1. Ophthalmic Preparations

2. Definition: 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

3. Categorization Solution/suspension into conjunctival sac
Lotions for irrigating & cleansing eye surface
Ointments/ creams/ gels for lid margin/ conjunctival sac
Contact lenses sol facilitate wearing & care of lenses
Parenterals (intracorneal,intraviterous, retrobulbar inj
Solids in conjunctival sac release over long period

4. Drugs used in the eye: Miotics e.g. pilocarpine Hcl
Mydriatics e.g. atropine
Cycloplegics e.g. atropine
Anti-inflammatories e.g. Corticosteroids, antihistamines
Anti-infectives (antibiotics, antivirals and antibacterials)
Anti-glucoma drugs e.g. pilocarpine Hcl, beta-blockers
Surgical adjuncts e.g. irrigating solutions
Diagnostic drugs e.g. sodiumfluorescein
Anesthetics e.g. tetracaine surgical procedurs
Astringent e.g. zinc sulphate
Diagnostic agents e.g fluorescein

5. Anatomy and Physiology of the Eye:

6. Formulation A.I/s therapeutic effect
Vehicle ,usu aq./ can be oil (tetracycline HCl)
Antimicrobial preservative , maintain sterility
Adjuvants, adjust tonicity, viscosity, pH to ↑comfort in use & stability of A.I
Suitable container for storage & use
Most important sterility

7. Preservatives:
Preservatives are included in multiple-dose eye solutions for maintaining the product sterility during use.
Preservatives not included in unit-dose package.
The use of preservatives is prohibited in ophthalmic products that are used at the of eye surgery because, if sufficient concentration of the preservative is contacted with the corneal endothelium, the cells can become damaged causing clouding of the cornea and possible loss of vision.
So these products should be packaged in sterile, unit-of-use containers.
The most common organism is Pseudomonas aeruginosa that grow in the cornea and cause loss of vision.

9. Benzalkonium chloride
Preservative of choice if not C/I for incompatibility or sensitivity
It is generally used in combination with % disodium edetate (EDTA). The chelating, EDTA has the ability to render the resistant strains of P.aeruginosa more sensitive to benzalkonium chloride.

10. Well-tolerated on the eye up to conc of 0.02%w/v, usu used at 0.01%w/v
Stable to sterilization by autoclave
Rapid bactericidal action G+ve/G-ve bacteria working on cell envelop
Active in the controlled aq. Environment & pH values of ophthalmic products
Activity is reduced in the presence of multivalent cations as they compete w/ the antibacterial for negatively charged sites on bacterial cell surface

11. Reduced activity if heated w/ methylcellulose or formulated with anionic & certain conc of nonionic surfactants
Incompatible w/ fluorescein ( large anion), & nitrates
It is sorbed from solutions through contact w/ rubber

12. Its antibacterial activity is enhanced by aromatic alcohols ( benzyl alcohol)
Its surface activity may be used to enhance the transcorneal passage of non-lipid-soluble drugs such as carbacol
It should not be used with local anesthetics as anesthetics will abolish blink reflex & preservative will result in drying & irritation of the cornea.

13. Chlorhexidine acetate / gluconate
Cationic biguanide bactericide
Antibacterial activity in aq soln similar to benzalkonium Cl
Activity reduced in presence of other formulation ingredents
Activity against G-ve bacteria is enhanced by presence of aromatic alcohols + di-Na edetate
Activity antagonized by multivalent cations
Stability is greatest at pH 5-6, less stable to autoclaving than benzalkonium Cl
Well tolerated by the eye but allergic rxns may occur

14. Chlorbutol Chlorinated alcohol used at 0.5% w/v
Compatible with most ophthalmic preparations
Disadvantages: volatility, absorption by plastic containers, lack of stability at high temp

