Hydrocortisone (micronised)
1.0 g
Acetic Acid (30 %) DAC
2.4 g
Propylene glycol
96.6 g
Total
100 g
In the case of an acute weeping otitis the cooling effect of water can be advantageous as in eardrops with aluminium acetate and tartrate (Table 9.2). They are applied on a piece of gauze or an ear tampon, which should be changed at least every 24 h. In the acute phase the ear tampon often is chosen. The treatment is then continued with acid ear drops combined with a corticosteroid.
Aluminium sulfate | 22.5 g |
Acetic acid (30 %) DAC | 25 mL |
Calcium carbonate | 10 g |
Tartaric acid | 4.5 g |
Water, purified | 75 mL |
In the case of a perforated eardrum propylene glycol should not be used because of the possible ototoxicity. In the aqueous ear drops (Table 9.2) the concentration of aluminium acetate or acetotartrate may be too high. Therefore a tenfold dilution is normally used as a matter of precaution.
The antibacterial action of acetic acid in these preparations is due to a specific effect of acetic acid as well as the lowering of the pH. There are two benefits, namely that acetic acid is bactericidal to Pseudomonas aeruginosa, the major pathogen isolated from otorrhoea, and that it also suppresses several fungi [3–5]. In chronic suppurative otitis media (CSOM), the most common organism is P. aeruginosa, followed by Staphylococcus aureus. These bacteria usually originate from the external ear canal and contaminate the middle ear [6].
For ear drops that are given to reduce pressure in the middle ear, as is often the case in inflammations, glycerol is used as the solvent, provided the eardrum is not perforated. A disadvantage of this kind of ear drops is that they make it difficult for the physician to clearly view the eardrum.
There are many different treatments for cleaning the external auditory canal or softening hard plugs of earwax. Some of them may be prescribed as a pharmacy preparation. These remedies vary from peanut oil or almond oil (of pharmacopoeia quality, not ordinary vegetable oil) to solutions of sodium carbonate in mixtures of glycerol and water. There are different opinions on the best way to soften earwax. Good research on the rationality of the different remedies is lacking. According to a Cochrane review, it is uncertain if one type of drop is better than another, although the use of any kind of drop is better than no treatment [7].
Theoretically, preparations with a fatty base are the first choice in dry external otitis. But because of practical problems in applying ointments and creams in the ear, ear drops are often preferred. Some guidelines recommend applying the ear drops, cream or ointment on an ear tampon that can be placed in the external auditory canal [8].
In the NRF ear drops with the antimycotic clotrimazol in peanut oil are included [Table 9.3]. This vehicle could be an alternative when propylene glycol would excessively irritate.
Clotrimazole | 1 g |
Arachis oil, refined | 99 g |
Total | 100 g |
Chronic as well as acute inflammations of the middle ear are treated with sterile, aqueous ear drops with antibiotics, sometimes in combination with a corticosteroid. Normally these are short-time treatments. Many medicines of this kind are commercially available.
Ear drops have the following advantages and disadvantages:
Advantages:
Simple application
Local application enables much higher tissue concentrations than would be possible with systemically administered medicines.
Low risk of systemic adverse effects.
Due to the higher tissue concentrations development of resistance against antibiotics is (at least theoretically) less likely [10]
Disadvantages:
Ototoxicity of many active substances, non-aqueous vehicles and other excipients.
For short term use only.
Risk of contact allergy.
Assessment of the eardrum may be difficult due to residues from ear drops.
Ear drops are not the only dosage form for treatment of diseases of the ear. Nose drops with decongestants are used to keep the Eustachian tube open to relieve the pressure and pain in otitis media, although the effect is not proven. In diseases of the middle ear nasal drops can be used
For the local administration of medicines in the inner ear and the cochlea highly sophisticated systems are used, like microcatheters, osmotic and peristaltic pumps. Current research on repairing patients hearing includes gene therapy, administration of neutrophins and stem cells [11, 12].
9.2 Definitions
The Ph. Eur. states that Ear preparations (Auricularia) are “liquid, semisolid or solid preparations intended for instillation, for spraying, for insufflation, or application to the auditory canal or as an ear wash. Ear preparations usually contain 1 or more active substances in a suitable vehicle. They may contain excipients to adjust tonicity or viscosity, to adjust or stabilise the pH, to increase the solubility of the active substances, to stabilise the preparation or to provide adequate antimicrobial properties. The excipients do not adversely affect the intended medicinal action of the preparation, or, at the concentrations used, cause toxicity or local irritation.
Preparations for application to the injured ear, particularly when the eardrum is perforated, or prior to surgery are sterile, free from antimicrobial preservatives and supplied in single-dose containers.
Ear preparations are supplied in multidose or single-dose containers provided, if necessary, with a suitable administration device which may be designed to avoid the introduction of contaminants.
