JP2002521333A - Ophthalmic composition for the treatment of high intraocular pressure - Google Patents

Abstract

  (57) [Summary] Prostaglandins, prostaglandin derivatives, prostaglandins or hypotensive lipids derived from prostaglandin derivatives or their ophthalmically acceptable salts and topical carbonic anhydrase inhibitors or their ophthalmically acceptable The resulting salt combinations are particularly useful in the treatment of ocular hypertension and glaucoma. The combination is characterized by improved efficacy and reduced side effects.

Description

DETAILED DESCRIPTION OF THE INVENTION

(Technical Field) (Background Art) Glaucoma is a degenerative disease of the eyeball in which the intraocular pressure becomes too high and normal eyeball functions cannot be performed. As a result, damage to the optic nerve head may occur, resulting in irreversible loss of vision. Without treatment, glaucoma can eventually lead to blindness. Many ophthalmologists now believe that high intraocular pressure, that is, high intraocular pressure without optic nerve head injury or characteristic glaucomatous visual field defects, is only the earliest stage of glaucoma onset. I have.

[0002] It has been found that many of the drugs used so far for the treatment of glaucoma are not very satisfactory. Early methods of treating glaucoma with pilocarpine produced undesirable local effects, which made this drug a valuable but inadequate first-line candidate. More recently, clinicians have recognized that β-adrenergic antagonists are effective in lowering intraocular pressure. While many of these drugs are effective for this purpose, there are patients in which their treatment is ineffective or ineffective. Many of these agents also have other properties, such as membrane stabilizing activity, which become apparent with increasing dose and are unacceptable for chronic ocular use.

[0003] Pilocarpine and β-adrenergic antagonists reduce intraocular pressure, but none of them exert their effects by inhibiting the enzyme, carbonic anhydrase, so that tufts formed by the carbonic anhydrase pathway It does not utilize the reduced contribution to water formation.

[0004] Drugs called carbonic anhydrases reduce aqueous humor production by inhibiting carbonic anhydrase. At present, treatment of intraocular pressure is performed by a systemic route using such a carbonic anhydrase inhibitor, but there is a distinct disadvantage that carbonic anhydrase is inhibited systemically. Such total disruption of the basic enzyme system can only be used during an acute attack of a surprising increase in intraocular pressure or when other drugs fail.

[0005] In recent years, it has been recognized that it is desirable to direct a carbonic anhydrase inhibitor to only the target tissue of the desired eye. Because carbonic anhydrase inhibitors are quite effective in altering basic physiological processes, avoiding systemic administration can lead to metabolic acidosis, vomiting, paralysis, stinging, general malaise, etc. Side effects caused by enzyme inhibition can be reduced even if they cannot be completely eliminated. Topically effective carbonic anhydrase inhibitors are described in US Pat. No. 4,386,098,
Nos. 4,416,890, 4,426,388, 4,686,976, 4,863,922 and 4,797,413.

[0006] Prostaglandins (or Pgs) are certain organic carboxylic acids that are found in tissues and organs of humans and most other mammals and exhibit a very wide range of biological activities. Natural Pgs has a prostanoic acid skeleton, a common structural feature shown in Formula I below.

[0007]

Embedded image

[0008] Some synthetic analogs have a slightly modified backbone. Primary prostaglandins are based on the structural features of the five-membered ring moiety, and include PGAs, PGBs, PGCs, PGs
D, PGEs, PGFs, PGGs, PGHs, PGIs, and PGJs are also classified based on the presence or absence of unsaturation and oxidation in the chain portion. Subscript 1: 13,14-unsaturated-15- OH, subscript 2: 5,6- and 13,14-diunsaturated-15-OH, subscript 3: 5,6-13,14- and 17,18-triunsaturated-15-OH You. Furthermore, PGFs are also subclassified as α or β according to the arrangement of the hydroxyl group at the 9-position.

