Ophthalmic Drug Delivery System

Ophthalmic Drug Delivery System

Pharmaceutical preparations are applied to the eye to treat surface or intraocular conditions including bacterial fungal and viral infection of the eye or eyelids allergic or infectious conjunctivitis, inflammation, elevated intraocular pressure glaucoma both systemic use and topical treatments.

The normal volume of tear fluid in the cul-de-sac of human eye is about 7 to 8 microliter. An eye does not blink can accumulate a maximum of about 30 microliter of fluid but blinked can retain only 10 microliter because the capacity of eye to retain liquid or semisolid is limited. The capacity of the eye to retain liquid and semisolid preparations is limited, topical preparations administered in small amounts, liquid drop wise & ointment a thin ribbon is applied to the margin of eye lid.

Larger volume of liquid preparation may use to flush or bath of eye (boric acid). Excessive liquid may be normally produced or delivered rapidly drained from the eyes.

Due to dynamics of lacrimal systems of the retention of time of ophthalmic solution on eye surface is short. A single drop of ophthalmic solution or suspension measure about 50 microliter so much or administer dose may be lost.

Pharmacological categories of ophthalmic drugs:

It includes Anesthetics, antibiotics & antimicrobial agents, Antifungal, Anti-inflammatory agents, Antiviral, Astringents, Beta adrenergic blocking, Miotic, other Glaucoma agents, Mydriatic and Cycloplegics, Protectants, Artificial tears, Vasoconstrictors and Ocular decongestants.

Anesthetic & Antibiotics:

Anesthetics are employed to provide pain relieve pre operatively and post operatively. For ophthalmic trauma of eye exhibition tetracycline and cocainare used. Anesthetics and antibiotic agents are used systemically to combat ophthalmic infections. Gentamicin, tetracycline, ciprofloxacin are most effective.

Antifungal & Anti-inflammatory:

Antifungals for example amphotericin are used topically for endophthamitis and fungal keratitis. Anti-inflammatory are used to treat inflammation of eye. Topical anti-inflammatory steroidal agents are prednisolone & dexamethasone. Non-steroidal and anti-inflammatory agents are diclofenac and flurbiprofen.

Pharmaceutical requirements of Ophthalmic drugs

The preparation of solutions and suspensions for ophthalmic use requires special consideration with regard to sterility.

The pharmaceutical considerations include;

Ø Sterility & Preservation:

The ophthalmic solutions and suspensions must be sterilized for safe use, although it is preferable to sterilize to sterilize in their final containers by autoclaving at 121⁰C for 15minutes under 20 pound pressure. The method sometimes causes thermal instability of the formulation.

As an alternative bacterial filters must be used, although the bacterial filters works with high efficacy but they are not reliable as autoclave.However, since final product testing is used to validate the absence of microbes. One advantage of the filtration is the retention of all particulate matter (microbes, dust, & fibers), bacterial filtration that may be used in extemporaneous preparation of ophthalmic solutions.

To maintain the sterility during used antimicrobial preservative is generally included in ophthalmic formulation. During pre-formulation studies antimicrobial preservative must demonstrate stability, chemical and physical compatibility with other formulation and packing components. Among the examples of antimicrobial agents there is benzalkonium chloride, chlrobutanol etc.Preservative free preparations are stored, packaged in in single dose containers.

Ø Isotonicity value:

Body fluids including blood and tears have osmotic pressure corresponding to 0.9% solution of sodium chloride. So, 0.9% solution of sodium chloride is said to be isosmotic or having same osmotic pressure equal to pharmacological fluids. The term isosmotic means equal tone and used for body fluids. If hyperosmotic solution is entered into the body it can cause shrinking of blood cells. If hyper osmotic solution is added to the body system then it may causes hemolysis. Tonicity disturbance always results in discomfort and irritations.

The isotonicity value for ophthalmic preparation of sodium chloride may range from 0.6% to 2%, without marked discomfort to the eye. Boric acid in a concentration of 1.9% produces the same osmotic pressure as 0.9% NaCl.

