Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics

Definitions

• Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma. Many of the drugs formerly used to treat glaucoma proved not entirely satisfactory.
• ⁇ -adrenergic antagonists are also effective in reducing intraocular pressure. While many of these agents are effective for this purpose, there exist some patients with whom this treatment is not effective or not sufficiently effective. Many of these agents also have other characteristics, e.g., membrane stabilizing activity, that become more apparent with increased doses and render them unacceptable for chronic ocular use.
• the ⁇ -adrenergic antagonist (S)-l-(tert-butylamino)-3-[(4- mo holino-l,2,5-thiadiazol-3-yl)-oxy]-2-propanol, timolol was found to reduce intraocular pressure and to be devoid of many unwanted side effects associated with pilocarpine and, in addition, to possess advantages over many other ⁇ -adrenergic antagonists, e.g., to be devoid of local anesthetic properties, to have a long duration of activity, and to display minimal loss of effect with increased duration of dosing.
• ⁇ -adrenergic antagonists reduce intraocular pressure, it does not manifest its action by inhibiting the enzyme carbonic anhydrase, and thus they do not take advantage of reducing the contribution to aqueous humor formation made by the carbonic anhydrase pathway.
• carbonic anhydrase decrease the formation of aqueous humor by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by systemic routes, they thereby have the distinct disadvantage of inhibiting carbonic anhydrase throughout the entire body. Such a gross disruption of a basic enzyme system is justified only during an acute attack of alarmingly elevated intraocular pressure, or when no other agent is effective.
• topically effective carbonic anhydrase inhibitor has become available for clinical use.
• ( l S',5')-(-)-5,6-Dihydro-4- ethylamino-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7- dioxide hydrochloride (dorzolamide HC1; MK507) is the active ingredient in TRUSOPT TM which is prescribed for the treatment of elevated intraocular pressure in ocular hypertension, open-angle glaucoma and pseudo-exfoliative glaucoma.
• Topically effective carbonic anhydrase inhibitors for example disclosed in U.S. Patent Nos. 4,386,098; 4,416,890; 4,426,388; 4,668,697; and 4,863,922 and 4,797,413, are now preferred.
• Prostaglandins are members of a class of organic carboxylic acids that are contained in human and most other mammalian tissues or organs and that exhibit a wide range of physiological activities. Naturally occurring Pgs possess a common structural feature, the prostanoic acid skelton, depicted in Formula I below:
• the primary PG's are classified based on the structural feature of the five-membered cycle moiety into PGA's, PGB's, PGC's, PGD's PGE's, PGF's PGG's PGH's PGI's and PGJ's and also on the presence or absence of unsaturation and oxidation in the chain moiety as: Subscript 1 13,14-unsaturated-15-OH,
• PGFs are subclassified as ⁇ or ⁇ according to the configuration of the hydroxy group at position 9.
• Prostaglandins and prostaglandin derivatives are known to lower intraocular pressure.
• U.S. Patent 4,824,857 to Goh et al. describes the use and synthesis of PGD2 and derivatives thereof in lowering intraocular pressure including derivatives wherein C-10 is replaced with nitrogen.
• U.S. Patent 5,001, 153 to Ueno et al. describes the use and synthesis of 13,14-dihydro-15-keto prostaglandins and prostaglandin derivatives to lower intraocular pressure.
• U.S. Patent 4,599,353 describes the use of eicosanoids and eicosanoid derivatives including prostaglandins and prostaglandin inhibitors in lowering intraocular pressure.
• Prostaglandin and prostaglandin derivatives lower intraocular pressure by increasing uveoscleral outflow. This is true for both the F type and A type of Pgs and hence presumably also for the B,C,D,E and J types of prostaglandins and derivatives thereof.
• a problem with using prostaglandin derivatives to lower intraocular pressure is that these compounds often induce an initial increase in intraocular pressure.