[0009] Prostaglandins and prostaglandin derivatives are known to reduce intraocular pressure. US Pat. No. 4,883,819 to Bito describes the use and synthesis of PGAs, PGBs and PGCs in reducing intraocular pressure. U.S. Pat. No. 4,824,857 to Goh et al.
The use and synthesis of PGD2 and its derivatives in reducing intraocular pressure, including derivatives wherein 10 is replaced by nitrogen, has been described. U.S. Pat. No. 5,001,153 to Ueno et al. Includes 13,14-dihydro-15- to reduce intraocular pressure.
It describes the use and synthesis of ketoprostaglandins and prostaglandin derivatives. U.S. Pat. No. 4,599,353 describes the use of eicosanoids and eicosanoid derivatives such as prostaglandins and prostaglandin inhibitors in lowering intraocular pressure.

[0010] Prostaglandins and prostaglandin derivatives reduce intraocular pressure by increasing uveoscleral outflow. This is true for both F-type and A-type Pgs, and probably for prostaglandins of type B, C, D, E and J and their derivatives. A problem with intraocular pressure reduction using prostaglandin derivatives is that they often induce an initial increase in intraocular pressure.

[0011] Because carbonic anhydrase inhibitors reduce intraocular pressure without causing the transient ocular hypertension exhibited by primary PGs, glaucoma, using a combination of carbonic anhydrase and a prostaglandin derivative, Diseases and conditions for which reduced intraocular pressure is desirable, such as high intraocular pressure and other diseases associated with increased intraocular pressure, can be treated.

[0012] Thus, when a carbonic anhydrase inhibitor that reduces aqueous humor formation is combined with a prostaglandin or prostaglandin derivative that increases aqueous outflow, intraocular pressure is reduced to below that obtained by any individual drug. Is obtained.

The activity of currently marketed carbonic anhydrase inhibitors gradually diminishes 6 to 8 hours after administration. That is, as single agents, these carbonic anhydrase inhibitors must be administered at least three times a day to maintain the intraocular pressure at the desired reduced level. The combination of the present invention maintains the intraocular pressure at the desired reduced level throughout the 12 hour period. Due to this extended duration of action, the combinations disclosed herein are effective when administered twice daily. It is expected that the patient's compliance rate will be higher with twice daily administration than with three times daily administration.

The combinations disclosed herein may be administered by co-administration of these agents in one solution or by administering a carbonic anhydrase inhibitor or prostaglandin derivative first, followed by administration of the other solution It is effective as a combination therapy performed. The use of a single solution containing both active pharmaceutical agents is preferred.

[0015] Since the combination of one or both of these drugs using the lowest dose is effective, the undesired effects of one or both of those drugs, which would be more apparent with chronic use at higher doses. There are patient populations that are unlikely to occur.

DISCLOSURE OF THE INVENTION The present invention provides a topical carbonic anhydrase inhibitor or an ophthalmically acceptable salt thereof and a prostaglandin or a prostaglandin derivative thereof or PGF.
The present invention relates to a novel ophthalmic composition comprising a hypotensive lipid derived from a prostaglandin such as 2α prostaglandin or a prostaglandin derivative thereof.

In one aspect of the invention, 0.025-5% (by weight) of 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
] -1,2-thiazine-6-sulfonamido-4- (ethylamino) -3,4-
Topical carbonic anhydrase inhibitors such as dihydro-2- (3-methoxypropyl) -1,1-dioxide and their trans-cis enantiomers, including racemates or their ophthalmically acceptable salts; Disclosed are compositions comprising 0.005 to 2% of prostaglandins and their anti-hypertensive lipids derived from their trans-cis enantiomers, including the racemates, or ophthalmically acceptable salts thereof. The composition may contain a gum belonging to the group consisting of gellan gum or xanthan gum.

Another aspect of the present invention relates to the use of the novel ophthalmic compositions in the treatment of ocular hypertension or glaucoma.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a topical carbonic anhydrase inhibitor or an ophthalmically acceptable salt thereof and prostaglandin or a prostaglandin derivative thereof, or a topical carbonate. A novel ophthalmic drug combination comprising a dehydrogenase inhibitor or an ophthalmically acceptable salt thereof and a hypotensive lipid derived from prostaglandin or a prostaglandin derivative thereof, comprising: It relates to those used for the treatment of glaucoma.

