FOR TREATING OPHTHALMIC AND SYSTEMIC DISEASES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application 63/302,384, filed January 24, 2022, which is incorporated by reference herein in its entirety.

BACKGROUND

[0002] Elevated intraocular pressure can damage the optic nerve resulting in loss of vision or blindness. Glaucoma and ocular hypertension are treated by administration of therapeutics which decrease intraocular pressure. Beta-blockers, such as timolol, are used to treat elevated intraocular pressure. Carbonic anhydrase inhibitors are used to treat elevated intraocular pressure. To control intraocular pressure, such drugs are administered over time. These drugs are most often applied topically in the form of drops, gels or ointments to the eyes. Systemic administration is less preferred due to possible systemic side effects of the drugs administered. While a number of therapeutics for controlling intraocular pressure are known, for many patients control of intraocular pressure cannot be maintained over the long-term due to loss of efficacy and/or undesirable adverse events, which leads ultimately to surgery. Thus, there remains a significant need for different drug therapies for treating and controlling high intraocular pressure.

[0003] Medicaments for treating elevated intraocular pressure are typically applied topically. Topical administration to the eye in the form of drops, ointment, gel, or cream has disadvantages with respect to the efficiency of application, accuracy of application, difficulty with self-administration and generally with patient compliance. Ocular surface adverse events are also common with topical therapeutics including redness, stinging, itching and disruption of the tear film. There is a significant need for treatments that avoid the negative impacts of topical and systemic delivery.

[0004] U.S. patent 6,297,240 relates to methods of treatment of ophthalmic disease using fast-dispersing dosage forms. The compositions are reported to be formulated to promote pre- gastric absorption of the ophthalmologically active compound. The patent refers to preparing a fast dispersing dosage form by subliming solvent from a solid composition comprising an ophthalmologically active compound, a solvent and a water-soluble or water-dispersible carrier that is inert towards the active compound. The patent reports dispersion of active ingredient into an aqueous gelatin/mannitol mixture followed by freeze-drying to form a solid dosage form. A 250 microgram timolol maleate dosage unit is reported. The patent also reports application of an ethanol solution of active ingredient to a gelatin/mannitol freeze-dried solid followed by evaporation of ethanol to form a solid dosage form. A 175 microgram tin unit is reported.

[0005] U.S. 5,888,534 relates to a composition providing a relatively slow release of water- soluble drugs, such as apomorphine, for delivery via the sublingual or buccal routes. The patent reports compositions having a T90 value (90% by weight release of active) in the range of more than about 25 minutes to about 300 minutes. Examples of preferred sublingual dosage forms are given. Timolol maleate is noted therein to be a water-soluble drug.

[0006] U.S. 7,906,140 relates to compositions for mucosal delivery of agents. The compositions are reported to contain one or more mucoadhesive proteins and an agent to be delivered.

[0007] U.S. 20030235617 relates to pharmaceutical compositions for intraoral administration for delivery via the oral mucosa. More specifically, the patent relates to a tablet having an intraorally disintegrable core and a coating comprising gellan gum.

[0008] U.S. 20080226717 relates to a sublingual coated tablet consisting of a compressed core devoid of active ingredient and comprising one or more diluting agents and a coating comprising an active ingredient.

[0009] CN 106924200 reports a dispersible tablet containing acetazolamide. The tablet is reported to contain 65-75 parts of acetazolamide, 1-5 parts of disintegrant, 0.5-1.2 parts of lubricant, 20-26 parts of filler, PVP 1-3 parts and 0.2-0.6 parts of lauryl sodium sulfate. The disintegrant is reported to be a mixture of sodium carboxymethyl starch, konjaku powder and Na- bentonite. Delivery to the oral mucosa is not described in the document.

[0010] CN 1704054 reports a dispersible tablet containing acetazolamide. The tablet is reported to contain (by weight): acetazolamide 70-80 wt%, carboxymethyl starch sodium 3.0-5.5 wt%, microcrystalline cellulose 15-21 wt%, magnesium stearate 0.5-1.0wt%, sodium lauryl sulfate 0.1-0.5 wt% and polyvinylpyrrolidone 1.0-3.0 wt%. Delivery to the oral mucosa is not described in the document.

[0011] S.A. Sadig & S.A. Vernon (1996) “Sublingual timolol-an alternative to topical medication in glaucoma?” Br. J. Ophthalmol. June 80(6):532-535 relates to the assessment of sublingual administration of timolol eye drops to lower raised intraocular pressure.

SUMMARY

[0012] The inventors have discovered, inter alia, that mucosal dosage forms that allow administration through the oral mucosa avoid many of the negative impacts of topical delivery and also largely decrease or avoid the problems of systemic administration for many indications, including but not limited to, ophthalmic indications including elevated intraocular pressure.

[0013] The invention provides a method for treating ophthalmic disease which comprises administering an effective amount of one or more beta-adrenergic blocking agent (beta-blocker) to a subject in need of such treatment, wherein the effective amount of o adrenergic blocking agent (beta- blocker) is formulated for oral mucosal delivery. In more specific embodiments, the one or more beta blocker is formulated in a solid dosage form for sublingual or buccal administration. In more specific embodiments, the effective amount of one or more betablocker is formulated as a disintegrable oral dosage form, such as a disintegrable tablet. In specific embodiments, disintegrable tablets comprising one or more beta-blockers disintegrate within 1 to 60 seconds, 5 to 60 seconds, or 10 to 30 seconds after oral administration. In related embodiments, the effective amount of one or more beta-blockers are formulated in a film that dissolves on contact with the oral mucosa. In specific embodiments, the films dissolve within 30 seconds to 2 hours after contact with the oral mucosa. In related specific embodiments, the one or more films dissolve within 10 seconds to 10 minutes after contact with the oral mucosa. In related embodiments, the one or more beta-blocker are formulated in liquid form, for example as a solution or suspension, in a suitable pharmaceutically acceptable solvent, such as water or a buffered aqueous solution, to be administered as drops or a spray for oral mucosal delivery.

[0014] In more specific embodiments, the effective amount of one or more beta-blocker in the dosage form for delivery to the oral mucosa ranges from 0.1 to 20 mg. In more specific embodiments, the effective amount of one or more beta-blocker in the dosage form for delivery to the oral mucosa ranges from 1 to 7.5 mg. In more specific embodiments, the effective amount of one or more beta-blocker in the dosage form for delivery to the oral mucosa ranges from 2 to 6 mg. In more specific embodiments, the effective amount of one or more carbonic anhydrase inhibitor ranges from 2.5 to 5 mg (+/-10%).

[0015] The invention further provides a method for treating ophthalmic disease which comprises administering an effective amount of one or more carbonic anhydrase inhibitor (CAI) to a subject in need of such treatment, wherein the effective amount of one or more carbonic anhydrase inhibitor (CAI) is formulated for oral mucosal delivery. In more specific embodiments, the one or more CAI is formulated in a solid dosage form for sublingual or buccal administration. In more specific embodiments, the effective amount of one or more CAI is formulated as a disintegrable oral dosage form, such as a disintegrable tablet. In more specific embodiments, disintegrable tablets comprising one or more CAI disintegrate within 1 to 60 seconds, 5-60 seconds, or 10-30 seconds after oral administration. In related embodiments, the effective amount of one or more CAI is formulated in a film that dissolves on contact with the oral mucosa. In specific embodiments, the film dissolves within 30 seconds to 2 hours after contact with the oral mucosa. In related specific embodiments, the one or more films dissolves within 10 seconds to 10 minutes after contact with the oral mucosa. In related embodiments, the one or more CAI are formulated in liquid form, for example as a solution or suspension, in a suitable pharmaceutically acceptable solvent, such as water or a buffered aqueous solution, to be administered as drops or a spray for oral mucosal delivery. [0016] In more specific embodiments, the effective amount of one dosage form for delivery to the oral mucosa ranges from 5 to 500 mg. In more specific embodiments, the effective amount of one or more CAI in the dosage form for delivery to the oral mucosa ranges from 10 to 250 mg. In more specific embodiments, the effective amount of one or more CAI in the dosage form for delivery to the oral mucosa ranges from 15 to 100 mg. In more specific embodiments, the effective amount of one or more carbonic anhydrase inhibitor in dosage form for delivery to the oral mucosa ranges from 20 to 60 mg. In more specific embodiments, the effective amount of one or more carbonic anhydrase inhibitor ranges from 25 to 50 mg (+/-10%).

[0017] The invention also provides a method for treating ophthalmic disease which comprises administering a combined effective amount of one or more beta-adrenergic blocking agent (beta-blocker), and one or more carbonic anhydrase inhibitor (CAI) to a subject in need of such treatment. Most generally, the combination therapy is formulated for any suitable form of delivery, including but not limited to, topical application to the eye or oral administration. In preferred embodiments, however, the one or more beta-adrenoceptor blocking agent and the one or more carbonic anhydrase inhibitor are both formulated for oral mucosal delivery.

[0018] In various embodiments herein, the ophthalmic disease exhibits high intraocular pressure that is lowered by treatment. In various embodiments, the ophthalmic disease exhibits high intraocular pressure that is lowered by treatment and the lowered intraocular pressure is maintained with continued treatment. In various embodiments, ophthalmic disease is ocular hypertension or any form of glaucoma or pre-glaucoma.

[0019] In embodiments for combination therapy, the one or more beta-adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated together. In related embodiments, the one or more beta-adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated together for sublingual or buccal administration.

[0020] In embodiments for combination therapy, the one or more beta-adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated separately and administered within 24 hours of each other. In related embodiments, the one or more beta- adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated separately and administered within 1 to 2 hours of each other. In additional embodiments, the one or more beta-adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated separately and administered at the same time, within 5 minutes. In additional embodiments, the one or more beta-adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated separately for sublingual or buccal administration and administered within 24 hours of each other. In additional embodiments, the one or more beta- adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated separately for sublingual or buccal administration and administered within 1 to 2 hours of each other. In additional embodiments, the one or more beta-adrenergic blocl or more carbonic anhydrase inhibitor are formulated separately for sublingual or buccal administration and administered at the same time, within 5 minutes of each other.

