Ocular drug delivery system

Ocular drug delivery system

Intended Learning Objectives

At the end of this session, students will be able to

•   Discuss about human eye

•   Enlist ocular dosage forms

•   Analyse the pros and cons of topical ocular administration of medicaments

•   Explain the routes of drug absorption after topical administration

•   Discuss the conventional topical ocular dosage forms

•   Classification ocular inserts

•   Explain the design and application of Ocusert

•   Discuss erodible ocular inserts

•   Discuss Contact lens as drug delivery device to the eye

•   Enlist the QC tests for ophthalmic dosage forms

•   Briefly explain packaging of eye drops

Ocular Drug Delivery System

• Eye is a complex organ with unique anatomy and physiology

• The anatomy of the eye can be studied by dividing it into anterior and posterior segments

• Anterior segment of the eye occupies approximately one-third

• Remaining portion is occupied by the posterior segment

Anatomy and Physiology of Human Eye

Anterior portion – Cornea, Conjunctiva, Aqueous humor, Iris, Ciliary body, Lens

Posterior Portion – Sclera, Choroid, Retina, Vitreous body

Cornea

• Devoid of blood vessels

• Derives nourishment form tear fluid and aqueous humor

• 12mm in diameter, 520µm in thickness

Conjunctiva

• Vascularized mucous membrane

• Lines the inner surface of the eyelids

• Generates mucous - Facilitates lubrication, helps with tear film adhesion

Sclera

• Whitish outermost layer

• Composed of collagen bundles, mucopolysaccharides and elastic fibres

• 10 times more permeable than cornea and half as permeable as the conjunctiva

Fate of Drugs Delivered by Ocular Route

Common Conditions Affecting the Eye

Anterior segment – Glaucoma, Allergic conjunctivitis, Anterior uveitis, Cataract

Posterior segment- Age-related macular degeneration (AMD), Diabetic retinopathy

Ocular drug delivery routes

Barriers for Ocular Drug Absorption

Depending on the route of administration

1. Topical

    Precorneal factors

       Solution drainage

       Blinking

       Tear film

       Tear turn over

       Induced lacrimation

    Physical barriers

       Cornea

       Sclera

       Conjuctiva                                 

2. Oral

3. Periocular and intravitreal

4. Parentetal

       Blood aqueous barrier

       Blood retinal barrier

Barriers for Ocular Drug Absorption – Topical Route

➢ Mostly in the form of eye drops         

➢ Employed to treat anterior segment diseases              

➢ Site of action is usually different layers of the cornea, conjunctiva, sclera, iris and ciliary body (anterior uvea)

➢ Precorneal factors

– Solution drainage, blinking, tear film, tear turn over, and induced lacrimation

– Human tear volume is estimated to be 7 μl

– Mucin present in the tear film plays a protective role by forming a hydrophilic layer that moves over the glycocalyx of the ocular surface and clears debris and pathogens

– Contact time with the absorptive membranes is lower

– Less than 5% of the applied dose reaches the intraocular tissues

Mechanical barriers for topical drug absorption

Cornea

• Limits the entry of exogenous substances into the eye and protects the ocular tissues

• Divided into the epithelium, stroma, and endothelium

• The corneal epithelium is lipoidal in nature

• Offers resistance for permeation of topically administered hydrophilic drugs

Corneal epithelium…

• Corneal epithelial cells are joined to one another by desmosomes

• Tight junctional complexes retards paracellular drug permeation from the tear film into intercellular spaces of the epithelium as well as inner layers of the cornea

Layers of the Cornea

Stroma

➢ Comprises 90% of the corneal thickness

➢ Highly hydrated structure

➢ Barrier to permeation of lipophilic drug molecules

Endothelium

➢ Endothelial junctions are leaky - facilitate the passage of macromolecules between the aqueous humor and stroma

➢ Drugs should have an amphipathic nature in order to permeate through these layers

Conjunctival drug absorption

➢ Considered to be non-productive

➢ Conjunctival blood capillaries and lymphatics, which can cause significant drug loss into the systemic circulation

➢ Conjunctival epithelial tight junctions further retard passive movement of hydrophilic molecules

Barriers for Ocular Drug Absorption – Topical Absorption

Sclera

➢ Consists of collagen fibers and proteoglycans embedded in an extracellular matrix

➢ Permeability - comparable to that of the corneal stroma

➢ Positively charged molecules exhibit poor permeability presumably due to their binding to the negatively charged proteoglycan matrix

➢ Permeability of drug molecules across the sclera is inversely proportional to the molecular radius

Barriers for Ocular Drug Absorption – Parenteral Route

• Anterior segment: blood–aqueous barrier

• Posterior segment: blood–retinal barrier

Blood–aqueous barrier

• Tight junctional complexes and prevent the entry of solutes into the intraocular environment such as the aqueous humor

Blood–retinal barrier

• Restricts the entry of the therapeutic agents from blood into the posterior segment.

