Eye, ear and nose formulations Dr Liesl Brown Department of Pharmacy University of Limpopo (Medunsa Campus)Module 2.3: Respiratory system, ear and eye (2011)
Pre-reading required Aulton, M.E. (Editor). Pharmaceutics: The Science of Dosage Form Design. Latest Edition. London: Churchill Livingstone. Chapter on solutions and chapter on nasal drug delivery. Collett, B.M., Aulton, M.E. Pharmaceutical Practice. Latest Edition. London: Churchill Livingstone. Chapter on ophthalmic products. Winfield, A.J., Richards, R.M.E. Pharmaceutical Practice. Latest Edition. Edinburgh: Elsevier, Churchill Livingstone. Chapter on ophthalmic products
Learning Objectives: Identify the components of eye drops, eye ointments and their special pharmaceutical needs; Briefly discuss the clinical effects regarding the formulation (not manufacture) of eye drops, such as the use of preservatives and the effect of chronic use of preservatives on the integrity of the cornea; and Identify the target sites in the eye and delivery of drugs to these sites as well as the design of a dosage form that achieve the desired effect.
Examples of eyepreparations used for a local effect Eye drops Contact lens solutions (solutions/suspensions) – facilitate wearing & – AI (active ingredient) care into conjuctival sac Parenteral products – Eye lotions - for intracorneal, irrigation & cleaning intravitreous or eye surface retrobulbar injection Eye ointments, Solid dosage forms - creams & gels – AI to placed in conjunctival lid margins and/or sac to release AI over conjunctival sac prolonged period
Examples of drugs used in eye preparations Anaesthetics – e.g. topical Diagnostic agents – e.g. & surgical procedures fluorescein – highlight Anti-infectives – e.g. damage to epithelial tissue antibacterials, antifungals, Miotics – e.g. pilocarpine – antivirals constrict pupil & contract Anti-inflammatories – e.g. ciliary muscle corticosteroids, Mydriatics & cycloplegics – antihistamines e.g. atropine – dilate pupil & Antiglaucoma agents – paralyse ciliary muscle to reduce intraocular pressure facilitate examination of e.g. beta-blockers interior of the eye Astringents – e.g. zinc sulphate
Properties of eye drops Sterile – NB! NB! NB! Isotonic with lachrymal Free of foreign secretion particles Hydrogen ion [ ] should be suitable for Free from irritating particular drug – ideally effect not too far from neutrality Contain suitable Chemically stable preservative – to prevent growth of micro organisms which may accidentally be introduced during use
Components used in eye preparations Adjuvants – adjust Active ingredient(s) tonicity, viscosity or pH – – desired therapeutic increase stability of AI effect Suitable container Vehicle - usually for administration – aqueous, occasionally oil maintain prep in stable form e.g. tetracycline & protect contamination during preparation, storage & hydrochloride use Antimicrobial preservative – eliminate microbial contamination during use & maintain sterility
Antimicrobial preservatives used in eye preparations Multiple dose containers must contain preservatives Capable of withstanding test of efficacy of preservatives (BP) Sterility of drops maintained during use Drops will not introduce contamination into eyes being treated Must not adsorb onto the container Efficacy must not be impaired by the pH of the solution / interactions with other ingredients IMPORTANT: Eye drops used during intraocular surgery should not contain a preservative due to risk of damage to the internal surfaces of the eye.!! Preservative may enter the anterior chamber of the eye anddamage the corneal endothelium.