[0021] In various embodiments herein, the one or more beta-adrenergic blocking agent comprises timolol or a pharmaceutically acceptable salt or solvate thereof. In more specific embodiments, the one or more beta-adrenergic blocking agent is timolol or a pharmaceutically acceptable salt or solvate thereof. In more specific embodiments, the one or more beta- adrenergic blocking agent is timolol maleate. In more specific embodiments, the one or more beta-adrenergic blocking agent is timolol hemihydrate. In more specific embodiments, the one or more carbonic anhydrase inhibitor comprises methazolamide or acetazolamide or salts or solvates thereof. In more specific embodiments, the one or more carbonic anhydrase inhibitor is methazolamide or acetazolamide. In more specific embodiments, the one or more carbonic anhydrase inhibitor is methazolamide. In more specific embodiments, the one or more carbonic anhydrase inhibitor is acetazolamide. In various embodiments herein, carbonic anhydrase inhibitors include those that are methazolamide salts or solvates or acetazolamide salts or solvates.

[0022] In various embodiments herein, the one or more carbonic anhydrase inhibitor is methazolamide or a salt or solvate thereof and the one or more beta-adrenergic blocking agent is timolol or a pharmaceutically acceptable salt or solvate thereof. In various embodiments herein, the one or more carbonic anhydrase inhibitor is methazolamide or a salt or solvate thereof and the one or more beta-adrenergic blocking agent is timolol maleate. In more specific embodiments, the one or more carbonic anhydrase inhibitor is methazolamide or a salt or solvate thereof and the one or more beta-adrenergic blocking agent is timolol hemihydrate. In more specific embodiments, the one or more carbonic anhydrase inhibitor is acetazolamide or a salt or a solvate thereof and the one or more beta-adrenergic blocking agent is timolol or a pharmaceutically acceptable salt or solvate thereof. In more specific embodiments, the one or more carbonic anhydrase inhibitor is acetazolamide or a salt or a solvate thereof and the one or more beta-adrenergic blocking agent is timolol maleate. In more specific embodiments, the one or more carbonic anhydrase inhibitor is acetazolamide or a salt or a solvate thereof and the one or more beta-adrenergic blocking agent is timolol hemihydrate.

[0023] In embodiments for combination therapy, the one or more beta-adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated separately or together in the form of disintegrable oral dosage form(s) for combined treatment. In embodiments, the one or more beta-adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated separately or together in the form of one or two disintegrable tablets. In specific embodiments, disintegrable tablets disintegrate within 1 to 60 seconds, 5-60 seconds, or 10-30 seconds after oral administration. [0024] In embodiments for combination therapy, the one or more t agent and the one or more carbonic anhydrase inhibitor are formulated separately or together in the form of one or two films that dissolve on contact with the oral mucosa. In embodiments, the one or more films dissolve within 30 seconds to 2 hours after contact with the oral mucosa. In embodiments, the one or more films dissolve within 10 seconds to 10 minutes after contact with the oral mucosa.

[0025] In embodiments for combination therapy, the one or more beta-adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated separately or together for topical application to the eye.

[0026] In embodiments for combination therapy, the one or more beta-adrenergic blocking agent and the one or more carbonic anhydrase inhibitor are formulated separately or together in liquid form, for example as a solution or suspension in a suitable pharmaceutically acceptable solvent, such as water or a buffered aqueous solution, to be administered as drops or a spray or oral mucosal delivery.

[0027] The invention also provides a pharmaceutical composition comprising one or more beta-adrenergic blocking agent and one or more carbonic anhydrase inhibitor formulated together with a pharmaceutically acceptable carrier in a single dosage form for administration to the oral mucosa. In embodiments, the carrier is a liquid or a solid. In embodiments, the single dosage form is for sublingual or buccal administration. In embodiments, the single dosage form is a disintegrable tablet. In embodiments, the single dosage form is a film that dissolves on contact with the oral mucosa. In embodiments, the single dosage form is a liquid solution or suspension to be administered to the oral mucosa in the form of one or more drops or a spray. [0028] In embodiments of the single-dosage form, the weight ratio of total beta-adrenergic blocking agent(s) to total carbonic anhydrase inhibitor(s) formulated together in the pharmaceutical composition ranges from 50:1 to 1 :50. In related embodiments, the weight ratio of total beta-adrenergic blocking agent(s) to total carbonic anhydrase inhibitor(s) formulated together in the composition ranges from 10:1 to 1 :10. In further embodiments, the weight ratio of total beta-adrenergic blocking agent(s) to total carbonic anhydrase inhibitor(s) formulated together in the composition ranges from 01: 20 to 1 :5. In further embodiments, the weight ratio of total beta-adrenergic blocking agent(s) to total carbonic anhydrase inhibitor(s) formulated together in the composition ranges from 0.9:10 to 1.1:10. In related embodiments, the total amount of beta-adrenergic blocking agent(s) in the single dosage form ranges from 0.1 to 20 mg and the total amount of carbonic anhydrase inhibitor(s) in the single dosage form ranges from 1 to 75 mg. In more specific embodiments, the total amount of beta-adrenergic blocking agent(s) in the single dosage form ranges from 1 to 7.5 mg and the total amount of carbonic anhydrase inhibitor(s) in the single dosage form ranges from 10 to 60 mg. In embodiments, the total amount of beta-adrenergic blocking agent(s) in the single dosage form ranges from 1 to 6 mg and the total amount of carbonic anhydrase inhibitor(s) in the single dosage form mg. In embodiments, the total amount of beta-adrenergic blocking agent(s) in the single dosage form ranges from 2 to 6 mg and the total amount of carbonic anhydrase inhibitor(s) in the single dosage form ranges from 20 to 55 mg. In embodiments, the total amount of beta-adrenergic blocking agent(s) in the single dosage form ranges from 2.5 to 5 mg (+/-10%) and the total amount of carbonic anhydrase inhibitor(s) in the single dosage form ranges from 25 to 50 mg (+/- 10%). In embodiments, the single dosage form is a disintegrable tablet. In embodiments, the single dosage form is a rapidly disintegrating tablet suitable for sublingual or buccal administration. In embodiments, the single dosage form is a liquid solution or a suspension comprising the active ingredients for administration to the eye or to the oral mucosa as one or more drops or a spray.

[0029] In embodiments of the single dosage form, the one or more beta-adrenergic blocking agent is timolol or a pharmaceutically acceptable salt or solvate thereof and the amount of timolol or pharmaceutically acceptable salt or solvate thereof in the single dosage form ranges from 0.3 to 5 mg on the basis of timolol maleate. In embodiments, the one or more carbonic anhydrase inhibitor is methazolamide and the amount of methazolamide in the single dosage form ranges from 1 to 7.5 mg. In embodiments, the one or more carbonic anhydrase inhibitor is acetazolamide and the amount of acetazolamide in the single dosage form ranges from 4 to 35 mg. Salts and solvates of methazolamide can be employed in place of methazolamide. Salts and solvates of acetazolamide can be employed in place of acetazolamide.

[0030] In embodiments, the weight ratio of total beta-adrenergic blocking agent(s) to total carbonic anhydrase inhibitor(s) formulated separately in two separate pharmaceutical compositions ranges from 50:1 to 1 :50. In embodiments, the weight ratio of total beta-adrenergic blocking agent(s) to total carbonic anhydrase inhibitor(s) formulated separately ranges from 10:1 to 1 :10. In embodiments, the total amount of beta-adrenergic blocking agent(s) in a separate dosage form ranges from 0.3 to 20 mg and the total amount of carbonic anhydrase inhibitor(s) in a separate dosage form ranges from 1 to 50 mg. In embodiments, the separate dosage forms are disintegrable tablets. In embodiments, the separate dosage forms are rapidly disintegrating tablets suitable for sublingual or buccal administration. In embodiments, the one or more beta- adrenergic blocking agent is timolol or a pharmaceutically acceptable salt or solvate thereof and the amount of timolol or pharmaceutically acceptable salt or solvate thereof in the separate dosage form ranges from 0.3 to 5 mg on the basis of timolol maleate. In embodiments, the one or more carbonic anhydrase inhibitor is methazolamide and the amount of methazolamide in the separate dosage form ranges from 1 to 7.5, 10 to 75, or 25 to 50 (+/-10%) mg. In embodiments, the one or more carbonic anhydrase inhibitor is acetazolamide and the amount of acetazolamide in the separate dosage form ranges from 4 to 40, 50 to 400 or 100 to 500 (+/- 10%) mg. [0031] In embodiments for combination therapy, the pharmaceutic dosage form comprising one or more beta-blocker and one or more Cl. In embodiments, the pharmaceutical composition is a solid dosage form comprising one or more beta-blocker and one or more Cl. In embodiments, the pharmaceutical composition is a disintegrable tablet which comprises one or more disintegrant. In embodiments, the disintegrant is a superdisintegrant. In embodiments, the disintegrant is a combination of two or more disintegrants. In embodiments, the disintegrant is a combination of a conventional disintegrant and a superdisintegrant. In embodiments, the pharmaceutical composition or dosage form further comprises one or more of a filler, binder, lubricant, glidant (flow-aid), or anti-adherent. In embodiments, the pharmaceutical composition or dosage form comprising one or more of a stablilizer, preservative, coloring agent or flavoring agent.

