Ophthalmic medicines are most frequently formulated as ophthalmic treatment fluids which are commonly administered to the eye by means of eye drops or ointment. The use of eye drops has a number of disadvantages, primarily as a consequence of the difficulty with which drops are accepted by the patient. The drops are relatively large, and the instinctive blink that is provoked by the arrival of a drop on the eye severely limits the amount of or proportion of fluid that actually contacts the target area on the eye. Typically less than 10% of a 50 .mu.l drop is effective, the remainder being lost by drainage, either externally or through nasolacrimal drainage. Such use of expensive treatment fluids is wasteful, as well as leading to substantial uncertainty regarding the effectiveness of a treatment since the delivery of a drop of a particular size requires considerable manual dexterity. Similar problems apply in the use of ointments, although levels of wastage can be reduced by careful delivery and, the greater viscosity of ointments reduces their tendency to drain or be washed away.
Another problem is that ophthalmic dropper bottles are difficult to use with any degree of accuracy since the delivery of a drop of a particular size requires considerable manual dexterity. Also, it is difficult, if not impossible, for the patient to see where the eye drops are to be instilled. Consequently, underdosing or overdosing frequently occurs. Indeed, since the majority of patients suffering from glaucoma are over 70 years of age and may have other health problems such as stroke, poor vision, arthritis, poor physical coordination etc., the use of an ophthalmic dropper bottle is often not a viable option for such patients. This problem is further exacerbated by the fact that many such patients live alone and may have difficulty in obtaining help in the administration of their medication.
Additionally, eye drops typically incorporate preservatives to prevent growth of microorganisms. These preservatives can cause irritation to the eyes of some patients. The unit dose oral system obviates the requirement for these potentially irritant preservatives.
A further disadvantage of eye drops is that their extended use can have a deleterious effect on the outcome of later corrective surgery.
Some attempts have been made to administer certain ophthalmic medicines, such as certain beta-adrenoceptor blocking agents, orally in the form of conventional tablets. However, the ophthalmic therapeutic effect of such medicines tends to be significantly reduced by slow and/or incomplete absorption followed by presystemic metabolism of the active ingredient in the tissues of the small intestine and/or liver (the first pass effect). Also, such conventional oral administration tends to produce other effects associated with beta-adrenoceptor blocking agents, such as markedly reduced systemic blood pressure and pulse rate, which are undesirable in the treatment of glaucoma as optic nerve perfusion may be reduced.
A recent clinical study by Sadig and Vernon (British Journal of Ophthalmology, 1996, 80, 532-535) showed that an ophthalmic solution of timolol maleate produced a substantial reduction in intra-ocular pressure following sub-lingual administration. This reduction in intra-ocular pressure was seen in both eyes simultaneously and was comparable to the reduction in intra-ocular pressure achieved by topical application of the same formulation whereas topical administration produced a marked reduction in intra-ocular pressure only in the treated eye. The lowering of intra-ocular pressure in both eyes is usually desirable as diseases characterized by elevated intra-ocular pressure normally occur simultaneously in both eyes. However, small drops of aqueous formulation are not a convenient way by which to administer drugs sub-lingually, particularly for patients suffering from glaucoma, as it is difficult for the patient to see the area to which the drops must be delivered and, as discussed above, dropper bottles are difficult to use and do not deliver an accurate dose of is the active ingredient.
It is therefore apparent from the above that it would be highly desirable from a clinical perspective to find a way of administering ophthalmic medicines which is easy for the patient to accomplish, which ensures the delivery of an accurate unit dose and which provides for rapid systemic absorption without significant first pass metabolism so that the bioavailability of the active ingredient is enhanced.