15. Phenylmercuric salts
They are slowly active over a wide pH range against bacteria & fungi
Activity increased by phenylethanol
Activity decreased by di-Na-edetate
Marked absorption by rubber
Not used if there is a suitable alternative
The organic mercurial's should not be used in eye drops which require prolonged usage as it can lead to IO deposition of mercury

16. Thiomersal Organic mercurial Bacteriostatic, fungistatic action
allergy

17. Tonicity
Eye drops are to be made isotonic with the lacrimal fluid (equivalent to 0.9% NaCl)
Eye can tolerate small volumes of eye drops with tonicity range equivalent to % w/v NaCl.
Common tonicity adjusting agents: NaCl, KCl, buffer salts, glycerin, propylene glycol, mannitol

18. Isotonicity
Lacrimal fluid is isotonic with blood having an isotonicity value
Corresponding to that of 0.9% Nacl solution

19. How many grams of NaCl should be used in compounding the following prescription?
Pilocarpine nitrate g
Sodium chloride q.s
Purified water ad ml
Make isotonic sol.
For the eye
Note : Pilocarpine nitrate NaCl equivalent 0.23

20. Viscosity enhancers: setting of particles)
(to retard the rate of
setting of particles)
Disadvantages: 1- produce blurring vision as when dry form
a dry film on the eye lids
2- make filteration more difficult

21. pH Adjustment and Buffers:
pH adjustment is very important as pH affects:
1- to render the formulation more stable
2- The comfort, safety and activity of the product.
Eye irritation increase in tear fluid secretion
Rapid loss of medication.
3- to enhance aqueous solubility of the drug.
4- to enhance the drug bioavailability
5- to maximize preservative efficacy
Examples: boric acid/borax, phosphate buffer, citrate buffer

22. pH Adjustment and Buffers:

23. pH & buffer

24. Antioxidants
To protect A.I from oxidation (adrenaline, proxymetacaine, sulphacetamide, phenylephrine)
Na metabisulphite (preferred at acid pH & has antimicrobial activity & enhances activity of phenylmercuric nitrate) & Na sulphite (preferred at basic pH) are used at 0.1% w/v . Stable at soln protected from light

25. Chelating agents
Such as di-Na-edetate are added to chelate heavy metal traces so enhance stability
It is also useful to enhance antibacterial activity & chemical stability at conc up to 0.1%

26. Bioavailability Most A.I are salts of weak bases
To penetrate the cornea the bases need to be at alkaline pH (unionized)
At tear pH they are able to penetrate the outer lipid layer of the lipid-water-lipid structure of the cornea
Inside the epithelium it will partially dissociate
So the water soluble moiety will traverse the middle aq stromal layer of the cornea

27. When it reaches the junction of the stroma & the endothelium it will again partially associate forming the lipid soluble moiety so it crosses the endothelium
Finally the drug dissociates into its water soluble form & enter aq humor
Then it can diffuse to the iris & the cillary body (site of action

28. Most effective penetration of lipophilic-hydrophilic-lipophilic corneal membrane is by A.I having both hydrophilic & lipophilic forms
Ex. Highly water soluble steroid phosphate ester have poor corneal penetration, but the less water soluble , more lipophilic steroid has much better corneal penetration

29. Storage conditions
To minimize degradation of eye drops storage temp & conditions must be considered at time of formulation.
The stability of several eye drops is improved by refrigerated storage (2-8C) ex. Chloramphenicol eye drops

30. Containers for eye drops
They should protect the eye drop from microbial contamination, moisture & air
Container material should not be shed or leached into solution, neither should any of the eye drop formulation be sorbed by the container
It should withstand sterilization method used if the product is to be sterilized in final container

31. Containers may be glass, plastic & may be single or multiple dose

32. Single dose containers

33. The minims is single dose eye drop container
Container sealed at its base & has a nozzle with a screw cap
Sterilized by autoclaving in an outer heat-sealed pouch with peel-off paper backing

34. Plastic bottle

35. Most commercially prepared eye drops are supplied in plastic dropper bottles
The bottles are made from polyethylene or polypropylene & are sterilized by ionizing radiation prior to filling with sterile formulation under aseptic conditions