[0032] In embodiments, the pharmaceutical composition or dosage form is coated or uncoated. In embodiments, the pharmaceutical composition or dosage form is uncoated. [0033] In additional embodiments, the invention provides a pharmaceutical composition or dosage form, which comprises a beta-blocker or a pharmaceutically acceptable salt or solvate thereof, formulated in the form of a disintegrable tablet for administration to the oral mucosa. In embodiments, the invention provides a pharmaceutical composition or dosage form, which comprises a beta-blocker or a pharmaceutically acceptable salt thereof as the only therapeutically active ingredient therein formulated in the form of a disintegrable tablet for administration to the oral mucosa. In additional embodiments, the invention provides a pharmaceutical composition or dosage form, which comprises timolol or a pharmaceutically acceptable salt or solvate thereof, such as timolol maleate or timolol hemihydrate, formulated in the form of a disintegrable tablet for administration to the oral mucosa. In embodiments, the invention provides a pharmaceutical composition or dosage form, which comprises timolol or a pharmaceutically acceptable salt or solvate thereof as the only active therapeutically ingredient therein formulated in the form of a disintegrable tablet for administration to the oral mucosa. In embodiments, the disintegrable tablet is formulated for sublingual or buccal administration. In embodiments, the pharmaceutical composition or dosage form comprises one or more disintegrant. In embodiments, the pharmaceutical composition or dosage form comprises one or more superdisintegrant. In embodiments, the pharmaceutical composition or dosage form comprises a combination of a conventional disintegrant with a superdisintegrant. In embodiments, the pharmaceutical composition or dosage form comprises one or more of a filler, binder, lubricant, glidant, or anti-adherent. In embodiments, the pharmaceutical composition or dosage form comprises one or more of a stablilizer, preservative, coloring agent or flavoring agent. In embodiments, the pharmaceutical composition or dosage form is in the form of a coated tablet or pill. In embodiments, the pharmaceutical composition or dosage form is in the form of an uncoated tablet or film. [0034] In additional embodiments, the invention provides a pharm; dosage form, which comprises a CAI and which is formulated for oral mucosal administration, preferably in the form of a disintegrable tablet for administration to the oral mucosa. In embodiments, the invention provides a pharmaceutical composition or dosage form, which comprises a CAI as the only therapeutically active ingredient therein and which is formulated for oral mucosal administration, preferably in the form of a disintegrable tablet for administration to the oral mucosa. In additional embodiments, the invention provides a pharmaceutical composition or dosage form, which comprises methazolamide and which is formulated for oral mucosal administration, preferably in the form of a disintegrable tablet for administration to the oral mucosa. In embodiments, the invention provides a pharmaceutical composition or dosage form, which comprises methazolamide as the only therapeutically active ingredient therein and which is formulated for oral mucosal administration, preferably in the form of a disintegrable tablet for administration to the oral mucosa. In additional embodiments, the invention provides a pharmaceutical composition or dosage form, which comprises acetazolamide or a salt or solvate thereof and which is formulated for oral mucosal administration, preferably in the form of a disintegrable tablet for administration to the oral mucosa. In embodiments, the invention provides a pharmaceutical composition or dosage form, which comprises acetazolamide or a salt or solvate thereof can be employed as the only active ingredient therein and which is formulated for oral mucosal administration, preferably in the form of a disintegrable tablet for administration to the oral mucosa. In embodiments, the disintegrable tablet is formulated for sublingual or buccal administration. In embodiments, the pharmaceutical composition or dosage form comprises one or more disintegrant. In embodiments, the pharmaceutical composition or dosage form comprises one or more superdisintegrant. In embodiments, the pharmaceutical composition or dosage form comprises a combination of a conventional disintegrant with a superdisintegrant. In embodiments, the pharmaceutical composition or dosage form comprises one or more of a filler, binder, lubricant, glidant, or anti-adherent. In embodiments, the pharmaceutical composition or dosage form comprises one or more of a stablilizer, preservative, coloring agent or flavoring agent. In embodiments, the pharmaceutical composition or dosage form is in the form of a coated tablet or pill. In embodiments, the pharmaceutical composition or dosage form is in the form of an uncoated tablet or film.

[0035] The invention also provides a method of making an oral mucosal dosage form which contains one or more beta-blockers, one or more CAI or a combination of one of more beta-blockers and one or more CAI. In specific embodiments, the oral mucosal dosage form is a solid. In specific embodiments, the oral mucosal dosage is a disintegrable tablet. In specific embodiments, the disintegrable tablet is formed by direct compression, mass extrusion, flash melting with spinning (cotton candy process) or melt granulation. In embodiments, the disintegrable tablet is formed by a process including at least one step of lyophilization, spray drying or sublimation. The invention provides a method for making an or comprising one or more beta-blockers, one or more CAI or a combination of one of more betablockers and one or more CAI for use in the treatment of ophthalmic disease, particularly for treating elevated intraocular pressure and more particularly for treating glaucoma.

[0036] In related embodiments, improved dosage forms for oral mucosal administration of beta-blockers or for oral mucosal administration of a CAI are provided and these improved dosage forms can be employed for the treatment of ophthalmic disease as well as disorders and conditions other than ophthalmic disease. In embodiments, these improved formulations for oral mucosal administration are useful for the treatment of elevated intraocular pressure. In embodiments, these improved formulations for oral mucosal administration are used to treat other disorders that can be treated with one or more beta-blocker, including anxiety, high blood pressure and migraines. In other embodiments, these improved formulations for oral mucosal administration are used to treat other disorders that can be treated with one or more CAI, including high altitude sickness and macular edema (diabetic or otherwise). Thus, the invention provides methods of treating anxiety, essential tremor, heart failure, high blood pressure and migraines or treating high altitude sickness and macular edema (diabetic or otherwise) employing these improved formulations. The invention provides methods for treating cystoid macular edema and retinal diseases that are associated with accumulation of fluid and/or blood, such as diabetic retinopathy and macular degeneration. The invention further provides a method for making a dosage form containing a beta-blocker for oral mucosal administration, particularly sublingual or buccal administration that is useful for treating anxiety, high blood pressure and migraines. The invention further provides a method for making a dosage form containing a CAI for oral mucosal administration, particularly sublingual or buccal administration that is useful for treating obesity, high altitude sickness and macular edema.

[0037] The invention also provides pharmaceutical compositions for use for treatment of ophthalmic disease, particular elevated intraocular pressure and more particularly, glaucoma. Such compositions include those formulated for oral mucosal administration and more particularly for sublingual and/or buccal administration. Such compositions include disintegrable tablets and other solid dosage forms and in particular rapidly disintegrable tablets and other solid dosage forms. In embodiments, these pharmaceutical compositions comprise one or more betablockers. In other embodiments, these pharmaceutical compositions comprise one or more CAI. In embodiments for combination therapy, these pharmaceutical compositions comprise one or more beta-blockers in combination with one or more CAI.

[0038] The invention also provides pharmaceutical compositions for use in the manufacture of a medicament for treatment of ophthalmic disease, particular elevated intraocular pressure and more particularly, glaucoma. Such compositions include those formulated for oral mucosal administration and more particularly for sublingual and/or buccal administration. Such compositions include disintegrable tablets and other solid dosage forms . disintegrable tablets and other solid dosage forms. In embodiments, these pharmaceutical compositions comprise one or more beta-blockers. In other embodiments, these pharmaceutical compositions comprise one or more CAI. In embodiments for combination therapy, these pharmaceutical compositions comprise one or more beta-blockers in combination with one or more CAI.

[0039] Improved solid dosage forms for oral mucosal delivery of one or more beta-blocker are provided. In embodiments, these improved dosage forms provide improvement in rate of disintegration or release of therapeutically active ingredient, or an improvement in lowering the dosage of the therapeutically active ingredient or an improvement in structure of the solid dosage form, e.g., suitable hardness, increased shelf-life, decreased hygroscopicity, or the like. In embodiments, improved dosage forms for mucosal delivery can employ dosage amounts of the one or more beta blocker and/or one or more CAI that are 10% or more less that analogous oral dosage forms. In embodiments, improved dosage forms for mucosal delivery can employ dosage amounts of the one or more beta blocker and/or one or more CAI that are 25% or more less that analogous oral dosage forms. In embodiments, improved dosage forms for mucosal delivery can employ dosage amounts of the one or more beta blocker and/or one or more CAI that are 50% or more less that analogous oral dosage forms. The invention provides for the use of such improved dosage forms for the treatment of ophthalmic disease, particular elevated intraocular pressure and more particularly, glaucoma. The invention provides for the use of such improved dosage forms for manufacture of a medicament for treatment of ophthalmic disease, particular elevated intraocular pressure and more particularly, glaucoma.

[0040] The invention further provides pharmaceutical compositions for use for treatment of anxiety, essential tremor, high blood pressure, heart failure and migraines. The invention further provides pharmaceutical compositions for use for the manufacture of a medicament for the treatment of anxiety, essential tremor, high blood pressure, heart failure and migraines. The compositions contain a beta-blocker and more specifically contain timolol or timolol maleate. The compositions are for oral mucosal administration and are preferably solid dosage forms for sublingual or buccal administration. Preferred compositions are in the form of disintegrable tablets or rapidly disintegrable tablets.

[0041] The invention further provides pharmaceutical compositions for use for treatment of obesity, high altitude sickness and macular edema. The invention further provides pharmaceutical compositions for use for the manufacture of medicaments for treatment of obesity, high altitude sickness and macular edema. The compositions contain a CAI and more specifically contain acetazolamide and/or methazolamide or a salt or solvate thereof. The compositions are for oral mucosal administration and are preferably solid dosage forms for sublingual or buccal administration. Preferred compositions are in the fo tablets or rapidly disintegrable tablets.

[0042] In embodiments herein of pharmaceutical compositions that contain one or more carbonic anhydrase inhibitor, the administration of the composition or dosage form is accompanied by electrolyte supplementation, particularly supplementation with potassium and/or magnesium and more specifically with potassium supplementation. Electrolyte supplementation can be provided in the form of an appropriate aqueous solution containing potassium and/or magnesium. Alternatively, electrolyte supplementation can be provided by inclusion of an appropriate amount of a potassium salt and/or magnesium slat in a solid dosage form for oral mucosal delivery. Such electrolyte solutions may also contain sodium in an amount appropriate for electrolyte supplementation. In specific embodiments, potassium supplementation is combined with administration of pharmaceutical compositions or dosage forms herein that contain one or more carbonic anhydrase inhibitors. In a more specific embodiment, solid dosage forms for oral mucosal delivery herein that contain one or more carbonic anhydrase inhibitors also contain an amount of a potassium salt and/or a magnesium salt effective for electrolyte supplementation. In more specific embodiments, solid dosage forms for oral mucosal delivery herein that contain acetoazolamide further contain a potassium salt and/or a magnesium salt in an amount effective for electrolyte supplementation.

[0043] In embodiments, any pharmaceutical composition or dosage form herein in tablet or pill form, the tablet or pill is colored, shaped or provided with patterns on its surface to facilitate identification by the subject or a health care professional of the tablet or pill and the active ingredients in the tablet or pill. Surface patterns can, for example, be indented shapes or raised shapes (e.g., lines, circles, triangles, letter shapes and the like).

[0044] Additional embodiments and aspects of the invention will be apparent to one of ordinary skill in the art on review of the detailed description provided below.

Detailed Description

[0045] The present invention relates to improved methods for treating ophthalmic disorders, particularly those associated with ocular hypertension and glaucoma.

