Ulllted States Patent
`
`[19]
`
`[11] Patent Number:
`
`6,011,062
`
`Schneider et al.
`
`[45] Date of Patent:
`
`*Jan. 4, 2000
`
`US006011062A
`
`STORAGE-STABLE PROSTAGLANDIN
`COMPOSITIONS
`
`514/530
`5/1997 Schneider .... ..
`5,631,287
`5,849,792 12/1998 Schneider .............................. .. 514/530
`
`FOREIGN PATENT DOCUMENTS
`0 132 027 A1
`1/1985 European Pat. Off.
`.
`0 330 511 A2
`6/1989 European Pat. Off.
`.
`0 407 148 A3
`1/1991
`European Pat. Off.
`.
`3
`g
`European 11:at~
`~
`.
`uropean at.
`.
`/
`0 435 682 A2
`European Pat. Off.
`.
`7/1991
`5 145 A3
`3/1995 European Pat. Off.
`.
`0 64
`4532513372: 1912:: 5:11:59
`WO95/05163
`2/1995 WIPO .
`W097/29752
`8/1997 WIPO .
`WO98/41208
`9/1998 WIPO .
`OTHER PUBLICATIONS
`
`Attwood and Florence, “Reactivity in surfactant systems, ”
`Surfactant Systems Their Chemistry Pharmacy and Biol-
`.
`’
`’
`083)’ 11698-777’ Chapman and Hall} Pub1'
`.
`.
`Foster et al., “Intraocular Penetration of Miconazole in
`Rabbits, ” Arch, Ophthalmol, 97/9, pp, 1703_1706 (1979)
`(abstract Only).
`‘Sax/ed, and Reptai “So1ubi1ization and stabilization of an
`mvestlgatlonal aHt1He9P1aSt1C,dru8 (NSC N0; 278214)m an
`intravenous formulation using an emulsion vehicle,
`”
`1”’e’"“” 1 0fP’Wm“Ce“’iCS> V°1~ 13 (1983)>PP~ 302'312~
`Primary Examiner—Robert Gerstl
`Attorney, Agent, or Firm—Patrick M. Ryan
`
`[54]
`
`[75]
`
`Inventors: L. Wayne Schneider, Crowley, Tex.;
`Rajan Bawa, Fort Collins, C0l0.; Alan
`L_ Weiner, Arlington, Tex,
`
`[73] Assignee: Alcon Laboratories, Inc., Fort Worth,
`Tex.
`
`,
`-
`[*] Notice.
`
`-
`-
`-
`-
`-
`This patent is subject to a terminal dis-
`
`[21] Appl. No.: 09/246,072
`.
`Ffled:
`
`Feb.9,1999
`
`[22]
`
`[63]
`
`Related US’ Application Data
`.
`.
`.
`.
`.
`Continuation—in—part of application No. 09/033,748, Feb. 24,
`1998, abandoned, which is a continuation—in—part of appli—
`cation No. 08/738,629, Oct. 29, 1996, Pat. No. 5,849,792,
`which is a division of application No. 08/362,677, Dec. 22,
`1994, Pat. No. 5,631,287.
`
`Int. Cl.7 ................................................. .. A61K 31/557
`[51]
`[52] U.s. Cl.
`.......................... 514/530, 514/570, 514/571,
`514/573
`[58] Field of Search ...................................... 514/530, 573
`_
`References Clted
`
`[56]
`
`U.S. PATENT DOCUMENTS
`
`[57]
`
`ABSTRACT
`
`The use of polyethoxylated Castor oils in prostaglandin
`.t.
`h
`th
`t
`1
`d.
`,
`h
`.
`1
`t b.1
`?’°mP°S1 1°“ 6“ ances
`6 Pros ag an 1“ S C emlca S a 1 '
`1ty~
`
`20 Claims, 3 Drawing Sheets
`
`2/1978 Joose
`10/1990 Nagy ............ ..
`3/1992 Nakajima et al.
`5/1992 Cherng—Chyi et al.
`2/1993 Ushio et al.
`......... ..
`5/1997 DeSantis, Jr. et al.
`
`
`
`424/237
`514/567
`.. 252/358
`.. 514/413
`.. 514/552
`............... .. 514/530
`
`4’075’333
`4,960,799
`5,098,606
`5,110,493
`5,185,372
`5,627,209
`
`000001
`
`Exhibit 1007
`
`Exhibit 1007
`ARGENTUM
`
`ARGENT
`
`000001
`
`

