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OCULAR DRUG DELIVERY SYSTEM
PRESENTED BY: SOMNATH NAVGIRE
M. PHARM II: (PHARMACEUTICS)
DEPARTMENT OF PHARMACEUTICAL
SCIENC...
IDEAL OPHTHALMIC DELIVERY SYSTEM
Good corneal penetration.
Prolong contact time with corneal tissue.
Simplicity of instill...
OCULAR DRUG DELIVERY SYSTEMS
ADVANCED
DELIVERY SYSTEMS
Scleral plugs
Gene therapy
Stem cell
CONTROLLED
DELIVERY SYSTEMS
Im...
LIMITATIONS OF CONVENTIONAL
DRUG DELIVERY
Rapid precorneal elimination
Solution drainage by gravity
Frequent instillation ...
Factors Affecting Intraocular Bioavailability:
1. Inflow & Outflow of Lacrimal fluids.
2. Efficient naso-lacrimal drainage...
NOVEL OCULAR DRUG DELIVERY SYSTEM
OBJECTIVES :
 To prolong the pre ocular retention
 To reduce the frequency of administ...
APPROACHES TO IMPROVE
OCULAR DRUG DELIVERY
ENHANCEMENT OF BIOAVAILABILITY
VISCOSITY IMPROVER
Solution Viscosity Solution Drainage.
 Enhances viscosity of the formul...
 USE OF PENETRATION ENHANCERS: Act by
increasing corneal uptake by modifying the integrity of the
corneal epithelium
 Su...
Classification
 Calcium chelators :
e.g. EDTA
 Surfactants :
e.g. palmiloyl carnitine, sodium caprate, Sodium dodecyl
su...
11
 Preservatives :
e.g. Benzalkonium chloride
 Glycosides :
e.g. saponins, Digitonon
 Fatty acids :
e.g. Caprylic acid...
PRODRUGS
Prodrugs enhance corneal drug permeability through modification
of the hydrophilic or lipophilicity of the drug.
...
USE OF MUCOADHESIVES IN OCULAR DRUG
DELIVERY
 Polymereric mucoadhesive vehicle: Retained in the eye due to
non-covalent b...
Mechanism of mucoadhesion
• The polymer undergoes swelling
in water,
• Entanglement of the polymer
chains with mucin on th...
PHASE TRANSITION SYSTEM
PHASE TRANSITION SYSTEM
PHASE TRANSITION SYSTEM
POLYMERS MECHANISM
Lutrol FC – 127 and
Poloxamer 407
Viscosity increased when
their temperature raised to
eye temperature....
PARTICULATE SYSTEM FOR OCULAR DRUG DELIVERY
NANOPARTICLES:
For water soluble drugs.
Size:10-1000nm
Drug is Dispersed, Enca...
Advantages of nanoparticles
• Sustained drug release and prolonged therapeutic activity
• Site-specific targeting
• Higher...
VESICULAR SYSTEM FOR
OCULAR DRUG DELIVERY
LIPOSOMES
22
• Vesicle composed of phospholipid bilayer enclosing aqueous
compartment in alternate fashion.
• Biodegradabl...
ADVANTAGES
• Drugs delivered intact to various
body tissues.
• Liposomes can be used for both
hydrophilic and hydrophobic ...
Degradation and Drug Release Of
Liposomes
24
1. Endocytosis
2. Fusion
Niosomes are non-ionic surfactant based
multilamellar(>0.05µm),small unilamellar(0.025-0.05µm) or large
unilamellar vesicl...
•ADVANTAGES:
•The vesicle suspension being water based offers greater patient
compliance over oil based systems
•Since the...
PHARMACOSOMES
• The vesicle formation takesplace not only just by association of
phospholipids but also by amphiphilic mol...
DISCOMES
• Soluble surface active agents when added in critical amount to
vesicular dispersion leads to solubilization or ...
Advantages of vesicular systems
1. No difficulty of insertion as in the case of ocular inserts
2. No tissue irritation and...
IONTOPHORESIS
 Iontophoresis is the process in which direct current drives ions into
cells or tissues.
If the drug mole...
 Iontophoretic application of antibiotics may enhance their
bactericidal activity and reduce the severity of disease
 Ca...
Iontophoresis
CYCLODEXTRINS:
Cyclodextrins (CDs) forming inclusion complexes with many guest
molecules. And aqueous solubility of hydro...