[0046] In one aspect, the invention relates to treatment of ophthalmic disorders, particularly those associated with ocular hypertension and glaucoma, employing one or more beta- adrenergic blocking agent (beta- blocker) or one or more carbonic anhydrate inhibitor (CAI) as active ingredients, where the one or more active ingredient is formulated for delivery to the oral mucosa. Delivery to the oral mucosa can provide for effective therapy at lower dosage of active ingredient(s) compared to oral delivery of the analogous active ingredient(s). In preferred embodiments, the active ingredient is administered in a solid dosage form suitable for oral mucosal delivery, e.g., for sublingual and/or buccal delivery. In preferred embodiments, the active ingredient is administered in the form of a rapidly disintegrable tab mucosal delivery.

[0047] In a second aspect, the invention relates to combination therapy employing one or more beta-adrenergic blocking agent (beta- blocker) and one or more carbonic anhydrase inhibitor (CAI). This combination therapy provides significant therapeutic improvement compared to the use of a beta-blocker or carbonic anhydrase inhibitor alone. Combination therapy provides improvement in therapeutic effectiveness and/or provides effective therapy at lower combined dosage of active ingredients. The combination therapy includes administration of one or more beta-blockers and one or more CAI in a combined therapeutically effective amount. In embodiments, the combination is administered in a single dosage form. In embodiments, the single dosage form contains a selected weight ratio of one or more beta blocker to one or more CAI. In alternative embodiments, the combination is administered in separate dosage forms at a selected relative time to enhance combined therapeutic action. In embodiments of separate administration, the CAI dosage form is administered prior to the beta-blocker dosage form. The combination is administered in any known formulation or dosage form appropriate for ocular administration. In preferred embodiments, the combination is administered in a dosage form suitable for oral mucosal delivery. In more preferred embodiments, the combination is administered in a solid dosage form suitable for oral mucosal delivery. In preferred embodiments, the combination is administered in the form of a rapidly disintegrable tablet suitable for oral mucosal delivery.

[0048] In an embodiment, the combination is administered separately or together in an ocularly appropriate solution, emulsion, gel or ointment for application to the eyes. In specific embodiments, the combination is administered topically to the eyes in the form of liquid solution or emulsion drops or in the form of a viscous emulsion, gel, or ointment to the eyes. In a preferred embodiment, the combination is administered separately or together in a dosage form for delivery to the mucosa of the oral cavity, including sublingual and/or buccal delivery. Any dosage form known in the art that is appropriate for oral mucosal delivery can be employed, including among others, liquid solution or emulsion drops, disintegrable tablets, or films. For efficacious delivery to the oral mucosa, the dosage form substantially dissolves or disintegrates in the mouth releasing active ingredient in contact with the oral mucosa. Preferably, the dosage form is taken without taking water and with little or no swallowing.

[0049] U.S. patents 4,855,326; 5,079,018; 5,120,549; 5,298,261 and 7,906,140; U.S. published application 2003/0235617; PCT applications WO 91/04757 and WO 93/12769; UK patent 1,548,022 and Chinese application CN 10692420 provide examples of fast-dispersing dosage forms that are useful in combination therapy methods herein and in the preparation of dosage forms for the combination of one or more beta-blockers and one or more CAI of this invention. Each of these references is incorporated by reference herein descriptions of pharmaceutical formulations therein.

[0050] In a specific aspect, the invention provides improved formulations of beta-blockers for oral mucosal administration. In specific embodiments, the improved dosage forms are solid dosage forms for sublingual or buccal administration and in more specific embodiments, the dosage forms are disintegrable tablets, particularly for sublingual or buccal administration. In specific embodiments, the beta-blocker of such improved formulations is timolol, timolol hemihydrate or timolol maleate. In embodiments of such formulations, the therapeutically active ingredient consists of one or more beta-blockers.

[0051] In a related specific aspect, the invention provides improved formulations of carbonic anhydrase inhibitors for oral mucosal administration. In specific embodiments, the improved dosage forms are solid dosage forms for sublingual or buccal administration and in more specific embodiments, the dosage forms are disintegrable tablets, particularly for sublingual or buccal administration. In specific embodiments, the carbonic anhydrase inhibitor of such improved formulations is methazolamide or acetazolamide or a salt or solvate thereof. In embodiments of such formulations, the therapeutically active ingredient consists of one or more carbonic anhydrase inhibitor.

[0052] Such improved formulations for oral mucosa administration are improved over known formulations, for example, by employing lower doses of the active ingredient, are improved with respect to more rapid disintegration or release of active ingredient; and/or are improved with respect to structural properties of the dosage form.

[0053] Beta-adrenergic blocking agents (beta-blockers) are a class of drugs that prevent the stimulation of the adrenergic receptors responsible for increased cardiac action. Betablockers are used to control heart rhythm, treat angina, and reduce high blood pressure. Betablockers are employed to reduce the intraocular pressure (IOP) by blockade of sympathetic nerve endings in the ciliary epithelium causing a fall in aqueous humour production. Useful betablockers include nonselective beta-blockers, which block both beta 1- and beta 2-adrenoceptors. Nonselective beta-blockers include timolol (as timolol hemihydrate or most often as timolol maleate), levobunolol, metipranolol and carteolol. Betaxolol is a cardioselective beta-blocker which is less preferred for treatment of elevated intraocular pressure. Timolol maleate is the preferred beta-blocker for treating elevated intraocular pressure.

[0054] Carbonic anhydrase inhibitors (CAI) are used in the management and treatment of glaucoma, idiopathic intracranial hypertension, altitude sickness, congestive heart failure, and epilepsy, among other diseases. Exemplary CAI include, among others, acetazolamide, methazolamide, dorzolamide, brinzolamide, diclofenamide, ethoxzolamide, and zonisamide and salts and solvates thereof. [0055] Most generally, pharmaceutical compositions herein compr therapeutically active ingredient in an amount effective for achieving the desired biological or therapeutic activity for a given form of administration to a given subject in need of treatment and optionally contain a pharmaceutically acceptable carrier. It will be appreciated by one of ordinary skill in the art that the effective amount of a given active ingredient having a given pharmaceutical (or therapeutic) activity can vary from other active ingredient having the same pharmaceutical (or therapeutic) activity. One or ordinary skill in the art can readily determine the effective amount of a given active ingredient needed for a selective dosage form or means of delivery of the active ingredient for treatment a given subject (patient) having a given disorder.

[0056] The pharmaceutically carrier can be in liquid or solid form and can be a combination of pharmaceutically acceptable ingredients having one or more selected properties in the composition. Pharmaceutical compositions can include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, fillers (diluents, bulking agents), and/or adjuvants (e.g., disintegrating agents, binders, lubricants, glidants, anti-adhesive agents), and optionally other biologically or therapeutically active ingredients. Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (19th Edition). In general, pharmaceutical compositions comprising the combination of one or more beta-blocker and one or more CAI herein include any suitable oral, topical or injectable formulations. Preferably, pharmaceutical compositions are formulated for oral mucosal administration in liquid or solid form and more preferably, are formulated for sublingual and/or buccal administration.

More preferably, pharmaceutical compositions are formulated for oral mucosal administration in a disintegrating tablet and yet more preferably in a rapidly disintegrating tablet.

[0057] Pharmaceutically acceptable carriers are generally those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable. Carriers can be a mixture of components. Carriers can be solid or liquid. It is currently contemplated that preferred carriers are solid carriers and more preferred carriers are solids which are appropriate for oral mucosal administration. Carriers can include one or more substances that can also act as solubilizers, suspending agents, fillers, glidants, compression aids, binders, tabletdisintegrating agents, or encapsulating materials. The solid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water (of appropriate purity, e.g., pyrogen-free, sterile, etc.), an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives sue solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Compositions for oral administration can be in either liquid or solid form. A preferred form of composition is a composition suitable for oral mucosal administration and more preferably is a rapidly disintegrating tablet.

[0058] Suitable examples of liquid carriers for oral and parenteral administration include water of appropriate purity, aqueous solutions (particularly containing additives, e.g. cellulose derivatives, sodium carboxymethyl cellulose solution), buffered aqueous solutions (e.g. those having pH between 6 to 8 or more preferably between 6.5 to 7.5, inclusive) alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant. Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form. The carrier can also be in the form of creams and ointments, pastes, and gels. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. More preferred dosage forms are for oral administration (liquid or solid) or for oral mucosal administration (liquid or solid). Preferred dosage forms are rapidly disintegrating tablets or related solid forms, particularly for sublingual or buccal administration.

[0059] A “therapeutically effective amount” of the disclosed compounds is a dosage of the compound (therapeutically active ingredient) that is sufficient to achieve a desired therapeutic effect, such as a lowering of ocular pressure. In embodiments herein, a combination of one or more beta-adrenergic blocking agent (beta-blocker), and one or more carbonic anhydrase inhibitor (Cl) is administered. Thus, a ’’combined therapeutically effective amount” refers to a dosage of the combination of one or more beta-blocker and one or more Cl, that may be administered separately (e.g., in the same type or different type of dosage forms), or together in a single dosage form, that provides a desired combined therapeutic effect. When the one or more beta-adrenergic blocking agent (beta-blocker), and the one or more carbonic anhydrase inhibitor (Cl) are administered separately, the relative timing of administration of the different drugs and or the order of administration of the different drugs is adjusted to achieve a desired combined therapeutic effect. In embodiments, the combined therapeutic effect is enhanced compared to the therapeutic effect achieved by separated administration of the components without selective timing/order of administration. In embodiments, the combined therapeutic effect of administration of the components in a single dosage form, is enhanced compared to the achieved by separate administration of the components without selective timing/order of administration. In embodiments, the combined therapeutic effect achieved with the combined administration is synergistic compared to separate administration of the components without selective timing/order of administration.

[0060] Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition in a subject after it has begun to develop. As used herein, the term ameliorating, with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. The phrase “treating a disease” is inclusive of inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease, or who has a disease. Preventing a disease or condition refers to prophylactically administering a composition to a subject who does not exhibit signs of a disease or exhibits only early signs of the disease, for the purpose of decreasing the risk of developing a pathology or condition or diminishing the severity of a pathology or condition.

[0061] Methods herein are employed to treat a subject in need of treatment. A subject includes any human or animal (including, for example, any mammal) in need of treatment. Pharmaceutical compositions and dosage forms described herein are useful for human and veterinary application.