`

`U.S. Patent
`
`Jan. 4,2000
`
`Sheet 1 of3
`
`6,011,062
`
`FIG.
`
`1
`
`Siobiliiy of Compound No. 2. of 65°C in pH 5.0
`Preserved Vehicle with Cremophor® EL.
`
`5% Cremophor® EL/0.01% Compound No. 2.
`1::
`0 0.5% Cremophor® EL /0.01% Compound No. 2.
`o 0.5% Cremophor® EL /0.001% Compound No. 2.
`A 0.05% Cremophor® EL /0.001% Compound No. 2.
`
`10°
`
`F'-
`
`
`
`
`_ .=-<%%%'%'f'_j—
`jn’¢‘£jI':i=§_!_i
`jjj“":'-..'o1.C_:Z:n—
`_:-‘ _:
`---K—:—§
`---------
`3 ---------
`3 IIIIIIIII
`U)E
`
`
`
`L“ 10 - _——
`
`L|J
`2 -.‘-_—-2)“-
`3 -—‘---E
`——E——————
`
`IIII.II‘:IIII
`
`
`
`
`
`
`O
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`TIME (DAYS)
`
`000002
`
`000002
`
`

`

`U.S. Patent
`
`Jan. 4,2000
`
`Sheet 2 of3
`
`6,011,062
`
`FIG. 2
`
`Sfabilify of 0.01% Compound No. 2. of 55°C in pH 5.0
`Preserved Vehicle wifh the indicated Surfac’ron’r.
`
`o 0.5% Cremophor® EL
`A 0.5% Alkomuls® EL-620
`
`<> Polysorbafe 80
`
`PERCENTOFSTANDARD
`
`TIME (DAYS)
`
`000003
`
`000003
`
`

`

`U.S. Patent
`
`Jan. 4,2000
`
`Sheet 3 of3
`
`6,011,062
`
`FIG. 3
`
`Stability of 0.01% Compound No. 2. at 55°C in pH 7.4
`Preserved Vehicle with The indicated Surfactant.
`
`o 0.5% Cremophor® EL
`A 0.5% A|kc|mu|s® EL—620
`
`0 0.5% Polysorbafe 80
`
`PERCENTOFSTANDARD
`
`TIME (DAYS)
`
`000004
`
`000004
`
`

`

`1
`STORAGE-STABLE PROSTAGLANDIN
`COMPOSITIONS
`
`2
`FIG. 3 compares the stabilizing effect of different surfac-
`tants in a preserved prostaglandin formulation at pH 7.4.
`
`6,011,062
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Prostaglandin esters are difficult to formulate in storage-
`stable solutions as they tend to be hydrolytically unstable. In
`some instances,
`the parent acids of some prostaglandin
`esters are also unstable. The pharmaceutical compositions of
`the present invention, however, are storage stable. These
`compositions contain a prostaglandin and a stability-
`enhancing amount of a polyethoxylated castor oil.
`
`The polyethoxylated castor oils useful in the composi-
`tions of the present invention are commercially available,
`and include those classified as PEG-2 to PEG-200 castor
`
`oils, as well as those classified as PEG-5 to PEG-200
`hydrogenated castor oils. Such polyethoxylated castor oils
`include those manufactured by Rhone-Poulenc (Cranbury,
`N.J under the Alkamuls® brand, those manufactured by
`BASF (Parsippany, N.J under the Cremophor® brand, and
`those manufactured by Nikko Chemical Co., Ltd. (Tokyo,
`Japan) under the Nikkol brand. Preferred polyethoxylated
`castor oils are those classified as PEG-15 to PEG-50 castor
`
`oils, and more preferred are PEG-30 to PEG-35 castor oils.
`It is most preferred to use those polyethoxylated castor oils
`known as Cremophor® EL and Alkamuls® EL-620. Pre-
`ferred polyethoxylated hydrogenated castor oils are those
`classified as PEG-25 to PEG-55 hydrogenated castor oils.
`The most preferred polyethoxylated hydrogenated castor oil
`is PEG40 hydrogenated castor oil, such as Nikkol HCO40.
`
`The terms “prostaglandin” and “PG” are generally used to
`describe a class of compounds which are analogues and
`derivatives of prostanoic acid (1):
`
`(1)
`
`20
`CH3
`
`(w—chain)
`
`1 C
`
`OOH (a-chain) 10
`
`11
`
`.
`
`This is a continuation-in-part application of U.S. patent
`application Ser. No. 09/033,748, filed Feb. 24, 1998, which
`is a continuation-in-part application of U.S. patent applica-
