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Topical drug delivery is a routine treatment for the treatment of ophthalmic diseases. Conventional topical ophthalmic formulations include solutions, suspensions, emulsions, gels, and ointments. However, the delicate structure of the eye, its unique anatomy, and biology, among other things, allow only a tiny fraction of locally administered drugs to reach the target tissues and do not allow effective delivery in the eye, resulting in low bioavailability of ocular drugs.
Recent advances in pharmacology, biotechnology, and materials science have led to the development of novel ophthalmic dosage forms that can provide sustained drug delivery, reduce dosing frequency, and improve the ocular bioavailability of drugs[2].
Medicilon’s ophthalmic drug formulation service covers four significant types of eye drops, injectables, gels, and ointments and has completed formulation safety studies for several new eye drops and vitreous injections and helped to obtain clinical approval.
Ophthalmic Formulations Background
The global ophthalmic drugs market size grew from US $ 277 billion to US $ 32.7 billion between 2016 and 2020, at a CAGR of 4.2%. With the development and launch of more innovative ophthalmic drugs in the future, it is expected to reach US $ 46.4 billion by 2025 and US $ 73.9 billion by 2030.
China’s ophthalmic drugs market grew from RMB 15.1 billion to RMB 18.8 billion from 2016 to 2020, at a CAGR of 5.7%, and is expected to reach RMB 44 billion in 2025 and RMB 108.4 billion in 2030.
Comparing the two graphs shows that domestic growth is expected to be greater than global growth and that the domestic ophthalmology market has great potential. Ophthalmic drugs have continued to be approved in recent years. To fill the market demand for ophthalmic drugs as soon as possible, more and more pharmaceutical companies have joined in the development and production of ophthalmic drugs. According to the database of pharnexcloud, there are 234 new ophthalmic drugs in China from 2014 to now, among which there are 15 drugs in the drug discovery stage, 61 drugs in the preclinical stage, and in terms of the clinical setting, the most products in phase II clinical, reaching 47.
What's the classification of Common 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.
The prevalence of dry eye and allergic conjunctivitis is higher. Most eye diseases, including cataracts, glaucoma, retinal diseases, refractive eye diseases, and other blinding eye diseases, are positively associated with population aging.
Eye diseases that may impair vision or even cause blindness include retinopathy, wet age-related macular degeneration, cataract, and glaucoma, among which the blindness of wet age-related macular degeneration and glaucoma is irreversible.
The current eye health situation in China is serious, and China has the most significant number of eye disease patients worldwide. With the development of the aging trend in China, the number of patients with cataracts, glaucoma, and dry eye disease is on the rise. The age of patients with retinopathy caused by hypertension and hyperglycemia is gradually getting younger. Myopia is the most common eye disease. The number of myopia patients in China has exceeded 600 million people. Myopia rate is as high as 48.5%, and the rate of teenagers’ myopia is even more than half.
What are the types of conventional topical ophthalmic formulations?
Due to the slow progress in basic research related to ophthalmic diseases, research and development regarding drugs in China has mainly focused on developing improved processes or dosage forms of approved drugs.
Solutions, suspensions, emulsions, gels, and ointments are conventional topical ophthalmic formulations. Eye drops have long dominated the ophthalmic market with various categories. Water-soluble drugs are formulated as aqueous solutions, and water-insoluble drugs are developed as aqueous suspensions, emulsions, gels, or ointments.
Eye drops:
Most ophthalmic preparations are eye drops. Solution dosage forms are relatively easy to handle and scale up and are well tolerated. However, an appropriate salt form with suitable solubility, buffering capacity, and tolerability needs to be selected.
Suspension-type eye drops:
About 20% of topical ophthalmic preparations are suspension-type eye drops. Lipophilic and slightly soluble drugs can be formulated as suspension drops. Drug particle size, morphology, shape, and crystallinity must be considered in preparing ophthalmic suspensions.
The average particle size of ophthalmic suspensions is approximately tenμm, with larger particle sizes prescribed for longer contact times, which may prolong bioavailability but cause irritation. Therefore, ophthalmic suspensions with smaller particle sizes are generally accepted but are rapidly absorbed by ocular tissues and cause less ocular irritation to patients.
Ophthalmic gels:
Gels are topical ophthalmic formulations formulated with polymers that dissolve 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. This results in lower dosing frequency, lower toxicity, and improved patient acceptability. In addition, the use of hydrophilic gel-like transparent does not affect the patient’s visual field.
Ophthalmic emulsions:
Emulsions are a dispersion system of two immiscible liquids, dispersed in one (dispersed phase) by an emulsifier in fine droplets in the other (dispersion medium). The poorly water-soluble drug is dissolved in a suitable oil, and the oil phase is dispersed in water. Trans-corneal permeation and bioavailability of ophthalmic emulsion drugs can be improved by adjusting the drug content in the oil phase of the emulsion.
Ophthalmic ointments:
Ointments are usually prepared with mineral oil or petrolatum. The contact time of the ointment with the cornea is significantly longer than other preparations. However, topical ophthalmic ointment use is limited by patient compliance due to the blurring of visible understanding that results. In addition, because ointments cannot be dosed, there is more significant variability in patients using ophthalmic ointments.