[0062] Combined administration includes administration of two or more therapeutically active ingredients at the same time or at times separated by minutes, hours or days as is found to be effective. Combined administration incudes, among others, a selected order of administration of two or more therapeutically active ingredients, where a selected active ingredient is administered first, followed by administration of a second selected active ingredient after a selected time delay of minutes, hours or days, which may be followed by administration of a third active ingredient after a selected time delay, etc. In specific embodiments, separate administration is administration by any appropriate administration route within 24 hours. In specific embodiments, separate administration is administration by any appropriate administration route within 1-12 hours. In specific embodiments, separate administration is administration by any appropriate administration route with within 1-6 hours. In specific embodiments, separate administration is administration by any appropriate administration route with within 1-2 hours. In specific embodiments, separate administration is administration by any appropriate administration route with within 30 minutes. In specific embodiments, separate administration is administration by any appropriate administration route with within 1-12 hours. In specific embodiments, ordered administration is separate administration blockers and one or more CAI, where the one or more CAI are administered first and the one or more beta-blockers are administered after a delay of up to 24 hours. In specific embodiments, ordered administration is separate administration of one or more beta-blockers and one or more CAI, where the one or more beta-blockers are administered first and the one or more CAI are administered after a delay of up to 24 hours. In specific embodiments, the delay between administration of the separate therapeutically active ingredients is within 1-12 hours, or within 1-6 hours, or within 1-2 hours, or within about 30 minutes. In specific embodiments, administration at the same time is within 5-10 minutes and more preferably within 5 minutes.

[0063] In embodiments, the invention provides dosage forms for oral mucosal administration of one or more beta-blockers, one or more CAI or combinations of one more betablocker with one or more CAI. These dosage forms may be liquid (drops or sprays), films or solid (rapidly disintegrating tablets or similar dosage forms). In preferred embodiments, the dosage forms for oral mucosal delivery are rapidly disintegrating tablets. In preferred embodiments, the dosage forms are solid dosage form formulated or sublingual or buccal administration/delivery. In embodiments, the rapidly disintegrating tablet comprises one or more beta-blockers, one or more CAI or a combination of one or more beta-blockers with one or more CAI and further comprises a disintegrant. In an embodiment, the disintegrant is a superdisintegrant. In further embodiments, the rapidly disintegrating tablet comprises one or more beta- blockers, one or more CAI or a combination of one or more beta-blockers with one or more CAI, a pharmaceutically acceptable filler and an appropriate disintegrant. In further embodiments, the rapidly disintegrating tablet comprises one or more beta- blockers, one or more CAI or a combination of one or more beta-blockers with one or more CAI, a pharmaceutically acceptable filler and appropriate disintegrant and optionally comprises one or more of a binder, lubricant, glidant (flowaid) or anti-adherent. In further embodiments, the rapidly disintegrating tablet comprises one or more beta- blockers, one or more CAI or a combination of one or more beta-blockers with one or more CAI, a pharmaceutically acceptable filler, an appropriate disintegrant and further comprises one or more of a binder, lubricant, glidant (flow-aid) or anti-adherent. Solid dosage forms can also contain one or more of a stablilizer, preservative, coloring agent, sweetening agent or flavoring agent. In embodiments, the solid dosage form can be coated or uncoated. In embodiments, the disintegrant in the solid dosage form is a superdisintegrant.

[0064] A disintegrant is an additive in a solid pharmaceutical dosage form that promotes disintegration (break-up) of the solid dosage form, particularly a tablet, into small fragments and fine particles when in contact with a liquid medium. Disintegrants may enhance solid break-up where binding agents are added to solid formulations to form tablets or pills. Disintegration generally increases surface area of the solid, dissolution of the solid, and release of active ingredients. Increased release of actives accelerates dissolution and/or uptake of the active ingredient in vivo. Disintegrants can function, for example, by swelling, c of gases, structural deformation, electrostatic repulsion, chemical or enzymatic reaction or combinations of such mechanisms.

[0065] It will be appreciated that disintegrating agents are preferably inert with respect to other formulation ingredients, as well as stable and compatible with respect to other formulation ingredients, are preferably colorless and/or odorless, preferably exhibit good compression and preferably exhibit low water-solubility. Disintegrants may be derived from natural sources. Disintegrants may be semisynthetic or synthetic. Certain disintegrants may promote water/liquid uptake and/or promote swelling of particles, or combination of such action, to induce rupture of the solid. Water/liquid uptake and disintegration may also be enhanced by capillary action where pores in the solid dosage form wick in the water/liquid.

[0066] Disintegrants also include species that release heat or a gas on contact with water/liquid, such as acids (e.g., citric acid, tartaric acid or the like) or a carbonate or bicarbonate salt (e. g., sodium bicarbonate) which releases CO2. For a given solid dosage form, a given disintegrant may exhibit more than one mode of action as a disintegrant and in a given solid dosage form, a combination of disintegrants, including those having different modes of action may be combined to achieve a desired rapid disintegration rate or a balance of desired properties of the solid dosage form.

[0067] It will be appreciated that disintegrants, particularly disintegrants other than superdisintegrants, can also function as other ingredients in solid formulations, such as fillers or diluents.

[0068] Disintegrant action may also be enhanced by introducing structural features, such as grooves or pores into the solid dosage form.

[0069] Conventional disintegrants include among others: starch and modified starch (including e.g., potato and corn starch, various pregelatinized starches, and hydroxypropyl starch), alginic acid and salts thereof (e.g., sodium alginate, calcium alginate, calcium sodium alginate), microcrystalline cellulose, modified cellulose (e.g., carboxymethyl cellulose, methyl cellulose, or hydroxypropyl cellulose), ion-exchange resins, docusate salts (e.g., sodium docusate), psyllium husk, sodium lauryl sulfate, and polysorbate.

[0070] Superdisintegrants are disintegrants that generally act more rapidly or are able to promote disintegration at lower concentrations compared to conventional disintegrants. Superdisintegrants include croscarmellose (cross-linked sodium carboxymethyl cellulose, particularly croscarmellose sodium), carboxymethylcellulose calcium calcium CMC), crospovidone (cross-linked PVP), starch glycolate salts (a modified form of starch, particularly sodium starch glycolate), silicate salts (particularly, calcium silicate, magnesium aluminum silicate), cross-linked alginic acid, cross-linked chitosan, alone or in combination, soy polysaacharides (e.g., EMCOSOY®). In embodiments, superdisintegrai fold within 30 seconds.

[0071] A given solid formulation may contain a combination of one or more conventional disintegrant in combination with one or more superdisintegrants. In specific embodiments, a solid dosage form will include a single disintegrant or superdisintegrant or a combination of a single conventional disintegrant with a single superdisintegrant.

[0072] The amount of a given disintegrant added to a solid formulation depends on the selected disintegrant, but typically can range from 0.5 to 20% by weight. In embodiments, superdisintegrants are typically added to a given solid formulation for rapid disintegration at lower levels ranging from 0.25 to 10% by weight, or more specifically from 0.5 to 5% by weight. When combinations of conventional disintegrants and/or combinations of superdisintegrants are employed, the combined amount of disintegrants added is typically adjusted to reflect the combination chosen.

[0073] The use of disintegrants and particularly superdisintegrants in rapidly disintegrating solid dosage forms, e.g., tablets, for oral mucosal administration delivery is of particular importance.

[0074] In specific embodiments, the sublingual tablets herein contain a disintegrant. In embodiments, the sublingual tablets herein contain from 0.5 to 20% by weight of a disintegrant. In specific embodiments herein, the sublingual tablets herein contain disintegrants that are solid acids such as citric acid or tartaric acid. In more specific embodiments, sublingual tablets herein contain superdisintegrants.

[0075] It will be appreciated that rapid disintegration or break up of solid dosage forms may be accompanied by undesirable structural/storage properties for the solid dosage form, such as, tablet softness, increased friability, increased sensitivity to temperature and/or humidity and decreased shelf-life, for example. It will also be appreciated that in preferred solid dosage forms rapid disintegration is balanced with such structural/storage properties of the solid dosage form. [0076] In the preparation of solid dosage forms, the disintegrant can be added before and/or after granulation. Thus, the disintegrant may be intragranular or extragranular or a combination of intragranular and extragranular.

[0077] It will be appreciated that solid dosage forms of this invention can be assessed by conventional methods for weight variation, thickness, friability, content uniformity, hardness, disintegration time, wetting time, in-vitro drug release, in-vitro and ex-vivo permeation studies. [0078] In specific embodiments herein, sublingual tablets comprise an effective amount or a combined effective amount of one or more beta blocker or one or more CAI or a combination of one or more beta blocker and one or more CAI. In more specific embodiments, sublingual tablets comprise an effective amount or a combined effective amount of timolol (or a salt or solvate thereof) or methazolamide (or a salt or solvate thereof) or a combination of timolol (or a salt or solvate thereof) and methazolamide (or a salt or solvate thereof), embodiments, the sublingual tablet further comprises one or more filler, and optionally comprises one or more disintegrant, one or more sweetener, and/or one or more flavoring agent. In additional specific embodiments, the sublingual tablet further comprises one or more filler, one or more disintegrant, and optionally comprises one or more sweetener, and/or one or more flavoring agent. In specific embodiments, the filler comprise lactose. In specific embodiments, the filler is lactose. In specific embodiments, the filler is spray-dried lactose. In specific embodiments, the filler is spray-dried lactose powder. In specific embodiments, the filler is spray-dried lactose monohydrate. In specific embodiments, the filler is spray-dried lactose monohydrate powder. In specific embodiments, the sweetener is a sugar (sucrose, fructose or the like). In specific embodiments, the sweetener is sucrose. In specific embodiments, the sweetener is powdered sugar (sucrose). In specific embodiments, the sweetener is a non-nutritive sweetener. In specific embodiments, the disintegrant is citric acid.

[0079] In embodiments, sublingual tablets contain from 2.5 to 55 mg of active ingredient or combined active ingredient. In embodiments, sublingual tablets contain from 2.5 to 5 mg of timolol (or a salt or solvate thereof) on the basis of timolol maleate. In embodiments, sublingual tablets contain from 2.5 to 5 mg of timolol maleate. In embodiments, sublingual tablets contain from 25 to 50 mg of methazolamide. In embodiments for combination therapy, sublingual tablets contain from 25 to 50 mg of methazolamide and from 2.5 to 5 mg of timolol maleate. In embodiments, sublingual tablets comprise filler and sweetener in a weight ratio ranging from 6:1 to 3:1 filler to sweetener. In embodiments, sublingual tablets comprise filler to sweetener in a weight ratio of 4:1 (+/-10%) filler to sweetener. In embodiments, sublingual tablets comprise spray-dried lactose monohydrate powder filler in combination with powdered sugar in a weight ratio ranging from 6:1 to 3:1 filler to sweetener. In embodiments, sublingual tablets comprise spray-dried lactose monohydrate powder filler in combination with powdered sugar in a weight ratio of 4:1 (+/- 10%) filler to sweetener.