`tion Ser. No. 08/738,629, filed Oct. 29, 1996, now U.S. Pat.
`No. 5,849,792, which is a divisional application of U.S.
`patent application Ser. No. 08/362,677, filed on Dec. 22,
`1994, now U.S. Pat. No. 5,631,287.
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates generally to prostaglandin
`compositions. In particular, the present invention relates to
`storage stable, pharmaceutical compositions containing
`prostaglandins and surfactants. As used herein,
`the term
`“prostaglandin” or “PG” shall refer to prostaglandins and
`derivatives and analogues thereof including pharmaceuti-
`cally acceptable salts and esters, except as otherwise indi-
`cated by context.
`Prostaglandins have notoriously low water solubility, and
`are generally unstable. Attempts have been made to solubi-
`lize and stabilize various prostaglandins by complexing
`them with different cyclodextrins. See, for example: EP 330
`511 A2 (Ueno et al.) and EP 435 682 A2 (Wheeler). These
`attempts have met with varying success.
`Surfactants and/or solubilizers have been used with other
`types of drugs having low water solubility. However, the
`addition of surfactants and/or solubilizers may enhance or
`adversely affect the chemical stability of drug compounds.
`See Surfactant Systems, Their Chemistry, Pharmacy, and
`Biology, (eds. Attwood et al.), Chapman and Hall, New
`York, 1983, Ch. 11, particularly pp. 698-714.
`The use of non-ionic surfactants, such as polyethoxylated
`castor oils, as solubilizing agents is known. See,
`for
`example, U.S. Pat. No. 4,960,799 (Nagy).
`The use of non-ionic surfactants such as polyethoxylated
`castor oils in stable emulsions is also known. U.S. Pat. No.
`
`intravenous emulsion
`4,075,333 (Josse) discloses stable,
`formulations of vitamins. El-Sayed et al., Int J. Pharm.,
`13:303—12 (1983) discloses stable oil-in-water emulsions of
`an antineoplastic drug. U.S. Pat. No. 5,185,372 (Ushio et al.)
`discloses topically administrable ophthalmic formulations of
`vitaminAwhich are stable preparations in which a non-ionic
`surfactant is used to form an emulsion of vitamin A in an
`
`aqueous medium.
`What is needed is a commercially viable, storage-stable
`prostaglandin composition.
`SUMMARY OF THE INVENTION
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`PG’s may be further classified, for example, according to
`their 5-membered ring structure, using a letter designation:
`
`0
`
`Prostaglandins of the A series (PGA’s):
`
`O
`
`The present invention is directed to the use of polyethoxy-
`lated castor oils in pharmaceutical compositions containing
`prostaglandins. It has now been unexpectedly discovered
`that the use of polyethoxylated castor oils in such compo-
`sitions enhances the chemical stability of prostaglandins.
`The compositions of the present invention can be adminis-
`tered to the body in a variety of ways. When topically
`applied to the eye, the compositions of the present invention
`provide both initial and continual comfort.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the stabilizing effect at different concentra-
`tions of a polyethoxylated castor oil in a preserved prostag-
`landin formulation at pH 5.0.
`FIG. 2 compares the stabilizing effect of different surfac-
`tants in a preserved prostaglandin formulation at pH 5.0.
`
`55
`
`60
`
`65
`
`000005
`
`000005
`
`