• the combination of the carbonic anhydrase inhibitor, ⁇ -adrenergic antagonists and the prostaglandin derivative can be used for the treatment of diseases and conditions in which the lowering of intraocular pressure is desired, for example glaucoma, ocular hypertension and other disease accompanied by an increase in intraocular pressure.
• the combinations disclosed herein are effective either by co-administration of the medicaments in one solution or as a combined therapy achieved by prior administration of one of the components, followed by administration of a different component and ending with the administration of the last component until all three components have been administered.
• the order in which each component is administered can be varied.
• a carbonic anhydrase inhibitor could be the first administered component, followed the administration of a prostaglandin and ending with the administration of a ⁇ -adrenergic antagonist.
• the use of a single solution containing the three active medicaments is preferred.
• This invention relates to novel ophthalmic compositions
• a pharmaceutically acceptable carrier comprising a topical carbonic anhydrase inhibitor or an ophthamologically acceptable salt thereof, a ⁇ - adrenergic antagonist or an ophthamologically acceptable salt thereof and a prostaglandin or prostaglandin derivative thereof such as a hypotensive lipid derived from PGF2 ⁇ prostaglandins.
• A is carbon or nitrogen, preferably carbon
• Z is -NHR or -OR, preferably -NHR;
• R is C,_ 6 alkyl, either straight or branched chain, preferably C,_ 4 alkyl such as ethyl, propyl or isobutyl;
• Q is (H, H), oxo or thioxo;
• R 1 is
• Another aspect of the invention is concerned with the use of the novel ophthalmic compositions in the treatment of ocular hypertension or glaucoma.
• This invention relates to novel ophthalmic combinations comprising a pharmaceutically acceptable carrier, a topical carbonic anhydrase inhibitor or an ophthamologically acceptable salt thereof, ⁇ - adrenergic antagonist or an ophthamologically acceptable salt thereof and a prostaglandin or prostaglandin derivative thereof, which are used in the treatment of ocular hypertension and glaucoma.
• R is - CH 2 CH 3 and R 1 is -CH 3 ; or R is -CH 2 CH 2 CH 3 and R 1 is - CH 2 CH 2 CH 2 OCH 3 ; or R is -CH 2 CH 3 and R 1 is -CH 2 CH,CH 3 ; or R is - CH 2 CH 2 (CH 3 ) 2 and R 1 is hydrogen; or R is -CH 2 CH 3 and R 1 is -CH 2 OCH,CH 3 ; and carbons 4 and 6 of the topical carbonic anhydrase inhibitor both have S absolute stereochemical configuration.
• R is - CH 2 CH 3 and R 1 is -CH 3 ; or R is -CH 2 CH 2 CH 3 and R 1 is - CH 2 CH 2 CH 2 OCH 3 ; or R is -CH 2 CH 3 and R 1 is -CH 2 CH 2 CH 3 ; or R is - CH 2 CH 2 (CH 3 ) 2 and R 1 is hydrogen; or R is -CH 2 CH 3 and R 1 is -CH 2 OCH 2 CH 3 .
• a preferred topical carbonic anhydrase inhibitor for use in the novel compositions of the present invention is 5,6-dihydro-4- ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7 dioxide hydrochloride or 2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide- 4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)- 1,1 -dioxide and their trans and cis enantiomers, or an ophthalmologically acceptable salt thereof, including racemic material.
• the carbon atoms to which Z and R 1 are bonded may be chiral. When named according to absolute configuration, e.g., (R,S) or
• the first letter represents the chirality the carbon atom to which Z is bonded and the second letter represents the chirality of A when A is carbon.
• the carbonic anhydrase inhibitors of this invention accordingly may be used as diastereomeric mixtures or single enantiomers or as racemic mixtures.
• Still another aspect of this invention is realized when the prostaglandin isl l, 15-dipivaloyl PGF2 , 11 -pi valoyl prostaglandin F2 ⁇ hydroxy ethyl ester,
• hypotensive lipids derived from a prostaglandin or prostaglandin derivative such as lipids derived from PGF 2ot prostaglandins, in which the carboxylic acid group on the ⁇ -chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents, is used.