[0080] In embodiments herein, administration of one or more carbonic anyhydrase inhibitors is combined with electrolyte supplementation. Carbonic anyhydrase inhibitors can function as diuretics and lead to depletion of electrolytes, particularly potassium and/or magnesium. Electrolyte supplementation can be in the form of oral administration of an aqueous electrolyte solution containing potassium and/or magnesium. Such aqueous electrolyte solutions contain potassium and/or magnesium and/or sodium in amounts appropriate for electrolyte supplementation in the subject. Aqueous electrolyte solutions contain effective amounts of pharmaceutically acceptable potassium and/or magnesium salts and optionally contain effective amounts of sodium and other mineral salts. The amount of electrolyte (e.g., amount of individual salts) needed for electrolyte supplementation depends on the specific subject to be treated. The daily needed intake of potassium for adults ranges from about 640 -1280 mg. The daily needed intake of magnesium for adults ranges from about 270 to 420 mg. A dos; more specifically 100-200 mg, of potassium can provide electrolyte supplementation again dependent upon the subject to be supplemented. A dosage of 25-350 mg, or more specifically 50-200 mg, of magnesium can provide electrolyte supplementation again dependent upon the subject to be supplemented. Potassium and/or magnesium can be provided in the form of organic or inorganic salts, including among others chloride, gluconate, lactate aspartate or citrate salts. Potassium can also be provided in the form of the phosphate salt. Magnesium can also be provided in the form of magnesium oxide. In specific embodiments of solid dosage forms for oral mucosal delivery herein that contain a carbonic anhydrase inhibitor, the solid dosage form further comprises an amount of electrolyte salts effective for electrolyte supplementation. In more specific embodiments, electrolyte salts include a potassium and/or magnesium salt. In more specific embodiments, electrolyte salts include a potassium and/or magnesium salt and optionally contain a sodium salt. In specific embodiments of solid dosage forms for oral mucosal delivery herein that contain a carbonic anhydrase inhibitor, the solid dosage form further comprises an amount of potassium effective for potassium supplementation. In specific embodiments of solid dosage forms for oral mucosal delivery herein that contain acetazolamide or a salt or solvate thereof, the solid dosage form further comprises an amount of potassium effective for potassium supplementation.

Oral Mucosal Dosage Forms

[0081] Solid dosage forms can be employed for conventional oral delivery, where a tablet, capsule, pill or other solid dosage form is swallowed, typically facilitated with water, and active ingredient is released in the gastrointestinal tract. Solid dosage forms can also be employed for delivery to the oral mucosa, for example, sublingual or buccal formulations. In such formulations, the solid dosage form dissolves or disintegrates releasing active ingredient into the mouth in contact with oral mucosa. Formulation for delivery to the oral mucosa are not intended to be swallowed and water is not needed to facilitate administration/dissolution. Oral mucosal formulations generally disintegrate/dissolve and release drug on contact with the normal moisture in the mouth. Oral mucosal formulations can be placed under the tongue (sublingual) or in between the gums and cheek (buccal) where the dosage form disintegrates or dissolves to release the active ingredient. Oral mucosal dosage forms can be solids, such as rapidly disintegrating/dissolving tablets, films gels or ointments which are placed in the mouth to disintegrate/dissolve, or liquids (solution and emulsions, for example) as drops or sprays which are introduced into the mouth. Preferred oral mucosal formulations of this invention are those in solid dosage form, which are placed in the mouth, either for sublingual, buccal or a combination thereof. Solid dosage forms for oral mucosal administration/delivery can also include lozenges that dissolve in the mouth and gums that are chewed. [0082] Preferred solid dosage forms for oral mucosal administratic invention are those that are rapidly disintegrating/dissolving solids, such as tablets and pills. Rapidly disintegrating solid dosage forms provide the desired rapid release of active ingredients, along with increased accuracy of dosage, and higher patient compliance in part because of ease of self-administration. Administration/drug delivery via the oral mucosa provides more efficient drug delivery because the active ingredient/drug is absorbed through the oral mucosa directly into the bloodstream avoiding passage of the drug generally through the gastrointestinal tract and by-passing the liver. In general, lower amounts of drugs are required for oral mucosal administration and onset of action of the drug is often increased compared to conventional oral administration.

[0083] Oral mucosal dosage forms are also useful for those patients that have trouble swallowing, or where an oral dosage form causes gastrointestinal upset. Preferred oral mucosal dosage forms disintegrate/dissolve rapidly in the mouth within 5-120 seconds, or preferably within 5-60 seconds or more preferably within about 10-30 seconds or within 5-30 seconds.

Such high rates of disintegration (rapid disintegration) can be achieved with rapidly disintegration solid dosage forms, for example. As noted above, film dosage forms can be used for oral mucosal delivery, but films can be made to release drug over a longer period of time where the film is retained in the mouth, e.g., seconds to minutes up to several hours, if desired.

[0084] In embodiments, herein preferred dosage forms for oral mucosal delivery exhibit release of 90% by weight of the one or more therapeutically active ingredients therein in a water solution in less than 20 minutes or more preferably within less than 10 minutes and yet more preferably within less than 5 minutes.

[0085] In embodiments of the combined formulation herein for oral mucosal administration, the weight ratio of beta-blocker to CAI in the formulation ranges from 50:1 to 1:50. In embodiments of the combined formulation herein for oral mucosal administration, the weight ratio of beta-blocker to CAI in the formulation ranges from 10:1 to 1:10. In embodiments of the combined formulation herein for oral mucosal administration, the weight ratio of beta-blocker to CAI in the formulation ranges from 3:1 to 1:3.

[0086] In embodiments of the combined formulation herein for oral mucosal administration, the amount of beta-blocker ranges from 0.3 to 20 mg. In embodiments of the combined formulation herein for oral mucosal administration, the amount of beta-blocker ranges from 0.3 to 10 mg. In embodiments of the combined formulation herein for oral mucosal administration, the amount of beta-blocker ranges from 0.5 to 15 mg. In embodiments of the combined formulation herein for oral mucosal administration, the amount of CAI in the formulation ranges from 1 to 50 mg. In embodiments of the combined formulation herein for oral mucosal administration, the amount of CAI in the formulation ranges from 2 to 35 mg. In embodiments of the combined formulation herein for oral mucosal administration, the amount of CAI in the formulation ranges from 3 to 25 mg. In embodiments of the combined formulation herein for administration, the amount of CAI in the formulation ranges from 5 to 40 mg. [0087] In embodiments of formulations containing one or more beta-blockers for oral mucosal administration, the amount of beta-blocker ranges from 0.5 to 30 mg. In embodiments of formulations containing one or more beta-blockers for oral mucosal administration, the amount of beta-blocker ranges from 1 to 20 mg. In embodiments of formulations containing one or more beta-blockers for oral mucosal administration, the amount of beta-blocker ranges from 5 to 30 mg. In embodiments of the formulation containing one or more CAI for oral mucosal administration, the amount of CAI in the formulation ranges from 1 to 60 mg. In embodiments of the formulation containing one or more CAI for oral mucosal administration, the amount of CAI in the formulation ranges from 1 to 50 mg. In embodiments of the formulation containing one or more CAI for oral mucosal administration, the amount of CAI in the formulation ranges from 3 to 25 mg. In embodiments of the formulation containing one or more CAI for oral mucosal administration, the amount of CAI in the formulation ranges from 5 to 50 mg.

[0088] Solid dosage forms, including those for oral mucosal administration, are generally processed by known methods for preparation of tablets and pills. Process conditions may be adjusted in view of the specific components employed in a given formulation and the ultimate desired properties of the solid dosage form. Steps in solid dosage form processing may include, without limitation one or more processing steps, including: direct compression; molding; mass extrusion; freeze drying/ lyophilisation; sublimation; melt spinning, particularly of sugars (cotton candy process); spray drying; dry granulation, wet granulation or melt granulation.

[0089] The invention provides pharmaceutical compositions and dosage forms, including improved dosage forms for the treatment of ophthalmic disease. Improved dosage forms include rapidly disintegrating tablets and other solid dosage forms for administration to the oral mucosa, particularly for sublingual and buccal administration. In particular, the invention provides pharmaceutical compositions and dosage forms, including improved dosage forms for the treatment of elevated ocular pressure. In particular, the invention provides pharmaceutical compositions and dosage forms, including improved dosage forms for the treatment of any form of glaucoma or pre-glaucoma. In specific embodiments, the pharmaceutic compositions for such treatment include one or more beta-blockers and one or more CAI to provide for combined treatment.

[0090] In specific embodiments, the pharmaceutic compositions for such treatment include formulations of one or more beta-blocker formulated for oral mucosal administration. In specific embodiments, the pharmaceutic compositions for such treatment include formulations for oral mucosal administration of one or more CAI formulated for oral mucosal administration. Such formulations for oral mucosa administration are improved over prior art formulations, for example, in employing lower doses of the active ingredient, or are improved with respect to more rapid disintegration or release of active ingredient; or are improved with respec of the dosage form or exhibit a combination of such improvements. In specific embodiments, the improved formulations for oral mucosal delivery are solid dosage forms, such as tablets or pills, and exhibit improved structural properties including suitable hardness, decreased friability, decreased hygroscopicity and/or increased shelf-life.

[0091] In specific embodiments, the oral mucosal dosage form is a rapidly disintegrating tablet. In specific embodiments, such improved oral mucosal dosage forms contain timolol or a pharmaceutically acceptable salt or solvate thereof, such as timolol maleate or timolol hemihydrate. In specific embodiments, such improved oral mucosal dosage forms contain methazolamide. In specific embodiments, such improved oral mucosal dosage forms contain acetazolamide.