MICROEMULSION
They can be easily prepared through emulsification method,
easily sterilized, and are more stable and have ...
NANOSUSPENSIONS
It is consist of pure, hydrophobic drugs (poorly water soluble),
suspended in appropriate dispersion mediu...
Ocular Control Release System: Ophthalmic Inserts
Definition:- Solid or Semisolid in nature,
- Placed in lower Fornix
- Co...
Advantages
1. Accurate dosing.
2. Absence of preservative.
3. Increase in shelf life due to
absence of water.
Limitations
...
CONTROLLED RELEASE
OCULAR DEVICES
INSERTS:
Ophthalmic inserts are solid devices intended to be placed in
the conjunctival ...
INSOLUBLE INSERTS
OCUSERTS:
Flexible, oval inserts
Consists of a medicated core reservior prepared out of hydrogel
polyme...
SOLUBLE OCULAR INSERTS
 LACRISERT:
It is a sterile ophthalmic insert use in treatment of dry eye
syndrome.
The insert is ...
• COLLAGEN SHIELDS
• Collagen is the structural protein of bones, tendons, ligaments and
• skin and comprises more than 25...
INTRAOCULAR INJECTIONS
Micro needle used to deliver drug to posterior segment as an
alternative to topical route.
It show...
INTRAOCULAR IMPLANTS
It employed to extend the release in ocular fluids and tissues
particularly in the posterior segment...
RETROMETABOLIC DELIVERY
SYSTEM
• Combination of SAR and SMR Retrometabolic drug design (RMDD)
• Metabolic activation of in...
 The chemical delivery systems(CDSs)- chemical compounds –
produced by synthetic chemical reaction(s) forming covalent
bo...
Drug targeting by CDS’s
1.enzymatic physical chemical
based targeting
2.site specific-enzyme activated
targeting
3.recepto...
CONCLUSION
The main efforts in ocular drug delivery is to prolong the residence time of
drugs
The development of ophthalmi...
REFERENCES
• Ophthalmic drug delivery system: Challenges and approaches
PB Patel, DH Shastri, PK Shelat, AK Shukla
Contro...
Ocular drug delivery
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Ocular drug delivery

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  • These are the different drug delivery systems which are used for the ocular therapy
  • Transcript of "Ocular drug delivery"

    1. 1. OCULAR DRUG DELIVERY SYSTEM PRESENTED BY: SOMNATH NAVGIRE M. PHARM II: (PHARMACEUTICS) DEPARTMENT OF PHARMACEUTICAL SCIENCES, RASHATRASANT TUKDOJI MAHARAJ NAGPUR UNIVERSITY, NAGPUR. 1
    2. 2. IDEAL OPHTHALMIC DELIVERY SYSTEM Good corneal penetration. Prolong contact time with corneal tissue. Simplicity of instillation for the patient. Non irritative and comfortable form Appropriate rheological properties
    3. 3. OCULAR DRUG DELIVERY SYSTEMS ADVANCED DELIVERY SYSTEMS Scleral plugs Gene therapy Stem cell CONTROLLED DELIVERY SYSTEMS Implants Hydrogels Dendrimers Iontophorosis Polymeric solution Penetration enhance Contact lenses Nano suspensions Micro emulsions Cyclodextrins Phase transition systems Mucoadhesive PARTICULATE SYSTEMS Nano particles Micro particles VESICULAR DELIVERY SYSTEMS Liposomes Neosomes Pharmacosomes discomes RETRO METABOLIC DELIVERY SYSTEMS Softdrug approach Chemical delivery systems SOLUTIONS GELS OINTMENTS SUSPENSIONS EYE DROPS CONVENTIONAL DOSAGE FORMS
    4. 4. LIMITATIONS OF CONVENTIONAL DRUG DELIVERY Rapid precorneal elimination Solution drainage by gravity Frequent instillation is necessary Conjuctival absorption ADVANTAGES OFAVANCED DUG DELIVERY Sustained and/or controlled drug release Site-specific targeting Protect the drug from chemical or enzymatic hydrolysis Increasing contact time and thus improving bioavailability Better patient compliance. 4
    5. 5. Factors Affecting Intraocular Bioavailability: 1. Inflow & Outflow of Lacrimal fluids. 2. Efficient naso-lacrimal drainage. 3. Interaction of drug with proteins of Lacrimal fluid. 4. Dilution with tears. 5. Limited and poor corneal permeability 6. Metabolism
    6. 6. NOVEL OCULAR DRUG DELIVERY SYSTEM OBJECTIVES :  To prolong the pre ocular retention  To reduce the frequency of administration  To provide controlled, continuous drug delivery  To avoid or minimize the initial drug concentration peak in the aqueous humour  To avoid periods of under-dosing that may occur between eye drop instillation.