`

`3
`
`4
`
`6,011,062
`
`Prostaglandins of the B series (PGB’s):
`
`PG2’s (13,14- and 5,6-unsaturated):
`
`O
`
`
`
`PG2: 10
`
`5
`
`9
`
`11
`
`8->““\\7
`
`12
`
`13
`
`6
`
`14
`
`5
`
`1:5
`
`SH
`
`4
`
`16
`
`3
`
`17
`
`2
`
`18
`
`(EOOH (alpha-chain)
`.
`
`CZIOH3(omega-chain)
`
`19
`
`Prostaglandins of the C series (PGC’s):
`
`10 PGJS (13’14- 5’6- and 17’18-unsaturated):
`
`0
`2:
`z
`
`O
`
`PG3: 10
`
`9
`
`11
`
`8...\“‘\7
`
`12
`
`13
`
`5
`
`14
`
`15
`
`5
`
`4
`
`3
`
`16
`
`17
`
`1.5
`(=)H
`
`2
`
`18
`
`(1;OOH(1h h")
`ap a—c am
`
`19
`
`2H3 (omega-chain)
`
`25
`
`30
`
`The prostaglandins which may be utilized in the present
`20 invention include all pharmaceutically acceptable
`prostaglandins, their derivatives and analogues, and their
`pharmaceutically acceptable esters and salts. Such prostag-
`landins include the natural compounds: PGE1, PGE2, PGE3,
`PGFM, PGFM, PGF3a, PGD2 and PGI2 (prostacyclin), as
`Well as analogues and derivatives of these compounds which
`have similar biological activities of either greater or lesser
`potencies. Analogues of the natural prostaglandins include
`but are not limited to: alkyl substitutions (e.g., 15-methyl or
`16,16-dimethyl), which confer enhanced or sustained
`potency by reducing biological metabolism or alter selec-
`tivity of action; saturation (e.g., 13,14-dihydro) or unsatura-
`tion (e.g., 2,3-didehydro, 13,14-didehydro), which confer
`sustained potency by ‘reducing. biological metabolism or
`alter selectivity of action; deletions or replacements (e.g.,
`11-deoxy, 9-deoxo-9-methylene), chloro (or halogen) for
`35 oxygen (e.g., 9[3-chloro), oxygen for carbon (e.g., 3-oxa),
`lower alkyl for oxygen (e.g., 9-methyl), hydrogen for oxy-
`gen (e.g., 1-CH2OH,1-CH2OAcyl) which enhance chemical
`stability and/or selectivity of action; and (1)-chain modifica-
`tions (e.g., 18,19,20-trinor-17-phenyl, 17,18,19,20-tetranor-
`40 16-phenoxy), which enhance selectivity of action and reduce
`biological metabolism. Derivatives of these prostaglandins
`include all pharmaceutically acceptable salts and esters,
`which may be attached to the 1-carboxyl group or any of the
`hydroxyl groups of the prostaglandin by use of the corre-
`sponding alcohol or organic acid reagent, as appropriate. It
`should be understood that
`the terms “analogues” and
`“derivatives” include compounds which exhibit functional
`and physical responses similar to those of prostaglandins per
`se.
`
`45
`
`Prostaglandins of the D series (PGD’s):
`
`O
`
`OIn....
`
`prostaghndins of the E Series (PGEIS);
`
`EEO;,,,,_ ..\\\O
`
`Prostaglandins Of the F Series (PGF’S)I
`
`0?
`
`50
`
`2.
`
`3.
`
`Specific examples of prostaglandins which are useful in
`the present invention include the following compounds:
`Compound No.
`1.
`(SZ)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid;
`(SZ)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid isopropyl ester;
`(SZ)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-
`d1hydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid t-butyl ester;
`(SZ)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-
`trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid
`isopropyl ester;
`(SZ)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid isopropyl ester;
`
`4.
`
`5.
`
`Prostaglandins of the J series (PGJ’s): 7
`PG’s may be further classified based on the number of 55
`unsaturated bonds on the Side Chain:
`
`PG1:5 (13>14'un5aturated)3
`
`9 3...\\\\\ §OOH
`
`(alphmhain)
`
`PG1: 10
`
`12
`
`13/(4
`
`11
`
`15
`5
`Olin
`
`H
`
`16
`
`17
`
`18
`
`19
`
`_
`§0H3(°mega'°ha1“)
`
`60
`
`65
`
`000006
`
`000006
`
`