In one embodiment of the present invention, the prostaglandin is 11,15-dipivaloyl PGF2α, (+)-(Z) -7- [1R, 2R, 3R, 5S) -3,5-dihydroxy-
Sodium 2-[(E) -1-octenyl] cyclopentyl] -5-heptenoate sesquihydrate, [1α, 2β, 3α, 5α] heptenoic acid methyl-5-cis-2- (phenylethylsulfonamidomethyl ) -3,5-dihydroxycyclopentyl], (+-)-5- [6- (1-hydroxy) hexyl) -1,3-benzodioxol-5-yl] -pentanol, 15-pivaloyl PGFα, 7- [3α, 5α, dihydroxy-2- (3a-hydroxy-5-1E-pentenyl) cyclopentyl] -5Z-heptenoic acid, (Z) -7-[(1R, 2R, 3R, 5S) -3,5 -Dihydroxy-2- [
(3R) -3-hydroxy-5-phenylpentyl] cyclopentyl] isopropyl-5-heptenoate, (+)-isopropylfluprostenol, [2R (1E, 3R), 3S (4Z), 4R] -7- ( Tetrahydro-2- [
Isopropyl 4- (3-chlorophenoxy) -3-hydroxy-1-butenyl) -4-hydroxy-3-furanyl] -4-heptanoate, 13,14-dihydro-15 (R) -17-phenyl-18, 19,20- trinor -PGF2α esters, 13,14-dihydro-15-keto-20-ethyl-PGF _2.alpha isopropyl ester, or 13,14-dihydro-15-keto-20-ethyl-PGF _2.alpha isopropyl ester trimethyl Realized when it is phenol-1-acetate.

[0021] Yet another aspect of the present invention relates to derivatives of PGF _2α prostaglandins in which the carboxylic acid group on the α-chain linkage of the basic prostaglandin structure has been replaced by an electrochemically neutral substituent. This is achieved when using blood pressure lowering lipids. As an example of a hypotensive lipid, the carboxylic acid group is OCH ₃ (PGF _2α 1-OCH ₃ )
And a C _1-6 alkoxy group or a hydroxyl group (PGF _2α 1-OH).

In still another embodiment of the present invention, wherein the prostaglandin is [2R (1E, 3R), 3
S (4Z), 4R] -7- (tetrahydro-2- [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl) -4-hydroxy-3-furanyl] -4-
Isopropyl heptanoate, (+)-isopropylfluprostenol or PG
A hypotensive lipid derived from F2α prostaglandins, wherein the topical carbonic anhydrase inhibitor is 5,6-dihydro-4-ethylamino-6-methyl-4H-thieno- [2,3-b] Thiopyran-2-sulfonamido-7,7-dioxide hydrochloride or 2H-thieno [3,2-e] -1,2-thiazine-6-sulfonamido-4- (ethylamino) -3,4-dihydro Realized when it is -2- (3-methoxypropyl) -1,1-dioxide.

Another embodiment of the present invention is directed to an ophthalmically acceptable carrier, 0.025-5% (by weight) of the topical carbonic anhydrase inhibitor 5,6-dihydro-4-ethylamino. -6-methyl-4H-thieno- [2,3-b] thiopyran-2-sulfonamido-7,7-dioxide hydrochloride and its cis-trans enantiomers, including racemates or their ophthalmologically Acceptable salts, and 0.005-2%
(By weight) prostaglandins and their cis-trans enantiomers, including racemates or their ophthalmically acceptable salts, wherein said prostaglandin is 11,15-dipivaloyl PGF2α, (+)- Isopropylfluprostenol or [2R (1E, 3R), 3S (4Z), 4R] -7- (tetrahydro-2- [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl) -4-hydroxy -3-furanyl] -4-isopropyl heptanate.