• Regulates drug permeation from blood to the retina

Barriers for Ocular Drug Absorption – Oral Route

• Limited accessibility to many of the targeted ocular tissues limits the utility of oral administration

• Necessitates high dosage to observe significant therapeutic efficacy

• Can result in systemic side effects

Barriers for Ocular Drug Absorption - Periocular and Intravitreal Administration

• To overcome the inefficiency of topical and systemic dosing to deliver therapeutic drug concentrations to the posterior segment

• The periocular route includes

– subconjunctival, subtenon, retrobulbar, and peribulbar administration

• Comparatively less invasive than intravitreal route

Ocular Dosage forms

• They are specialized dosage forms designed to be instilled onto the external surface of the eye (topical), administered inside (intraocular) or adjacent (periocular) to the eye or used in conjunction with an ophthalmic device

• The most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments

• The newest dosage forms for ophthalmic drug delivery are: gels, gel-forming solutions, ocular inserts, intravitreal injections and implants

Ocular Drug Delivery Systems

1. Liquids

     Solutions

     Suspensions

     Powders for reconstitution

     Sol to gel systems

2. Semisolids

     Ointments

     Gels

3. Solid

     Ocular inserts

     Contact lens

4. Intraocular dosage form

     Injections

     Irrigating solutions

     Implants

Topical Application

•   Applying the drug product to the ocular surface, where it mixes with the lacrimal fluid

•   Used to treat anterior segment diseases

Ocular surface

• Dry eye disease or infections - Needs retention of drug in tear film

Cornea and conjunctiva

• Infection, inflammation, or neovascularization - Absorbed by the cornea or conjunctiva

Tissues surrounding the anterior chamber

• Elevated intraocular pressure, inflammation, or infection - Permeate across the cornea and/or conjunctiva

 

Topical Application Advantages  

•   The administration of the dosage form locally to the eye may be easily performed by the patient

• The application of the therapeutic agents directly to the site of action ensures that the therapeutic agent is available at higher concentrations than may be achieved following oral administration

• They have quick absorption and less visual and systemic side effects

Topical Application Disadvantages

• The very short time the solution stays at the eye surface

• Poor bioavailability

• The instability of the dissolved drug

• The necessity of using preservative

Absorption of topically applied drugs

• Corneal route

– Drug Instillation

– Dilution in tear fluid

– Diffusion from mucin layer

– Corneal penetration

– Diffusion into aqueous humor

• Non corneal route

– Conjuctival route

– Scleral route

Non corneal route

Through the conjunctiva and sclera → Iris and ciliary body

This route is important for the absorption of hydrophilic small molecules, and a viable option for large molecules, because the intercellular spaces in the conjunctival epithelium are wider than in the cornea, being more permeable to larger molecules

In the conjunctiva, compounds with molecular weights up to 5 kDa are able to permeate, whereas the sclera allows passage of macromolecules (e.g., molecular weight of 100 kDa)

Corneal Route

• The bioavailability of topically applied ocular drugs in the aqueous humor is usually in the range of 0.001–0.05 (i.e. 0.1–5%)

Reasons

• Short retention of eye drops on the ocular surface

• Flow from the ocular surface to the nasal cavity

• Drug absorption across the conjunctiva and into the blood stream (Example, 50% of instilled pilocarpine is absorbed from the lacrimal fluid directly into the blood circulation)

• The intercellular tight junctions on the surface of the corneal epithelium limit absorption of small molecules and block the permeation of macromolecules, such as proteins

Characteristics Required to Optimize Ocular Drug Delivery System

• Good corneal penetration

• Prolong contact time with corneal tissue

• Simplicity of instillation for the patient

• Non irritative and comfortable form (viscous solution should not provoke lachrymal secretion and reflex blinking)

• Appropriate rheological properties concentrations of the viscous system

Ocular Dosage forms

Conventional topical ocular dosage forms

•   Eye drops/ solutions

•   Suspensions

•   Emulsions

•   Ointments

Eye Drops/ Solutions

❖ The  administration  of  these  to  the  eye  is  usually  performed using a dropper (or a container with a dropper nozzle) or a tube with a nozzle

