Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-08
2001-10-02
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S912000, C514S913000
Reexamination Certificate
active
06297240
ABSTRACT:
DESCRIPTION
TECHNICAL FIELD
This invention relates to pharmaceutical compositions, a process for preparing such compositions and the use of such compositions for the treatment of ophthalmic diseases, particularly diseases caused by elevated intra-ocular pressure, such as ocular hypertension and glaucoma.
BACKGROUND OF THE INVENTION
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 &mgr;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.
SUMMARY OF THE INVENTION
According to the present invention there is therefore provided a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, an ophthalmologically active compound, characterized in that the composition is formulated to promote pre-gastric absorption of the ophthalmologically active compound.
The term “pre-gastric absorption” is used to refer to absorption of the active ingredient from that part of the alimentary canal prior to the stomach and includes buccal, sublingual, oropharyngeal and esophageal absorption.
It is envisaged that such pre-gastric absorption will occur primarily across the mucous membranes in the mouth, pharynx and oesophagus. Accordingly, it is preferred that the composition of the invention is formulated to promote absorption of the ophthalmologically active compound through the buccal, sublingual, pharyngeal and/or esophageal mucous membranes.
It is therefore preferred that the composition of the invention should be in a form which ensures contact of the active ingredient with the buccal, sublingual, pharyngeal and/or esophageal mucous membranes.
Preferably, the composition of the invention is in the form of a viscous emulsion, syrup or elixir, a sublingual tablet, a suckable or chewable tablet, softgel or lozenge, chewing gum, a laminated system or patch, hydrogel, adhesive film, hollow fiber, microsphere or other dosage form designed to release the active ingredient in a controlled manner to saliva or to the buccal, pharyngeal and/or esophageal mucous membranes, a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity, or a bioadherent system.
The term “bioadherent system” refers to a solid or liquid dosage form which, at body temperature, exhibits controlled release and bioadherence characteristics. This type of dosage form may be an emulsion which is water in oil in nature and whose internal phase is greater than that of the external phase. Examples of such bioadherent systems may be found in U.S. Pat. No. 5055303.
Active ingredients absorbed by such pre-gastric absorption pass straight into the systemic circulatory system thereby avoiding first pass metabolism in the liver. Accordingly, bioavailability of the active ingredient in this way may also be increased. This means that the dose of active ingredient may be minimized while still producing the desired beneficial effects and unwanted side-effects will therefore also be minimized.
It has been found that fast-dispersing dosage forms can promote pre-gastric absorption of the active ingredient. In addition, clinical studies have shown that such fast dispersing dosage forms, which disintegrate rapidly in the mouth, are easier for patients to take and easier for carers to administer.
One example of a fast-dispersing dosage form is described in U.S. Pat. No. 4855326 in which a melt spinnable carrier agent, such as sugar, is combined with an active ingredient and the resulting mixture spun into a “candy-floss” preparation. The spun “candy-floss” product is then compressed into a rapidly dispersing, highly porous solid dosage form.
U.S. Pat. No. 5120549 discloses a fast-dispersing matrix system which is prepared by first
Christus Daniel N.
Fay Zohreh
Nickey Donald O.
R.P. Scherer Limited
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