Antimicrobial preservatives used in eye preparations : Benzalkonium chloride Preservative of choice Activity enhanced Present in 70% of aromatic alcohols commercially produced chelating agents e.g. eye drops disodium edetate Enhance transcorneal passage Stable to autoclaving of non-lipid-soluble drugs e.g. Bactericidal carbachol Activity reduced: CAUTION: Do not use with In the presence of local anaesthetics. multivalent cations (Mg2+, Ca2+) When heated with The combination of the methylcellulose anaesthetic abolishing the blink Incompatible – fluorescein, reflex and the preservative nitrates solubilising the outer oily Sorbed by rubber protective layer of the precorneal film results in drying of the eye and irritation of the cornea
Chlorhexidine acetate / gluconate (0.01% w/v) Bactericide Activity reduced – in presence of other formulation ingredients Activity enhanced – by aromatic alcohols & disodium edetate Stable – pH 5-6 Less stable to autoclaving
Chlorbutol (0.5% w/v) Effective against bacteria & fungi Compatible – most ophthalmic products Disadvantage volatility absorption by plastic containers lack of stability at high temp e.g. autoclaving
Phenyl mercuric salts (0.001 – 0.04% w/v) Active against CAUTION: do not bacteria & fungi use in eyes for Activity increased – prolonged time – phenyl ethanol intraocular deposition Activity decreased – of mercury sodium edetate Sorbs to rubber
Isotonic modifiers Eye drops should be made iso-osmotic with tissue fluid (lachrymal fluid) – to avoid pain & irritation Only added after all other additives have been added – each ingredient will contribute towards the overall osmotic pressure of the solution E.g. dextrose, sodium chloride
Viscosity enhancers Gelling agents e.g. methylcellulose, polyvinyl alcohol Increasing viscosity – increase residence time of drop in eye resulting in increased penetration & therapeutic action of drug
Buffers (pH adjustment) pH offering best stability during preparation & storage pH offering best therapeutic activity Comfort of the patient – avoid irritation Acidic solutions (e.g. pilocarpine HCl) buffred to reduce stinging on installation E.g. borate buffer, phosphate buffer, citrate buffer
Antioxidants Added to protect AI from oxidation e.g. adrenaline, sulphacetamide, amethocaine, phenylephrine, physostigmine Physostigmine – antioxidant prevents discoloration (cosmetic acceptability) E.g. sodium metabisulphite, sodium sulphite
Chelating agents Heavy metals catalyse breakdown of AI by oxidation Chelating agents included to chelate metal ions & enhance stability Enhance antibacterial activity & chemical stability E.g. disodium edetate
Bioavailability of eye drops Active ingredients should have both hydrophilic and lipophilic forms At tear pH (7.4) they are able to penetrate the outer lipid layer of the lipid-water-lipid sandwich which constitutes the physiochemical structure of the cornea Once inside the epithelium the dissociated, free drug will partially dissociate The water-soluble dissociated moiety will then traverse the middle aqueous stromal layer of the cornea
Bioavailability of eye drops When the dissociated drug reaches the junction of the stroma and the endothelium it will again partially associate forming the lipid- soluble moiety and thus cross the endothelium Finally the drug will dissociate into its water- soluble form and enter the aqueous humour From here it can diffuse to the iris and the ciliary body which are the sites of its pharmacological action
Storage conditions Consider storage temp & conditions at time of formulation Refrigerated storage (2-8˚C) can improve stability of the active ingredient E.g. chloramphenicol; neomycin, epinephrine
Containers Made of glass / plastic Single dose / multiple dose (should not contain >10 ml)
Properties of containers Protect eye drop from - Internal surfaces treated microbial contamination, during manufacturing to moisture, air, light; reduce release of alkali Material should not be when in contact with shed/leached into the aqueous solution; solution; Seal properly; Formulation should not Rubber components be sorbed by container should be treated with Withstand autoclaving; preservative; Comply with test for Comply with poisons alkalinity of glass – glass regulation; composition (neutral glass / soda Non-glass components glass) – should all be inert
Formulation of eye drops 1. Preparation of solution Prepare vehicle containing preservative, antioxidant, stabilizer, tonicity modifier, viscolizer or buffer Add active ingredient Vehicle made up to volume 2. Clarification No particulate matter left in solution Make use of sintered glass filters/membrane filters (0.45 – 1.2 µg pore size) Clarified solution is then filled into final containers Sealed and Sterilized