`

`5
`
`6
`
`6,011,062
`
`(5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-
`29.
`trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid
`isopropyl ester;
`30.
`(5Z, 13E)-(9S,11R,15R)-9,11,15-trihydroXy-16-(3-
`chlorophenoXy)-17,18,19,20-tetranor-5,13-
`prostadienoic acid amide;
`31. PGFZOL isopropyl ester;
`32. Fluprostenol isopropyl ester;
`33. Isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-
`(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroXy-
`3-furanyl]-4-heptenoate;
`34. 15-keto Latanoprost (PhXA40);
`All of the foregoing compounds are known. Preferred
`prostaglandins for use in the compositions of the present
`invention are Compounds 2-8, 24, and 32-34 above . Most
`preferred are Compounds 2, 3, 32 (especially the isomer
`1R-[1ot(Z),2[3(1E,3R*),3ot,5ot]-7-[3,5-dihydroXy-2-[3-
`hydroxy-4-[3-(trifluoromethyl)phenoXy]-1-butenyl]
`cyclopentyl]-5-heptenoic acid, 1 -methylethyl ester) and 33
`above. The structures of Compounds 2 and 3 are shown
`below.
`
`5
`
`10
`
`15
`
`20
`
`9.
`
`6.
`
`7.
`
`8.
`
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid amide;
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid N,N-dimethylamide;
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid 1-methylcyclohexyl ester;
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid 1-methylcyclopentyl ester;
`10.
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid cyclopentyl ester;
`11.
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid 2,2-dimethylpropyl ester;
`12.
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid adamantyl ester;
`13.
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid 2,6-diisopropylphenyl ester;
`14.
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid 2,6-dimethylphenyl ester;
`15.
`(5Z, 13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroXy-
`16-(3-chlorophenoxy)-17, 18,19,20-tetranor-5,13-
`prostadienoic acid isopropyl ester;
`16.
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11-
`hydroXy-15-methoXy-3-oXa-16,17,18,19,20-pentanor-
`5 -prostenoic acid t-butyl ester;
`17.
`(5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-
`trihydroXy-16,17,18,19,20-pentanor-5-prostenoic acid
`isopropyl ester;
`18.
`(5E)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenoic acid isopropyl ester;
`19.
`(5Z)-(9R,11R)-9-chloro-15-cycloheXyl-11-hydroXy-
`3-oXa-15-oxo-16,17,18,19,20-pentanor-5-prostenoic
`acid tertbutyl ester;
`20.
`(5Z)-(9S,11R,15R)-3-oXa-17-phenyl-9,11,15-
`trihydroxy-18,19,20-trinor-5-prostenoic acid isopropyl
`ester;
`
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-1-
`21.
`(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-
`prostene-11,15-diol;
`22.
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`prostenol;
`23. (9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroXy-3-
`thia-16,17,18,19,20-pentanor-13-prostynoic acid;
`24. Latanoprost (PhXA41);
`25. Cloprostenol isopropyl ester;
`26.
`(5Z)-(9S,11R,15R)-1-decarboxy-1 -(pivaloyloxy)
`methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oXy]-
`17,18,19,20-tetranor-5-prostenoic acid;
`27.
`(5Z)-(9S,11R,15R)-1-decarboxy-1 -(pivaloyloxy)
`methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oXy]-
`17,18,19,20-tetranor-5,13-prostadienoic acid;
`28.
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid
`isopropyl ester;
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`000007
`
`EOlIIu-
`
`The prostaglandin compositions of the present invention
`contain one or more polyethoxylated castor oils in an
`amount effective to enhance the stability of the prostaglan-
`din. As FIG. 1 illustrates the stabilizing effect of the poly-
`ethoxylated castor oil increases with increasing polyethoXy-
`lated castor oil concentration. However, other factors may
`limit the amount of polyethoxylated castor oil to be utilized
`in the compositions of the present invention. For example,
`too much polyethoxylated castor oil should not be used in
`order to avoid adversely affecting the prostaglandin’s phar-
`macologic activity.
`In general, compositions of the present invention will
`include one or more polyethoxylated castor oils in an
`amount between about 0.02 and about 20.0 percent by
`weight (wt %) and one or more prostaglandins in an amount
`between about 0.00001 and about 0.2 wt %. It is preferred
`to use one or more polyethoxylated castor oils in an amount
`between about 0.1 and about 5.0 wt %, and it is especially
`preferred to use an amount between about 0.5 and about 2.0
`wt %. It is preferred to use one or more prostaglandins in an
`amount between about 0.0001 and about 0.1 wt %, depend-
`ing on the potency of the prostaglandin. In the case where
`the prostaglandin compound is Compound 32, prostaglandin
`concentrations of 0.0015% (w/v) and 0.004% (w/v) are
`
`(2)
`
`(3)
`
`25
`
`Cl
`
`\¥\OK\COOCH(CH3)2
`
`
`
`EO|IIu-
`
`.\am-‘ ‘ : 0/\CooC(CH3)3
`
`(:1
`
`H6
`
`000007
`
`