36. Glass bottles
Most extemporaneously prepared eye drops are supplied in amber partially ribbed glass bottle bottle

37. Made from neutral /soda glass which had the inetrnal surface treated during manufacture to reduce release of alkali when in contact with sol
Neutral can be autoclaved more than once
Soda autoclaved once

38. Teat made from synthetic or natural rubber
Natural withstand autoclaving at 115⁰C for 30 min but not the high temp of dry heat sterilization
Silicone rubber will withstand dry heat sterilization & are suitable for use with oily eye drops . They are permeable to water vapor (susp become cake)

39. So aq eye drops having rubber teat have shelf life of 3 months whichcan be lengthened by supplying the sterile eye drop in bottle with an ordinary screw cap together with a separately wrapped & sterilized silicone rubber dropper
Teats & caps are used once only\
All components are thoroughly washed with filtered distilled or deionized water dried & stored in a clean area until required

40. Rubber teats sorb preservatives & antioxidants during autoclaving & storage
Studies are to be done individually to counteract this loss

41. Preparation of eye drops
Preparation involves
Preparation of the solution
Clarification
Filling & sterilization

42. Preparation of the solution
The aq eye drop vehicle containing any necessary preservatives, antioxidant, stabilizer, tonicity modifier, viscosity enhancer or buffer should be prepared first
Then A.I is added & vehicle made up to vol.

43. Clarification
They should be free from particulate matter & BP has stringent requirement for their absence
Sintered glass filter or membrane filter of µm pore size are suitable
The clarified sol is either filled directly into the final container which are sealed prior to heat sterilization or filled into a suitable container to filtration sterilization
Clarified vehicle is used to prepare eye drops susp. Which are filled into final container & sealed prior to sterilization

44. Sterilization Autoclaving at 115⁰C for 30 min or 121⁰C for 15 min
Heating at ⁰C for 30 min together with either benzalkonium Cl or phenylmercuric acetate or nitrate or thiomersal. This method is described in BP but is no longer a pharmacopeial recommendation method

45. Filtration through a membrane filter having 0
Filtration through a membrane filter having 0.22 µm pore size into sterile container using strict aseptic technique
Dry heat sterilization at 160⁰C for 2 hours employed for non-aqueous preparation, Silicone rubber teat must be used
Immediately following sterilization the eye containers must be covered with a readily breakable seal to distinguish btw opened & unopened containers

46. How to Use Eye Ointments and Gels Properly?

47. Formulation of eye lotions
eye lotions used to assist in the cleaning of the external surface of the eye.
Remove non-impacted foreign body or clean away conjunctival discharge
For surgical use in surgical or 1st aid procedure should not contain antimicrobial preservative & should be in single-use container
Preparation is very simple, most common consist of NS

48. Requirements
Sterile & usu containing no preservative
Isotonic w/ lacrimal fluid
Neutral pH
Large vol. but not greater than 200ml
Non-irritant to occular tissue

49. Labels include Title identifying the product & conc of contents
Sterile until open
Not to be taken
Use once & discard the remaining solution
Expiray date

50. Preserved eye lotions would need additional label
Avoid contamination of contents during use
Discard remaining solutions not more than 4 weeks after 1st opening
Lotions should be supplied in coloured fluted bottles & sealed to exclude MO

51. Formulation of eye ointments
Disadvantage: temporarily interfering w/ vision
Advantage: provide greater total drug bioavailability
But they take longer time to reach peak absorption

52. Must be sterile
Contain suitable antimicrobial preservative, antioxidant & stabilizer
USP offers:chlorobutol, parabens, organic mercurials
Must be free from particulate
Particle size be reduced ‹25 µm

53. Basic components Liquid parrafin 1part Wool fat 1 part
Yellow sof parafinn 8 parts
Hard parrafin as required to produce required consistency in hot climates

