OCULAR DRUG DELIVERY SYSTEM - NDDS

 

OCULAR DRUG DELIVERY SYSTEM

NDDS

B.PHARMA SEMESTER 7

Jsmasipharmacy.blogspot.com

 

Introduction, intra ocular barriers and methods to overcome –Preliminary study, ocular formulations and ocuserts

 

Ocular administration of the drug is primarily associated with need to treat ophthalmic disease

Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain vicinity of front of the eye for prolong period of the time.

Mechanism of ocular absorption

1.     Non corneal absorption:

·         penetration across sclera and conjunctiva into intraocular tissue

·         non productive because penetrated drug is absorbed by general circulation

2.     corneal absorption :

·         outer epithelium : rate limiting barrier , with pore size 60a only access to small ionic and lipophilic molecule

·         trans cellular transport between corneal epithelium and stroma.

Factor affecting intraocular bioavailability

·         inflow and outflow of laominal fluids

·         efficient naso-lacrimal drainage

·         intraction of drug with proteins of lacrimal fluid

·         dilution with tears

·         corneal barriers

·         active ion transport at cornea

BARRIERS IN OCULAR ABSORPTION

Precorneal Constraints It include –

•         Solution drainage

•          Lacrimation

•         Tear dilution

•         Tear turnover

•          Conjunctival absorption

Corneal constraints

•         Cornea as rate limiting barrier

•         Anatomy of cornea

1.Outer- Epithelium(lipophilic),

2.Middle- Stroma(hydrophilic),

3.Inner- Endothelium(lipophilic)

 

opthalmic dosage forms

ophthalmic preparation are starile products essentially free from forign particles , suitably compounded and paekaged for instillation in to eye.

Following dosage form have been developed to ophthalmic drugs.

1.      Conventional : solution , suspention , emulsion , ointment , insert , gels

2.      Vesicular : liposomes , niosomes , discomes , pharmacosomes

3.      Particulate : microparticals , nanoparticals

4.      Control release : implants , hydrogels,dendrimers,iontoporesis,collagen shieid , polymeric solutions, contact lenses , cyclodexrin , microneedle , microimulsion  , nano suspension

5.      Advanced : sclera plugs , gene delivery , Si RNA , STEM cell , ECT

 

 

ADVANTAGE

·         They are easily administered by the nurse

·         They are easily administered by the patient himself.

·         They have the quick absorption and effect.

·         less visual and systemic side effects.

·         better patient compliance.

DISADVANTAGE

·          The very short time the solution stays at the eye surface.

·          Its poor bioavailability.

·          The instability of the dissolved drug.

·         The necessity of using preservative.

IDEAL CHARACTERISTICS

·         Sterility

·         Isotonicity

·         Buffer/pH adjustment

·         Less drainage tendency

·         Minimum protein binding

 

 

A. CONVENTIONAL

1.Eye Drops:

•         Drugs which are active at eye or eye surface are widely administered in the form of Solutions, Emulsion and Suspension.

•          Various properties of eye drops like hydrogen ion concentration, osmolality, viscosity and instilled volume can influence retention of a solution in the eye.

•          Less than 5 % of the dose is absorbed after topical administration into the eye.

•         The dose is mostly absorbed to the systemic blood circulation via the conjunctival and nasal blood vessels.

 

2. SOLUTIONS

2.1ADVANTAGE-

•         Ease of bulk scale manufacturing

•          High pt. Aceptibility

•          Drug product efficacy

•         Stability

•         Cost effectiveness

3.EMULSION

•         A Fine dispersion of minute droplets of one liquid into another liquid in which it is generally not soluble or misceble.

•         Emulsion are of 2 types-

•         1.Oil in Water- use in ophthal bcoz of less irritance nd better tolerance

•         2. Water in Oil  Eg.- Difluprednate 0.05% , Difluprednate 0.05% + Moxifloxacin 0.5% , E/d Cyclosporin is Emulsion

•         Eg.- Fluribrophen axetil + Castor oil have better bioavailability and less irritation

•          Eg,- Chitosan coating and HPMC coating of indomethacin increase precorneal residence time

3.1 Advantage of emulsion

•         Improve residence time

•         Drug corneal permeation increase

•          Sustain drug release

4. SUSPENSION

•         Disperssion of finely divided insoluble API in an aqueous solvent consisting of suitable suspending and dispersing agent

•          Its activity is particle size dependent. So if size is optimum then optimal activity is achieved.