`

`6,011,062
`
`7
`preferred. In the case where the prostaglandin compound is
`Compound 33, a prostaglandin concentration of 0.01% (w/v)
`is preferred.
`The compositions of the present invention may be admin-
`istered to the body in a variety of ways. The compositions
`may be administered by mouth, by intravenous injection or
`by topical application to the skin, nose or eyes. Most
`preferred are compositions prepared for topical administra-
`tion to the eye.
`In addition to the above-described principal active
`ingredients, the compositions of the present invention may
`further comprise various formulatory ingredients, such as
`antimicrobial preservatives,
`tonicity agents, and buffers.
`Examples of suitable antimicrobial preservatives include:
`benzalkonium chloride, thimerosal, chlorobutanol, methyl
`paraben, propyl paraben, phenylethyl alcohol, edetate
`disodium, sorbic acid, Polyquad® and other agents equally
`well known to those skilled in the art. Such preservatives, if
`utilized, will typically be employed in an amount between
`about 0.001 and about 1.0 wt %. Examples of suitable agents
`which may be utilized to adjust the tonicity or osmolality of
`the formulations include sodium chloride, potassium
`chloride, mannitol, dextrose, glycerine and propylene gly-
`col. Such agents, if utilized, will be employed in an amount
`between about 0.1 and about 10.0 wt %. Examples of
`suitable buffering agents include acetic acid, citric acid,
`carbonic acid, phosphoric acid, boric acid, the pharmaceu-
`tically acceptable salts of the foregoing, and tromethamine.
`Such buffers, if utilized, will be employed in an amount
`between about 0.001 and about 1.0 wt %.
`
`The compositions of the present invention may addition-
`ally include components to provide sustained release and/or
`comfort. Such components include high molecular weight,
`anionic mucomimetic polymers and gelling
`polysaccharides, such as those described in U.S. Pat. No.
`4,861,760 (Mazuel et al), U.S. Pat. No. 4,911,920 (Jani et
`al.), and in commonly assigned U.S. Ser. No. 08/108,824
`(Lang et al.). The contents of these patents and patent
`applications relating to the polymers cited above are incor-
`porated herein by reference.
`the
`As will be appreciated by those skilled in the art,
`compositions may be formulated in various dosage forms
`suitable for topical ophthalmic delivery, including solutions,
`suspensions, emulsions, gels and erodible solid ocular
`inserts. The compositions are preferably aqueous, have a pH
`between 3.5 to 8.0 and an osmolality between 260 to 320
`milliOsmoles per kilogram (mOsm/kg).
`The present
`invention is also directed to methods of
`treating glaucoma and other ophthalmic diseases and abnor-
`malities. The methods comprise topically applying to the
`affected eye(s) of the patient a therapeutically effective
`amount of a composition according to the present invention.
`The frequency and amount of dosage will be determined by
`the clinician based on various clinical factors. The methods
`
`will typically comprise topical application of one or two
`drops (approximately 30 microliters) of a
`liquid
`composition, or an equivalent amount of a solid or semi-
`solid dosage form, to the affected eye one to two times per
`day.
`
`EXAMPLE 1
`
`The following topically administrable ophthalmic formu-
`lations are representative of the compositions of the present
`invention.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`INGREDIENT
`
`Compound 2
`Compound 3
`Cremophor ® EL
`Sodium Acetate
`(Trihydrate)
`Tromethamine
`Boric Acid
`Mannitol
`Disodium EDTA
`Benzalkonium Chloride
`NaOH and/or HCl
`Purified Water
`
`FORMULATION wt %
`
`A
`
`0.01
`—
`0.5
`0.07
`
`B
`
`—
`0.01
`0.5
`0.07
`
`C
`
`0.01
`—
`0.5
`—
`
`0.12
`—
`—
`0.3
`—
`—
`4.6
`4.6
`4.6
`0.1
`0.1
`0.1
`0.01
`0.01
`0.01
`q.s. to pH 7
`q.s. to pH 5
`q.s. to pH 5
`q.s. to 100% q.s. to 100% q.s. to 100%
`
`Preparation of Formulations A—C:
`To a clean glass vessel of appropriate size was added
`approximately 75% of the batch volume of water. To this
`was sequentially added sodium acetate, tromethamine, boric
`acid, mannitol, EDTA, benzalkonium chloride and Cremo-
`phor® EL so that there was complete dissolution of one
`ingredient prior to the addition of the next ingredient. Next
`the pH of the solution was adjusted using NaOH and/or HCl,
`and the water was added to bring the volume to 100%.
`In a separate clean glass vessel, the appropriate quantity
`of prostaglandin was added, followed by the appropriate
`quantity of the vehicle whose preparation was described
`above. The vessel was then tightly capped and sonicated in
`an ultrasonic bath for one hour or alternatively stirred with
`a magnetic stir bar overnight, until the prostaglandin was
`completely dissolved. The resulting solution was then sterile
`filtered (0.2 micron filter) into sterile containers. These
`containers were then aseptically plugged, capped and
`labelled.
`
`The stabilizing effect of polyethoxylated castor oils in the
`compositions of the present invention was evaluated accord-
`ing to the following procedure.
`1. Pipet the required quantity of 1% w/v prostaglandin
`ethanolic stock solution into 1.5 mL high performance
`liquid chromatograph (HPLC) sample vials.
`2. Dry the sample vials under a stream of helium.
`3. Add 1 mL of the appropriate vehicle (or HPLC mobile
`phase for standards).
`4. Sonicate the vials one hour to dissolve the prostaglan-
`din.
`
`5. Run initial HPLC assays.
`6. Place the HPLC sample vials into 20 cc scintillation
`vials with several mIs of deionized water and cap
`tightly. (Note: This prevents loss due to evaporation.)
`Standards are stored with HPLC mobile phase in the
`scintillation vial.
`
`7. Place the vials in the appropriate controlled tempera-
`ture ovens and reassay periodically by HPLC. Stan-
`dards are stored in a refrigerator.
`8. HPLC Data Analysis: Divide Sample Peak Area by
`Standard Peak Area and multiply by 100 to obtain
`Percent of Standard for each sample at each time point.
`9. Plot Percent of Standard versus time on a semiloga-
`rithmic graph. Fit a monoexponential equation to the
`data. The slope times 2.303 is the apparent first-order
`degradation rate constant for each plot (Note: The
`factor of 2.303 converts common logarithm to natural
`logarithm).
`FIG. 1 demonstrates the effect of increasing polyethoxy-
`lated castor oil concentration in Formulation A. The chemi-
`
`000008
`
`000008
`
`