54. Containers for eye ointments
Small sterilized collapsible metal tubes made of metal or plastic
The tube should not contain more than 5 g of preparation & must be fitted or provided w/ a nozzle of suitable shape to facilitate application to the eye & surrounds w/o contamination
The tubes must be suitably sealed to prevent microbial contamination

55. Preparation of eye ointments
Prepared using aseptic techniques to incorporate the finely powdered active ingredient or a sterilized concentrated solution of the medicament into the sterile eye oint basis
Immediately after preparation the eye oint is filled into the sterile container which are then sealed to exclude MO
The screw cap should be covered with a readily breakable seal
Certain eye oint can be sterilized in their final container using ionizing radiation

56. Preparation of eye oint basis
The parrafin & wool fat are heated together & filtered, while molten, through a coarse filter paper in a heated funnel into a container which can withstand dry heat sterilization temp
The container is closed to exclude MO & contents are maintained at 160 ⁰C for 2 hrs

57. Labelling Names & % of A.I Expire date
Storage conditions- normally not exceeding 25⁰C
Name & conc of antimicrobial preservative or any added substance
Statement to effect that the contents are sterile provided the container has not been opened

58. Contact lenses & their solutions popularity, problems, risks
Popularity from their cosmetics appeal, optical advantage, useful in sport activities
Many prefer extended wear soft lenses to daily wear soft & hard lenses (convenient)

59. Problem: Inadequate education of wearer about lens care
Risks: recurrent corneal abrasions, corneal scaring, corneal vascularization, microbial ulcerative keratitis or corneal ulcer if untreated can lead to loss of vision
Cornea can resist bacterial infection as long as the surface epithelium is intact

60. Risk for corneal ulceration is 9-15 times greater for extended wear lenses worn overnight than for daily wear lenses worn only during day
Risk increases with the no. of consecutive days that lens are worn w/o removal
Rare complication from nonsterile water in care of lenses is infection with acanthamoeba which is hard to treat & can lead to loss of vision

61. Relevant properties of the eye
Cornea, lens & humor compartments are avascular →facilitate ligh transmission/ vision
Exchange of nutrients & waste products takes place almost entirely by diffusion process through the aq humor, through lens , through cornea & through lacrimal fluid
Contact lenses reduce the diffusion of oxygen through cornea so can affect corneal metabolism

62. Secretions
Tears lubricates, cleans, & disinfect interior surface of the eye
Lachrymal fluid
The fluid forming the precorneal film is produced by differing groups of glands. It contains mucus, water & oil
These fluid are stratisfied in 3 distinct layers

63. The surface-active mucoid layer spreads on the corneal surface & associates w/ the intermediate aq layer externally
The aq layer is surfaced w an oily layer which lubricates & protects the mucus membranes of the internal lid surface

64. Tear electrolyte content:
Similar to serum except K+ (4-6 times greater) protein content is mainly albumin& globulin app. Tenth of that in serum

65. Tear production:
Produced in response to:
Emotional via psychological factors
Sensory via external irritant
Continuousvia automatic nervous control
Systemic via chemicals in the bloodstream affecting the nerves innovating the lachrymal gland

66. Tear pH:
Have sufficient buffering capacity to adjust rapidly the pH of small vol of weakly buffered solutions pH

68. Eye lids:
Protecting & cleaning fxn
Outer margin of eyelids close slightly before the inner margin & sweep the fluids across the eye toward the lachrymal duct at the inner angle of the eye & into nasal chamber
Systemic absorption of excess eye drops may take place via the nasal mucosa
Conversely by gentle pressure on it medication may be maintained on eye surface longer.