•         Suspension must be resuspended by shaking to provide accurate dosage.

•         Eg.- Tobramycin 0.3% + Dexa 0.1% (but have high viscosity)

•          Tobra 0.3% + Dexa 0.05% (TobraDex ST) have very low settling rate

•          Moxi 0.5% + Prednisolone 1%

•          Prednisolone 1%

•          Nepafenac 0.1% eye drop is suspension

•          Natamycin

•          Brinzolamode

5. GELS

•         Eg.- pilocarpine 4% gel

•          Eg.- several artificial tear preparations are formulated as ophthalmic gels

•          Eg.- treatment with Timolol 0.5% gel once daily in the morning acheives intraocular pressure level equal to twice daily solution

6. OINTMENTS

·         Mixture of semisolid and solid hydrocarbons (parrfins) that have melting point at ocular temp. (34⁰ c).

·          When applied to inferior conjuctival sac, ointments melt quickly and the excess spread out onto the lid margin, lashes, skin of lids.

·          It has a therapeutic effect for 6hr.

·          This method may be of practical value in paediatric and geriartic age group.

·         Early formulations of ointment contained waxy grades of petroleum or unwashed lanolin which interfered with corneal wound healing.

·          Newer ointments not contain these but should be used cautiously in ulcer with impending perforation. And should not be used in any surgical wound in which there is a question of wound integrity, such as when difficulty is experienced maintaining the Ant. Chamber at surgery.

 

 

B. VESICULAR SYSTEM

·         Vesicular drug delivery system can be defined as highly ordered assemblies consisting of one or more concentric bilayers formed as a result of self-assembling of amphiphilic building blocks in presence of water.

·          Vesicular drug delivery systems are particularly important for targeted delivery of drugs because of their ability to localize the activity of drug at the site or organ of action thereby lowering its concentration at the other sites in body.

VESICULAR SYSTEM TYPES

·         LIPOSOMES

·         NIOSOMES

·         DISCOSOMES

·         PHARMACOSOMES

1.  LIPOSOMES

·         Liposomes are biocompatible and biodegradable lipid vesicles made up of natural lipids and about 25–10 000 nm in diameter.

·          They are having an intimate contact with the corneal and conjunctival surfaces which is desirable for drugs that are poorly absorbed, the drugs with low partition coefficient, poor solubility or those with medium to high molecular weights and thus increases the probability of ocular drug absorption.

2. NIOSOMES AND DISCOMES

·         The major limitations of liposomes are chemical instability, oxidative degradation of phospholipids, cost and purity of natural phospholipids.

·          To avoid this niosomes are developed as they are chemically stable as compared to liposomes and can entrap both hydrophobic and hydrophilic drugs.

·          They are non toxic and do not require special handling techniques.

·         Niosomes are nonionic surfactant vesicles that have potential applications in the delivery of hydrophobic or amphiphilic drugs. Discomes may act as potential drug delivery carriers as they released drug in a sustained manner at the ocular site.

·         Discosomes are giant niosomes (about 20 um size) containing poly- 24- oxy ethylene cholesteryl ether or otherwise known as Solulan 24. Pharmacosomes: This term is used for pure drug vesicles formed by the amphiphilic drugs.

·          The amphiphilic prodrug is converted to pharmacosomes on dilution with water.

·         Niosomes are microscopic lamellar structures, which are formed on the admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media.

·         Structurally, niosomes are similar to liposomes, in that they are also made up of a bilayer. However, the bilayer in the case of niosomes is made up of non- ionic surface active agents rather than phospholipids as seen in the case of liposomes.

 

 

.C. CONTROL RELEASE SYSTEM

·         IMPLANTS

·         IONTOPHORESIS

·         DENDRIMER

·         MICROEMULSION

·         NANOSUSPENSION

·          MICRONEEDLE

·         MUCOADHESIVE POLYMER

·         INSERTS

.1.  IMPLANTS

·         Implants help in circumventing multiple introcular injection and associated complications.

·          Implants use for drug delivery in posterior ocular tissue

·         For chronic ocular diseases like cytomegalovirus (CMV) retinitis, implants are effective drug delivery system. Earlier non biodegradable polymers were used but they needed surgical procedures for insertion and removal.