Disadvantages - Explained

•   Retention of the drug at the site of action is relatively Poor 7 µl for the blinking eye, 30 µl for the non-blinking eye

➢ The  typical  volume  of  two  drops  of  a  solution  formulation  is approximately  100  µl and therefore the majority of the applied dose is lost either through spillage on to the face or via the lacrimal duct

• To overcome these deficiencies in practice, the patient is required to administer the ocular solution formulations (containing high concentrations of therapeutic agent) frequently, which is inconvenient and may lead to patient non-compliance

•   Ocular formulations are sterile and therefore specialised facilities are required for the manufacture of these dosage forms

• Local side-effects may be experienced to ocular dosage forms (to either the high concentration of therapeutic agent (5% w/w) or excipients used in the formulation). Typically pain and irritation are the major side-effects encountered by patients

Sawtooth Pattern of Therapy Following Administration of Ophthalmic Drugs as Eye Drops

Methods to improve ocular bioavailability with eye drops

1. Incorporating viscosity enhancers like HMC, HEC, sod CMC, HPMC

    Reduces solution drainage and increases the contact time

2. Using permeation enhancers like benzalkonium chloride, cyclodextrins, sod EDTA in the formulation

    Improves permeation across the corneal barrier

Aqueous ophthalmic solution

▪ Manufactured by dissolution of the active ingredients and a portion of the excipients into all portion of water

▪ The sterilization of this solution done by heat or by sterilizing filtration through sterile depth or membrane filter media into a sterile receptacle

▪ This sterile solution is then mixed with the additional required sterile components such as viscosity –imparting agents, preservatives and so and the solution is brought to final volume with additional sterile water

Suspension

⚫ If the drug is not sufficiently soluble, it can be formulated as a suspension

⚫ A suspension may also be desired to improve stability, Bioavailability, and efficacy

⚫ The major topical ophthalmic suspensions are the steroid anti-inflammatory agents

⚫ An ophthalmic suspension should use the drug in a microfine form; usually 95% or more of the particles have a diameter of 10µm or less

• Prednisolone acetate suspension

• Besifloxacin suspension

• Blephamidesuspension

• Fluorometholone

Advantages

•   Patient compliance

•   Best for drug with slow dissolution

Disadvantages

•   Drug properties decide performance

•   Loss of both solution and suspended solid

Emulsion

Advantages

•   Prolonged drug release

Disadvantages

•   Blurred vision

•   Patient non compliance

•   Possible oil entrapment

Packaging of eye drops

• Ophthalmic liquids can be packaged in sterile glass bottles with separate dropper or in plastic bottles with self-contained dropper tips

Glass bottle packaging

•   Dropper bottle for eye drops are fitted with a cap, rubber teat and dropper as the closure

•   The bottles are used at a capacity of 10 ml or 20 ml

•   Glass containers are used in only a very few instances because of stability limitations

•   Type  1  glass  vials  with  appropriate  stoppers  are  used  for ophthalmic products

Plastic packaging

• Currently all most all commercially available ophthalmic products are packaged in plastic containers

• Advantages of plastic containers are ease of use, little breakage, less spillage. This led to universal acceptance of   plastic containers.

• Plastic packaging components consists of bottle fitment and closure

• It has multi-component single-drop dispenser. Eye drops must be sterilezed after   filling into the containers and sealing, by autoclaving at a temperature of 90-100oC for 30 mins, or alternatively they may be pre sterilized and filled aseptically into previously sterilised containers

• The containers are usually fitted with droppers attached to the closures

Two types of dose preparations in plastic packaging

•   Single dose preparations

•   Multiple dose preparations

Single dose preparations

• The ideal type of packaging for eye drops is a disposable one shot container which eliminates the need for any preservative and reduces the risk of infecting the eye during applications almost to zero

• Single dose packs are available in which the solutions can be sterilised by autoclaving in air ballasted autoclaves these solutions can therefore be formulated without a preservative

• Single-use vials, when filled under sterile conditions, have the additional advantage of enabling the product to be formulated without preservatives

•   Most products in multi-use containers need preservatives to counteract microorganisms after each use

Multiple dose preparations

• Multiple dose preparations must contain an antimicrobial preservative to prevent proliferation of contaminants during use and to support the maintenance of sterility

• Examples of preservatives are phenyl mercuric nitrate or acetate, chlorhexidine acetate or benzalkonium chloride