Within the scope of the present invention, the term “prostaglandin or prostaglandin derivative” refers to natural prostaglandins useful in lowering intraocular pressure, specifically prostaglandins A, B, C , D, E, F and J and 15-keto (oxo group at position 15 instead of OH) 13,15-dihydro (single bond instead of double bond between positions 13 and 14) and Synthetically modified prostaglandins, such as, but not limited to, the following esters:

Class F prostaglandins, especially PGF _2α derivatives, are known to be particularly potent in reducing intraocular pressure. PGF _2α prostaglandin-induced hypotensive lipids, in which the carboxylic acid group on the α-chain linkage of the basic prostaglandin structure is replaced by an electrochemically neutral substituent, are also particularly potent in reducing intraocular pressure It has been known. In particular, the hypotensive lipids for the claimed invention do not interact significantly with the FP prostaglandin receptor and have multiple prostanoid receptors (DP, E
Compounds that increase aqueous humor outflow with little stimulation of PI1-4, IP, TP). Examples of such lipids are described in US Pat. No. 4,494,274, 50344.
No. 13, 5665635, 5516791, 5385945, 56888
Nos. 19, 5352708 and 5607978, all of which are incorporated herein by reference.

Although Formula I shows a basic skeleton having 20 carbon atoms, the prostaglandin compounds used in the present invention are not limited to those having the same number of 10 carbon atoms. The carbon atoms in formula (I) are numbered from 2 to 7 on the α chain starting from the α carbon atom adjacent to the carboxylic acid carbon atom numbered 1, and towards the 5-membered ring, Starting from the carbon atom to which the chain is attached, they are numbered from 8 to 12 on the ring, and 13 on the ω chain starting from the carbon atom adjacent to the ring.
Numbers are assigned from to. When the number of carbon atoms on the α-chain decreases, the number decreases sequentially starting from the 2-position, and when the number of carbon atoms increases on the α-chain, the compound substitutes a substituent at the 1-position instead of the carboxyl group of C-1. Is referred to as having a substituted derivative. Similarly, as the number of carbon atoms in the ω chain decreases, the number decreases sequentially starting at position 20, and as the number of carbon atoms increases on the ω chain, the compound becomes a substituted derivative with an individual substituent at position 20. Called. Therefore, one having 10 carbon atoms in the ω chain
The 3,14-dihydro-15-keto-PG compound is 13,14-dihydro-15-
Keto-20-ethyl PGs. The term prostaglandin derivative includes:
Also included are esters of C-1 carboxylic acid groups, such as _C1-5 alkyl esters.

The antihypertensive lipids envisioned by the claimed invention include PGF_2αDifferent from
Thus, recombinantly or constitutively expressed FP receptors (human,
PGF showing no significant interaction with mice, cats)_2αThere are lipid analogs and the like.
Furthermore, the PGF_2αLipid analogs are identified by other prostanoid receptors (DP, EP _1-4 , TP) with little or no interaction. Prostanoid receiver
Cannot interact with the body, but has an electrochemically neutral substituent
This PGF_2αLipid analogs are potent and effective in lowering intraocular pressure (IOP)
is there. Examples of such lipids are described in U.S. Pat. Nos. 4,494,274, 5034413,
Nos. 5,656,535, 5,385,945, 5,688,819, 5,352,708
And 5,079,978, which are all incorporated herein by reference.
Document. A particular ocular hypotensive is called AGN 192024.
And Van Denburgh et al., Investigat.
ive Oph. and Vis.Sci. March 15, 1998, Vol.39, No.4.p.S258 abstract 117
7 and at the May 10-15, 1998 Association for Research in Vision and Opht
halmology (ARVO) meeting by Allergan of Irvine, California).

The novel ophthalmic formulation of the present invention comprises from about 0.025 to 5% by weight of a carbonic anhydrase inhibitor as described 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] -1,2-thiazine-6
-Sulfonamido-4- (ethylamino) -3,4-dihydro-2- (3-methoxypropyl) -1,1-dioxide and their trans-cis enantiomers, including racemates, or their ophthalmologically Acceptable salt; usually about 0.5
３3% (by weight), more preferably about 0.7 to about 2% (by weight) and about 0%
. 005-2.0% (by weight), preferably about 0.1-1% (by weight) of a prostaglandin or prostaglandin derivative as described herein, preferably 13,14-dihydro-15. (R) -17-phenyl-18,19,20-
Trinor-PGF2a esters or 13,14-dihydro-15-keto-2
0-ethyl-PGF2α isopropyl esters, more preferably (Z) -7-
[(1R, 2R, 3R, 5S) -3,5-dihydroxy-2-[(3R) -3-
Hydroxy-5-phenylpentyl] cyclopentyl] -5-heptenoate isopropyl, (+)-isopropylfluprostenol, [2R (1E, 3R), 3
S (4Z), 4R] -7- (tetrahydro-2- [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl) -4-hydroxy-3-furanyl] -4-
It contains isopropyl heptanoate or 13,14-dihydro-15-keto-20-ethyl-PGF _2α- isopropyl ester trimethylphenol-1-acetate and is administered once or twice daily.