`

`6,011,062
`
`9
`cal stability of a given concentration of prostaglandin is
`increased as the concentration of Cremophor® EL is
`increased.
`
`FIG. 2 demonstrates the superior stabilizing effect of the
`polyethoxylated castor oils, Cremophor® EL and Alkam-
`uls® EL-620, over Polysorbate 80 in a type A Formulation
`(pH=5.0).
`FIG. 3 demonstrates the superior stabilizing effect of the
`polyethoxylated castor oils, Cremophor® EL and Alkam-
`uls® EL-620, over Polysorbate 80 in a type C formulation
`(pH=7.4).
`The data shown in FIGS. 1-3 were generated using a
`Phenomenex 250 X 4.6 mm HPLC column with Spher-
`isorb® 10 ODS(2) packing. The mobile phase was 50/50
`acetonitrile/0.1% phosphoric acid at pH 3 with NaOH, 5
`mM tetrabutylammonium hydroxide, and 5 mM sodium
`dodecylsulfate. The flow rate was 2 mL/minute, the detec-
`tion was 190-192 nm UV, and the injection quantity was 25
`mcL.
`
`EXAMPLE 2
`
`The following topically administrable ophthalmic formu-
`lation is representative of the compositions of the present
`invention.
`
`10
`chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,
`20-pentanor-5-prostenoic acid isopropyl ester;
`(5Z)-(9R,
`11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroXy-3-oXa-
`16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;
`(5Z)(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-
`trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid iso-
`propyl ester;
`(5Z)-(9R,11R,15S)-9-chloro-15-cycloheXyl-
`11,15-dihydroXy-3-oXa-16,17,18,19,20-pentanor-5-
`prostenoic acid isopropyl ester;
`(5Z)-(9R,11R,15R)-9-
`chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,
`20-pentanor-5-prostenoic acid amide; (5Z)-(9R,11R,15R)-
`9-chloro-15-cycloheXyl-11,15-dihydroXy-3-oXa-16,17,18,
`19,20-pentanor-5-prostenoic acid N,N-dimethylamide;
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroXy-3-oXa-16,17,18,19,20-pentanor-5-prostenoic
`acid 1-methylcyclohexyl ester;
`(5Z)-(9R,11R,15R)-9-
`chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,
`20-pentanor-5-prostenoic acid 1-methylcyclopentyl ester;
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15-
`dihydroXy-3-oXa-16,17,18,19,20-pentanor-5-prostenoic
`acid cyclopentyl ester;
`(5Z)-(9R,11R,15R)-9-chloro-15-
`cyclohexyl-11,15-dihydroxy-3-oxa-1 6,17,18,19,20-
`pentanor-5-prostenoic acid 2,2-dimethylpropyl ester; (5Z)-
`(9R,11R,15R)-9-chloro-15-cycloheXyl-11,15 -dihydroXy-3-
`oxa-16,17,18,19,20-pentanor-5-prostenoic acid adamantyl
`
`10
`
`15
`
`20
`
`INGREDIENT
`
`Compound 32*
`Compound 33
`Brimonidine
`PEG-40 hydrogenated castor oil
`Tromethamine
`Boric acid
`Mannitol
`Edetate Disodium
`Benzalkonium Chloride
`NaOH/HCl
`Purified Water
`
`A
`% (w/V)
`
`B
`% (w/V)
`
`C
`%(w/V)
`
`0.002
`—
`0.001—0.005
`—
`0.001—0.005
`—
`0.2
`—
`—
`0.5
`0.5
`0.5
`0.785
`0.12
`0.12
`0.6
`0.3
`0.3
`4.25
`4.6
`4.6
`0.01
`0.01
`0.01
`0.015
`0.015
`0.015
`q.s. to pH 6 2 0.2 q.s. to pH 6 1 0.2 q.s. to pH 6 1 0.2
`q.s. to 100%
`q.s. to 100%
`q.s. to 100%
`
`*preferably 1R-[1oL(Z),2[5(1E,3R*),3oL,5oL]-7-[3,5-dihydroxy-2-[3-hydroXy-4-[3-
`(trifluoromethyl)phenoXy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl ester
`
`The invention has been described by reference to certain
`preferred embodiments; however, it should be understood
`that it may be embodied in other specific forms or variations
`thereof without departing from its spirit or essential char-
`acteristics. The embodiments described above are therefore
`considered to be illustrative in all respects and not
`restrictive, the scope of the invention being indicated by the
`appended claims rather than by the foregoing description.
`What is claimed is:
`1. An aqueous pharmaceutical composition comprising a
`therapeutically effective amount of a prostaglandin, a poly-
`ethoxylated castor oil in an amount effective to enhance the
`chemical stability of the prostaglandin, an antimicrobial
`preservative and a pharmaceutically acceptable vehicle,
`wherein the polyethoxylated castor oil is selected from the
`group consisting of PEG-5 to PEG-200 hydrogenated castor
`oils.
`2. The composition of claim 1 wherein the polyethoXy-
`lated castor oil is selected from the group consisting of
`PEG-25 to PEG-55 hydrogenated castor oils.
`3. The composition of claim 2 wherein the polyethoXy-
`lated castor oil is PEG-40 hydrogenated castor oil.
`4. The composition of claim 1 wherein the prostaglandin
`is selected from the group consisting of (5Z)-(9R,11R,15R)-
`9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oXa-16,17,18,
`19,20-pentanor-5-prostenoic acid;
`(5Z)-(9R,11R,15R)-9-
`
`45
`
`50
`
`55
`
`60
`
`65
`
`(5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-
`ester;
`dihydroXy-3-oXa-16,17,18,19,20-pentanor-5-prostenoic
`acid 2,6-diisopropylphenyl ester;
`(5Z)-(9R,11R,15R)-9-
`chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,
`20-pentanor-5-prostenoic acid 2,6-dimethylphenyl ester;
`(5Z, 13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroXy-16-(3-
`chlorophenoXy)-17,18,19,20-tetranor-5,13-prostadienoic
`acid isopropyl ester;
`(5Z)-(9R,11R,15R)-9-chloro-15-
`cyclohexyl-11-hydroXy-15-methoXy-3-oXa-16,17,18,19,20-
`pentanor-5-prostenoic acid t-butyl ester;
`(5Z)-(9R,11R,
`15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,
`20-pentanor-5-prostenoic acid isopropyl ester;
`(5E)-(9R,
`11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroXy-3-oXa-
`16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
`(5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroXy-3-oXa-
`15-oxo-16,17,18,19,20-pentanor-5-prostenoic acid tertbutyl
`ester;
`(5Z)-(9S,11R,15R)-3-oXa-17-phenyl-9,11,15-
`trihydroXy-18,19,20-trinor-5-prostenoic acid isopropyl
`ester;
`(5Z)-(9R,11R,15R)-9-chloro-15-cycloheXyl-1-
`(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-
`prostene-11,15-diol;
`(5Z)-(9R,11R,15R)-9-chloro-15-
`cycloheXyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-
`pentanor-5-prostenol; 9R,11R,15R)-9-chloro-15-
`cycloheXyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-
`prostynoic acid;
`latanoprost; 15-keto latanoprost;
`cloprostenol
`isopropyl ester;
`(5Z)-(9S,11R,15R)-1-
`
`000009
`
`000009
`
`

