What is an Ophthalmic Preparation?

Ophthalmic preparations refer to sterile preparations that are directly used to treat the eye. As the most important sensory organ of human beings, the eye is highly sensitive. The tissue structure of the eye is complex and special, and there are many barriers. More effective therapeutic drugs and more appropriate drug delivery systems still need to be developed and applied. Common ophthalmic preparations are divided into ophthalmic liquid preparations and ophthalmic semi-solid preparations.

Anatomy of the human eye. (Aldrich, D. S., 2013)

Types of ophthalmic preparations

Eye drops: A sterile liquid preparation made of APIs and suitable excipients for injection into the eye. It is the most commonly used ophthalmic dosage form, which is absorbed quickly and plays a fast role. Because the conjunctival sac holds only 20mL of fluid, while the volume of 1 drop of eye fluid is about 39mL, coupled with the corneal tissue barrier and tear dilution, the absorption amount of eye drops after entering the eye is less than 10%. In addition, frequent administration of eye drops produces many side effects, and inconvenient administration at night, which makes pharmacological peaks and valleys prominent. Eye drops are the treatment of choice for many eye conditions such as infections, inflammation, glaucoma, dry eye and allergies, accounting for 90% of the five commercial products in the global eye medicine market. True solutions account for the vast majority of the number of eye drops, in addition, ophthalmic suspensions are also a significant part of this category.

Eye wash: A sterile, clear aqueous solution made from active pharmaceutical ingredients, used as an eye liquid preparation to flush foreign bodies or secretions from the eye and to neutralize foreign chemicals.

Ophthalmic injection solutions: A sterile liquid made of APIs and suitable excipients for the periocular tissues (including subconjunctival bulbar, subfascia and posterior bulbar) or intraocular injection (including anterior chamber injection, anterior chamber irrigation, intravitreal injection, intravitreal infusion, etc.). The injection can immediately inject the effective concentration of the drug into the site of action, and the dose and concentration of the drug are small and the curative effect is good. However, intraocular injection may cause damage to the structure of intraocular tissues and even the eyeball, and the tolerance of intraocular tissues to the drug should be fully considered when injecting drugs into the eye.

Ophthalmic ointment: It is a semi-solid sterile eye preparation made of a solution or suspension paste, which is evenly mixed with a suitable substrate. Because the matrix is fat soluble, it can increase the absorption of drugs in the eye, so it has a long time of action, but it is easy to cause blurred vision.

Ophthalmic emulsion: The preparation method of local eye emulsion is generally to dissolve or disperse the active ingredients into the oil phase, add the appropriate emulsifier and suspension agent, and vigorously mix with water to form a uniform oil-in-water emulsion. Each phase is usually sterilized before or during entry into the mixing container. The high shear homogenization can reduce the size of the oil droplets to the submicron level, thereby improving the physical stability of the oil micelles and preventing them from aggregating. The resulting dosage form should contain small oil droplets, uniformly suspended.

Ophthalmic gel: It is a semi-solid eye preparation made of aseptic gel form by medicine and suitable excipients. Its viscosity is large, easy to mix with tears, and can prolong the action time of drugs.

Ophthalmic film: A sterile film made of raw drug and high polymer, a solid preparation for the eye that can be placed in the conjunctival sac to slowly release the drug.

Ophthalmic inserts: A sterile ophthalmic solid preparation of appropriate size and shape made of raw medicine and appropriate excipients for insertion into the conjunctival sac for the slow release of medicine.

Ophthalmic suspension

An ophthalmic suspension is an eye drop characterized by the presence of solid particles that are not completely dissolved. These particles are evenly dispersed in the liquid matrix, allowing the drug to provide a sustained release effect when dropped into the eye. Ophthalmic suspensions are often used to treat eye conditions that require slow release or sustained effects, such as certain types of eye inflammation or glaucoma.

The ophthalmic suspension needs to be shaken well before use to ensure that the drug particles are evenly dispersed. Due to their solid content, these eye drops may precipitate during storage, so shaking is an important step before use. In addition, the design of the ophthalmic suspension also takes into account the need to ensure that the drug particles do not irritate the eye and can safely and effectively pass through the natural barrier of the eye. Due to its special formulation and release properties, ophthalmic suspensions provide an important mode of drug delivery in ophthalmic therapy, especially in situations where the rate of drug release needs to be controlled or the therapeutic effect enhanced.