Ø Buffering:

The pH of the ophthalmic preparation may be adjusted or buffered for one or more of following purpose;

·         For greater comfort to eye

·         To render the formulation more soluble

·         To enhance the aqueous solubility of drug

·         To the drug bioavailability

·         To maximize the preservative activity

Ø Viscosity & Thickening:

Viscosity is the property of the liquid related to the resistance to flow. The reciprocal of viscosity is fluidity. More simply it can be considered as relative property with water as reference material and all viscosities are explain in terms of viscosity of pure water at 20⁰C.

A suitable grade of methyl cellulose or other thickening agent is frequently added to increase the viscosity and maintaining the contact with tissue to enhance therapeutic effectiveness.

Ø Ocular Bioavailability:

It is an important factor in the effectiveness of an applied medication. Physiologic factor that can affect a drug’s ocular bioavailability includes;

·         Protein binding

·         Drug metabolism

·         Lacrimal drainage

Protein binding:protein bound drugs are capable of penetrating the corneal epithelium because of size of protein drug complex.

Normally tears contain 0.6% to 2% proteins including albumin and globulins but disease state can raise this protein level. The ocular protein binding is variable. Tear turnover results in loss of both bound and unbound drug.

Ø Additional considerations:

Ophthalmic solutions must be sparkling clear and free of all particulate matter for comfort and safety. Drug particles must be finally subdivided, usually micronize. The suspended particles must not associate to form large particles upon storage and must be easily and uniformly redistributed by gentle shaking of container prior to use.

Ø Packaging of ophthalmic solution and suspension:

Fixed built in droppers – this type of packing is preferred as it both facilitate administration and protect the drug from external confirmation a few commercial ophthalmic solutions and suspensions are packaged in small glass containers with separate glass dropper. Ophthalmic solutions and suspensions are commonly packaged in containers holding 2, 2.5, 5, 10, 15 and 30ml of product. Patient must be careful to protect and ophthalmic solution from external contamination.

Ø Proper administration of ophthalmic solution and suspension:

Prior to use of ophthalmic solution and suspension the patient or the care giver should washed the hand. If ophthalmic drops are supplied with separate dropper the patient should inject the dropper to make sure it has no dust. Ophthalmic preparations should be inspected for color and clarity. Out of date and decolorized solution must be discarded. Ophthalmic suspension must be shaken thoroughly prior to administration to distribute the suspension evenly. The cap of an eye drop container should be removed immediately prior to use.

Solution for contact lenses

Contact lenses:

The no. of people wearing lenses is growing every year. Their popularity and increased use has fostered the development of new types of lenses and lens care products. 3 types of contact lens are classified by their chemical composition and physical properties;

·         Hard contact lenses

·         Soft contact lenses

·         Rigid gas permeable

    Hard lenses:

Hard contact lenses provide durability and clear crisp vision. They are made up of rigid plastic resin poly methyl methacrylate PMMA. The lenses are 7mm to 10mm in diameter designed to cover any part of cornea.

    Soft lenses:

Soft contact lenses are more popular then hard lenses because of their greater comfort. They range of about 13mm to 15mm in diameter and cover the entire cornea. Because of their size and coverage soft lenses are less likely to permit irritating for ex-dust or pollen.

Soft lenses are made up of hydrophilic plastic Hydroxy ethyl methacrylate HEMA with small amount of cross linked agents that provide hydrogel network. Soft lenses contain 30% to 80% water which enhance permeability to oxygen.

Disposable soft lenses:Don’t require cleaning and disinfection for the commoner period of use. They are simply discarded and replaced by a new pair of lenses. Patients should be advised to resist any transfer to wear the lenses for longer period of time then recommended to avoid risk of eye infection.

