EMULSIONS

EMULSIONS. 1299. Lecture 1 OPHTHALMIC PHARMACEUTICAL PRODUCTS.

Ophthalmic pharmaceutical dosage forms are commonly used to treat local ocular disorders such as infection and inflammation, as well as intraocular disorders such as glaucoma Ocular dosage forms are principally solutions, suspensions and ointments. Intraocular injections are available for the treatment of more serious disorders Drugs that are ingested orally or administered by the intravenous route for ocular therapy are inefficient because: a- They are widely distributed and diluted throughout the body b- Penetration of orally or injected drugs into the tissues of the eye is extremely limited because, like the brain, the eye is protected by highly restrictive blood- retinal barrier.

Limitations for Ophthalmic Drug Delivery. Poor Ocular Bioavailability.

Advantages/Disadvantages of ocular delivery. Advantages: 1- The application of the therapeutic agents directly to the site of action ensures that the therapeutic agent is available at higher concentration than may be achieved following oral administration 2- The local administration of the drug ensures that the incidence of side effects is minimized 3- Ease of administration by the patient Disadvantages: 1- Poor retention of the drug in the eye due to low tear volume (7-30 µl). The typical volume of two drops of a solution formulation is about 100 µl so the majority of the applied dose is lost by spillage on the face or via the lacrimal duct 2- Poor retention of applied solutions on the surface of the eye (unless mucoadhesive ) 3- Ocular formulations have to be sterile, therefore they need special facilities for manufacturing 4- If ocular formulations have high concentration of therapeutic agents or excipients they may lead to pain and irritation 5- Ocular ointments result in temporary blurring of vision.

Ideal ophthalmic delivery system. An ideal topical ophthalmic formulation would enhance bioavailability by.

Structure of the Eye. Comea Iris Conjuncti•a Sulcus circularis corneæ Posterior cnamtE' Lens Rectus lateralis Vitreous Nerve sneatn Optic nenæ BOdY Sulcus circularis corneae Ciliary body Zonular spaces Hyaloid canal Rectus medialis Sclera Choroid Retina Fovea centralis A. centralis retinae.

The cornea. It is the true barrier for drugs, it is composed of three layers: Epithelium which is multi-layered that is rich in lipids Stroma which is aqueous matrix composed of collagen and keratocytes Endothelium which is a lipid rich single cellular epithelium The diffusion of drugs to the inner chambers of the eye is controlled by the cornea To be effectively absorbed, drugs must exhibit immediate solubility in the lipid layers (epithelium and endothelium) and the stroma , and must be of low molecular weight The cornea is negatively charged.

Lacrimal fluid. Lacrimal fluid is secreted from lacrimal glands and is located on the surface of the eye The pH of the lacrimal fluid is 7.4 and it possesses a good buffering capacity, therefore it can neutralize unbuffered formulations over a wide range of pH (3.5-10) Lacrimal fluid is isotonic with the blood. Ocular formulations may be formulated to be isotonic (0.9% NaCl equivalent) or covering a range between 0.7%-1.5% There’s a physiological turn-over for lacrimal fluid to remove drug/formulation from the eye surface.

Classification Of Ocular Drug Delivery Systems. L IQUIDS Solutions Suspensions Ointments Powders for reconstitution Sol to gel systems Gels SEMISOLIDS.

Ophthalmic solutions: sterile (by autoclaving or filtration), essentially free from foreign particles Preparation of an ophthalmic solution requires careful consideration of such factors as : - inherent toxicity of the drug itself - Isotonicity value - the need for buffering agents - the need for a preservative (and, if needed, its selection ) - sterilization - proper packaging.

CLASSES OF OPHTHALMIC PRODUCTS 1 . Topical Eye drops (Solutions).

Salt form Discomfort reaction pH range Buffer capacity Epinephrine bitartarate Epinephrine hydrochloride Epinephrine borate Moderate to severe stinging (most acidic) Mild to moderate stinging (relatively acidic) Only occasional mild stinging (low acidity) 3-4 3.5-4.5 5.5 7.5 High Medium Low.