• a hypotensive lipid is that in which the carboxylic acid group is replaced with a C,. 6 alkoxy group such as OCH 3 (PGF 2a 1- OCH 3 ), or a hydroxy group (PGF 2a 1-OH).
• the novel ophthalmic compositions of this invention comprise a pharmaceuticallly acceptable carrier, a therapeutically effective amount of 7-[3 ,5 dihydroxy-2- (3a-hydroxy-5— lE- ⁇ entenyl)cyclopentyl]-5Z-heptenoic acid; isopropyl (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5- pheny lpenty 1] cy clopentyl] -5 -heptenoate ;
• prostaglandin or prostaglandin derivative refers to those naturally occurring prostaglandins that are useful for lowering intraocular pressure, specifically prostaglandins A,B,C,D,E,F and J class as well as synthetically modified prostaglandins including but not limited to 15-keto (oxo group in place of OH at 15) 13,14-dihydro (single bond in place of double bond between positions 13 and 14), and esters thereof.
• Prostaglandins of the F class particularly PGF 2 ⁇ derivatives are known to be particularly potent at lowering intraocular pressure.
• PGF 2 ⁇ prostaglandin derived hypotensive lipids in which the carboxylic acid group on the ⁇ -chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents, are also known to be particularly potent at lowering intraocular pressure.
• the hypotensive lipids intended for the claimed invention are those compounds which increase aqueous humor outflow without any meaningful interaction with the FP prostaglandin receptor and little or no stimulation of the other prostanoid receptors (DP, EP1-4, IP, TP). Examples of such lipids are taught in US Patent Nos. 4,494,274; 5,034,413; 5,656,635; 5,516,791, 5,385,945, 5,688,819, 5,352,708 and 5,607978 all incorporated herein by reference.
• Formula I shows a basic skeleton having twenty carbon atoms
• the prostaglandin compounds used in the present invention are not limited to those having the same number of carbon 10 atoms.
• the carbon atoms in Formula (I) are numbered 2 to 7 on the ( ⁇ -chain starting from the ⁇ -carbon atom adjacent to the carboxylic carbon atom which is numbered I and towards the five membered ring 8 to 12 on the ring starting from the carbon atom on which the ⁇ -chain is attached, and 13 to 20 on the co-chain starting from the carbon atom adjacent to the ring.
• 13,14-dihydro- 15 -keto-PG compounds having 10 carbon atoms in the ⁇ -chain are 13,14-dihydro- 15-keto-20-ethyl PGs.
• prostaglandin derivative also includes esters of the C- 1 carboxyl group, such as the C 1-5 alkyl esters.
• hypotensive lipids contemplated by the claimed invention include PGF 2 ⁇ lipid analogs which, unlike PGF 2 ⁇ ,, exhibit no meaningful interaction with recombinant or constitutively expressed FP receptors (human, moust, cat). Further the PGF 2 ⁇ lipid analogs exhibit only either minimal or absent interaction with other prostanoid receptors (DP, EP 1 4 , TP). Even with their inability to interact with with prostanoid receptors the subject PGF 2cc lipid analogs, having electrochemically neutral substituents, are potent and efficacious at lowering elevated intraocular pressure (IOP). Examples of such lipids are taught in US Patent Nos.
• a particular ocular hypotensive agent is referred to as AGN 192024, disclosed in VanDenburgh et al., Investigative Oph. and Vis. Sci. March 15, 1998, Vol. 39, No.4.
• p. S258 abstract 1177 and at the May 10-15, 1998 Association for Research in Vision and Ophthalmology (ARVO) meeting by Allergan of Irvine, California.