    Rigid gas permeable:

These contact lenses take advantage and feature of both safe and hard lenses. They are oxygen permeable but hydrophobic. Thus they permit greater movement of oxygen through the lenses. The basic type of lens is intended for daily wear some of newer permeable. Rigid gas lenses are extended for suitable wear.

Color additive:Contact lenses manufacturer produces cleared and colored lenses. The use of color additive in contact lenses is regulated by FDA. Color additive that come into direct contact with body for a significant period must be demonstrated to be safe for consumer use. The FDA permits the use of specific color additive in contact lenses, only after reviewing and approving a manufacturers official color additive pattern.

Instruction for user:

It is important that contact lenses receive an appropriate care to retain their shape and optical characteristic for safe use. The user should be instructed about technique of insertion and removal of the lenses, method of cleaning and disinfecting and storage, with the exception of disposable soft contact lenses all soft lenses require routine care program that include;

·         Cleaning and removing lipid and protein deposits.

·         Rinsing to remove the cleaning solution

·         Disinfection to kill micro-organisms.

·         If lenses are not maintained at proper intervals as they are prone to deposit buildups, discoloration and microbial contamination.

Product for soft contact lenses:

Because of the porous composition of contact lenses tends to accommodate the proteinases material that forms a film on lenses, decreasing clarity and serving as potential medium for microbial growth. The two main categories of cleaner are surfactants which emulsify accumulated oils, liquids and inorganic compounds. Or by the enzymatic cleaner which break down and remove protein deposits.

Rinsing and storage solution:

Saline solution for the soft lenses should be isotonic. Besides rinsing the lens, solution should be used for storage to maintain curvature, diameter and optical characteristics. The solution also facilitates the lens hydration, preventing the lens from drying and becoming brittle.

Disinfection and neutralization:

Disinfection can be accomplished by two methods;

·         Thermal

·         Chemical

Due to introduction of H₂O₂Hydrogen peroxide chemical disinfection is becoming more popular. For thermal disinfection lenses placed in specialy designed heating unit with saline solution. The solution is heated sufficiently for 10 min at 56⁰C.

Product for hard contact lenses:

·         Cleaners

·         Soaking and storage solution

·         Wetting solution

·         Combination solution

Nasal preparations

Nasal preparations, solutions, sprays or jellies are isotonic to nasal fluids buffered to maintain drug stability. The normal pH value is 5.5 to 6.5 of nasal fluid. The vast majorities of preparation intended for intra nasal use contains adrenergic agents and are employed for their decongestant activity;

1.       Nasal drugs

2.       Nasal sprays

3.       Nasal jellies

4.       Nasal inhalers

Most nasal decongestant solutions are aqueous preparation rendered isotonic to nasal fluid buffered to maintain drug stability and preserved as required.

Antimicrobial preservatives which mostly used are;

§  Benzalkonium chloride

§  Benzthonium chloride

§  Chlorobutanol.

The concentration of adrenergic agents in majority of nasal decongestant solution is quite low ranging from 0.05% to 1.0%. There are certain commercial solutions which are available for both pediatric and adult use. Most adrenergic drug used in Nasal drug system are synthetic compounds similar in chemical structure, pharmacological activity and side effect to parent compound.

Example:The naturally occurring is epinephrine. While among the synthetic there is oxymetrazole and phenylepinephrine.

Packaging:

·         Most packing solutions for nasal use are packed in dropper bottles or in plastic bottle sprays, usually contain 15ml to 30ml medication.

·         Container must not interfere with stability of medication and should be closed tightly.

·         Patient should be advised that should discard the solution if it is discolored and precipated.

Uses:

1.       They are used for rhinitis of common cold.

2.       Allergic rhinitis including hay fever & sinusitis.

Their frequent use or use for prolonged period may lead to chronic edema of nasal mucous i.e. rhinitis medicamentosa aggravating the symptoms for which they are intended to relieve. Thus they are used for short intervals i.e. 3 to 5 days with the patients advice not to exceed the recommended dosage and frequence of use.

