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.
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