·          Presently biodegradable polymers such as Poly Lactic Acid (PLA) are safe and effective to deliver drugs in the vitreous cavity and show no toxic signs

·         Eg. Of Implants-

·          NONBIODEGRADABLE-

o    VITRASERT- controlled release of ganciclovir for t/t of CMV retinitis.

o   RETISERT- release of Fluocinolone acetonide for t/t of chronic uveitis of post. Segment.

·         BIODEGRADABLE-

o    SURODEX- release Dexamethasone for controle of postop inflamation.

o    OZURDEX- for t/t of Macular Edema

2. IONTOPHORESIS

·         In Iontophoresis direct current drives ions into cells or tissues. For iontophoresis the ions of importance should be charged molecules of the drug.

·         Positively charged of drug are driven into the tissues at the anode and vice versa.

·          Ocular iontophoresis delivery is not only fast, painless and safe but it can also deliver high concentration of the drug to a specific site.

·         Types of iontophoresis- 1. transcorneal 2. transscleral

3. DENDRIMER

·         Dendrimer are nanosized, highly branched, star shaped polymerise system

·          Its highly branched structure allow incorporation of wide range of drugs (Hydrophobic and Hydrophilic )

·          Dendrimers can successfully used for different routes of drug administration and have better water-solubility, bioavailability and biocompatibility.

4. MICROEMULSION

·         Microemulsion is dispersion of water and oil stabilized using surfactant and co- surfactant to reduce interfacial tension and usually characterized by small droplet size (100 nm), higher thermodynamic stability and clear appearance.

·         Selection of aqueous phase, organic phase and surfactant/co-surfactant systems are critical parameters which can affect stability of the system

5. NANOSUSPENSION

·         Nanosuspensions have emerged as a promising strategy for the efficient delivery of hydrophobic drugs because they enhanced not only the rate and extent of ophthalmic drug absorption but also the intensity of drug action with significant extended duration of drug effect.

·         For commercial preparation of nanosuspensions, techniques like media milling and high-pressure homogenization have been used.

 6. MICRONEEDLE

·         Microneedle had shown prominent in vitro penetration into sclera and rapid dissolution of coating solution after insertion while in vivo drug level was found to be significantly higher than the level observed following topical drug administration like pilocarpine

·         Microneedle is minimum invasive mode to deliver in posterior ocular tissue.

·         Penetrate only 100 um of sclera so deposite drug into sclera or into suprachoroid space.

7. MUCOADHESIVE POLYMER

·         In this dosage form adhere to the precorneal mucus and residue in the eye until the polymer dissolve or mucin replace itself.

·          These are in early phase of research.

·          They are basically macromolecular hydrocolloids with plentiful hydrophilic functional groups, such as hydroxyl, carboxyl, amide and sulphate having capability for establishing electrostatic interactions.

·         Some mucoadhesives are- carboxymethycellulose. Carbopol, polymethymethacrylate, acrylic acid, polycarbophil, sodium alginate. A mucoadhesive drug formulation for the treatment of glaucoma was developed using a highly potent beta blocker drug, levobetaxolol (LB) hydrochloride and partially neutralized poly acrylic acid (PAA).

8. INSERTS

·         The ocular insert represents a significant advancement in the therapy of eye disease. Ocular inserts are defined as sterile, thin, multilayered, drug-impregnated, solid or semisolid consistency devices placed into the cul-de-sac or conjuctival sac, whose size and shape are especially designed for ophthalmic application.

8.1 Ocular Inserts as an Ocular Sustained Release Drug Delivery System

·         The main objective of the ophthalmic inserts is to increase the contact time between the preparation and the conjunctival tissue, to ensure a sustained release suited for topical or systemic treatment.

·          The advantages of ocular inserts over the traditional ophthalmic preparation can be summarized as follows-

8.2 ADVANTAGE

·         Increased ocular residence, hence, prolonged drug activity and higher bioavailability with respect to standard vehicles.

·          Release of drugs at a slow, constant rate

·          Accurate dosing (insert contains a precise dose, which is fully retained at the administration site).

·          Reduction of systemic absorption.

·         Better patient compliance, due to reduced frequency of administration and less incidence of visual and systemic side-effects.