    7. 7. APPROACHES TO IMPROVE OCULAR DRUG DELIVERY
    8. 8. ENHANCEMENT OF BIOAVAILABILITY VISCOSITY IMPROVER Solution Viscosity Solution Drainage.  Enhances viscosity of the formulation.  Slows elimination rate from the precorneal area and enhance contact time.  Generally hydrophilic polymers- e. Methyl cellulose, polyvinyl alcohols, polyacrylic acids, sodium carboxy methyl cellulose,carbomer is used  A minimum viscosity of 20 cst is needed for optimum corneal absorption.
    9. 9.  USE OF PENETRATION ENHANCERS: Act by increasing corneal uptake by modifying the integrity of the corneal epithelium  Substances which increases the permeability characteristics of the cornea by modifying the integrity of corneal epithelium are known as penetration enhancers. Modes of actions  By increasing the permeability of the cell membrane.  Acting mainly on tight junctions.
    10. 10. Classification  Calcium chelators : e.g. EDTA  Surfactants : e.g. palmiloyl carnitine, sodium caprate, Sodium dodecyl sulphate  Bile acids and salts : e.g. Sodium deoxycholate, Sodium taurodeoxycholate, Taurocholic acid 10
    11. 11. 11  Preservatives : e.g. Benzalkonium chloride  Glycosides : e.g. saponins, Digitonon  Fatty acids : e.g. Caprylic acid  Miscellaneous : e.g. Azone, Cytochalasins
    12. 12. PRODRUGS Prodrugs enhance corneal drug permeability through modification of the hydrophilic or lipophilicity of the drug. The method includes modification of chemical structure of the drug molecule, thus making it selective, site specific and a safe ocular drug delivery system. Drugs with increased penetrability through prodrug formulations are epinehrine, phenylephrine, timolol, pilocarpine
    13. 13. USE OF MUCOADHESIVES IN OCULAR DRUG DELIVERY  Polymereric mucoadhesive vehicle: Retained in the eye due to non-covalent bonding with conjuctival mucine.  Mucine is capable of picking of 40-80 times of weight of water. Thus prolongs the residence time of drug in the conjuctival sac. • Mucoadhesives contain the dosage form which remains adhered to cornea until the polymer is degraded or mucus replaces itself. • Types- 1. Naturally Occurring Mucoadhesives- Lectins, Fibronectins 2. Synthetic Mucoadhesives-PVA,Carbopol, carboxy methyl cellulose, cross-linked polyacrylic acid • Drugs incarporated in to this are pilocarpine, lidocaine, benzocaine and prednisolone acetate. 13
    14. 14. Mechanism of mucoadhesion • The polymer undergoes swelling in water, • Entanglement of the polymer chains with mucin on the epithelial surface. • The un-ionized carboxylic acid residues on the polymer form hydrogen bonds with the mucin. • The water-swellable yet water- insoluble systems are preferred 14
    15. 15. PHASE TRANSITION SYSTEM
    16. 16. PHASE TRANSITION SYSTEM
    17. 17. PHASE TRANSITION SYSTEM
    18. 18. POLYMERS MECHANISM Lutrol FC – 127 and Poloxamer 407 Viscosity increased when their temperature raised to eye temperature. Cellulose acetate phthalate latex Coagulates when its native pH 4.5 raised by tear fluid to pH 7.4 Gelrite Forms clear gel in the presence of cations PHASE TRANSITION SYSTEM 18
    19. 19. PARTICULATE SYSTEM FOR OCULAR DRUG DELIVERY NANOPARTICLES: For water soluble drugs. Size:10-1000nm Drug is Dispersed, Encapsulated, or Absorbed Produced by Emulsion Polymerization • Chemical initiation, Gamma irradiation, Visible light. Polymerization is carried out by : Emulsifier stabilizes polymer particle Polymer used are Biodegradable. E.g. :- Nanoparticle of Pilocarpine enhances Mitotic response by 20-23%.