`

`6,011,062
`
`11
`
`decarboxy-1-(piValoyloXy)methyl-9,11,15-trihydroXy-16-
`[(3-chlorophenyl)oXy]-17,18,19,20-tetranor-5-prostenoic
`acid;
`(5Z)-(9S,11R,15R)-1-decarboXy-1-(pivaloyloxy)
`methyl-9,11,15-trihydroXy-16-[(3-chlorophenyl)oXy]-17,
`18,19,20-tetranor-5,13-prostadienoic acid;
`(5Z)-(9R,11R,
`15R)-9-chloro-15-cyclohexyl-11,15-dihydroXy-16,17,18,
`19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9S,
`11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,
`20-pentanor-5-prostenoic acid isopropyl ester; (5Z, 13E)-
`(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoXy)-
`17,18,19,20-tetranor-5,13-prostadienoic acid amide; PGFZOL
`isopropyl ester; fluprostenol isopropyl ester; and isopropyl
`[2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-
`chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroXy-3-
`furanyl]-4-heptenoate.
`5. The composition of claim 4 wherein the prostaglandin
`is selected from the group consisting of fluprostenol isopro-
`pyl ester; isopropyl [2R(1E,3R),3S(4Z),4R]-7 -[tetrahydro-
`2-[4-(3-chlorophenoxy)-3-hydroXy-1 -butenyl]-4-hydroXy-
`3-furanyl]-4-heptenoate;
`latanoprost; and 15-keto
`latanoprost.
`6. The composition of claim 1 wherein the composition is
`a topically administrable ophthalmic composition and the
`prostaglandin is selected from the group consisting of flu-
`prostenol isopropyl ester and isopropyl [2R(1E,3R),3S(4Z),
`4R]-7-[tetrahydro-2-[4-(3-chlorophenoXy)-3-hydroXy-1-
`butenyl]-4-hydroXy-3-furanyl]-4-heptenoate.
`7. The composition of claim 6 wherein the fluprostenol
`isopropyl ester is 1R-[1ot(Z),2[3(1E,3R*),3oL,5ot]-7-[3,5-
`dihydroxy-2-[3-hydroXy-4-[3-(trifluoromethyl)-phenoXy]-
`1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethyl
`ester.
`
`8. The composition of claim 7 wherein the composition
`has a pH of 5.8-6.2 and comprises 0.0001-0.005%(w/V)
`1R-[1ot(Z),2[3(1E,3R*),3ot,5ot]-7-[3,5-dihydroXy-2-[3-
`hydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]
`cyclopentyl]-5-heptenoic acid, 1-methylethyl ester; 0.5%(w/
`V) PEG-40 hydrogenated castor oil; 0.12%(w/V)
`tromethamine; 0.3%(w/V) boric acid; 4.6%(w/V) mannitol;
`0.01%(w/V) disodium edetate; and 0.015%(w/V) benzalko-
`nium chloride.
`
`9. The composition of claim 8 wherein the concentration
`of 1R-[1ot(Z),2[3(1E,3R*),3ot,5ot]-7-[3,5-dihydroXy-2-[3-
`hydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]
`cyclopentyl]-5-heptenoic acid, 1-methylethyl ester is
`selected from the group consisting of 0.0015%(w/V) and
`0.004%(w/V).
`10. The composition of claim 1 wherein the composition
`has a pH of 5.8-6.2 and comprises 0.01%(w/V) isopropyl
`[2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-
`chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroXy-3-
`furanyl]-4-heptenoate; 0.5%(w/V) PEG-40 hydrogenated
`castor oil; 0.12%(w/V) tromethamine; 0.3%(w/V) boric acid;
`4.6%(w/V) mannitol; 0.01%(w/V) disodium edetate; and
`0.015%(w/V) benzalkonium chloride.
`11. The composition o