has developed rapidly in recent years.

Compared with ordinary eye drops, nanoemulsions have the advantage of slowing down the elimination speed of the eye and prolonging the action time. New ophthalmic lipid nano-preparations such as solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and liposomes can prolong the ocular residence time of drugs and improve their biological properties. Utilization and after adding hydrophilic polymer excipients, the viscosity of the preparation is suitable, the biocompatibility is better, and the compliance of patients when used is also improved. [3]

Although nanotechnology-based formulations are few and far between, they are currently considered the most promising systems for improving API delivery into the eye. By the end of 2020, there were 11 FDA-approved ophthalmic formulations based on nanotechnology, of which three were nanoemulsions, three nanosuspensions, three biodegradable and non-degradable implants, and one liposome, one nanoparticle. The marketed ophthalmic nano-DDS includes micelles (Cequa), liposomes (VISUDYNE, Lacrisek, Artelac Rebalance), and nanoemulsions (Restasis, Cyclokat, Ikervis, Durezol, Xelpros, Systane, Complete), and several nanoemulsions In the clinical evaluation stage.

These include:

Restasis, 0.05% Cyclosporin A Emulsion, for dry eye

Cyclokat, French Novagali cyclosporine formula, for the treatment of dry eye

Ikervis, cyclosporine developed by Santen Pharma in Japan

Durezol, a difluprednate 0.05% ophthalmic emulsion from Sirion Pharmaceuticals

Xelpros, Latanoprost Ophthalmic Emulsion, 0.005%, for use in patients with open-angle glaucoma or ocular hypertension

  Vekacia (cationic nanoemulsion of 0.05% or 0.1% cyclosporine A) for keratoconjunctivitis and

Catioprost (a nanoemulsion containing 0.005% latanoprost) for treating glaucoma.

Nanoemulsions provide a larger contact area between the carrier and the eyeball, which can improve corneal permeability, and provide local bioavailability and efficacy.

The surfactant in the nanoemulsion can improve the mixing of the nanodroplets with the precorneal components, so that the drug can diffuse more through the cornea. Therefore, the contact time of the drug with the corneal epithelium can be prolonged, and the effect can be achieved rapidly.

Medicilon Ophthalmic Preparation Development Platform

In response to the needs of the ophthalmology market, Medicilon has established an ophthalmic preparation development platform to help the development of the ophthalmology industry. The Medicilon Preparation Department can undertake the development of dosage forms, including ophthalmic liquid preparations and ophthalmic semi-solid preparations. Medicilon has solutions, suspensions, emulsions, gels, ointments, creams, and other platforms. The completed project categories include eye drops 1, 2, and 4, all of which have been successfully declared and are currently undergoing clinical trials. At the same time, Medicilon can undertake preclinical research in ophthalmology. The ophthalmology platform has a special intraocular drug delivery technology and is equipped with an advanced ophthalmic surgery microscope. Animal species such as dogs, miniature pigs, and non-human primates achieve unique fine-grained dosing.

[1]: Gawin-Mikołajewicz A, et al. Ophthalmic Nanoemulsions: From Composition to Technological Processes and Quality Control. Mol Pharm. 2021 Oct 4;18(10):3719-3740

[2]. Furqan A. Maulvi, et al. Recent advances in ophthalmic preparations: Ocular barriers, dosage forms and routes of administration. International Journal of Pharmaceutics, Volume 608, 25 October 2021, 121105

  [3] Yang Long, Chen Lingyun, Wei Gang. Research Progress of Ophthalmic Lipid Nano-Preparation [J]. China Journal of Pharmaceutical Industry, 2016, 47(12): 1592-1599. DOI: 10.16522/j.cnki.cjph .2016.12.022.

[4]. Jin Yiguang et al. Application of nanotechnology in drug delivery.