[0092] These improved formulations for oral mucosal administration are useful for the treatment of elevated intraocular pressure. In other embodiments, these improved formulations for oral mucosal administration are used to treat other disorders that can be treated with one or more beta-blocker, including anxiety, essential tremor, heart failure, high blood pressure and migraines. In other embodiments, these improved formulations for oral mucosal administration are used to treat other disorders that can be treated with one or more CAI, including obesity, high altitude sickness and macular edema. Thus, the invention provides methods of treating anxiety, high blood pressure and migraines or treating high altitude sickness and macular edema employing these improved formulations.

Components of Formulations

Fillers/Diluents/Bul king Agents

[0093] Fillers, also called diluents or bulking agents, as is known in the art, are employed in pharmaceutical formulations to increase the volume or size of the formulation, particularly when the amount of active ingredient is small, to facilitate manufacture of the formulation and improve reliability and reproducibility of the process. These agents are often included in solid dosage forms and may facilitate compression of tablets or pills. Fillers include, among others, cellulose, microcrystalline cellulose, dibasic calcium phosphate, vegetable oils or fats (for capsule formulations), lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and any combinations thereof. As is known in the art, the amount of filler added to a given formulation depends upon the amount of active ingredients in the formulation and the desired size (volume/weight) of the final dosage form. In embodiments fillers can represent from 1% to 99.9% (by weight or volume) of the formulation, including among others a range of 1 % to 99.5 % by weight or volume, but more typically represent 20 to 80% (by weight or volume) of the formulation.

[0094] In specific embodiments, sublingual tablets herein comprise a mixture of lactose and sucrose. In specific embodiments, lactose filler is spray-dried lactose monohydrate. In specific embodiments, lactose filler and sucrose filler are in powdered foi weight ratio of sucrose filler to lactose filler ranges from 1 :2 to 1 :5. In more specific embodiments, the weight ratio of sucrose filler to lactose filler ranges from 1 :4.5 to 1 :5.5. In specific embodiments, sublingual tablets herein comprise 99.9% to about 75% (by weight or volume) of filler. In specific embodiments, sublingual tablets herein comprise 90% to 75 % (by weight or volume) of filler. In specific embodiments, sublingual tablets herein comprise 99.9% to about 75% (by weight or volume) of a combination of sucrose and lactose filler. In specific embodiments, sublingual tablets herein comprise 90% to 75 % (by weight or volume) of a combination of sucrose and lactose filler. In specific embodiments, the filler is a combination of spray-dried lactose and sucrose. In specific embodiments, the filler is a combination of spray- dried lactose monohydrate and powdered sucrose. In specific embodiments, the filler is a combination of powdered spray-dried lactose monohydrate and powdered sucrose.

[0095] Binders (also adhesives), as is known in the art, serve as a binding agent in a pharmaceutical formulation. Starch, carboxymethyl cellulose, acacia are common binders. Addition of a binder can be used to agglomerate fine particles into large particles (or granules). Such agglomeration can improve flow properties and compressibility, particularly of solid dosage forms. Binders can facilitate compression of solid dosage forms into tablets and pills. Binder can be added either dry (dry granulation) or in liquid form (wet granulation) to facilitated formation of granules or to promote direct compression of tablets. In addition, addition of binders can facilitate retention of tablet shape after compression. Binders typically are used to facilitate manufacture of a dosage form, particularly a solid dosage form that is subjected to granulation. Binders include dry binders most often used when dry granulation is employed and include, for example, cellulose and modified cellulose (e.g., methyl cellulose, ethyl cellulose, zein, gelatin, hydroxypropylmethyl cellulose, sodium/calcium carboxymethyl cellulose), starch, pregelatinized starch, modified starch (e.g., hydroxypropyl starch), inulin, maltodextrin, alginate, copovidone, carbome, chitosan hydrochloride, sugars, dextrates, dextrin, polyethylene oxide, polymethacrylates, natural or processed gums (acacia, guar, quar galactomannan), polyvinyl pyrrolidone (PVP), and polyethylene glycol. Binders also include solution binders which are used in wet granulation processes. These binders are dissolved in an appropriate solvent (such as water (e.g., buffered water), or isopropyl alcohol). Examples of solution binders include, for example, cellulose and cellulose derivatives, polyvinyl pyrrolidone, gelatin, starch, sucrose, mannitol, polyethylene glycol, and liquid glucose. The amount of binder employed depends upon a given binder or given formulation and the manufacturing method employed, but generally can range from 0.5 % to 50 % by weight and more specifically from 1% to about 20% by weight of the formulation being processed. [0096] In embodiments herein, fillers and binders in the solid dosa number average molecular weight less than 75,000 daltons, or preferably less than 50,000 daltons.

[0097] Lubricants, as is known in the art, are typically added to solid dosage forms to reduce friction that can occur during manufacture of a dosage form, particularly a solid dosage form that is formed into a tablet or pill. Lubricants are used, for example, to prevent sticking of tablets to dies and punches employed in manufacture. Lubricants are typically added to solid formulations in relatively low amounts ranging from 0.25 to 5% by weight. Lubricants include, for example, talc, stearic acid (and other fatty acids), fatty acid esters (including for example, glyceride and sugar esters) and magnesium stearate (and other metallic salts of fatty acids).

[0098] Glidants (or flow-aids), as is known in the art, are added to pharmaceutical formulations, particularly those derived from powders, to promote the flowability of the powder or of granules. Commonly used glidants includes talc, starch, colloidal silica, and silicates that are believed to enhance the flow of a granular mixture by reducing interparticle friction.

[0099] Anti-adherents, as is known in the art, provide non-sticking properties. Antiadherents can decrease or prevent adhesion of a tablet surface to the wall of the cavity where the tablet is produced. Water-insoluble lubricants such as magnesium stearate, talc and starch are typically used as anti-adherents.

[0100] There is overlap among excipients called lubricants, glidants and anti-adherents. A given lubricant may also be useful as a glidant or an anti-adhesive and a glidant or anti-adhesive may be useful as a lubricant. These excipients are generally useful to facilitate manufacture of solid dosage forms, such as tablets, and are typically used in relatively low concentration in the formulation, from 0.25 to 5% and preferably from 0.25% to 1%. One of ordinary skill in the art can select a lubricant, glidant and/or anti-adherent or combination thereof and the amount of lubricant, glidant and/or anti-adherent to be added to a given formulation in view of the other components of the formulation, the processing step(s) employed to make the solid dosage form and what is known in the art. Such selection may require experimentation, but the level of experimentation for one of ordinary skill in the art is not undue.

[0101] Pharmaceutical compositions of this invention may also include coloring agents, sweetening agents, which are added to mask bitter or otherwise unpleasant taste of a drug, flavoring agents, which impart desirable flavor or odor to the formulation. It will be apparent to one of ordinary skill in the art that other excipients known in the art can be added to the formulations as described herein to achieve the desired type of administration of active ingredients. One of ordinary skill in the art can readily chose such additional excipients and the amount to be added to the formulation in view of what is known in the art, and the disclosures herein. In embodiments herein, the solid dosage for oral mucosal delivery is other than a freeze- dried solid. In embodiments herein, the solid dosage form for mucosal delivery does not contain a mixture of gelatin and a sugar alcohol, such as mannitol. In embodime dosage for oral mucosal delivery does not contain gelatin. In embodiments, herein the solid dosage from for oral mucosal delivery contains less than 50% by weight of total therapeutically active ingredients. In embodiments, herein the solid dosage from for oral mucosal delivery contains less than 40% by weight of total therapeutically active ingredients. In embodiments, herein the solid dosage from for oral mucosal delivery contains less than 30% by weight of total therapeutically active ingredients.

[0102] In embodiments herein, the solid dosage form for oral mucosal delivery contains equal to or greater than 6% by weight of total disintegrant. In embodiments herein, the solid dosage form for oral mucosal delivery contains more than 10% by weight of total disintegrant. In embodiments herein, the disintegrant is other than a mixture of sodium carboxymethyl starch, konjaku powder and Na-bentonite. In embodiments herein the disintegrant does not comprise sodium bentonite. In embodiments herein the disintegrant does not comprise sodium carboxymethyl starch. In embodiments herein, the solid dosage form for oral mucosal delivery does not contain PVP. In embodiments herein, the solid dosage form for oral mucosal delivery does not contain microcrystalline cellulose.

[0103] In specific embodiments herein, the solid dosage form for mucosal delivery contains a combination of filler and an acid disintegrant along with one or more active ingredients. In specific embodiments herein, the solid dosage form for mucosal delivery contains a combination of filler, sweetener and acid disintegrant along with one or more active ingredients. In embodiments, the solid dosage form for mucosal delivery comprises one or more flavoring agents. In embodiments, the filler is lactose. In embodiments, the filler is lactose monohydrate. In embodiments, the filler is spray-dried lactose monohydrate. In embodiments, the sweetener is sucrose. In embodiments, the sweetener is powdered sugar. In embodiments, the sweetener is a non-nutritive sweetener. In embodiments, the disintegrant is citric acid. In embodiments, the filler represents from 20% to 80% by weight of the solid dosage form. In embodiments, the filler represents from 40% to 80% by weight of the solid dosage form. In embodiments, the filler represents from 50% to 70% by weight of the solid dosage form. In embodiments, the sweetener represents from 1% to 25% by weight of the solid dosage form. In embodiments, sucrose represents from 5% to 25% of the solid dosage form. In embodiments, the disintegrant represents 6% or more by weight of the solid dosage form. In embodiments, the weight ratio of sweetener to acid disintegrant ranges from 1 :10 to 2:10 in the solid dosage form. In embodiments, the weight ratio of sweetener to acid disintegrant ranges from 1:2 to 2:1 in the solid dosage form. In embodiments, the weight ratio of sucrose to acid disintegrant ranges from 1:2 to 2:1 in the solid dosage form. In embodiments, filler represents from 40% to 80%, and the combination of sweetener and acid disintegrant represents from 15% to 55% by weight of the solid dosage form. In embodiments, the solid dosage form contains 1% to 20% by weight of active ingredients, 40% to 80% of filler, 10% to 20% by weight sweetene acid disintegrant. In embodiments, the solid dosage form contains 1% to 25% by weight of active ingredients, 40% to 80% of lactose, 10% to 20% by weight sucrose and 10-20% by weight citric acid. In embodiments, the solid dosage form contains 1% to 25% by weight of active ingredients, 50% to 60% of lactose, 12% to 17% by weight sucrose and 12-17% by weight citric acid.