Formulation of eye drops 3. Sterilization Autoclaving - 115ºC for 30 min or 121ºfor 15 min Heating – 98-100ºC for 30 min with benzalkonium chloride /ect Filtration – membrane filter 0.22 µg pore size into sterile containers using strict aseptic technique (Grade A laminar airflow conditions) Dry heat sterilization - 160ºC for 2 hours – for non-aqueous preparations e.g. liquid paraffin eye drops – silicone rubber teats must be used 4. Cover with readily breakable seal e.g. viskring – to distinguish between opened and unopened containers 5. Labelling of container
Labeling requirements Fully identify the Ensure correct use e.g. product state: “Shake the bottle” Specify storage for eye suspensions conditions: cool place Do not use more than 30 /protect from light days after first opening Expiry date Keep out of reach of Warning label children indicated: “Not to be taken” Specify volume
Formulation of eye lotions - Uses - Cleaning of external surfaces of the eye Help remove a non-impacted foreign body Clean away conjunctival discharge Very simple – most consist of sterile normal saline Are not formulated to deliver the active ingredient to the eye
Formulation of eye lotions - Requirements - Sterile Lotions for surgical & Usually containing first-aid procedures no preservatives No antimicrobial preservatives Isotonic with Single-use containers lachrymal fluid Supplied in coloured Large volume - not fluted bottles greater than 200 ml Sealed to exclude Non-irritant to microorganisms ocular tissue
Formulation of eye lotions- Labeling requirements - Title identifying the product “Sterile until opened” “Not to be taken” “Use once and discard the remaining solution” Expiry date Preserved eye lotions “Avoid contamination of contents during use” “Discard remaining solutions not more than 4 weeks after first opening”
Formulation of eye ointments Advantages: Disadvantages: Provide greater total Temporarily drug bioavailability interfering with vision than liquids However, takes a longer time to reach peak absorption
Formulation of eye ointments - Requirements - Sterile Suitable antimicrobial preservatives – BP states chlorbutol / the parabens / organic mercurials to be used Antioxidants Stabilizers Free from particulate matter (<25 µm)
Formulation of eye lotions - Components - Liquid paraffin 1 part Wool fat 1 part – to facilitate incorporation of water Yellow soft paraffin 8 parts Hard paraffin as required – to produce required consistency in hot climates
Formulation of eyeointments - Containers - Small sterilized collapsible tubes – made of metal / suitable plastic Must not contain more than 5 g of preparation Fitted / provided with nozzle – to facilitate application to eye & surrounds without allowing contamination of contents Suitably sealed – to prevent microbial contamination
Formulation of eyeointments - Preparation - Aseptic techniques – all apparatus clean & sterile Finely powdered active ingredient / sterilized concentrated solution incorporated into sterile ointment base Filled into sterile containers Sealed – to exclude microorganisms Screw cap cover with readily breakable seal Sometimes sterilized in final containers – ionising radiation
Formulation of eye ointments - Labeling - Names and % of active ingredients Contain an expiry date Storage conditions – not >25˚C Name & [ ] antimicrobial preservative / other substance added Statement to effect that contents are sterile - proving the container has not been opened
Ear preparations (aka otic/aural products)Uses / examples: Active agents for local use Antibiotic – treat infections Antifungal agents – polysorbate, gentian violet, nystatin Anti-inflammatory Antiseptics Cleansing solutions Wax softeners
Ear preparations - Dosage forms - Drops Sprays Washes
Ear preparations - Formulation aspects - No special difficulties Solutions of drugs in water (purified water/boiled & cooled water) diluted alcohol (alcohol/water mixtures) glycerol propylene alcohol Apparatus & containers – should be thoroughly cleaned & rinsed before use Eye dropper bottles may be used
Ear preparations - Containers - Small glass or plastic containers – with a dropper
Ear preparations - Labeling - “For external use only” and “Not to be taken” in addition to any special directions
Nasal preparations Benefits of nasal administration: Convenient Useful area for absorbing drugs Good systemic blood supply