    20. 20. Advantages of nanoparticles • Sustained drug release and prolonged therapeutic activity • Site-specific targeting • Higher cellular permeability • Protect the drug from chemical or enzymatic hydrolysis • Efficient in crossing membrane barriers -blood retinal barrier • Act as an inert carrier for ophthalmic drugs • Poly alkyl cyano acrylate(PACA) nanoparticles and nanocapsules improve corneal penetration of hydrophilic and lipophilic drugs. • Poly- ԑ-caprolactone(PECL) nanocapsules increase ocular penetration of lipophilic drugs such as metipranolol,betaxolol. 20
    21. 21. VESICULAR SYSTEM FOR OCULAR DRUG DELIVERY
    22. 22. LIPOSOMES 22 • Vesicle composed of phospholipid bilayer enclosing aqueous compartment in alternate fashion. • Biodegradable, Non-toxic in nature. • Types :1.MLV 2.ULV-SUV(upto 100 nm) LUV(more than 100 nm) • Polar drugs are incorporated in aqeous compartment while lipophilic drugs are intercalated into the liposome membrane • Phospholipids used- Phosphotidylcholine, Phosphotidic acid, Sphingomyline, Phosphotidyleserine,Cardiolipine
    23. 23. ADVANTAGES • Drugs delivered intact to various body tissues. • Liposomes can be used for both hydrophilic and hydrophobic drug. • Possibility of targeting and decrease drug toxicity. • The size, charge and other characteristics can be altered according to drug and desired tissue. DISADVANTAGES OF LIPOSOMES • Their tendency to be uptaken by RI system. • They need many modification for drug delivery to special organs. • Cost . 23
    24. 24. Degradation and Drug Release Of Liposomes 24 1. Endocytosis 2. Fusion
    25. 25. Niosomes are non-ionic surfactant based multilamellar(>0.05µm),small unilamellar(0.025-0.05µm) or large unilamellar vesicles(>0.1µm) in which an aqueous solution of solute(s) is entirely enclosed by a membrane resulted from organization of surfactant macromolecules as bilayers STRUCTURAL COMPONENTS USED • Surfactants (dialkyl polyoxy ethylene ether non ionic surfactant) • Cholesterol. NEOSOMES
    26. 26. •ADVANTAGES: •The vesicle suspension being water based offers greater patient compliance over oil based systems •Since the structure of the niosome offers place to accommodate hydrophilic, lipophilic as well as ampiphilic drug moieties, they can be used for a variety of drugs. •The characteristics such as size, lamellarity etc. of the vesicle can be varied depending on the requirement. •The vesicles can act as a depot to release the drug slowly and offer a controlled release. •They are osmotically active and stable. •They increase the stability of the entrapped drug •Improves therapeutic performance of the drug by protecting it from the biological environment and restricting effects to target cells, thereby reducing the clearance of the drug. •DISADVANTAGES • Physical instability, Aggregation, Leaking of entrapped drug, Fusion,a
    27. 27. PHARMACOSOMES • The vesicle formation takesplace not only just by association of phospholipids but also by amphiphilic molecular association • Since many drugs are also amphiphiles, they can form the vesicles Advantages: • Drug metabolism can be decreased • Controled release profile can be achieved
    28. 28. DISCOMES • Soluble surface active agents when added in critical amount to vesicular dispersion leads to solubilization or breakdown of vesicles & translates them into mixed micellar systems • e.g: Egg yolk phosphatidyl choline liposomes by the addition of non ionic surfactants of poly oxy ethylene cetyl ether till the lamellar and mixed lamellar coexist • Advantages: • Minimal opacity imposes no hinderance to vision • Increased patient compliance • Zero order release can be easily attained
    29. 29. Advantages of vesicular systems 1. No difficulty of insertion as in the case of ocular inserts 2. No tissue irritation and damage as caused by penetration enhancers 3. Provide patient compliance as there is no difficulty of insertion as observed in the case of inserts 4. The vesicular carriers are biocompatable and have minimum side effects 5. Degradation products formed after the release of drugs are biocompatable 6. They prevent the metabolism of drugs from the enzymes present at tear/corneal epithelium interface 7. Provide a prolong and sustained release of drug
    30. 30. IONTOPHORESIS  Iontophoresis is the process in which direct current drives ions into cells or tissues. If the drug molecules carry a positive charge, they are driven into the tissues at the anode; if negatively charged, at the cathode. Requires a mild electric current which is applied to enhance ionized drug penetration into tissue. Ocular iontophoresis offers a drug delivery system that is fast, painless, safe, and results in the delivery of a high concentration of the drug to a specific site.  Ocular iontophoresis has gained significant interest recently due to its non-invasive nature of delivery to both anterior and posterior segment.