Particle size is critical for suspended eye drops, and the particle size of suspended eye drops should generally be less than 10 microns to reduce irritation. Suspension eye drops need to be shaken well before use to ensure that the drug particles are evenly dispersed. However, due to the small particles and small doses, coupled with the opacity of many packaging materials, the precipitation is not easy to observe. In order to improve patient compliance, drugs should be designed with in mind how the suspension can be easily redispersed and has ideal fluidity. Suspension eye drops are aseptic preparations and need to meet aseptic conditions. However, due to its special nature, it is impossible to use bactericidal filtration as a sterilization method, so aseptic processes need to be considered in the production process. Autoclave may cause the drug to partially dissolve and precipitate larger crystals as it cools, causing unpredictable changes in particle size, so autoclave is generally avoided.

Formulation of eye drops

The formulation of eye drops is a complex process designed to ensure the stability, effectiveness and safety of the final product. Key steps include:

Solvent selection

The choice of solvent depends on the solubility and stability of the active ingredient (API). Common solvents include purified water, isotonic saline and buffer solutions to ensure good compatibility with ocular surface tissue.

Dissolution technique

To improve the solubility of insoluble apis, a variety of dissolution techniques can be used, such as adjusting the pH, using cosolvents, and adding surfactants or complexing agents. These techniques ensure that the API remains in the solution in order to play a therapeutic role.

pH and buffering

Adjust the pH of the eye drops with a suitable buffer to ensure compatibility with the eye surface and API stability. Common buffers include phosphate and citrate buffers, which are able to maintain the desired pH range.

Viscosity regulation

In order to increase the retention time of the drug on the ocular surface, viscosifiers such as hydroxypropyl methylcellulose (HPMC) or polyvinyl alcohol (PVA) are usually added to extend the contact time between the drug and the eye, thereby improving the therapeutic effect.

Add preservative

For multi-dose eye drop formulations, adding the appropriate preservatives can prevent microbial growth. The selection of preservatives needs to consider the pH value of the formula, ionic strength and other factors to ensure its effectiveness.

Sterilization

Different techniques of sterilization can be used such as sterile filtration, autoclaving, irradiation or treatment with ethylene oxide and gas plasma. Heat-sensitive formulations can be filtered through a 0.22 micron filter, while heat-stable formulations are suitable for autoclaving.

Evaluation of ophthalmic preparations

Sterility test

Sterility testing is performed to ensure that the formulation does not contain living microorganisms. Common methods include membrane filtration and direct inoculation. These tests detect the presence of contaminants and ensure that the product meets sterile standards.

Particle detection

Particulate testing is used to detect and quantify foreign particles in formulations. Especially for ophthalmic suspensions, this test is important to ensure uniformity and safety of the preparation and to avoid irritation or damage to the ocular surface.

pH and osmolality tests

The pH and osmotic pressure of the formulations are measured to ensure that they are within an acceptable range for eye use. These parameters are essential to maintain the compatibility of the formula with the tear film and to minimize irritation.

Viscosity measurement

The viscosity of the formula is measured to ensure that it provides the best retention time without causing discomfort. Rheological studies help to determine the flow characteristics of the formulation and its suitability when administered to the eye.

Drug release studies in vitro

Conduct in vitro drug release studies to evaluate API release from formulations. These studies help predict the in vivo performance of the product, providing insight into the bioavailability and therapeutic effects of the drug.

Stability test

Stability tests are used to assess the shelf life and storage conditions of the formulation. This involves exposing the formula to different environmental conditions, such as temperature and humidity, and monitoring its physical and chemical stability over time.

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Research progress of ophthalmic preparations

In order to improve the therapeutic effect of eye drops, researchers have developed a variety of new eye drop preparations, mainly including the following:

In situ gel system: Using stimulus-responsive materials such as temperature sensitive, pH sensitive or ion sensitive, gel is formed in the eye to extend the residence time of the drug on the ocular surface. Common in-situ gel materials include PNIPAAm, Xyloglucan, Carbopol®, and chitosan.

Principle of 'sol-gel transition' of different types of in situ gel used for ocular drug delivery. (A) Schematic principle of sol-gel transition of different types of stimuli-responsive materials. Images of sol-gel transition of thermo-responsive PNIPAAm (B) and ion-responsive gellan gum (C). (Jumelle, C., 2020)

Nanoparticle drug delivery system: Nanoparticles are used to coat drugs to improve drug bioavailability by increasing drug adhesion, improving drug distribution on the ocular surface, and reducing drug degradation. Nanoparticle materials include natural polymers (such as chitosan, sodium alginate) and synthetic polymers (such as PLGA, PCL).

Liposome carrier: Liposome is a kind of microvesicle composed of phospholipid bilayer, which can encapsulate lipophilic or hydrophilic drugs, and improve the permeability and bioavailability of drugs by fusion into the cell membrane. Liposomes can be used alone or combined with polymers to form composite carriers.