Medicilon’s ophthalmic drug formulation service covers four significant types of eye drops, injectables, gels, and ointments and has completed formulation safety studies for several new eye drops and vitreous injections and helped to obtain clinical approval.
Injectable ophthalmic drugs encounter more obstacles than other dosage forms at the R&D stage due to the difficulty of their delivery methods. Medicilon’s preclinical ophthalmic research platform can realize special, fine drug delivery to animal species such as rabbits, dogs, mini pigs, and non-human primates, including Subretinal Injection under a microscope, Suprachoroidal Injection, Intravitreal injection, etc. Using years of rich practical experience and advanced equipment. We can solve various complex problems of customers regarding ophthalmic research, focus on details, control quality, and provide customers with stable and high-quality research services.
The Development of Nanotechnology Ophthalmic Formulation
Improving the bioavailability of formulations in the eye is still challenging for pharmacists. Most ocular diseases are treated by topical administration. Because of their low price and easy preparation, eye drops have been the most commonly used formulations for ocular administration.
Due to the particular physiological structure of the eye, there are the corneal barrier, conjunctival barrier, blood-atrial fluid barrier, blood-retinal barrier, etc. The drug drops are constantly diluted by tear fluid and rapidly lost through the nasolacrimal duct after being inserted into the conjunctival sac, resulting in poor bioavailability [3].
Currently, ocular drug delivery faces non-physiological concentrations of substances administered into the eye,blinking, and tearing, which cause rapid drug elimination. Also, the drug is bound to tear proteins, which may be metabolized by enzymes in the tear, in addition to poor corneal permeability. These challenges are faced by most commercially available ophthalmic formulations in the form of eye drops and suspensions.
Recent advances in ophthalmic formulations allow prescribers to select the appropriate dosage for the targeted ocular condition.
Advanced ophthalmic delivery systems have been specifically designed and tailored to enable continuous or extended drug delivery to reduce dosing frequency and improve ocular bioavailability. Improving or extending the visual residence time of drugs is challenging. Residence times range from a few seconds with eye drops to several months with implants/intraocular devices[2].
In addition to traditional ophthalmic solutions, emulsions, suspensions, gels, and ointments, increasing interest has turned to developing new,advanced ophthalmic carriers, including nano micelles, nanoemulsions, liposomes, nano mixes, in situ gels, and others. Lipid nanoformulations include nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, liposomes, and other dosage forms, which have developed rapidly in recent years for ophthalmic applications.
Compared with ordinary eye drops, nanoemulsions have advantages such as slower ocular elimination and longer duration of action. Solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), liposomes, and other new ophthalmic lipid nanoformulations can prolong the ocular retention time of drugs and improve their bioavailability. The formulation has suitable viscosity and better biocompatibility by adding hydrophilic polymeric excipients, improving patient compliance[3].
Although nanotechnology-based formulations are currently scarce, they are considered the most promising systems capable of improving API delivery into the eye.
By the end of 2020, 11 nanotechnology-based ophthalmic agents were approved by the FDA, of which 3 are nanoemulsions, three nanohybrids, three biodegradable and non-biodegradable implants, one liposome, and one nanoparticle. Marketed ocular nano-DDS include micelles (Cequa), liposomes (VISUDYNE, Lacrisek, Artelac Rebalance), and nanoemulsions (Restasis, Cyclokat, Ikervis, Durezol, Xelpros, Systane, Complete), with several more in clinical evaluation. Several nanoemulsions are in the clinical evaluation phase.
These include:
Restasis, 0.05% cyclosporine A emulsion for dry eye
Cyclokat, a French Novagali cyclosporine formulation for dry eye
Ikervis,Cyclosporine developed by Santen Pharma, Japan
Durezol, 0.05% difluprednate ophthalmic emulsion from Sirion Pharmaceuticals, Inc.
Xelpros, Latanoprost ophthalmic emulsion, 0.005%, for patients with open-angle glaucoma or high intraocular pressure
Vekacia, (0.05% or 0.1% cationic nanoemulsion of cyclosporine A) for the treatment of keratoconjunctivitis and
Catioprost, (nanoemulsion containing 0.005% latanoprost) for the treatment of glaucoma.
Nanoemulsions provide a larger contact area between the carrier and the eye, improving corneal permeability and providing topical bioavailability and efficacy.
The surfactant in the nanoemulsion improves the mixing of the nanodroplet with the pre-corneal component so that the drug can diffuse more through the cornea. As a result, the contact time between the drug and the corneal epithelium can be prolonged, and rapid onset of action can be achieved.
In response to the market demand for ophthalmology, Medicilon has established an ophthalmic formulation development platform to help develop the ophthalmic industry. Medicilon’s ophthalmic formulation department can create dosage forms, including ophthalmic liquid formulations and semi-solid formulations. Medicilon has various technology platforms such as solutions, suspensions, emulsions, gels, ointments, creams, etc. Completed project categories include Class 1, 2, and 4 eye drops, all successfully filed and undergoing clinical trials.
Also, Medicilon can undertake preclinical studies in ophthalmology. The ophthalmic platform has a unique intra-ocular spherical drug delivery technology, equipped with an advanced ophthalmic surgical microscope, which enables special and delicate drug delivery to animal species such as rabbits, dogs, mini-pigs, and non-human primates, in addition to conventional eye drops and ophthalmic ointment delivery.