• novel ophthalmic formulations of this invention comprise about 0.025 to 5% (w/w), usually about 0.5 to 3% (w/w) and more preferably about 0.7 to about 2% (w/w) of the carbonic anhydrase inhibitors discussed herein, preferably 5,6-dihydro-4-ethylamino-6- methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7 dioxide hydrochloride or 2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-4- (ethylamino)-3,4-dihydro-2-(3-methoxypropyl)- 1, 1 -dioxide and their trans and cis enantiomers, or an ophthalmologically acceptable salt thereof, including racemic material, 0.01 to 1.0%, preferably about 0.1 to 0.5% (w/w) of a ⁇ -adrenergic antagonist such as betaxolol
• 13,14-dihydro-15-keto-20-ethyl-PGF 2 ⁇ isopropyl ester trimethylphenol- 1-acetate, (+)-isopropyl fluprostenol; 13,14-dihydro-PGF 2 ⁇ isoprpopyl esters; [2R(1E, 3R),3S(4Z),4R]-isopropyl-7-(tetrahydro-2-[4-(3- chlorophenoxy)-3-hydroxy- 1 -butenyl)-4-hydroxy-3-furanyl]-4- heptanoate; or a hypotensive lipid derived from a prostaglandin or prostaglandin derivative such as lipids derived from PGF 2 ⁇ , prostaglandins, in which the carboxylic acid on the ⁇ -chain has been replaced by an electrochemically neutral substituent, to be administered on a 1 to 2 times a day schedule.
• a novel method of this invention comprises the topical ocular administration of about 0.025 to about 5 mg per day, preferably about 0.25 to about 3 mg per day of a carbonic anhydrase inhibitor, concomitant, prior or previous administration of about 0.005 to about 1 mg per day, preferably about 0.05 to about 0.5 mg per day of ⁇ - adrenergic antagonist and concomitant, prior, or previous administration of about 0.001 to 2 mg per day, preferably about 0.1 to 1.0 mg per day, of prostaglandin or prostaglandin derivative to each eye.
• Suitable subjects for the administration of the formulation of the present invention include mammals, primates, man, and other animals, particularly man and domesticated animals such as cats and dogs.
• the novel formulations of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of each active component or some submultiple thereof.
• Typical ophthalmologically acceptable carriers for the novel formulations are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers.
• the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, phenylethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetate, or gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine
• the formulation may also include a gum such as gellan gum at a concentration of 0.1% to 2% by weight so that the aqueous eyedrops gel on contact with the eye, thus providing the advantages of a solid ophthalmic insert as described in U.S. Patent 4,861,760.
• a gum such as gellan gum at a concentration of 0.1% to 2% by weight so that the aqueous eyedrops gel on contact with the eye, thus providing the advantages of a solid ophthalmic insert as described in U.S. Patent 4,861,760.
• the formulation may also include a gum such as xanthan gum at a concentration of 0.1 to 2%, preferably 0.4 to 0.7%(w/w). Particularly preferred is KELTROLTMT xanthan gum from Monsanto Performance Materials.
• xanthan gum will be a hypotonic solution, with a freezing point depression between about -0.28°C and -0.4°C, and preferably between about -0.31°C and -0.37°C.
• the hypotonicity of the ophthalmic solutoins of the present invention employing xanthan gum will be between about 150 and 215 mOs/kg, and preferably between 170 and 200 mOs/kg.
• Coventional ophthalmic solutions are usually prepared as isotonic solutions using tonicity adjusting agents as potassium chloride, sodium chloride, mannitol, dextrose and glycerin.
• An isotonic solution will have a freezing point depression of approximately -0.54 C.
• Tonicity may also be measured by the osmolality of the solution, an isotonic solution having an osmolality of about 290 milliosmoles per kilogram (mOs/kg).
• the pharmaceutical preparation may also be in the form of a solid insert such as one which after dispensing the drug remains essentially intact as described in U.S. Patents 4,256,108; 4,160,452; and 4,265,874; or a bio-erodible insert that either is soluble in lacrimal fluids, or otherwise disintegrates as described in U.S. Patent 4,287,175 or EPO publication 0,077,261.