Nasal preparations - Properties - Effective Acceptable safety and stability (chemical & microbiological) Acceptable to patient – ensure compliance
Nasal preparations - Uses / Examples - Active agents for local use: Antibiotics Anti-inflammatory Decongestants
Nasal preparations - Dosage forms - Dosage forms should be designed in order for drugs to be: deposited in the anterior (back) part of nasal cavity as it is: better absorbed there nasal residence time increased
Nasal preparations - Dosage forms -Liquid formulation Usually aqueous solutions - (simple to develop) Have a lower microbiological & chemical stability - requiring the use of various preservatives (disadv: can cause irritation/ciliotoxicity) Nose drops – simplest way of nasal drug administration, but its cheapness & convenience are outweighed by the inaccuracy of dosing volume and likelihood of too-rapid clearance by the nose liquid running straight into oesophagus This is improved by unit-dose packs
Nasal preparations - Dosage forms – (cont.)Squeezed bottles Better absorption – directing formulation into the anterior part of the cavity – covering a large part of nasal mucosa Subject to contamination – “suck-back” action as external material can be drawn into the container as pressure on it is released
Nasal preparations- Dosage forms – (cont.)Metered-dose pump system Greater control over dosing Deliver solutions, suspensions, emulsions – predetermined volume of 25 – 200 μL – offering deposition over large area Have control over size and localisation of dose by changing various factors E.g. Cone angle (angle at which spray leaves nozzle) will affect where formulation is deposited e.g. small angle (35º) deposited towards back of nasal cavity; larger angle (90º) will go to the front nasal area Optimum particle size – for deposition in nasal cavity is 10 μm Particulate formulations e.g. those that have a longer residence time than liquids are removed more slowly by mucociliary clearance, hence their nasal deposition time is longer
Nasal preparations- Strategies to improve drug bioavailability - Improve nasal residence time Enhance nasal absorption Modify drug structure to change physiochemical properties
Nasal preparations- Physico-chemical factorsaffecting drug absorption - Size of drug molecule Charge of drug molecule Degree of hydrophilicity/lipophilicity
Nasal preparations - Formulation aspects - Formulated as small volume solutions in an aqueous vehicle (oils no longer used for nasal administration) Increase nasal residence time by adding viscosity increasing agents (e.g. methylcellulose, hydroxypropylmethylcellulose, polyacrylic acid [Carbopol]) delay mucociliary clearance - which acts to remove foreign bodies from the nasal mucosa as quickly as possible (does not necessarily increase absorption) Absorption enhancers – should not damage or permanently change epithelial cells e.g. bile salts, cyclodextrins
Nasal preparations - Formulation aspects - Absorption enhancers – should not damage or permanently change epithelial cells e.g. bile salts, cyclodextrins Modifying drug structure – more favourable physiochemical properties Isotonic with nasal secretions (adjusting pH 5.5 – 6.5) – use salts e.g. NaCl - nasal mucous has low buffering capacity – to prevent damage to the ciliary transport in the nose Antioxidants e.g. butylated hydroxytoluene Solubilising agents e.g. glycerol derivatives Antimicrobial preservatives e.g. benzalkonium chloride Humectants to minimise irritation e.g. glycerol
Nasal preparations - Containers - Drops: Amber, ribbed hexagonal glass bottle fitted with rubber teat & dropper Nasal solutions: Flexible plastic bottles which deliver a fine spray when squeezed Plain glass bottle with pump spray or dropper
Pharmaceutical Care Eye preparations Ear preparations (drops)Nose preparations (drops/sprays)
Learning Objective: Describe the steps in counselling a patient on correct eye drop/ointment use, including storage and disposal
Eye preparations- Installation of eye drops - 1. Wash your hands. 2. Do not touch the dropper opening. 3. Look upward. 4. Pull the lower eyelid down to make a „gutter. 5. Bring the dropper as close to the gutter as possible without touching it or the eye. 6. Apply the prescribed amount of drops in the gutter. 7. Close the eye for about two minutes. Do not shut the eye too tight. 8. Excess fluid can be removed with a tissue. 9. If more than one kind of eye-drop is used wait at least five minutes before applying the next drops. 10. Eye-drops may cause a burning feeling but this should not last for more than a few minutes. If it does last longer consult a doctor or pharmacist.