Inactive Ingredients in Topical Drops. The inactive ingredients in ophthalmic solution and suspension dosage forms are necessary to perform one or more of the following functions: Adjust tonicity Buffer ( adjust pH) Stabilize the active ingredients against decomposition (antioxidants) Increase solubility (surfactants) Impart viscosity the use of ingredients to impart a color, odor, or flavor is prohibited.

So. pH Adjustment and Buffers. Any formulation having different pH than 7.4 will be neutralized by tears.

What about the pH partition theory???? For drugs that require significant ocular absorption for diseases such as glaucoma, the drug must exhibit significant amounts of unionized form, which is determined by the pka of the drug.

Tonicity and Tonicity-Adjusting Agents. Lacrimal fluid is isotonic with blood, having an isotonicity value corresponding to that of a 0.9% NaCl solution.

Stabilizers Antioxidants. Added to decrease the rate of decomposition of the active ingredients by oxidation. Example of Antioxidants used; Sodium bisulfite or metabisulfite (up to 0.3 % ) ascorbic acid, acetylcysteine , and Sodium thiosulfate ..

Surfactants. The order of surfactant toxicity is: anionic > cationic >> nonionic Several nonionic surfactants are used in relatively low concentrations to improve solution clarity ( solubility of drugs). Those principally used are Polysorbates ( Tween 20 and 80).

Viscosity-Imparting Agents ( mucoadhesives ). Polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose , and Carbomers , are commonly used to increase the viscosity of ophthalmic solutions and suspensions. They increase the ocular contact time , thereby decreasing the drainage rate, increase the mucosdhesiveness and increasing drug ocular bioavailability . * A secondary benefit of the polymer solutions is a lubricating effect . The major commercial viscous vehicles are hydroxypropyl methylcellulose ( Isopto ®) and polyvinyl alcohol ( Liquifilm ®) The viscosity of the commercially available product doesn’t exceed 30 mPa /s to avoid blockage of lacrimal ducts The mucoadhesive should be easily filtered/autoclaved, and compatible with other components.

Vehicles ( water). Ophthalmic drops: ( using purified water USP ) as the solvent. Purified water meeting USP standards may be obtained by: distillation, deionization, or reverse osmosis . Oils can be included in the vehicles for several topical emulsion eye drop products When oils are used in the vehicle of ophthalmic fluids owing to instability of drug in water, they must be of the highest purity. Vegetable oils such as olive oil, castor oil, and sesame oil have been used but they are subject to rancidity and, therefore, must be used carefully..

Contamination occur. Preservatives. Ophthalmic products may be packaged in multiple-dose containers when intended for the individual use of one patient.

2- Gel-Forming Solutions. Solutions that are liquid in the container and thus can be instilled as eye drops but gel on contact with the tear fluid and provide increased contact time with the possibility of improved drug absorption and increased duration of therapeutic effect * Liquid-gel phase transition-dependent delivery systems vary according to the particular polymer(s) employed and their mechanism(s) for triggering the transition to a gel phase in the eye take advantage of changes in temperature, pH, ion sensitivity , or lysozymes upon contact with tear fluid.

In Situ Forming Gels. Temperature. Ion (Ca). pH. Poloxamer Xyloglucan.

2- Gel-Forming Solutions. Example of Gel-forming ophthalmic solutions in the market is; Timolol maleate, which is used to reduce elevated intraocular pressure (IOP) in the management of glaucoma.. With the gel-forming solutions, IOP-lowering efficacy was extended from 12 to 24 hours and thus required only once-a-day dosing..

3 -Suspensions. If the drug is not sufficiently soluble , or if suffers from chemical instability when soluble, or if the potency of the lipophilic drug is greater than that of the water soluble salts: it can be formulated as a suspension. Ophthalmic suspensions are required to be made with the insoluble drug in a micronized form to prevent irritation or scratching of the cornea (95% diameter ˂ or = 10 µm)..