69. Bacterial flora:
Staphylococci, diphtheroids, G-ve enteric bacilli can be found
Care should be taken in wearing contact lenses to avoid abrading the corneal epithelium

70. Contact lenses Properties Correct pt vision
Maintain their position on the eye
Allow respiration of the cornea
Permit free flow of tears round or through the lens
Not release toxic substances
Not introduce microbial contamination
Be wearable throughout day
Be easy to handle & economical to use

71. Hard lenses Prepared from Polymethyl methacrylate
Lenses need to be wetted before use to eliminate pt discomfort as lachrymal fluid cannot wet them (contain hydrophobic material)
They need wetting solution to facilitate wear & need for a storage, hydrating, decontaminating solution to facilitate care of the lens when not being worn

72. Modern hard lenses are designed to be gas permeable , more user friendly than old ones problems

73. The original gas-permeable lenses consisted of cellulose acetate butyrate (CAB) which was readily wettable & proved quite acceptable
More recently lenses based on silicone & fluorine have been produced which have greater gas permeability
Silicone methacrylate copolymers are very popular

74. The silicone composition controls the permeability properties
Polymethyl methacrylate composition controls the degree of rigidity

75. Similarly flurosilicone methacrylate copolymers which have very high oxygen permeability properties & good wetting properties are proving to be popular
These gas-permeable lenses are cared for using hard-lenses solution
These lenses are less subject than soft lenses to deposits of lipid, protein & othersubstanses from lachrymal fluid
Have better optical properties & easier to care for

76. Soft lenses
The hydroxyethyl ester of polymethacrylic acid (poly-HEMA) is prepared
Hydrophilic
Poly-HEMA is flexible & can absorb 47% of its wt of water
So lenses are comfortable & easy to wear
But more difficult to care than hard

77. Problem : uptake of antibacterial preservative & subsequent release & irritancy during wear
A wetting solution is not needed
Cleaning, storing, hydrating, decontamination are required for solutions

78. Copolymers of poly-HEMA with vinylpyrrolidone (VP) are produced which can absorb up to 80% by weight of water depending on the HEMA/VP ratio
The higher the water content lenses have the advantage of gas permeability & comfort than poly-HEMA lenses which may occasionally cause corneal edema
They are more fragile, difficult to care for than poly-HEMA
Have greater tendency to attract deposits
More solution problems
Less precise optical properties

80. Disposable lenses May be discarded after 1 month, 1 week even 1 day
1 day would obviate the need for the use of solutions & theoretically increase the safety & acceptability of lens wear
Offers greater advantage to those who wear lenses on an irregular basis

81. Hard lenses solution Wetting solution suitable for placing in the eye
Soaking/storing/decontaminating solution must not have contact w/ the eye
Both are needed for wear & care of lenses

82. Wetting solution Purpose:
Achieves rapid wetting by the lachrymal fluid & thus promotes comfort
Facilitates insertion of the lens
Provides cushioning & lubrication
Enables cleaning after removal
Non-irritant during daily use
Formulation:
Wetting & viscolizing agents- polyvinylalcohol & hypermellose
Viscosity 15-20mPas for comfort
Tonicity % NaCl
Antimicrobial benzalkonium Cl plus di-Na-edetate

83. Storing solution Purpose: Achieves cleaning & microbial inactivation
Hydrating
Formulation:
Surface-active agent not inactivating antimicrobials
Antimicrobial- benzalkonium Cl 0.01% plus di-Na edetate

84. Soft lenses solutions cleaning solution
Purpose:
To remove deposits such as lipoprotein adhering to the lens after wear
Formulation:
Viscolizing surface-active agent such as hyperomellose to enable suitable gentle friction with fingertip
Antibacterial-fast acting benzalkonium Cl 0.004% may be used if contact time is only second

85. Storing solution Purpose: Hydrating Cleaning
Inactivation of microbial contamination
Formulation:
isotonic 0.9% NaCl
Antibacterial 3% hydrogen peroxide for 30 min followed by suitable inactivation w sodium pyruvate or platinum catalyst or other suitable method to facilitate subsequent safe wearing of lens. H₂O₂ has good activity against Acanthamoeba contamination