Unless otherwise justified, aqueous ear preparations supplied in multidose containers contain a suitable antimicrobial preservative at a suitable concentration, except where the preparation itself has adequate antimicrobial properties.”
An example of this is Bacicoline B®. These ear drops contain a borate buffer, but no preservative. This was accepted by the licensing authorities because borate buffers have some antimicrobial properties and because the beyond-use date is 10 days after opening.
In the monograph Ear Preparations of the Ph. Eur. the following categories are distinguished:
Ear drops and sprays
Semisolid ear preparations
Ear powders
Ear washes
Ear tampons
9.3 Biopharmaceutics
9.3.1 Anatomy of the Ear
Looking from the outside to the inside the ear consists of the auricle, the external auditory canal, the middle ear and the inner ear (Fig. 9.1).
Fig. 9.1
Anatomy of the ear. Source: Recepteerkunde 2009, ©KNMP
The middle ear is connected to the nasal pharynx by the Eustachian tube and to the inner ear via the oval and the round window.
The inner ear consists of the cochlea and the labyrinth, organs for hearing and balance respectively, with the eighth cranial nerve. This nerve has an auditory and a vestibular portion. The inner ear is filled with liquid. When sound waves strike the eardrum, between the external canal and the middle ear, this causes movements of the ear bones (hammer, anvil and stirrup). These movements are transferred into vibrations of the liquid in the inner ear, where the hair cells convert the movements to nerve impulses. The signals are sent to the brain through the auditory nerve.
More information about the anatomy and the physiology of the inner ear can be found in [11].
9.3.2 Passing the Eardrum
In external otitis, and, less often, for diseases of the middle ear, local application of medicines – i.e. in ear drops, may be necessary. Pharmacokinetic data of substances after administration to the middle ear have been reported in the literature [11].
Administration of preparations in the external auditory canal means that (theoretically) there is a chance that some substances will pass the eardrum and thus may damage the hearing organ. To be ototoxic a substance has to reach the inner ear. To do this from the external canal, first the eardrum has to be passed, and secondly from the middle ear the round or oval window. All of these membranes appear to be more or less permeable for the ingredients of ear drops [13]. Factors affecting permeability include the thickness of the membrane, concentration of the solution, electrical charge, and facilitating agents (prostaglandins, leukotrienes, staphylococcal and streptococcal exotoxins) [14, 15].
Factors that make the passage more difficult are contaminating substances in the external canal, and a swollen mucosa or purulence in the middle ear.
Especially in the case of a perforated eardrum preparations for the external auditory canal could accidentally reach the middle ear and thus the inner ear. Still, in acute situations treatment can be necessary, even when the condition of the eardrum is not known. Use of ear drops should then be restricted to a couple of days.
Preparations intended for the middle ear are aqueous and sterile. They are mostly used in middle ear infections, because in that condition the drops will be unlikely to reach the inner ear.
9.4 Ototoxicity
Ototoxicity may be caused by the active substance, the excipients or the solvent [11, 13, 16]. The risk of ototoxicity as a result of the use of ear drops can be limited by not giving ear drops when the middle ear (and thus also the inner ear) is easily accessible. A traumatic eardrum perforation, the presence of a tympanostomy tube without inflammation, or other ailments where the middle ear is accessible, but not affected, are examples of this situation. In infections of the middle ear the inner ear cannot easily be reached, and eardrops may be used. Aqueous preparations are then preferred, and the period of use should preferably not exceed 10 days.
It has been explained (Sect. 9.3.2) that the chance of passage of substances to the hearing organ is at the greatest when the middle ear is ‘clean and healthy’. Theoretically all active substances and excipients that can reach the middle ear and subsequently diffuse into the inner ear may be ototoxic. There are a few exceptions, like azole antimycotics that show no ototoxicity [13, 17].
There is discussion in literature [13, 18] on the seriousness of the ototoxicity of aminoglycosides (e.g. neomycin, gentamycin). In clinical practice ototoxicity is seldom seen [18], but loss of hearing has been reported [11]. In the treatment of some forms of external, otitis, omitting aminoglycosides may be more harmful than a short term treatment with this kind of antibiotic, as secretion of puss may also be ototoxic [18]. Fluoquinolones, mostly considered as a standby medication, are less ototoxic than aminoglycosides. In some parts of the world (USA, Australia) ear drops with fluoquinolones are commercially available. Where this is not the case, as in many European countries, eye drops with ofloxacin or ciprofloxacin are prescribed for use as ear drops.
Vehicles such as propylene glycol and macrogol (polyethylene glycol) not only are ototoxic, but they can also enhance the passage of their solutes through membranes. The longer substances are in contact with the middle or inner ear, the greater is the chance of damage. Shortening the period of contact may thus limit the risk.
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