·          Possibility of targeting internal ocular tissues through non- corneal (conjunctival scleral) routes.

·          Increased shelf life with respect to aqueous solutions.

·          Exclusion of preservatives, thus reducing the risk of sensitivity reactions.

·          Incorporation of various novel chemical / technological approaches, such as pro-drugs, mucoadhesives, permeation enhancers, micro particulates, salts acting as a buffer.

8.3 Disadvantage

·         A major disadvantage of ocular inserts resides in their ‘solidity’, that is, they are felt by the (often oversensitive) patients as an extraneous body in the eye. This may constitute a difficult physical and psychological barrier to patient compliance.

·          Their movement around the eye, in rare instances, the simple removal is made more difficult by unwanted migration of the insert to the upper fornix.

·          The occasional unintentional loss during sleep or while rubbing the eyes.

·          Their interference with vision.

·         Difficulty in placement of the ocular inserts

 

 A) Insoluble inserts-

1. Diffusional Inserts :

·         Central reservoir of drug enclosed in Semi permeable or microporous membrane for diffusion of drug.

·         Diffusion is controlled by Lacrimal Fluid penetrating through it.

·         Release follows : Zero Order Kinetics.

·         e.g. Ocusert®:

·          20-40µg/hr for 7day

·          Annular ring : Impregnated with Ti02 : For Visibility 5

2) Osmotic inserts

·         A central part surrounded by a peripheral part

·         Central part-single reservoir or two distinct compartments.

·         Peripheral part- an insoluble semi permeable polymer.

·         The tear fluid diffuse and induces dissolution.

·         Solubilized deposits generate a hydrostatic pressure.

·         Drug is then released through these aperture

3) Contact Lens :

·         Presoaked Hydrophilic lens.

·         Drug Release : within 1st 30 Min.

·          Alternate approach : incorporate drug either as soln or suspension .e.g. Pilocarpine.

·          Release rate is up to : 180 hr.

·          Use in treatment of Bullous keratopathy, Dry eye syndrome, corneal condition requiring protection such as traumatic corneal abrasion or erosions.

 

 B) Soluble Inserts

1.SODI: Soluble Ocular Drug Insert.

·         Small water soluble made of soluble synthetic polymers.

·         Composition : Acryl amide, Vinyl Pyrolidone, Ethylacrylate.

·          Weight 15-16 mg. In 10-15 sec Softens; In 10-15 min. turns in Viscous Liquids; After 30-60min. Becomes Polymeric Solution.

Advantages of SODI

·         Single SODI application : replaces 4-12 eye drops Instillation, or 3-6 application of Ointments.

·         Once a day treatment of Glaucoma.

2.The corneal collagen shield

·         A disposable, short-term therapeutic bandage lens for the cornea.

·          It conforms to the shape of the eye, protects the corneal surface, and provides lubrication as it dissolves.

·          The shields are derived from bovine collagen and are 14.5 mm in diameter.

·          Sterilized by gamma irradiation.

·         Disadvantages 1. It is not optically clear. 2. The collagen shield causes some discomfort.

·         Clinical uses 1. Wound healing. 2. Treatment of dry eye. 58

C) Biodegradable inserts

1.Lacrisert:

·         Sterile, Rod Shaped device.

·          Composition: HPC.

·          Weight:5mg,

·         Dimension:Diameter:12.5mm, Length:3.5mm

·         Use:-Dry eye treatment.

2.Minidisc:

·         It is made up of counter disc with Convex front & Concave back surface in contact with eye ball.

·          4-5mm in diameter.

·          Composition : Silicon based polymer.

·          Drug release upto170 hr. 62

 

 

PARTICULATES (NANOPARTICLES AND MICROPARTICLES)

·         Nanoparticle- <1 micrometre Microparticle- >1 micrometre

·         The maximum size limit for microparticles for ophthalmic administration is about 5-10 micrometer above which a scratching feeling in the eye can result upon ocular instillation.

·          That is why micro and nanoparticles are promising drug carriers for ophthalmic application.

·         Nanopaticles are produced by emulsion polymerisation.

·         Polyalkylcyanoacrylate are most commonly used ophthalmic nanoparicles.

·          Many antiglaucoma drugs loaded onto nanoparicles for testing efficacy.

 

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