Eye Targeted Nano Drug Delivery System
The eye is divided into anterior and posterior segments. The anterior segment includes the cornea, conjunctiva, iris, aqueous humor, and ciliary body. The posterior segment includes the vitreous, retina, choroid, and sclera. The physiological barriers of the eye include the corneal and conjunctival barriers, the aqueous humoral barrier, and the blood-retinal barrier. The cornea and retina are barriers that are not easily penetrated by drugs. The drug absorption of eye drops usually has a corneal route and a non-corneal route. Fat-soluble drugs enter the aqueous humor from tears mainly through the corneal pathway. In the non-corneal pathway, the drug penetrates into the human eye tissue through the conjunctiva and sclera, but the drug is easily eliminated from the choroidal blood flow. Only when the drug has high permeability to retinal pigment epithelial cells (RPE), when there is a local storage effect and a continuous concentration gradient. and it can reach a certain concentration in the later stage. The blood-eye barrier includes the blood-aqueous barrier and the blood-retinal barrier. Among them, the blood aqueous barrier is composed of epithelial cells in the pigment layer, preventing plasma proteins from entering the aqueous humor, and also restricting water-soluble drugs from entering the aqueous humor from the plasma. Local inflammation may disrupt the integrity of the barrier, resulting in unrestricted distribution of some drugs to the anterior chamber. The blood-retinal barrier consists of a tight connection between the RPE and the capillary wall of the retina. Different from the retina, the choroidal blood flow is large, and the blood vessel wall leaks. The drug is more likely to leak out of the blood vessel, but it still only accounts for a small part of the systemic blood flow. Drug distribution to the retina is restricted by RPE and retinal vascular endothelial cells. Without a targeting system, only trace amounts of drugs from human vein or oral blood can enter the retina and choroid.
Advantages Of Nano-Eye Targeting
Many eye diseases, such as age-related macular degeneration, pigmented retinitis, diabetic retinopathy, and proliferative vitreoretinopathy, need to be delivered to the back of the eye during treatment. Ophthalmic drug delivery is challenging due to the particular nature of the physiological barrier and ocular drug metabolism. Studies on eye-targeted drug delivery systems include: ① increasing drug penetration, such as iontophoresis and transscleral drug delivery systems; ② controlling drug release, such as microspheres and intraocular implants; ③ targeted drugs, such as high molecular weight drugs and immunoconjugates. Ophthalmic implants and intravitreal long-acting injection preparations can avoid the physiological barrier of the eye, but they have the disadvantages of inconvenient medication and poor compliance. And the penetration enhancers that improve drug penetration are irritating and damaging. Therefore, the advantages of nanotechnology-based drug delivery systems in ocular targeting show unique advantages, mainly in the following aspects: ① Insoluble drugs such as dexamethasone and ganciclovir are made into solid fats Nanoparticles and nanoliposomes can solve the problem of low drug solubility; ② due to the charge, surface characteristics and relative hydrophobicity of the surface of the nanocarrier particles, the blood-retinal barrier can be effectively overcome; ③ The drug is contained in the nanocarrier. It can avoid drug degradation, delay drug release, and further improve the efficiency of drug targeting in the eye. The following nanoparticles have been used in the research of nanoparticle eye targeting systems and have achieved certain results.
Microemulsion
Microemulsion has a particle size of 10 to 100 nm and is thermodynamically stable. Its industrial preparation and sterilization processes are relatively simple and the production cost is low. The presence of surfactants and co-surfactants in microemulsions can improve membrane permeability and increase drug cell uptake. Microemulsion has slow corneal absorption, which can increase the bioavailability of the drug in eye tissues. The microemulsion also has a sustained release effect, which can reduce the number of administrations.
Certain biodegradable materials, such as PLGA, albumin, and chitosan nanoparticles, can be injected into the vitreous and migrate to the retina, where they finally gather in retinal pigment epithelial cells and remain for 4 months. In addition, vitreous injection can non-specifically activate retinal microglial cells, cause a mild temporary inflammatory response, and change the permeability of the membrane, which is conducive to drug administration in the back of the eye. In addition, the positively-charged chitosan and the negatively-charged intraocular tissue have an electrostatic interaction, and the drug is introduced into the eye by penetrating through the corneal epithelial cells, increasing the drug concentration in the aqueous humor.
In Situ Forming Gel
The dispersion medium of ophthalmic nanoparticles should have a certain viscosity so as to be retained in a small volume in the eye. The in situ gel is in a solution state at normal temperature, and a phase change occurs at the drug application site to form a non-chemically cross-linked semi-solid preparation. According to its formation mechanism, it can be divided into temperature sensitive, pH sensitive, and ionic strength sensitive. Common temperature-sensitive materials include Poloxamer F127, Poloxamer 407, ethylhydroxyethylcellulose, xylan and the like. The in situ gel used for the eye is a free-flowing liquid in vitro and immediately turns into a gel when dropped into the eye. When the nanoparticles and the in situ gel are compounded, the stability of the nanoparticles can be improved, and the eye retention of the nanoparticles can be prolonged.
Ophthalmic liposomes can improve the penetration rate of the cornea to the drug, increase the cornea’s targeting and adhesion, protect the drug from the metabolism of enzymes in the eye, slowly release the drug, reduce drug toxicity, and can be used under the conjunctiva or in the eye Injected and used to carry monoclonal antibodies or genes.
Niosomes
Niosomes are vesicles composed of non-ionic surfactants. Preparation of timolol maleate niosomes, which were administered to rabbit eyes. The concentration of timolol maleate in aqueous humor was measured by microdialysis. It was found that the peak concentration in aqueous humor was 1.7 times that of the solution, and the disc-shaped niosomes was 2.34 times, and maintain effective concentration within 2h. This shows that disc-shaped niosomes are ideal carriers for ophthalmic water-soluble drugs.
A dendrimer is a dendritic skeleton composed of continuous repeating units, with perfect monodispersity. The surface contains multiple amino, carboxyl or hydroxyl drugs. The molecule can be wrapped inside or covalently attached to the polymer surface. The particle size of dendrimer from G1 to Gio generation is 1 ~ 15nm, and it will not exceed 30nm after drug coupling. Commonly used dendrimers are polyamideamine (PAMAM), polypropyleneimine (PPI), and polyethyleneimine (PEI). Puerarin can form a complex with PAMAM of different generations through hydrogen bonding. Compared with pure puerarin, the complex has a significantly slower drug release rate and a slow release effect. The compound eye drops stay longer in the eye and do not damage epithelial and endothelial cells.
Contact Lens With Nanoparticles
Nanoparticle-containing contact lenses disperse drug-loaded nanoparticles in lens materials. Contact lens materials include rigid air-impermeable materials, soft air-impermeable materials, soft non-aqueous materials and hydrogel materials. Among them, the hydrogel as the main material. The contact lens swells after coming into contact with tear fluid, and the drug slowly diffuses from the nanoparticles into the swollen contact lens matrix. After the drug and the contact lens matrix reach equilibrium, the drug is released to the cornea. The system is characterized by a long drug retention time, which can reduce the number of administrations, facilitate corneal absorption, reduce the drug’s entry into the conjunctiva and nasolacrimal duct, and reduce systemic side effects. The microemulsion was added to poly (hydroxyethyl methylpropionate) (PHEMA) to make a contact lens, which remained transparent and did not affect vision, and sustained drug release for 8 days. The drug release rate could be controlled by particle size and drug loading. . This system can not only be used for controlled-release drugs, but also store lubricants to solve dryness caused by contact lenses.