    31. 31.  Iontophoretic application of antibiotics may enhance their bactericidal activity and reduce the severity of disease  Can overcome the potential side effects associated with intraocular injections and implants.  iontophoresis is useful for the treatment of bacterial keratitis.
    32. 32. Iontophoresis
    33. 33. CYCLODEXTRINS: Cyclodextrins (CDs) forming inclusion complexes with many guest molecules. And aqueous solubility of hydrophobic drugs can be enhanced without changing their molecular structure and their intrinsic ability to permeate biological membranes. They increase corneal permeation of drugs and increase ocular bioavailability of poorly water soluble drugs. Applied in the form of eye drops. DENDRIMERS: These are macromolecular compounds made up of a series of branches around a central core. Their nanosize, ease of preparation, functionalization and possibility to attach multiple surface groups provides suitable alternative vehicle for ophthalmic drug delivery. This system can entrap both hydrophilic and lipophilic drugs into their structure.
    34. 34. MICROEMULSION They can be easily prepared through emulsification method, easily sterilized, and are more stable and have a high capacity for dissolving drugs. The presence of surfactants and co-surfactants in microemulsion increase the dug molecules permeability, thereby increasing bioavailability of drugs. they act as penetration enhancers to facilitate corneal drug delivery
    35. 35. NANOSUSPENSIONS It is consist of pure, hydrophobic drugs (poorly water soluble), suspended in appropriate dispersion medium.. It offer advantages such as more residence time and avoidance of the high tonicity created by water-soluble drugs, their performance depends on the intrinsic solubility of the drug in lachrymal fluids after administration. Thus, they controlled its release and increase ocular bioavailability.
    36. 36. Ocular Control Release System: Ophthalmic Inserts Definition:- Solid or Semisolid in nature, - Placed in lower Fornix - Composed of Polymeric vehicle containing drug. Desired Criteria For Control Release Ocular Inserts. Comfort Ease of handling Reproducibility of release kinetics Sterility Stability Ease of mfg.
    37. 37. Advantages 1. Accurate dosing. 2. Absence of preservative. 3. Increase in shelf life due to absence of water. Limitations • 1. Perceived by patient as foreign body. • 2. Movement around the eye. • 3. Occasional loss during sleep or while rubbing eyes. • 4. Interference with vision. • 5. Difficulty in placement & removal.
    38. 38. CONTROLLED RELEASE OCULAR DEVICES INSERTS: Ophthalmic inserts are solid devices intended to be placed in the conjunctival sac and to deliver the drug at a comparatively slow rate Increased ocular permeation with respect to standard vehicles, hence prolonged drug activity and a higher drug bioavailability; Accurate dosing -theoretically, all of the drug is retained at the absorption site; Capacity to provide, in some cases, a constant rate of drug release;
    39. 39. INSOLUBLE INSERTS OCUSERTS: Flexible, oval inserts Consists of a medicated core reservior prepared out of hydrogel polymer sandwiched between two sheets of transperant lipophilic,rate controlling polymer like ethylene/vinyl acetate copolymer membrane. CONTACT LENS : The most widely used Material is poly-2-hydroxyethylmethacrylate. Its copolymers with PVP are used to correct eyesight , hold and deliver drugs. Controlled release can be obtained by binding the active ingredient via biodegradable covalent linkages.
    40. 40. SOLUBLE OCULAR INSERTS  LACRISERT: It is a sterile ophthalmic insert use in treatment of dry eye syndrome. The insert is composed of 5mg of HPC in rod-shaped form about 1.27 mm diameter by about 3.5 m long  MINIDISC: It is made up of counter disc with convex front & concave back surface in contact with eye ball. Composition: silicon based pre polymer Hydrophillic or hydrophobic.