To rebound the symptoms induced by frequent use following measures are taken;

1.       Withdraw the application of decongestant completely but it will cause bilateral vasodilation with almost total nasal obstruction.

2.       A more acceptable method is to withdraw application of drug is only one nostril and use the medication continuously in other nostril.

Once the rebound congestion subside in the drug free nostrils, a total withdraw is then instilled. Different topical decongestants have duration of effect.

Example:

·         Phenylepinephrine (3-4) then should be repeated.

·         Oxymetrazole (12 hours) and should be repeated.

Inhalants

They are drugs or combinations of drugs that due to high vapor pressure carried out their effects on nasal passage. The device which hold such drug and form which they administered are called inhalers.

Decongestant inhalers:

Certain nasal decongestants are volatile in room temperature can be employed in the form of inhalants.

Example:propyl hexedrine

The medication which has amine like odor is usually masked with added aromatics. The inhalers are effective as long as the volatile drug remain present. To ensure that drug dose not escape during period of non-use the caps on the inhalers should be tightly closed. As with other nasal decongestants excessive use of inhalers can result in nasal edema and increased congestion rather than decreased.

Otic or Aural preparation

Mostly otic preparations are solutions but few are suspensions and ointments. Ear preparations are usually placed in ear canal by drop for; the removal of excessive cerumen, the treatment of ear infection, inflammation or pain.

Cerumenremoving preparations:

Cerumen is the combination of secretions of sweat and sebaceous glands of external auditory canal and is also called as ear wax, which upon drying form sticky semisolid which holds shed epithelial cells, fallen hairs, dust and other foreign bodies. So cerumen serves as protective wall but excessive accumulation may lead to itching, pain, impaired hearing and difficulty in otologic examination.

Cerumen removal:

Light mineral oils, volatile oils, hydrogen peroxide, recently solutions of synthetic surfactants have been used for their cerumen lytic activity in removal of ear wax.

Example:Commercially,  Propane glycol is used to emulsify the cerumen to facilitates its removal.

Carbamide peroxide in glycerin or propylene glycol releases oxygen on contact with cerumen which disrupts the integrity of impacted wax allowing its easy removal.

Application of preparations:

Place the otic solution in the ear canal with the patients head tilted at 45^o inserting a cotton plug to retain medication in the ear for 15 to 30 minutes. Flush the ear canal with warm water using soft rubber ear syringe.

Anti-infecting, Anti-inflammatory and Analgesic Ear preparations:

Drugs used against bacterial infection are;

§  Chlorophenicol

§  Polymyxin b sulphate

§  Colistinsulphate

Drugs used as viral infections are;

§  Neomycin

§  Nystatin

These drugs are formulated into ear drops i.e. solutions or suspensions in a vehicle.

Vehicles used for preparations:

Anhydrous glycerin & propylene glycol, these vehicles are viscous and hygroscopic. The viscous vehicles permit maximum contact time between drug and ear tissues. Hygroscopic vehicles draw the moisture from tissue thereby reducing the inflammation and the moisture.

The hygroscopicity of these vehicles draws moisture from tissues resulting in reduced swelling as well as reduced microbial growth.

Analgesic agents:

Infection is always associated with pain so most of the ear preparation contain;

·         Analgesic agent example antipyrine

·         Local anesthetic example lidocaine, benzocaine

Along with the topical treatment of infectious systemic anti infection therapy is also necessary. Anti-inflammatory agents are hydrocortisone, pexamethasone.

Aside from antibiotic steroid combination used to treat otitis externa (swimmer ear). These agents are used to re-acidify the ear canal and dry the ear canal to check on microbial growth. The two preparations used are;

§  Acetic acid (2%) alu-acetate solution

§  Boric acid (2.75%) in isopropyl alcohol

Preservative:

Some otic preparations require preservative. The commonly used preservatives are; chlorobutanol (0.5%), thimerosal (0.01%) and various combinations of parabeans.

Packaged:

Otic preparations are mostly packed in small glass or lastic containers with dropper.