Eye Ointment

• The ointment vehicles used in ophthalmology is mixture of Mineral oil and petrolatum base

• The  mineral  oil  is  used  to  modify  melting  point  and  modify consistency

•  Petrolatum  vehicle  used  as  a  ocular  lubricate  to  treat  dry  Eye syndromes

• They are mostly used as adjunct night time therapy, while eye drops are administered during the day

• It is suitable for moisture sensitive drugs and has longer contact time than drops

Manufacturing Techniques

➢ The ointment base is sterilized by heat and appropriately filtered while molten to remove foreign particulate matter

➢ It is then placed into a sterile steam jacket kettle to maintain the ointment in a molten state under aseptic conditions, and the previously sterilized active ingredient(s) and excipients are added aseptically

➢ The entire ointment may be passed through a previously sterilized colloid mill for adequate dispersion of the insoluble components. After the product is compounded in an aseptic manner, it is filled into a previously sterilized container

Advantages

•   Flexibility in drug choice

•   Improved drug stability

Disadvantages

•   Sticking of eye lids

•   Blurred vision

•   Poor patient compliance

•   Drug choice limited by partition coefficient

Packaging

Ophthalmic ointment are packaged in:

1. Small collapsible tin tube usually holding 3.5g of product. The pure tin tube is compatible with a wide range of drugs in petrolatum-based ointments

2. Aluminum tubes have been used because of their lower cost and as an alternative

3. Plastic tubes made from flexible LDPE resins have also been considered as an alternative material

•   Filled tubes may be tested for leakers

•   The screw cap is made of polyethylene or polypropylene

•   The tube can be a source of metal particles and must be cleaned carefully before sterilization (by autoclaving or ethylene oxide)

Recent Formulation Trends in Ocular Controlled Drug Delivery System

Ocular Insert

Non erodible inserts

• The Ocusert therapeutic system is a flat, flexible, elliptical device designed to be placed in the inferior cul-de-sac between the sclera and the eyelid and to release Pilocarpine continuously at a steady rate for 7 days

Ocusert

The device consists of 3 layers…..

• Outer layer – ethylene vinyl acetate copolymer layer.

• Inner Core – Pilocarpine gelled with alginate main polymer.

• A retaining ring - of EVA impregnated with titanium dioxide

The ocuserts available in two forms.

•   Pilo – 20 (20 microgram / hour)

•   Pilo – 40 (40 microgram / hour)

Use: Chronic glaucoma

Advantages

• Reduced local side effects and toxicity.

• Around the clock control of IOP.

• Improved compliance.

Disadvantages

• Retention in the eye for the full 7 days.

• Periodical check of unit.

• Replacement of contaminated unit

• Expensive.

Erodible Inserts

• The solid inserts absorb the aqueous tear fluid and gradually erode or disintegrate

• The drug is slowly leached from the hydrophilic matrix

• They quickly lose their solid integrity and are squeezed out of the eye with eye movement and blinking

• Do not have to be removed at the end of their use

Three types

•   LACRISERTS

•   SODI

•   MINIDISC

1. LACRISERTS

• Sterile rod shaped device made up of hydroxy propyl cellulose without any preservative

• For the treatment of dry eye syndromes

• It weighs 5 mg & measures 1.27 mm in diameter with a length of 3.5 mm

•   It is inserted into the inferior fornix

2. SODI

– Soluble Ocular Drug Inserts

– Small oval wafer

– Sterile thin film of oval shape

– Weighs 15-16 mg

– Introduced into the inferior cul-de-sac.

Use – glaucoma

Advantage – single application

3. MINIDISC

•   Countered disc with a convex front and a concave back surface

•   Diameter – 4 to 5 mm

Composition

• Soluble copolymers consisting of actylamide, N-vinyl pyrrolidone and ethyl acetate Iontophoresis

Contact Lens

• Contact lenses are thin, and curved shape plastic disks which are designed to cover the cornea

• After application, contact lens adheres to the film of tears over the cornea due to the surface tension

• 1930 Polymethyl methacrylate (PMMA) was used as the first successful contact lens (CL) material

• 1965 Use of soft contact lens (SCL) for ophthalmic drug delivery (Sedlacek)

• 1960s Discovery of hydrogels (Witcherle and Lim)

• 1970,s benefits of CL for ocular drug delivery (Kaufman)

