Title:  Method for treating ophthalmic disease through fast dispersing dosage forms

United States Patent:  6,297,240

Assignee:  R.P. Scherer Limited (GB)

Filed:  February 8, 1999

Foreign Application Priority Data:  Aug 08, 1996[GB]  (9616672)

This invention relates to pharmaceutical compositions 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. A process for preparing such compositions and the use of such compositions for the treatment of ophthalmic diseases, particularly diseases caused by elevated intro-ocular pressure, such as ocular hypertension and glaucoma, are also provided.

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 solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix-forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix.

U.S. Pat. No. 5079018 discloses a fast-dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0^oC. or below to leave spaces in place of hydration liquid.

Published International Application No. WO 93/12769 (PCT/JP93/01631) describes fast-dispersing dosage forms of very low density formed by gelling, with agar, aqueous systems containing the matrix-forming elements and active ingredient, and then removing water by forced air or vacuum drying.

U.S. Pat. No. 5298261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.

Published International Application No. WO 91/04757 (PCT/US90/05206) discloses fast-dispersing dosage forms which contain an effervescent disintegration agent designed to effervesce on contact with saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity.

The term "fast-dispersing dosage form" therefore encompasses all the types of dosage form described in the preceding paragraphs. However, it is particularly preferred that the fast-dispersing dosage form is of the type described in U.K. Patent No. 1,548,022, that is, a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water-dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.

It is preferred that the composition of the invention disintegrates within 1 to 60 seconds, more preferably 1 to 30 seconds, particularly 1 to 10 seconds and especially 2 to 8 seconds, of being placed in the oral cavity.

In the case of the preferred type of fast-dispersing dosage form described above, the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components. Matrix forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes.

Other matrix forming agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.

One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification. The matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant. In addition to forming the matrix, the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution or suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.

Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the composition. Suitable coloring agents include red, black and yellow iron oxides and FD & C dyes such as FD & C blue No. 2 and FD & C red No. 40 available from Ellis & Everard. Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations of these. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatic. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives.

Suitable ophthalmologically active compounds that may be utilized in the composition of the invention include anti-glaucoma/intra-ocular pressure lowering compounds such as:

a) alpha-adrenoceptor blocking agents, e.g. apraclonidine, brimonidine, AGN 192836, AGN 193080, etc.

b) beta-adrenoceptor blocking agents, e.g. carteolol, betaxolol, levobunolol, metipranolol, timolol, vaninolol, adaprolol, etc.

c) Miotics, e.g. pilocarpine, carbachol, physostigmine, etc.

d) Sympathomimetics, e.g. adrenaline, dipivefrine, etc.

e) Carbonic anhydrase inhibitors, e.g. acetazolamide, dorzolamide, etc., and

f) Prostaglandins, e.g. PGF-2 alpha or its prodrug latanoprost.

The above compounds may be in the form of free acids or bases or alternatively as salts of these. Combinations of compounds e.g. a beta-adrenoceptor blocking agent with a prostaglandin may be desirable for the optimization of therapy in some instances. The compounds may be formulated as aqueous or non-aqueous (e.g. oil) solutions or suspensions for incorporation into the fast-dispersing dosage form of the invention. Formulations may optionally contain other formulation excipients, for example, mucoadhesives and polymers.

The composition of the invention is particularly suitable for the oral administration of agents for the reduction of intra-ocular pressure. Beta-adrenoceptor blocking agents are the primary therapeutic regimen for the treatment of diseases caused by elevated intra-ocular pressure, such as ocular hypertension and glaucoma, although alpha-adrenoceptor blocking agents have also been used in such treatment. Accordingly, it is preferred that the agent for the reduction of intra-ocular pressure is an alpha-adrenoceptor blocking agent or a beta-adrenoceptor blocking agent and, of these, beta-adrenoceptor blocking agents are particularly preferred.

Beta-adrenoceptor blocking agents lower intra-ocular pressure by reducing the rate of production of aqueous humour, the fluid present in the anterior chamber of the eyeball, and they do this by blocking beta-adrenoceptors in the iris-cilary body.