The novel method of the present invention comprises topical ocular administration of about 0.025 to about 5 mg / day, preferably about 0.25 to about 3 mg / day of a carbonic anhydrase inhibitor to each eye, It includes administration of about 0.005-2 mg / day, preferably about 0.1-1.0 mg / day, of a prostaglandin or prostaglandin derivative simultaneously, before or after.

Suitable patients to be administered the formulations of the present invention include mammals, primates, humans and other animals, particularly humans and domestic animals such as cats and dogs. For topical ophthalmic administration, the novel formulations of the present invention may take the form of solutions, gels, ointments, suspensions or solid inserts, wherein the unit dosage is a therapeutically effective amount of each active ingredient or a multiple of that. It can be formulated to contain an amount.

Representative ophthalmically acceptable carriers for the novel formulations include, for example, water, mixtures of water with water-miscible solvents such as lower alkanols or aralkanols, vegetable oils,
Polyalkylene glycols, petroleum-based jelly, ethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally used acceptable carriers. Pharmaceutically acceptable formulations include non-toxic auxiliary substances such as emulsifiers, preservatives, wetting agents, thickeners (eg, polyethylene glycol 200, 300, 400 and 600, carbowax 10).
00, 1500, 4000, 6000 and 10000) quaternary ammonium compounds, phenylmercury compounds known to be low-temperature sterilizable and harmless to use, thimerosal, benzalkonium chloride, methyl and propylparaben, Antibacterial components such as benzyl dodecinium bromide, benzyl alcohol and phenylethanol; buffer components such as sodium chloride, sodium borate, sodium acetate or gluconic acid buffer; and sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan mono Other conventional ingredients such as carmitylate, dioctyl sodium sulfosuccinate, monothioglycerin, thiosorbitol, ethylenediamine tetraacetate, etc., can also be included. In addition, any suitable ophthalmic vehicle may be used as a carrier medium for the present invention, including conventional phosphate buffered media systems, isotonic boric acid media, isotonic sodium chloride media, isotonic borate media. Sodium acid medium and the like.

The formulation contains a gum such as gellan gum at a concentration of 0.1% to 2% by weight to obtain an aqueous ophthalmic gel that comes into contact with the eyeballs and is a solid ophthalmic insert as described in US Pat. No. 4,861,760. Can be used.

In the preparation, a gum such as xanthan gum is used at a concentration of 0.1 to 2%, preferably 0.4 to 2%.
０．７0.7% (by weight) may be contained. Particularly preferred is KE
LTROL® T Xanthan Gum (Monsanto Performance Materials)
It is. The formulation of the present invention using xanthan gum is about -0.28C to -0.4C.
, Preferably a hypotonic solution having a freezing point depression of about -0.31 ° C to -0.37 ° C. Alternatively, the hypotonicity of the ophthalmic solution of the present invention using xanthan gum has a hypotonicity of about 1
It is 50 to 215 mOs / kg, preferably 170 to 200 mOs / kg. Conventional ophthalmic solutions are usually formulated as isotonic solutions with isotonic agents such as potassium chloride, sodium chloride, mannitol, glucose and glycerin. Isotonic solutions have a freezing point depression of about -0.54 ° C. Isotonicity can also be measured by the osmolarity of the solution, which is approximately 290 milliosmoles / kilogram (mO
s / kg).

The pharmaceutical formulations are described in US Pat. Nos. 4,256,108, 4,160,452 and 426
Solid inserts, such as those in which the drug remains almost intact after dispensing as described in US Pat. No. 5,874, or US Pat. No. 4,287,175 or EPO Publication 0077.
No. 261, may be in the form of a bioerodible insert soluble in tears or other disintegrants. The pharmaceutical formulation has a pH of more than 10 μg / mL and less than 1000 μg / mL at pH 7.4. Water solubility, octanol / water partition coefficient (DC) measured at pH 7.4 from 1.0 to 150 and suspension using carbonic anhydrase inhibitor (CAI) with a dissociation constant (K _i ) of 1.0 nM or less. It can also be in the form of a suspension. For example, water solubility
The CAI is measured in its neutral or salt form by mixing in 0.1 M phosphate buffer, pH 7.4. The mixture is then brought to about 1 while maintaining the pH at 7.4.
Stir for 6-24 hours. If the mixture is a solution, add a small amount of a crystal seed of neutral CAI and stir the mixture for about 16-24 hours. The solid / liquid mixture is filtered through a 0.45 μm filter and the filtrate is analyzed by HPLC in comparison to a standard. The measured solubility includes both neutral and ionic forms of CAI. pH 7.4
Under these conditions, the CAI used in the suspension is hardly ionized and there may be 10-20% of the sulfonamide in anionic form (
Determined by the pKa of the main sulfonamide group). For example, suspension forms within the meaning of the invention are those produced by the reaction of 0.1 to 10.9% by weight of a carbonic anhydrase inhibitor and 2 to 200 moles of ethylene oxide per mole of castor oil.
From 0.01 to 10.0% by weight of a polyethoxylated derivative of castor oil, which may be hydrogenated.

The dissociation constant was determined using a fluorescent HCAII: dansylamide complex and a fluorescence competition assay known in the art (Chen et al., J. Biol. Chem., 242, 5813 (1967) and Pontic).
ello et al., J. Med. Chem., 30, 591 (1987)). The relative _{K i} for the suspension is less than 3.3.

The following are examples of ophthalmic preparations, but the present invention is not limited thereto.

Embodiment 1

[0038]

[Table 1]

Active Compound, Phosphate Buffer Salt, Benzalkonium Chloride and Polysorbate 8
0 is added to water and suspended or dissolved therein. Adjust the pH of the composition to 5.5-6.0 and dilute to 30 to the specified volume. The composition is sterilized by filtration through a sterile filter.

[0040]Examples 2 to 6  Following the procedure of Example 1 and substituting the following compound for the carbonic anhydrase inhibitor,
Formulation of the drug.

[0041]

[Table 2]

Example 7 (Suspension)

[0043]

[Table 3]

A suspension can be prepared by heating 400 mL of purified water to boiling. HPMC (30.0 g) is added and the mixture is stirred vigorously until homogenous. In addition, sodium chloride (7.0 g), disodium phosphate (2.0 g), EDT
A solution consisting of A2 sodium (0.1 g), polysorbate 80 (0.5 g) and benzalkonium chloride (10.5 mL of a 1% solution) is added, and purified water is added to a final volume of 900 mL. The mixture was stirred and cooled in an ice bath to room temperature, HCl
Adjust pH to 7.2 using (3.5 mL of 1N solution). The mixture is diluted with purified water to a final weight (1010 g total) and filtered through a 10 micron filter. A formulation was prepared by adding the above HPMC vehicle (15.014 g) to the above TCAI (0.3074 g) and prostaglandin (1.0 g) and mixing the mixture to about 45
Ball mill with 3 mm glass beads (5 g) over time.

[0045]Examples 8 to 15  The prostaglandin derivative was switched to the following compound and the procedure of Example 1 was followed.
To prepare a liquid preparation.

[0046]

[Table 4]

Embodiment 16

[0048]

[Table 5]

The active compound, Gelrite gellan gum, phosphate buffer salt, benzyldodecinium bromide and polysorbate 80 are added to water and suspended or dissolved. Adjust the pH of the composition to 5.5-6.0 and dilute to the prescribed dose. The composition is sterilized by ionizing radiation.

[0050]Examples 17 to 21  Following the procedure of Example 16, replacing the carbonic anhydrase inhibitor with the following compound:
Perform liquid formulation.

[0051]

[Table 6]

[0052]Examples 22 to 29  The prostaglandin derivative was switched to the following compound, and the procedure of Example 16 was followed.
Accordingly, a liquid preparation is prepared.

[0053]

[Table 7]

Embodiment 30

[0055]

[Table 8]

The active compound, sodium chloride and benzalkonium chloride are dissolved in water for injection. The pH of the composition is adjusted to 5.6 by adding 0.2N sodium hydroxide solution and water for injection is used until the composition weight is 75 parts (I) of the final weight or 65 parts (II) of the final weight. Add. The composition is filter sterilized and the solution is blown with sterile nitrogen. 2%
A clear steam sterilized concentrate of xanthan gum is added to the drug solution and the resulting solution is homogenized by stirring. The solution is aseptically dispensed into sterile vials and sealed.

[0057]Examples 31 to 35  According to the procedure of Example 30, replacing the carbonic anhydrase inhibitor with the following compound:
Perform liquid formulation.

[0058]

[Table 9]

[0059]Examples 36 to 43  The prostaglandin derivative was switched to the following compound, and the procedure of Example 30 was followed.
Accordingly, a liquid preparation is prepared.

[0060]

[Table 10]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/36 A61K 47/36 A61P 27/06 A61P 27/06 // C07D 495/04 111 C07D 495/04 111 513/04 371 513/04 371 (A61K 31/5575 (A61K 31/5575 31: 382) 31: 382) (A61K 31/5575 (A61K 31/5575 A61K 31:54) A61K 31:54) (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU , CZ, EE, GD, GE, HR, HU, ID, IL, IN, IS, JP, KG, KR, KZ, LC, LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TJ, TM, TR, TT, UA, US, UZ, VN, YU, ZA (72) Inventor Sugloo, Michael F. United States of America, New York Jersey 07065, Lowway, East Lincoln Avenue Avenue 126 F-term (reference) 4C071 AA01 BB01 CC22 DD12 EE13 FF25 GG01 HH05 HH13 LL01 4C072 AA01 BB02 CC01 CC17 EE15 FF19 GG07 GG08 UU01 4C22 DD19 ACC DDB EE32 EE58 FF17 FF35 4C084 A A19 MA02 MA23 MA58 NA05 ZA332 ZC202 4C086 AA01 AA02 CA04 CB29 DA01 MA01 MA04 MA23 MA58 NA05 NA06 ZA33 ZC20 ZC75

Claims (20)

[Claims] 1. An ophthalmic formulation for the treatment of ocular hypertension and glaucoma in a patient in need of treatment, a pharmaceutically acceptable carrier, 0.025-5% (by weight) topical carbonic anhydrase. Inhibitors or trans-cis enantiomers thereof, including racemates or ophthalmically acceptable salts thereof, and 0.005 to 2% (by weight) of prostaglandins or prostaglandin derivatives and racemates A formulation comprising hypotensive lipids derived from their trans-cis enantiomers or their ophthalmically acceptable salts. 2. The method of claim 1, wherein the topical carbonic anhydrase inhibitor is 5,6-dihydro-4-.
Ethylamino-6-methyl-4H-thieno- [2,3-b] thiopyran-2-sulfonamido-7,7-dioxide hydrochloride or 2H-thieno [3,2-e]
-1,2-thiazine-6-sulfonamido-4- (ethylamino) -3,4-dihydro-2- (3-methoxypropyl) -1,1-dioxide and their trans. The ophthalmic preparation according to claim 1, which is a cis enantiomer or an ophthalmically acceptable salt thereof. 3. The ophthalmic preparation according to claim 1, wherein the hypotensive lipid is derived from PGF _2α prostaglandins. 4. The blood pressure-lowering lipid derived from the PGF _2α prostaglandins, wherein the carboxylate group on the α-chain link of the basic prostaglandin structure is replaced by an electrochemically neutral substituent. The preparation according to claim 3, having the formula: 5. The method according to claim 1, wherein the concentration of the carbonic anhydrase inhibitor is 0.5% to 3%.
The formulation according to claim 1, wherein the concentration of the hypotensive lipid is 0.1% to 1.0%. 6. The method according to claim 1, wherein the carbonic anhydrase inhibitor is 10 μg / mL at pH 7.4.
The formulation of claim 1 having a water solubility of greater than 1000 μg / mL and a Ki of 1.0 nM or less. 7. The preparation according to claim 6, which is a suspension. 8. The formulation of claim 1, which may comprise from about 0.1% to about 2% gellan gum. 9. The formulation of claim 1, which may comprise from about 0.1% to about 2% (by weight) xanthan gum. 10. A hypotonic solution comprising from about 0.4% to about 0.7% (by weight) of xanthan gum, wherein the xanthan gum has a freezing point depression of about -0.28 ° C to -0.4 ° C. The preparation according to claim 9. 11. The formulation of claim 10, wherein the gum is KELTROL® T xanthan gum in a hypotonic solution having a freezing point depression of about -0.31 ° C to -0.37 ° C. 12. An ophthalmologically acceptable carrier in an ophthalmic formulation for the treatment of ocular hypertension and glaucoma in a patient in need of treatment; 0.5-3% (by weight)
Topical carbonic anhydrase inhibitors or their trans-cis enantiomers, including racemic or ophthalmically acceptable salts thereof; and 0.1-1.0% (by weight) of prostaglandin or prostaglandin Trans-cis enantiomers, including the glandin derivatives and racemates or their ophthalmically acceptable salts; and about 0.1% to about 2% gellan gum or about 0.1% to about 2%
A formulation comprising a gum belonging to the group consisting of (by weight) xanthan gum. 13. The method of claim 12, wherein the topical carbonic anhydrase inhibitor 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
] -1,2-thiazine-6-sulfonamido-4- (ethylamino) -3,4-
Dihydro-2- (3-methoxypropyl) -1,1-dioxide and their trans-cis enantiomers, including racemates or their ophthalmically acceptable salts; 13. PGF _{2 α} prostaglandins having an electrochemically neutral substituent in place of the carboxylic acid group on the α-chain linkage of the general prostaglandin structure; wherein the gum is xanthan gum. A formulation as described. 14. A hypotonic solution comprising about 0.4% to about 0.7% (by weight) xanthan gum, wherein the xanthan gum has a freezing point depression of about -0.28 ° C to -0.4 ° C. The preparation according to claim 13. 15. The formulation of claim 14, wherein said gum is KELTROL® T xanthan gum in a hypotonic solution having a freezing point depression of about −0.31 ° C. to −0.37 ° C. 16. An ophthalmically acceptable carrier in an ophthalmic formulation for the treatment of ocular hypertension and glaucoma in a patient in need of treatment; 0.025-5% (by weight) topical carbonic anhydrase 5,6-dihydro-4-ethylamino- which is an inhibitor
6-methyl-4H-thieno- [2,3-b] thiopyran-2-sulfonamide-
7,7-dioxide hydrochloride and its trans-cis enantiomer, including the racemate or an ophthalmically acceptable salt thereof; and 0.005 to 2% (by weight) of prostaglandin and the racemate. Wherein the prostaglandin comprises 11,15-dipivaloyl PGF2α, (+)-isopropylfluprostenol or [2R (1E, 3R) , 3S (4Z), 4R] -7- (tetrahydro-2- [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl)
Ophthalmic preparation, which is isopropyl-4-heptanoate. 17. A method for treating ocular hypertension and glaucoma, comprising the step of topically administering a unit dose of the preparation according to claim 1 to a patient in need of treatment. 18. A method for treating ocular hypertension and glaucoma, comprising the step of topically administering a unit dose of the preparation according to claim 7 to a patient in need of treatment. 19. A method for treating ocular hypertension and glaucoma, comprising the step of topically administering a unit dose of the preparation according to claim 12 to a patient in need of treatment. 20. A method for treating ocular hypertension and glaucoma, comprising the step of topically administering a unit dose of the preparation according to claim 16 to a patient in need of treatment.