Eye preparations - Installation of eye drops into the eye of a minor -1. Let the child lie back with head straight.2. The childs eyes should be closed.3. Drip the amount of drops prescribed into the corner of the eye.4. Keep the head straight.5. Remove excess fluid.
Eye preparations-Installation of eye ointment- 1. Wash your hands. 2. Do not touch anything with the tip of the tube. 3. Tilt the head backwards a little. 4. Take the tube in one hand, and pull down the lower eyelid with the other hand, to make a gutter. 5. Bring the tip of the tube as close to the gutter as possible. 6. Apply the amount of ointment prescribed. 7. Close the eye for two minutes. 8. Remove excess ointment with a tissue. 9. Clean the tip of the tube with another tissue.
Counseling aspects, storage and disposal of eye preparations Preparations use for the eye should be sterile Keep opened eye drops for 30 days only, then discard / return to your pharmacist for proper disposal Never touch eye lashes or eye with eye dropper / opening of eye ointment container, as this may lead to repeated reinfection Never share eye drops/ointment - eye drops or ointments should never be administrated to different patients from the same container When multidose containers or fluorescein are used, special care should be taken to avoid contamination. Corneal abrasions are natural portals to infection, and as Pseudomonas aeroginosa grows in fluorescein, this agent has often been implicated in introducing infection. Single dose containers are more expensive, but are preferred for their safety Wash your hands before and after application of ophthalmic agent
Counseling aspects, storage and disposal of eye preparations (cont.) Keep drops/ointment at room temperature unless otherwise advised / indicated General OTC ophthalmic agents shouldnt be used for more than 3 days without a doctors supervision When using drops - apply to uncovered eye early and frequently at least hourly When using ointments - apply under the eye pad for ulcers and injuries to the eye. Apply at night. When applying sulphur drugs -never use if the eye has excessive pus, as the pus inactivates its action When using steroids, care should be exercised in their use as they are extremely dangerous in herpetic infections and injuries caused by cellulose Antiallergic agents (e.g. antihistamines) have generally little effect topically, and may be used prophylactically When using wetting agents - apply only to dry eyes
Ear preparations- Installation of ear drops - Warm the ear-drops by keeping them in the hand or the armpit for several minutes. Do not use hot water tap, no temperature control! Tilt head sideways or lie on one Adult side with the ear upward. Gently pull the lobe to expose the ear canal. Child Apply the amount of drops prescribed. Wait five minutes before turning to the other ear. Use cotton wool to close the ear canal after applying the drops ONLY if the manufacturer explicitly recommends this. Ear-drops should not burn or sting longer than a few minutes.
Nose preparations- Installation of nose drops - Blow the nose. Sit down and tilt head backward strongly or lie down with a pillow under the shoulders; keep head straight. Insert the dropper one centimetre into the nostril. cm Apply the amount of drops 1 prescribed and remove the dropper. Immediately afterward tilt head forward strongly (head between knees). Sit up after a few seconds, the drops will then drip into the pharynx. Repeat the procedure for the other nostril, if necessary. Rinse the dropper with boiled water.
Nose preparations- Installation of nasal spray - Blow the nose. Sit with the head slightly tiled forward. Shake the spray. Insert the tip in one nostril. Close the other nostril and mouth. Spray by squeezing the vial (flask, container) and sniff slowly. Remove the tip from the nose and bend the head forward strongly (head between the knees). Sit up after a few seconds; the spray will drip down the pharynx. Breathe through the mouth. Repeat the procedure for the other nostril, if necessary. Rinse the tip with boiled water.
References Alton, M.E. (Editor). Pharmaceutics: The Science of Dosage Form Design. Latest edition. London: Churchill Livingstone. Chapters on Solutions / Nasal Drug Delivery Collett, B.M., Alton, M.E. Pharmaceutical Practice. Latest edition. London: Churchill Livingstone, Chapter on Ophthalmic products Winfield, A.J., Richards, R.M.E. Pharmaceutical Practice. Latest Edition. Edinburgh: Elsevier, Churchill Livingstone. Chapter on Ophthalmic Products