The major topical ophthalmic suspensions are the steroid anti-inflammatory agents prednisolone acetate, dexamethasone Water-soluble salts of prednisolone phosphate and dexametasone phosphate are available; however, they have a lower steroid potency and are poorly absorbed . Another example is the β-blocker betaxolol HCL ( Betoptic ® ) , which is an effective IOP-lowering agent. The ophthalmic solution cause discomfort and transient burning upon instillation, while insoluble form suspension of increased the ocular bioavailability of betaxolol and the ocular tolerance ..

4 -Powders for Reconstitution. Drugs that have only limited stability in liquid form are prepared as sterile powders for reconstitution by the pharmacist prior to dispensing to the patient . These drugs include α-chymotrypsin, and acetylcholine . The sterile powder is usually manufactured by lyophilization in individual glass vials..

B-Semisolid Dosage Forms: Ophthalmic Ointments and Gels.

OCULAR INSERTS NON ERODIBLE OCUSERT SOFT CONTACT LENSES ERODIBLE SODI COLLAGEN SHIELDS.

C . Solid Dosage Forms 1 . Non erodible Ocular Inserts.

OCUSERT. OCULAR DDS. 31. Slide3_1.

C. Solid Dosage Forms 2. (Erodible Ocular Inserts).

Types Based on natural polymers e.g . collagen b) Based on synthetic or semi synthetic polymers e.g . Cellulose derivatives – Hydroxypropyl cellulose, methylcellulose or Polyvinyl alcohol, ethylene vinyl acetate copolymer The system softens in 10-15 sec after introduction into the conjuctival sac, gradually dissolves within 1 h, while releasing the drug..

Examples: 1. LACRISERTS 2.SODI (soluble ocular drug inserts) 3. MINIDISC.

D. Intraocular Dosage Forms. They are Ophthalmic products that introduced into the interior structures of the eye primarily during ocular surgery or to treat cytomegalovirus or other deep eye diseases. Topical and systemic administration often fails to achieve therapeutic concentrations in the vitreous cavity . This has led to the development of improved: *irrigating solutions, * intraocular injections * vitreous inserts.

D. Intraocular Dosage Forms 1. Intraocular Irrigating Solutions.

D. Intraocular Dosage Forms Intraocular Injections.

D. Intraocular Dosage Forms Viscoelastics. Highly purified fractions of sodium hyaluronate have become an important ocular surgical adjunct because of their lubricant and viscoelastic properties . They are injected into the anterior chamber of the eye during surgery in cataract surgery and for corneal transplantation and other intraocular surgeries. They provide essential protection of the corneal endothelium Chondroitin sulfate is also used in combination with sodium hyaluronate as a viscoelastic surgical aid to provide higher viscosities, which may provide additional tissue protection. Sterile hydroxypropyl methylcellulose are also used as ocular surgical aids similar to the viscoelastics in cataract surgery ( OcuCoat ®)..

D. Intraocular Dosage Forms Intravitreal Injection.

Manufacturing of ocular formulations. Production under clean conditions followed by sterilisation by autoclaving Typically ophthalmic solutions may be manufactured and packaged in the final container under clean conditions. Sterilisation may then be performed using moist-heat sterilisation (assuming the therapeutic agent is chemically stabile under these conditions)..

Some novel ocular delivery systems prepared in our department.

Some novel ocular delivery systems prepared in our department.

5B 83-4* at Intemational Joumal of Pharmaceutics journal homepage: v.ww_elseviercomnoc-ateyijpharm In vitm stabilization and in livo improvement of ocular pharmacokinetics of the multi-therapeutic agent baicalin: [Elineating the most suitable vesicular systems Orchid Ashraf, Maha Nasrb•e••, Marianne Nebsend, Azm Mohamed Ahmed Saide, Oma ima Sammourb.

Some novel ocular delivery systems prepared in our department.

Thank you.