    41. 41. • COLLAGEN SHIELDS • Collagen is the structural protein of bones, tendons, ligaments and • skin and comprises more than 25% of the total body protein in mammals.  Collagen shields have been used in animal model and in humans (eg. Antibiotics, antiviral etc.,) or combination of these drugs often produces higher drug concentration in the cornea and aqueous humor when compared with eye drops and contact lens • They are manufactured from porcine scleral tissue, which bears a collagen composition similar to that of hu-man cornea. • They are hydrated before being placed on the eye and the drug is loaded with the collagen shield simply by soaking it in the drug solution. • They provide a layer of collagen solution that lubricates the eye.
    42. 42. INTRAOCULAR INJECTIONS Micro needle used to deliver drug to posterior segment as an alternative to topical route. It shows excellent in vitro penetration into sclera and rapid dissolution of coating solution after insertion. In-vivo drug level was found to be significantly higher than the level observed following topical drug administration. To deliver anti-infective, corticosteroids and anesthetic product to achieve higher therapeutic condition intraocularly, FDA approved intraocular Injections includes miotics, viscoelastics, and anti-viral agents for intravitreal injection
    43. 43. INTRAOCULAR IMPLANTS It employed to extend the release in ocular fluids and tissues particularly in the posterior segment. It may be biodegradable and non-biodegradable. With implants, the delivery rate could be modulated by varying polymer composition. Implants can be in the form of solid, semi-solid or particulate based delivery systems. These implants have been applied in the treatment of diseases affecting both anterior and posterior segments of the eye. Implant containing gancyclovir or, anti-neoplastic agents is release drug over a 5 to 8 months.
    44. 44. RETROMETABOLIC DELIVERY SYSTEM • Combination of SAR and SMR Retrometabolic drug design (RMDD) • Metabolic activation of inactive delivery forms: chemical delivery systems CDS Drug inactive active Alkyl oxime datives oximes(enzymes located in iris-celiary body) • Metabolic deactivation of specifically designed active species:soft drugs SD Mi Active inactive metabolites hydrocartisone spirothiazolidine • RMDD represent novel, systemic approach to achieve these goles include two distinct methods aimed to increase the therapeutic index  SOFT DRUG design  CHEMICAL DELIVERY SYSTEM design
    45. 45.  The chemical delivery systems(CDSs)- chemical compounds – produced by synthetic chemical reaction(s) forming covalent bonds between the drug(D) and specifically designed ‘carrier ’ and other moieties. At least one chemical bond needs to be broken for active compound (D) to be released. The release of active compound from CDSs takes pace by enzymatic or hydrolytic cleavage.  The basic principle of retrometabolic drug design approaches is that the drug metabolism considerations should actually be involved at a very early stage of the design process- not as an after thought inorder to explain some of the behaviours of the drug  SAR+SMR=RETROMETABOLIC DRUG DELIVERY SYSTEM
    46. 46. Drug targeting by CDS’s 1.enzymatic physical chemical based targeting 2.site specific-enzyme activated targeting 3.receptor based chemical targeting Drug targeting by soft drugs 1.soft drug analogs 2.activated soft coompounds 3.active metabolite type soft drugs 4.controlled release of endogenous soft compounds 5.Inactive metabolic approach
    47. 47. CONCLUSION The main efforts in ocular drug delivery is to prolong the residence time of drugs The development of ophthalmic drug delivery systems is easy because we can easily target the eye to treat ocular diseases the eye has specific characteristics such as eye protecting mechanism, which make ocular delivery systems extremely difficult. The most widely developed drug delivery system is represented by the conventional and non-conventional ophthalmic formulations to polymeric hydrogels, nanoparticle, nanosuspensions, microemulsions, iontophorosis and ocular inserts. In future an ideal system should be able to achieve an effective drug concentration at the target tissue for an extended period of time, while minimizing systemic exposure and the system should be both comfortable and easy to use.
    48. 48. REFERENCES • Ophthalmic drug delivery system: Challenges and approaches PB Patel, DH Shastri, PK Shelat, AK Shukla Controlled drug delivery – Concepts and Advances, by S.P. Vyas and Roop K. Khar, page no.: 383 – 410. Ansel’s Pharmaceutical dosage forms and drug delivery systems, by Loyd V. Allen, Nicholas G. Popovich and Howard c. Ansel page no.: 661 – 663. Advances in Controlled and Novel drug delivery, edited by N.K. Jain, page no.: 219 – 223.  . http://www.pharmainfo.net/reviews/recent advances in opthalmic drug delivery system.
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