At present, all beta-adrenoceptor blocking agents used to treat elevated intra-ocular pressure are administered topically to the eye as sterile ophthalmic solutions. Following topical administration, there are four possible mechanisms by which beta blockers could reach their receptor targets: (1) transcorneal diffusion; (2) scleral diffusion; (3) re-absorption from the local vasculature and (4) re-absorption from the systemic circulation. It has traditionally been assumed that transcorneal diffusion is the most important of these mechanisms. However, the work of Sadiq and Vernon (British Journal of Ophthalmology, 1996, 80, 532-535) referred to earlier suggests that, at least for timolol, this assumption may be incorrect as therapeutically active concentrations reached the iris-cilary body following re-absorption from the systemic circulation after sublingual application of an ophthalmic solution of timolol maleate. However, as discussed above, small drops of aqueous formulation are not a convenient way to administer drugs sub-lingually as, not only is it difficult for the patient to deliver the drops to an area which is not clearly visible to the patient, but it is also difficult for the patient to deliver accurate reproducible quantities of the aqueous formulation using a dropper bottle. Accordingly, it is preferred that beta-adrenoceptor blocking agents be incorporated into a single unit dosage form of the type described above which can be easily introduced into the oral cavity and contains an accurately defined dose of the active ingredient.

Suitable beta-adrenoceptor blocking agents include propranolol, acebutolol, alprenolol, atenolol, betaxolol, bufetolol, bufuralol, bunitrolol, bunolol, bupranolol, carteolol, cetamolol, dexpropranolol, labetalol, levobunolol, metipranolol, metoprolol, nadolol, nifenalol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, sotalol, timolol, tolamolol and toliprolol and pharmaceutically acceptable salts thereof. Of these, propranolol, atenolol, betaxolol, bupranolol, carteolol, levobunolol, metipranolol, metoprolol, nadolol, pindolol and timolol and pharmaceutically acceptable salts thereof are preferred and betaxolol, carteolol, levobunolol; metipranolol and timolol and pharmaceutically acceptable salts thereof are particularly preferred. Timolol or a pharmaceutically acceptable salt thereof, especially the maleate, is especially preferred.

The precise quantity of active ingredient will depend on the beta-adrenoceptor blocking agent chosen but will preferably be in the range of 10 to 2000 .mu.g. However, it should be noted that the quantity of the beta-adrenoceptor blocking agent required for ophthalmic treatment is much less than is required for other indications, such as anti-hypertensive applications. For instance, in the case of timolol or a pharmaceutically acceptable salt thereof, this may be present for ophthalmic applications in an amount of 10 to 1000 .mu.g, preferably 50 to 800 .mu.g and especially 100 to 600 .mu.g. The preferred dosage range for timolol maleate is 100 .mu.g to 400 .mu.g, more preferably 150 .mu.g to 380 .mu.g. In the case of timolol in the form of the free base, the preferred dosage range is 100 .mu.g to 300 .mu.g, especially 125 .mu.g to 250 .mu.g. If timolol is used in the form of the free base, it is preferred that this is incorporated into an oil solution before this is, in turn, incorporated into a fast-dispersing dosage form according to the invention. This is in contrast to conventional applications where timolol is used as a non-cardioselective beta blocker at a typical dose of 10 mg.

According to another aspect of the invention there is provided a composition as defined above for use in the treatment of ophthalmic diseases such as diseases caused by elevated intra-ocular pressure and, in particular, ocular hypertension or glaucoma.

According to a further aspect of the invention there is provided a pharmaceutical composition as defined above which comprises bringing a carrier into association with the active ingredient.

The use of a composition for the manufacture of a medicament for the treatment of ophthalmic diseases, such as diseases caused by elevated intra-ocular pressure and, in particular, ocular hypertension or glaucoma, is also provided.

As a further aspect of the invention, there is also provided a method of treating ophthalmic diseases, such as diseases caused by elevated intra-ocular pressure and, in particular, ocular hypertension or glaucoma, which comprises administering a therapeutically effective amount of a composition as defined above to a patient suffering from any of the aforesaid diseases.

Claim 1 of 10 Claims

I claim:

1. A method of treating ophthalmic diseases comprising the steps of:

a) preparing a fast dispersing dosage form which disintegrates within 1 to 60 seconds of being placed in the oral cavity by subliming solvent from a solid composition comprising an ophthalmologically active compound, a solvent and a water soluble or water dispersable carrier which is inert towards the active compound; and

b) orally administering said fast dispersing dosage form composition to a patient.

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