[0104] In embodiments herein, the solid dosage form comprises a disintegrable core containing one or more therapeutically active ingredients. In embodiments herein, the solid dosage form comprises a disintegrable core containing one or more therapeutically active ingredients and a coating which does not contain therapeutically active ingredients. In an embodiment herein, the coating of the disintegrable core does not contain gellan gum. In embodiments herein, the solid dosage form for oral mucosal delivery does not contain a mucoadhesive protein.

[0105] Solid dosage forms for sublingual or buccal delivery are preferably sized and shaped for convenient administration. Sublingual/buccal tablets preferably have dimensions of 3 X 3 cm (diameter/thickness) or less. More preferred are sublingual/buccal tablets of dimensions 2 X 2 cm or less. Preferred sublingual/buccal dosage forms are round or oval tablets minimizing sharp edges or corners.

[0106] All references throughout this application, for example patent documents including issued or granted patents or equivalents; patent application publications; and non-patent literature documents or other source material; are hereby incorporated by reference herein in their entireties, as though individually incorporated by reference. All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. References cited herein are incorporated by reference herein in their entirety to indicate the state of the art, in some cases as of their filing date, and it is intended that this information can be employed herein, if needed, to exclude (e.g., to disclaim) specific embodiments that are in the prior art. For example, when a compound is claimed, it should be understood that compounds known in the prior art, including certain compounds disclosed in the references disclosed herein (particularly in referenced patent documents), are not intended to be included in the claim.

[0107] When a group of substituents is disclosed herein, it is understood that all individual members of the group and all subgroups, including any isomers and enantiomers of the group members, and classes of compounds that can be formed using the substituents are disclosed separately. When a compound is claimed, it should be understood that compounds known in the art including the compounds disclosed in the references disclosed herein are not intended to be included. When a Markush group or other grouping is used herein, all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the invention. [0108] When a compound is described herein such that a particulc diastereomer of the compound is not specified, for example, in a formula or in a chemical name, that description is intended to include each isomers and enantiomer (e.g., cis/trans isomers, R/S enantiomers) of the compound described individual or in any combination. Additionally, unless otherwise specified, all isotopic variants of compounds disclosed herein are intended to be encompassed by the invention. For example, it will be understood that any one or more hydrogens in a molecule disclosed can be replaced with deuterium or tritium. Isotopic variants of a molecule are generally useful as standards in assays for the molecule and in chemical and biological research related to the molecule or its use. Isotopic variants, including those carrying radioisotopes, may also be useful in diagnostic assays and in therapeutics. Methods for making such isotopic variants are known in the art.

[0109] Compounds and particularly therapeutically active compounds herein may contain one or more ionizable groups [groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)]. All possible ionic forms of such compounds and salts thereof are intended to be included individually in the invention herein. With regard to salts of the compounds herein, one of ordinary skill in the art can select from among a wide variety of available counterions those that are appropriate for preparation of salts of this invention for a given application. In specific applications, the selection of a given anion or cation for preparation of a salt may result in increased or decreased solubility of that salt.

[0110] Compounds and particularly therapeutically active compounds herein can be in the form of salts, for example ammonium salts, with a selected anion or quaternized ammonium salts. The salts can be formed as is known in the art by addition of an acid to the free base. Salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.

[0111] In specific embodiments, compounds particularly therapeutically active compounds herein can contain one or more negatively charged groups (free acids) which may be in the form of salts. Exemplary salts of free acids are formed with inorganic base include, but are not limited to, alkali metal salts (e.g., Li+, Na+, K+), alkaline earth metal salts (e.g., Ca2+, Mg2+), non-toxic heavy metal salts and ammonium (NH4+) and substituted ammonium (N(R')4+ salts, where R' is hydrogen, alkyl, or substituted alkyl, i.e., including, methyl, ethyl, or hydroxyethyl, specifically, trimethyl ammonium, triethyl ammonium, and triethanol ammonium salts), salts of cationic forms of lysine, arginine, N-ethylpiperidine, piperidine, and the like. Compounds of the invention can also be present in the form of zwitterions. Compounds herein can be in the form of pharmaceutically acceptable salts, which refers to those salts which reta effectiveness and properties of the free bases or free acids, and which are not biologically or otherwise undesirable.

[0112] Compounds and particularly therapeutically active compounds herein can be in the form of a solvate, in which one or more molecules of solvent are associated with one or more molecules of a solute (the compound). A specific solvent is water, where solvates of water are designated hydrates. Solvates include those in which one molecule of solvent is associated with two molecules of solute, e.g., a hemihydrate. Solvates also include those in which 1, 2, 3, 4, 5 or 6 molecules of solvent are associated with a solute.

[0113] Every formulation, compound or combination of components described or exemplified herein can be used to practice the invention, unless otherwise stated. Specific names of compounds are intended to be exemplary, as it is known that one of ordinary skill in the art can name the same compounds differently. When a compound is described herein such that a particular isomer or enantiomer of the compound is not specified, for example, in a formula or in a chemical name, that description is intended to include each isomers and enantiomer of the compound described individual or in any combination.

[0114] One of ordinary skill in the art will appreciate that methods, alternative therapies, starting materials, and synthetic methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such methods, device elements, starting materials, and synthetic methods are intended to be included in this invention. Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the invention. The disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that may be formed by such values. For any individual number or number in a range, it will be appreciated that some variation in the specific value can be accommodated without loss of significant benefit or without significant detriment. In this regard, such a nondetrimental variation allowed for a given number or range is typically 10% or less of the stated number or range. Also disclosed herein are any and all ratios (and ranges of any such ratios) that may be formed by dividing a recited numeric value into any other recited numeric value.

Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios may be unambiguously derived from the numerical values presented herein and in all instances such ratios, ranges, and ranges of ratios represent various embodiments of the present invention.

[0115] The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. The term “comprises” means “includes.” Also, “comf including A or B, or A and B, unless the context clearly indicates otherwise. It is to be further understood that all molecular weight or molecular mass values given for compounds are approximate and are provided for description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0116] As used herein, “comprising” is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any recitation herein of the term “comprising”, particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

[0117] Without wishing to be bound by any particular theory, there can be discussion herein of beliefs or understandings of underlying principles relating to the invention. It is recognized that regardless of the ultimate correctness of any mechanistic explanation or hypothesis, an embodiment of the invention can nonetheless be operative and useful.

[0118] The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

THE EXAMPLES

Example 1 : Preparation of a sublingual tablet containing methazolamide.

[0119] All listed powder ingredients are combined and mixed and wet with a mixture of water and alcohol (e.g., ethanol). The wet mixture is packed in a suitable tablet mold and dried for 1-2 days at room temperature and ambient pressure (atmospheric pressure at given local altitude).

The solid ingredients include: Methazolamide powder - 0.025 to 0.050 g

Lactose Monohydrate (spray-dried) - 0.132 g

Sucrose powder (i.e. , powdered sugar or Confectioner’s sugar) - 0.033 g

Peppermint oil- 0.0005 mL

[0120] The solid ingredients with oil are then wet with water (e.g., sterile water for irrigation) - 0.0082 mL and ethyl alcohol (95%) - 0.024 mL. A round or oval tablet of dimensions 3 X 3 cm (diameter/thickness) and preferably of dimensions 2 X 2 cm (diameter/thickness) is employed for sublingual/buccal administration.

Example 2: Preparation of a sublingual tablet containing timolol maleate.

[0121] All listed powder ingredients are combined and mixed and wet with a mixture of water and alcohol (e.g., ethanol). The wet mixture is packed in a suitable tablet mold and dried for 1-2 days at room temperature and ambient pressure

The solid ingredients include:

Timolol maleate- 0.0025-0.005 g

Lactose Monohydrate (spray-dried) - 0.132 g

Sucrose powder (i.e., powdered sugar or Confectioner’s sugar) - 0.033 g

Peppermint oil- 0.0005 mL

[0122] The solid ingredients with oil are then wet with water (e.g., sterile water for irrigation) - 0.0082 mL and ethyl alcohol (95%) - 0.024 mL A round or oval tablet of dimensions 3 X 3 cm (diameter/thickness) and preferably of dimensions 2 X 2 cm (diameter/thickness) is employed for sublingual/buccal administration.

Example 3: Preparation of a sublingual tablet containing methazolamide and timolol maleate.

[0123] All listed powder ingredients are combined and mixed and wet with a mixture of water and alcohol (e.g., ethanol). The wet mixture is packed in a suitable tablet mold and dried for 1-2 days at room temperature and ambient pressure.

The solid ingredients include:

Methazolamide powder: 0.025 - 0.050 g;

Timolol maleate: 0.0025-0.005 g;

Lactose Monohydrate (spray-dried): 0.132 g; and

Sucrose powder (i.e., powdered sugar or Confectioner’s sugar): 0.033 g Peppermint oil: 0.0005 mL is mixed with solid ingredients.

[0124] The solid ingredients with oil are then wet with water (e.g., sterile water for irrigation); 0.0082 mL and ethyl alcohol (95%); 0.024 mL. A round or oval tablet of dimensions 3 X 3 cm (diameter/thickness) and preferably of dimensions 2 X 2 cm (diar employed for sublingual/buccal administration.

Example 4: Preparation of a sublingual tablet containing active ingredient(s) and citric acid.

[0125] The solid ingredients include:

Active ingredient(s): Methazolamide powder: 0.025 - 0.050 g and/or

Timolol maleate: 0.0025-0.005 g;

Lactose monohydrate (spray-dried): 0.132 g

Sucrose powder: 0.033 g

Citric Acid: 0.033 g

[0126] The solid ingredients with oil are then wet with water (e.g., sterile water for irrigation); 0.0082 mL and ethyl alcohol (95%); 0.024 mL. A round or oval tablet of dimensions 3 X 3 cm (diameter/thickness) and preferably of dimensions 2 X 2 cm (diameter/thickness) is employed for sublingual/buccal administration.

Example 5: Exemplary Clinical Trial

[0127] Methazolamide sublingual tablets containing 0.025 g (25 mg) of methazolamide as prepared in Example 1 were administered to patients who presented with elevated intraocular pressure. Ocular pressure was measured by Goldmann tonometry prior to first administration and then at 30 min and one hour post administration. Patients were administered methazolamide sublingual tablets containing the same dose of methazolamide every morning. Pressure measurements were repeated at one week intervals. An average drop in ocular pressure of 20% (+/-3%) is observed at 30 min and of 30% (=/-7%) across all other time points.