• Early Conventional Hydrogel (CH) CLs did not provide adequate oxygen transmission to the cornea, resulting in hypoxia related complications during overnight wear, limiting their long term therapeutic potential

• 1990,s Highly oxygen permeable Silicone Hydrogel (SH) CLs were introduced

Advantages of Contact lens

• Located   in   the   immediate vicinity of the cornea

• Limited mixing in the tear film between the lens and the cornea leads to a residence time of more than 30 minutes   (Compared to 5min for eye drops)

•   Increase in bioavailability

Materials for Contact Lens

• Hydrogels - good transmission of visible light, high chemical and mechanical stability, reasonable cost and high oxygen transmissibility

•   Poly HEMA - water content of about 38%

• Methacrylic acid (MAA) with HEMA, soft contact lenses (SCLs) with different water contents, hardness, strength and oxygen permeabilities can be created

Strategies/Techniques for Contact Lens Based Drug Delivery System

Soaking Method

•   Involves soaking the preformed contact lenses in the drug solution, followed by drug uptake and release in pre- and post-lens tear film

• Contact lenses have internal channels/cavity for receiving/accommodating the drug molecules

• Drug loading depends on the water content, thickness of lenses, the molecular weight of the drug, soaking time period and concentration of drug in soaking solution

Limitations

• High molecular weight drugs or polymers like hyaluronic acid, do not penetrate the aqueous channels of contact lenses and remain on the surface only

 

• Contact lenses have low affinity for most of the ophthalmic drugs like timolol maleate, olopatadine HCl, brimonidine tartrate, etc.

• Effects of sterilization and packaging processes on the stability of therapeutic contact lenses - may cause premature release of the drug

Molecular Imprinting (MI)

•   Monomers are polymerised in the presence of drug template followed by removal of the template

•   Resulting in formation of tailored active sites or imprinted pockets called macromolecular memory sites

Limitation

• Highly cross-linked structure of hydrogel affects the optical and physical performance of contact lens

• The drug-loading capacity is limited by the template molecules and functional monomers, and the deformation (change in dimension) of contact lenses after release of drug was also noted

• The fall in water content (decrease in swelling) leads to an insufficient ion and oxygen permeability which limit the use of contact lenses for extended wear

Quality Control of Ophthalmic Products

•   Universal tests

– Description

– Identification

– Assay

– Impurities

•   IPQC & FPQC

– pH

– Isotonicity

– Viscosity

– Therapeutic efficacy

– Compatibility

– Clarity

– Particulate matter

– Insoluble particulate matter

– Particle size

– Uniformity of volume

– Uniformity of content

– Uniformity of weight

– Bacterial endotoxin

– Sterility testing

Summary

• Anatomy and Physiology of Human Eye

Anterior portion – Cornea, Conjunctiva, Aqueous humor, Iris, Ciliary body, Lens

Posterior Portion – Sclera, Choroid, Retina, Vitreous body

• Common Conditions Affecting the Eye

Anterior segment – Glaucoma, Allergic conjunctivitis, Anterior uveitis, Cataract

Posterior segment- Age-related macular degeneration (AMD), Diabetic retinopathy

• Conventional topical ocular dosage forms

Eye drops/ solutions

Suspensions

Emulsions

Ointments

• Packaging of eye drops

Ophthalmic liquids can be packaged in sterile glass bottles with separate dropper or in plastic bottles with self-contained dropper tips

•   Ocular inserts – Non-erodible and erodible

•   Non-erodible – Ocuserts and contact lens

•   Erodible – Lacrisert, SODI, Minidisc

•   Ocusert – Containing pilocarpine for glaucoma treatment

•   Lacrisert – Dry eye syndrome

• Contact lens

Contact lenses are thin, and curved shape plastic disks which are designed to cover the cornea

After application, contact lens adheres to the film of tears over the cornea due to the surface tension

• Advantages of Contact lens

Located in the immediate vicinity of the cornea

Limited mixing in the tear film between the lens and the cornea leads to a residence time of more than 30 minutes (Compared to 5min for eye drops)

Increase in bioavailability

• Quality Control of Ophthalmic Products

Universal tests

– Description

– Identification

– Assay

– Impurities

IPQC & FPQC

– pH

– Isotonicity

– Viscosity

– Therapeutic efficacy

– Compatibility

– Clarity

– Particulate matter

– Insoluble particulate matter

– Particle size

– Uniformity of volume

– Uniformity of content

– Uniformity of weight

– Bacterial endotoxin

– Sterility testing

For PDF Notes Click on Download Button