86. Enzyme protein digest Purpose
Occasional cleaning procedure followed by suitable washing & cleaning before wear
Frequency will vary w/ individual & state of health. Ex influenza or hay fever may increase the need
Formulation:
Proteolytic enzyme, such as papain as a solution tablet to produce a suitable solution when dissolved in a stated vol of aq vehicle
Lipid digest or combined protein & lipid digest systems are also available

87. All-purpose solutions
These have been available for hard lens wearers who have found compliance w/ 2 solution regimen difficult to adhere
The all purpose solutions have represented a compromise & have not been as effective as 2 solution regimen but have been superior to using no solution
Single solution care systems are also available for soft lenses

88. The majority of all-purpose soft-lens solutions incorporates polyhexamide as the antimicrobial preservative as it is active against wide range of bacteria & Acanthamoeba

89. Containers Contact lenses are usu packed in plastic container
It is imperative that the low conc of antimicrobial present in these products are not reduced to ineffective level due to sorption effect w/ the plastic
These containers are kept in a hygienic conditions by keeping them clean & using a disinfecting storage solution strictly as instructions

90. Advice to the patient
Contact lenses wearer w red eye should be referred to ophthalmologist
May have infection by Acanthamoeba

91. Effect of medication & physical condition
Certain medications can affect the eye surface & lachrymal fluid production so influence the comfort of contact lens wear
Drugs w/ Anticholinergic properties (sedative antihistamines, antispasmodics, TCA, neuroleptics) can all reduce lachrymal fluid production
With resultant lack of lubrication which may cause discomfort from & increased risk lens deposits

92. OCP may cause corneal edema, decreased aq & increased mucus & protein production so lead to lens intolerance
Pregnancy may also be associated w/ increased lens awareness & discomfort possibly associated w/ reduced tear flow & changes in corneal thickness & the curvature of the eye

93. Disease state leading to dry eye syndrome which is mostly confined to menopausal women having osteoarithritis will also adversely affect ability to wear contact lenses
Oral drugs (labetolol, nitrofurantoin, phenolphthalin, rifampicin, sulphasalazine, tetracyclines ) may cause lens discoloration via lachrymal fluid

94. Topical Eye drops: Administration: Pull down the eyelid
Tilting the head backwards
Look at the ceiling after the tip is pointed close to the lower lid
Apply a slight pressure to the rubber bulb or plastic bottle to allow a drop to fall into the eye.
Do not squeeze lids
To prevent contamination:
Clean hands
Do not touch the dropper tip to the eye and surrounding tissue

95. Solid Dosage Forms Ocular Inserts
Ophthalmic inserts are defined as sterile solid or semisolid preparations, with a thin, flexible and multilayered structure, for insertion in the conjunctival sac.

96. C. Solid Dosage Forms Ocular Inserts
Advantages:
Increasing contact time and improving bioavailability.
Providing a prolong drug release and thus a better efficacy.
Reduction of adverse effects.
Reduction of the number administrations and thus better patient compliance.

97. C. Ocular Inserts I. Insoluble inserts:
Insoluble insert is a multilayered structure consisting of a drug containing core surrounded on each side by a layer of copolymer membranes through which the drug diffuses at a constant rate.
The rate of drug diffusion is controlled by:
The polymer composition
The membrane thickness
The solubility of the drug
e.g. The Ocusert® Pilo-20 and Pilo-40 Ocular system
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 for treatment of glucoma.
- consists of (a) a drug reservoir, pilocarpine (free base), and a carrier material, alginic acid: (b) a rate controller ethylene vinyl acetate (EVA) copolymer membrane.

98. C. Ocular Inserts I. Insoluble inserts:

99. II.Soluble Ocular inserts:
Soluble inserts consists of all monolytic polymeric devices that at the end of their release, the device dissolve or erode.
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 soften in sec after introduction into the upper conjuctivall sac, gradually dissolves within 1 h, while releasing the drug.
- Advantage: being entirely soluble so that they do not need to be removed from their site of application.

100. II.Soluble Ocular inserts: