Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE IN~IENTION
OPHTHALMIC COrvIPOSITIONS FOR TREATING OCULAR
HYPERTENSION
BACKGROUND OF~ THE INVENTION
Glaucoma is a degenerative disease of the eye wherein the
intraocular pressure its 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 ophthalrriologists to represent merely the earliest phase in
the onset of glaucoma.
Many of the drugs formerly used to treat glaucoma proved
not entirely satisfactory. The early methods of treatment of glaucoma
employing pilocarpine produced undesirable local effects that made this
drug, though valuable, unsatisfactory as a first line drug. More
recently, clinicians have noted that many ~3-adrenergic antagonists are
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 effecaive 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.
Although pilocarpine and 13-adrenergic antagonists reduce
intraocular pressure, none of these drugs manifests 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.
Agents referred to as carbonic anhydrase decrease the
formation of aqueou:~ humor by inhibiting the enzyme carbonic
anhydrase. While such carbonic anhydrase inhibitors are now used to
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treat intraocular pressure by systemic routes, they thereby have the
distinct disadvantages 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.
For several years, the desirability of directing the carbonic
anhydrase inhibitor t:o only the' desired ocular target tissue has been
recognized. Becausf: carbonic anhydrase inhibitors have a profound
effect in altering basic physiological processes, the avoidance of a
systemic route of ad~ministation serves to diminish, if not entirely
eliminate, those side effects caused by inhibition of carbonic anhydrase
such as metabolic acidosis, vomiting, numbness, tingling, general
malaise and the like. Topically effective carbonic anhydrase inhibitors
are disclosed in U.S. Patent Nos. 4,386,098; 4,416,890; 4,426,388;
4,668,697; and 4,863,922 and 4,797,4I3.
Prostagl.andins, or Pgs, 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 s:kelton, depicted in Formula I below:
9 7 5 3
COON (a-chain)
10 g ! ~~ 4 2 (1)
12 14 16 lg 20
I CH3 (w-chain)
13 15 17 I9
Some synthetic analogues have somewhat modified
skeletons. The primary PG's are classified based on the structural
feature of the five-m~embered 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-1S-OH,
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Subscript 2 5,6- and 13,14-diunsaturated -15-OH,
Subscript 3 5,6-13,14-, and 17,18-triunsaturated
15-OH
Further, PGFs are subclassified as a or (3 according to the configuration
of the hydroxy group at position 9.
Prostaglandins and prostaglandin derivatives are known to
lower intraocular pressure. U,.S. Patent 4,883,819 to Bito descibes the
use and synthesis of IPGAs, PGBs and PGCs in reducing intraocular
pressure. U.S. Patent 4,824,857 to Goh et al. describes the use and
synthesis of PGD2 and derivatives thereof in lawering intraocular
pressure including derivatives wherein C-10 is replaced with nitrogen.
U.S. Patent 5,OOI,153 to Ueno et al. describes the use and synthesis of
13,14-dihydro-15-kel:o 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 3 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.
Since the carbonic anhydrase inhibitor lowers intraocular
pressure without accompanying transient ocular hypertension exhibited
by the primary PGs, the combination of the carbonic anhydrase
inhibitor and the pro:>taglandin derivative can be used for the treatment
of diseases and condiaions in which the lowering of intraocular pressure
is desired, for example glaucoma, ocular hypertension and other disease
accompanied by an increase in intraocular pressure.
Thus, when a carbonic anhydrase inhibitor, which decreases
the formation of aqueous humor, is combined with a prostaglandin or
prostaglandin derivative, which increases the outflow of aqueous humor,
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there is experienced an effect that reduces intraocular pressure below
that obtained by either medicament individually.
The activity of the carbonic anhydrase inhibitor currently
marketed wanes 6 to 8 hours post-dose, meaning that as single agents
these carbonic anhydrase inhibitors must be administered at least three
times day to maintai~a the desired lowering of intraocular pressure. The
combination of this invention maintains the desired lowering of
intraocular pessure for a full twelve hours. Because of this
increased duration of action, the combination disclosed herein is
effective when administered only twice a day. Patient compliance is
anticipated to be greater with twice a day administration than with three
times a day administ~~ation.
The conribinations disclosed herein are effective either by
co-administration of the medicaments in one solution or as a combined
therapy achieved by prior administration of either the carbonic
anhydrase inhibitor or the prostaglandin derivative followed by
administration of the other solution. The use of a single solution
containing both active medicaments is preferred.
There exists a patient population who will benefit from a
combination where tlxe minimal dosage of one or both of the
medicaments is employed, thus minimizing the possibility of the
occurrence of undesirable effects of one or both of the medicaments
which would be more; likely to become apparent with chronic use at the
higher dosage.
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SUMMARY OF THE INVENTION
This invention relates to novel ophthalmic compositions
comprising a topical carbonic anhydrase inhibitor or an
ophthamologically acceptable salt thereof and a prostaglandin or
prostaglandin derivative thereof or a hypotensive lipid derived from a
prostaglandin or pro:~taglandin derivative such as a PGF2a
prostaglandin.
In one aspect of the invention a composition comprising
0.025 to 5% (w/w) of a topical carbonic anhydrase inhibitor such as 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]-I,2-thiazine-
6-sulfonamide-4-{ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-I,1-
dioxide and their traps and cis enantiomers, or an ophthalmologically
acceptable salt thereof, including racemic material and 0.005 to 2% a
hypotensive Iipid derived from prostaglandins and their traps and cis
enantiomers, ox an ophthalmologically acceptable salt thereof, including
racemic material is disclosed. Said composition can optionally contain a
gum belonging to the; group consisting of gellan gum or xanthan gum.
Another aspect of the invention is concerned with the use of
the novel ophthalmic: compositions in the treatment of ocular
hypertension or glaucoma.
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DETAILED DESCRIPTION OF THE INDENTION
This invention relates to novel ophthalmic combinations
comprising a topical carbonic anhydrase inhibitor or an
ophthamologically acceptable salt thereof and a prostaglandin or
prostaglandin derivative thereof, or a topical carbonic anhydrase
inhibitor or an ophthalmologically acceptable salt thereof and a
hypotensive lipid derived from' a prostaglandin or prostaglandin
derivative, which are used in the treatment of ocular hypertension and
glaucoma.
An aspect of this invention is realized when the
prostaglandin is
11, 1S-dipivaloyl PGF2oc,
11-pivaloyi prostaglandin F2oe hydroxyethyl ester,
{+)-(Z)-sodium-7-[1R, 2R, 3R, 5S)-3,5-dihydroxy-2-[(E)-1-
octenyl]cyclopentyl]-5-heptenoate sesquihydrate,
[ l a,2(3,3oc,5oc]methyl-5-cis-2-(phenylethylsulfonamidomethyl}-3,5-
dihydroxycyclopentyl heptenoate,
(+-)-5-[6-( 1-hydroxy }hexyl)-1,3-benzodioxol-5-yl]-pentanol,
15-pivaloyl PGFa,
7-[3a,5oc dihydroxy-~2-(3a-hydroxy-5--lE-pentenyl)cyclopentyl]-5Z-
heptenoic acid,
isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R}-3-hydroxy-5-
phenylpentyl]cyclopentyl]-5-heptenoate,
(+)-isopropyl fluprostenol;
[2R(lE, 3R),3S(4Z),~~R]-isopropyl-7-(tetrahydro-2-[4-(3-
chlorophenoxy)-3-hydroxy-I-butenyl)-4-hydroxy-3-furanyl]-4-
heptanoate;
13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2oc esters,
13,14-dihydro-15-keto-20-ethyl-PGF2a isopropyl ester or
13,14-dihydro-15-keto-20-ethyl-PGFZa isopropyl ester trimethylphenol-
1-acetate.
Another aspect of this invention is realized when
hypotensive lipids derived from PGFZa prostaglandins, in which the
carboxylic acid group on the oc-chain link of the basic prostaglandin
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structure is replaced with electrochemically neutral substituents, is used.
An example of a hypotensive lipid is that in which the carboxylic acid
group is replaced with a C1_~ alkoxy group such as OCH3 (PGF2~ 1-
OCH3), or a hydroXy group (PGF2a 1-OH).
A further aspect of this invention is realized when the
prostaglandin is
[2R( 1 E, 3R},3S (4Z),4R]-isopropyl-7-(tetrahydro-2-[4-(3-
chlorophenoxy)-3-hydroxy-1-butenyl)-4-hydroxy-3-furanyl]-4-
heptanoate;
(+)-isopropyl fluprostenol;
or a hypotensive lipid derived from PGF2oc prostaglandins and the
topical carbonic anh:ydrase 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-a]-1,2-thiazine-6-sulfonamide-4-
(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-1;1-dioxide.
Another embodiment of the invention is concerned with a
novel ophthalmic composition comprising an ophthalmologically
acceptable carrier, 0.025 to 5% (wJw) of a topical carbonic anhydrase
inhibitor, 5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-
b]thiopyran-2-sulfonamide-7,7 dioxide hydrochloride, and its trans and
cis enantiomers, or an ophthalmologically acceptable salt thereof,
including racemic material and 0.005 to 2% (w/w) of a prostaglandin
and its trans and cis c~nantiomers, or an ophthalmologically acceptable
salt thereof, including racemic material, wherein the prostaglandin isll,
15-dipivaloyl PGF2cx; (+)-isopropyl fluprostenol; or [2R(lE,
3R},3S(4Z),4R]-isopropyl-7-(tetrahydro-2-[4-(3-chlorophenoxy}-3-
hydroxy-1-butenyl)-4-hydroxy-3-furanyl]-4-heptanoate.
The terns "prostaglandin or prostaglandin derivative",
within this invention 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 inclucEing but not limited to 15-keto (oxo group in place
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of OH at 15 ) 13,14-dihydro {single bond in place of double bond
between positions I3 and 14), and esters thereof.
Prostaglandins of the F class, particularly PGF2«
derivatives are known to be particularly potent at lowering intraocular
pressure. PGF2« prostaglandin derived hypotensive lipids, in which the
carboxylic acid group on the oc-chain link of the basic prostaglandin
structure is replaced with electrochemically neutral substituents, are also
known to be particularly potent at lowering intraocular pressure. In
particular, 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; 5,656,63si; 5,516,791, 5,385,945, 5,688,819, 5,352,708 and
5,607978 all incorporated herein by reference.
Althouglh 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
(a-chain starting from the oc-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 a-chain is
attached, and 13 to 2~0 on the cz~-chain starting from the carbon atom
adjacent to the ring. When the number of carbon atoms is decreased on
the a-chain, the number is deleted in order starting from position 2 and
when the number of carbon atoms is increased in the oc-chain
compounds are named as substituted derivatives having, substituents at
position I in place of~ carboxy group at C-I. Similarly, when the
number of carbon atc>ms is decreased in the c~-chain, the number is
deleted in order starting from position 20 and when the number of
carbon atoms is increased on the ceZ-chain, compounds are named as
substituted derivatives having respective substituent at position 20.
Thus, 13, I4-dihydro-15-keto-PG compounds having 10 carbon atoms in
the c~-chain are 13,14-dihydro-15-keto-20-ethyl PGs. The term
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prostaglandin derivative also includes esters of the C-1 carboxyl group,
such as the C 1 _5 alkyl esters.
The hypotensive lipids contemplated by the claimed
invention include P(sFZa lipid analogs which, unlike PGF2a" exhibit no
meaningful interaction with recombinant ~r constitutively expressed FP
receptors {human, rrioust, cat). Further the PGF2a lipid analogs exhibit
only either minimal or absent interaction with other prostanoid
receptors {DP, EP,_4, TP). Even with their inability to interact with
with prostanoid receptors the subject PGF2a lipid analogs, having
electrochemically neutral substituents, are potent and efficacious at
lowering elevated in.traocular pressure (IOP). Examples of such lipids
are taught in US Patent Nos. 4,494,274; 5,034,413; 5,656,635;
5,385,945, 5,688,81!x, 5,352,708 and 5,607978 all incorporated herein
by reference. A particular ocular hypotensive agent is referred to as
AGN 192024, disclosed in VanDenburgh et al., Investigative Oph. and
Vis. Sci. March 15, 1998, VoI. 39, No.4. p. S258 abstract 1177 and at
the May 10-15, 199f~ Association for Research in Vision and
Ophthalmology (ARVO) meeting by Allergan of Irvine, California.
The novel ophthalmic formulations of this invention
comprise about 0.025 to 5% {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]-1,2-thiazine-6-sulfonamide-4-(ethylamino)-3,4-dihydro-2-
(3-methoxypropyl}-l.,l-dioxide and their trans and cis enantiomers, or
an ophthalmological:ly acceptable salt thereof, including racemic
material, usually about 0.5 to 3% (w/w} and more preferably about 0.7
to about 2% {w/w) and about 0.005 to 2.0% (w/w), preferably about O.I
to 1 % (wlw) of the I>rostaglandin or prostaglandin derivatives discussed
herein, preferablys :l 3,14-dihydro-15 (R)-17-phenyl-18,19,20-trinor-
PGF2a esters or 13, 14-dihydro-15-keto-20-ethyl-PGF2oc isopropryl
esters, and more preferably isopropyl (Z)-7-[( 1 R,2R,3R,SS)-3,S-
dihydroxy-2-[{3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate,
(+)-isopropyl fluprostenol, [2R{lE, 3R),3S(4Z),4R]-isopropyl-7-
(tetrahydro-2-[4-(3-c:hlorophenoxy}-3-hydroxy-1-butenyl)-4-hydroxy-
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3-fuxanyl]-4-heptanoate; or 13,14-dihydro-15-keto-20-ethyl-PGF2oc
isopropyl ester trimethylphenol-1-acetate, 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
and concomitant, prior, or previous administration of about 0.005 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. For topical ocular administration the novel formulations of this
invention may take tl:~e 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 b00, 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, triethan~lamine,
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polyoxyethylene sorbitan monopalmitylate, dioctyl sodium
sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetra
acetic acid, and the Iike. Additionally, suitable ophthalmic vehicles can
be used as carrier media for the present purpose including conventional
phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic
sodium chloride vehicles, isotonic sodium borate vehicles and the like.
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 t:he 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 front Monsanto
Performance Materials. The formulation of the instant invention
1.5 employing xanthan ~;um will be a hypotonic solution, with a freezing
point depression between about -0.28°C and -0.4°C, and
preferably
between about -0.3 I "C and -0.37°C. Alternatively, the hypotonicity of
the ophthalmic solutions of the present invention employing xanthan
gum will be between. about 150 and 215 mOslkg, and preferably
between 170 and 20C) 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-e;rodible 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
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aqueous solubilities ,greater than 10 ~.glmL but less than 1000 p.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.
The aqueous solubility is measured, for example, by mixing the CAI, in
its neutral or salt form in 0.1 M phosphate buffer at a pH of 7.4: The
mixture is then agitated for approximately 1.6 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. Under these conditions, at pH 7.4, the CAI's
employed for the suspension are predominantly unionized, with the
possibility of 10 to 20% of the anionic sulfonamide present (depending
on the pKa of the primary sulfonamide group). By way of an example,
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
HCAII:dansylamide complex and is well known in the art, Chen et al., J.
Biol. Chem., 242, 5f.13 (1967) and Ponticello et al., J. Med. Chem., 30,
591 ( 1987). The relative Kis for the suspension are less than 3.3 nM.
The following examples of ophthalmic formulations are
given by way of illu;>tration and are not limitative of the invention.
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EXAMPLE 1
SOLUTION COMPOSITION I II III
(S,S)-(-)-5,6-dihydro-4-ethyl-
amino-6-methyl-4H-thieno-
[2,3b~thiopyran-2-sulfonamide-
7,7-dioxide monohydrochloride 22.26 g 22.26 g 1.113 g
(carbonic anhydrase inhibitor)
(+)-isopropyl fluprostenol;
(prostaglandin derivative) 10.0 g 1.0 g 1.0 g
Sodium citrate.2H20 2.940 g 2.940 g 2.940 g
Benzalkonium Chloride 0.075 g 0.075 g 0.075
Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g
Sodium hydroxide q,.s. pH = 6.0 pH = 6.0 pH = 6.0
Mannitol 16.00 g 21.00 g 35.90 g
Water for injection y.s. ad. 1000 g 1000 g 1000 g
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 S.S-6.0
and diluted 30 to volume. The composition is rendered sterile by
filtration through a sterilizing filter.
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EXAMPLES 2-6
Following the procedures of Example 1, solutions axe
prepared substituting the compounds below for the carbonic anhydrase
inhibitors:
Compound Example No.
(S,S)-(-)-5,6-dihydro-4-ethyl- 2
amino-6-methyl-4H--thieno-
[2,3b]thiopyran-2-sulfonamide-
to 7;7-dioxide
{S,S)-(-)- 3,4-dihydro-4-ethylamino-2-methyl-
2H-thieno[3,2-a]-1,2,-thiazine-6-sulfon- 3
amide-l,l-dioxide hydrochloride
R-(+)-3,4-dihydro-4-ethylamino-2-
methyl-2H-thieno[3,2-a]-1,2- 4
thiazine-6-sulfonamiide-l,l-dioxide
hydrochloride
R-(+)-3,4-dihydro-4-ethylamino-2-
(2-methoxy)ethyl-2H-thieno[3,2-a]-1,2- 5
thiazine-6-sulfonamide-l, l-dioxide
hydrochloride
(S,S)-(-)-5,6-dihydro-4-ethylamino- 6
6-propyl-4H-thieno[2,3b]thiopyran-
2-sulfonamide-7,7-dioxide
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EXAMPLE 7(Suspension CONCENTRATION
WT/V%
R-(+)-4-ethylamino-3,4-dihydro-2-(3-methoxy)
propyl-2H-thieno[3,:2-a]- I,2-thiazine-6-sulfonamide
1,1-dioxide 2%+2% xs
13,14-dihydro-15-kf;to-20-ethyl-
PGF2. isopropyl ester
{prostaglandin derivative) 0.5%
Hydroxypropylmeth;ylcellulose 3 %
Dibasic Sodium Phosphate 0.2%
Z5 Sodium Chloride 0.~%
Disodium Edetate 0.01 %
Polysorbate 80 0.05%
Benzalkonium Chloride 0.01 %
NaOH/HCl pH adjust
25 Purified Water q.s. 100%
The suspension may be prepared by heating 400 mL of
purified water to boiling. HPMC (30.Og) is added and the mixture
stirred vigorously until homegeneous. To this is added a solution
30 consisting of sodium chloride (7.0 g), dibasic sodium phosphate {2.Og),
disodium edta (O.lg), polysorbate 80 (0.5g) and benzalkonium chloride
( 10.5 mL of a 1 % solution) and purified water is added to a final
volume of 900 mL. The mixture is stirred and cooled in an ice bath to
room temperature and the pH is adjusted to 7.2 employing HCl (3.5 mL
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6 i
of a 1 N solution. The mixture is q.s. to the final weight with purified
water (total 1010g) and filtered through a 10 micron filter. The
formulation is prepared by the addition of the above HPMC vehicle
( 15.014 g) to the above TCAy (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.
EXAMPLES 8-15
Following the procedures of Example l , solutions are
prepared substituting the compounds below for the prostaglandin
derivative
Compound Example No.
PGF2a,-1-isopropyl estex g
PGA2 9
13,14-dihydro-15-keto-PGE2 10
methyl ester
15-keto-PGF2oc 11
PGF2oc tromethamine salt 12
PGA 1 13
(+)-isopropyl fluprostenol 14
[2R(lE, 3R),3S(4Z),4R]-isopropyl- 15
7-(tetrahydro-2-[4-(3-chlorophenoxy)-
3-hydroxy-1-butenyl)-4-hydroxy-3-
furanyl]-4-heptanoat~e;
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EXAMPLE 16
SOLUTION COMPOSITION I II
5,6-dihydro-4-ethylamino
6-methyl-4H-thieno[2,3b]thiopyran-
2-sulfonamide-7,7-dioxide
monohydrochloride 2.0 mg 0.2 mg
(carbonic anhydrase inhibitor)
13,14-dihydro-15-keto-20-ethyl-
PGF2oc isopropyl ester
trimethylphenol-1-acetate 0.1 mg 1.0 mg
GelriteTM gellan gum 6.0 mg 6.0 mg
Monobasic sodium phosphate Quantity sufficient to
give .2H20
Dibasic sodium phosphate final pH 5.5 - 6.0
.12H20
Benzyldodecinium bromide 0.10 mg 0.10 mg
Polysorbate 80 0.2 mg 0.2 mg
Water for injection q.s. ad. 1.0 mL 1.0 mL
The active compounds, Gelrite'
gellan gum, phosphate
buffer salts, benzyldodecinium
bromide and Polysorbate 80
are added to
and suspended or dissolved in The pH of the composition is
water.
adjusted to 5.5-6.0 and diluted
to volume. The composition
is rendered
sterile by ionizing radiation.
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EXAMPLES i 7-21
Following the procedures of Example I6, solutions are prepared
substituting the compounds below for the carbonic anhydrase inhibitors:
Compound Example No.
{S,S)-(-)-5,6-dihydro-4-ethylamino-
6-methyl-4H-thien6[:?,3b)thiopyran- I7
2-sulfonamide-7,7-dioxide
3,4-dihydro-4-ethylamaino-2-methyl-
2H-thieno[3,2-e]-1,2-thiazine-6-sulfon- 18
amide-I,l dioxide hydrochloride
R-(+)-3,4-dihydro-4-ethylami.no-2-
methyl-2H-thieno[3,2-a]-1,2- I9
thiazine-6-sulfonamide-1,1-dioxide
hydrochloride
R-(+)-3,4-dihydro-4~-ethylamino-2- 20
(2-methoxy)ethyl-2H(-thieno[3,2-a]-1,2-
thiazine-6-sulfonamide-l,l-dioxide
hydrochloride
{S,S)-trans-5,6-dihidro-4-ethylamino- 2I
6-propyl-4H-thieno[2,3b)thiopyran-
2-sulfonamide-7,7- dioxide
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EXAMPLES 22-29
Following the procedures of Example 16,
solutions are
prepared substitutin,~ the compounds for the prostaglandin
below
derivative.
Compound Example
PGF2oc,-1-isopropyl ester 22
PGA2 23
13, I4-dihydro-15-keto-PGE2 24
methyl ester
I5-keto-PGF,2cc 25
PGF2a tromethamine salt 26
PGA 1 2~
(+)-isopropyl fluprostenol; 2g
[2R(lE, 3R),3S(4Z),4R]-isopropyl- 29
7-(tetrahydro-2-[4-(3-chlorophenoxy)-
3-hydroxy-1-butenyl)-4-hydroxy-3-
furanyl]-4-heptanoate;
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EXAMPLE 30
SOLUTION COMPOSITION I II
5,6-dihydro-4-ethylamino
6-methyl-4H-thieno(:2,3b)thiopyran-
2-sulfonamide-7,7-dioxide
monohydrochloride ~ 2% 2%
(carbonic anhydrase inhibitor) ',
13,14-dihydro-15-keto-20-ethyl-
PGF2oc isopropyl ester
trimethylphenol-1-acetate 0.1 % 1.0 %
Xanthan gum 0.5% 0.7%
Sodium Chloride 0.2% 0.2%
Benzalkonium Chloride 0.0075% 0.0075%
Sodium Hydroxide qs pH5.6 pH 5.6
Water qs 100% 100%
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.
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EXAMPLES 31-35
Followiing the procedures of .Example 30, solutions are
prepared substituting the compounds below for the carbonic anhydrase
inhibitors:
Compound Example No.
(S,S)-(-)-5,6-dihydxo-4-ethylamino-
6-methyl-4H-thien6~:2,3b]thiopyran- 31
2-sulfonamide-7,7-dioxide
3,4-dihydro-4-ethylamino-2-methyl-
2H-thieno[3,2-a]-1,2,-thiazine-6-sulfon- 32
amide-1,1 dioxide hydrochloride
R-(+)-3,4-dihydro-4-ethylamino-2-
methyl-2H-thieno[3,2-a]-1,2- 33
thiazine-6-sulfonamude-1,1-dioxide
hydrochloride
R-(+)-3,4-dihydro-4-ethylamino-2- 34
(2-methoxy)ethyl-21H-thieno[3,2-a]-1,2-
thiazine-6-sulfonamide-l,l-dioxide
hydrochloride
(S,S)-traps-5,6-dihidlro-4-ethylamino- 35
6-propyl-4H-thieno[;Z,3b]thiopyran-
2-sulfonamide-7,7- dioxide
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EXAMPLES 36-43
Following the procedures of Example 30> solutions are
prepared substitutiril; the compounds below for the prostaglandin
derivative.
Compound ~ Examule
T
PGF2oc-1-isopropyl ester 36
PGA2 37
13,14-dihydro-15-ke;to-PGE2 3g
methyl ester
15-keto-PGF,2oc 39
PGF2oc tromethamine salt 40
PGA 1 41
{+}-isopropyl fluprostenol 42
[2R(lE, 3R),3S(4Z),4RJ-isopropyl- 43
7-(tetrahydro-2-j4-(3-chlorophenoxy)-
3-hydroxy-1-butenyl.)-4-hydroxy-3-
furanylJ-4-heptanoate;