• the pharmaceutical preparation may also be in the form of a suspension utilizing carbonic anhydrase inhibitors (CAI's) having aqueous solubilities greater than 10 ⁇ g/mL but less than 1000 ⁇ g/mL at pH 7.4, octanol/water distribution coefficients (DC) measured at pH 7.4 of from 1.0 to 150 and dissociation constants (Ki) of 1.0 nM or lower.
• CAI's carbonic anhydrase inhibitors
• the aqueous solubility is measured, for example, by mixing the CAI, in its neutral or salt form in 0.1M phosphate buffer at a pH of 7.4. The mixture is then agitated for approximately 16 to 24 hours, while maintaining a pH of 7.4. If the mixture is a solution, a small amount of a seed crystal of the neutral CAI is added and the mixture is stirred for approximately 16 to 24 hours. The solid/liquid mixture is filtered throught a 0.45 ⁇ m filter and the filtrated is assayed by HPLC against standards.
• the solubility as measured includes both the neutral and ionized forms of the CAI.
• the suspension encompassed within the meaning of this invention is one which comprises 0.1-10.9 wt% of a carbonic anhydrase inhibitor and 0.01-10.0 wt.% of a polyethoxylated derivative of castor oil resulting from the reaction of from 2-200 moles of ethylene oxide per 1 mole of castor oil, wherein the derivatives can be hydrogenated.
• the measure of the dissociation constant is determined using the fluorescence competition assay which uses the fluorescent HCAILdansylamide complex and is well known in the art, Chen et al., J. Biol. Chem., 242, 5813 (1967) and Ponticello et al, J. Med. Chem., 30, 591 (1987).
• the relative Kis for the suspension are less than 3.3.
• the active compounds, phosphate buffer salts, benzalkonium chloride, and Polysorbate 80 are added to and suspended or dissolved in water.
• the pH of the composition is adjusted to 5.5-6.0 and diluted 30 to volume.
• the composition is rendered sterile by filtration through a sterilizing filter.
• the formulation is prepared by the addition of the above HPMC vehicle (15.014 g) to the above TCAI (0.3074 g) and prostaglandin (1.0 g) and the mixture ias ball milled with 3 mm glass beads (5 g) for approximately 45 hours.
• the active compounds Gelrite' gellan gum, phosphate buffer salts, benzyldodecinium bromide and Polysorbate 80 are added to and suspended or dissolved in water.
• the pH of the composition is adjusted to 5.5-6.0 and diluted to volume.
• the composition is rendered sterile by ionizing radiation.
• the active compounds, sodium chloride and benzalkonium chloride are dissolved in water for injection.
• the pH of the composition is adjusted to 5.6 by addition of 0.2N sodium hydroxide solution, and water for injection is added until the weight of the composition is equal to 75 parts of the final weight (I) or 65 parts of the final weight (II).
• the composition is sterilized by filtration, and the solution flushed with sterile nitrogen. Then a clarified, steam sterilized concentrate of 2% xanthan gum is added to the solution of drug and the resulting solution is homogenized by stirring.
• the solution is aseptically subdivided into sterile vials and sealed.
• (+)-isopropyl fluprostenol 48 [2R(1E, 3R),3S(4Z),4R]-isopropyl- 7-(tetrahydro-2-[4-(3-chlorophenoxy)- 3-hydroxy- 1 -butenyl)-4-hydroxy-3-furanyl]- 4-heptanoate;

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• 1999
  • 1999-07-16 CA CA002337399A patent/CA2337399A1/en not_active Abandoned
  • 1999-07-16 JP JP2000560891A patent/JP2002521332A/ja not_active Withdrawn
  • 1999-07-16 EP EP99934101A patent/EP1109546A1/de not_active Withdrawn
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