IIIMIIIIIIIIIII
`
`U800563 1287A
`
`United States Patent
`
`[19]
`
`Schneider
`
`5,631,287
`[11] Patent Number:
`
`[45} Date of Patent:
`May 20, 1997
`
`[54] STORAGE-STABLE PROSTAGIANDIN
`C0
`SITIONS
`
`.
`_
`Inventor. L. Wayne Schneider. Crowley, "Rex.
`
`['75]
`
`[73] ASSigIICC: Alcon Lawratofifiq 1110-, Fort Worth.
`Tex.
`
`FOREIGN PATENT DOCUMENTS
`0132027Al
`111985 European Pat.01I .
`0407148A3
`li'1991 Eumpean Pat. 01f. .
`0645145A3
`31,1995 Eu:
`Pat. on. .
`0667le 8f1995 European Pat. Off. .
`wogsmslfis
`421.1995 WIPO .
`UFHER PUBUCMTONS
`
`[21] App]. No.: 362,677
`.
`_
`Dec. 22, 1994
`[22] Fjlcd.
`A61K 311557
`[51]
`Int. CLG m“...
`
`[52] US. Cl.
`...............
`5141530; 514153; 560nm
`[58] Field of Search
`514.3530, 573;
`560nm, 121; 562503
`
`[56]
`
`.
`Referenm Clad
`U.S. 13mm DOCUMENTS
`
`Poster et aL, “Intraocular Penetration of Miconazole in
`Rabbits.” Arch Ophthalmol. 97x9. pp. 1703-4706 (1979)
`(abstract only).
`Primry Examiner—Robert Gerstl
`Attorney, Agent, or Finn—Patrick M. Ryan
`
`ABSIRACT
`[57]
`The use of polyethoxylated caster oils in prostaglandin
`compositions greatly enhances the prostaglandin’s chemical
`Stability
`
`5,004,752
`
`4I'199l Radllechel .. 5141530
`
`12 Claims, 3 Drawing Sheets
`
`000001
`
`IPR2017-01053
`
`Exhibit 1 103
`
`ARGENTUM
`
`Exhibit 1103
`ARGENTUM
`IPR2017-01053
`
`000001
`
`

`

`US. Patent
`
`May 20, 1997
`
`Sheet 1 of 3
`
`5,631,287
`
`FIG.
`
`1
`
`Stability of Compound No. 2. of 65°C in pH 5.0
`Preserved Vehicle with Cremophor® EL.
`
`D 5% Cremophor® EL /0.01% Compound No. 2.
`0 0.5% Cromophor® 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.
`
`
`100 a 'i
`
`
`
`.IIIIIII-IllfllllllIIl'll
`Illllllll-Illlll’mIIIIIIuII-IllllmnIIIIyIII-Illllifl
`l-II.III’IIFl-IIIIIII1‘JI
`.IIIflIII-IllllllllHIIIIIII-Illlflllll
`
` PERCENTOFSTANDARD 3 r,0
`IIIflIIII-II.1
`
`
`
`.
`
`.IIIIII'I
`
`0 51015202530354045
`
`TIME (DAYS)
`
`000002
`
`000002
`
`

`

`US. Patent
`
`May 20, 1997
`
`Sheet 2 of 3
`
`5,631,287
`
`FIG. 2
`
`Siabilify of 0.01% Compound No. 2. at 55°C in pH 5.0
`Preserved Vehicle with the indicated Surfactant.
`
`o 0.5% Cremophor® EL
`A 0.5% Alkamu|s® EL-620
`<> Polysorba’re 80
`
` PERCENTOFSTANDARD
`
`TIME (DAYS)
`
`000003
`
`000003
`
`

`

`US. Patent
`
`May 20, 1997
`
`Sheet 3 of 3
`
`5,631,287
`
`FIG. 3
`
`Sfabiliiy of 0.01% Compound No. 2. of 55°C in pH 7.4
`Preserved Vehicle with ’rhe indicated Surfactant
`
`0 0.5% Cremophor® EL
`A 0.5% Alkomuls® EL-620
`
`0 0.5% Polysorbafe 80
`
`PERCENTOFSTANDARD
`
`TIME (DAYS)
`
`000004
`
`000004
`
`

`

`5,631,287
`
`2
`
`1
`STORAGE—STABLE PROSTAGLANDIN
`COMPOSITIONS
`
`BACKGROUND OF THE NVENHON
`
`The present invention relates generally to prostaglandjn
`compositions. In particular. the present invention relates to
`storage stable. pharmaceutical compositions containing
`postaglandins 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 odterwise 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 compiexing
`them with different cyclodextrins- See. for example: EP 330
`511 A2 {Ueno et a1.) and EP 435 682 A2 (Wheeler). These
`attempts have met with varying success.
`Surfactants andfor solubilizers have been used with other
`types of drugs having low water solubility. However. the
`addition of surfactants andfor solubilizers may enhance or
`adversely affect the chemical stability of drug compounds.
`See Surfactant Systems, Their Chemisn-y, Pharmacy; and
`Biology, (eds. Attwood et at). Chapman and Hall, New
`York. 1983.01. 11. particularly pp. 698—714.
`The use of non-ionic surfactants, such as polyethoxylated
`castor oils. as soiubilizing agents is known. See, for
`example. U.S. Pat. No. 4,960,799 (Nagy).
`The use of non-ionic surfactants such as polyethoxylated
`caster oils in stable emulsions is also known. U.S. Pat. No.
`4.075.333 (Josse) discloses stable, intravenous emulsion
`formulations of vitamins. El-Sayed et al._. Int. J. Pham._.
`13:303—12 (1933) discloses stable oil—inwwater emulsions of
`an antineoplastic drug. U.S. Pat. No. 5.185.372 {Ushio et a1.)
`discloses topically administrable ophthalmic formulations of
`vitamin Awhich 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.
`SUNIMARY OF THE INVENTION
`
`The present invention is directed to the use ofpolyethoxy—
`lated castor oils in pharmaceutical compositions containing
`prostaglandins. It has now been unexpectedly discovered
`that the use of such polyethoxylated castor oils in such
`compositions enhances the chemical stability of prostaglan-
`dins in pharmaceutical compositions. The compositions of
`the present invention can be administered 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 difl’erent concentra-
`tions of a polyethoxylated castor oil in a preserved. prostag—
`landin formulation at pH 5.0.
`FIG. 2 compares the stabilizing eifect of different surfac—
`tants in a preserved prostaglandin formulation at pH 5.0.
`FIG. 3 compares the stabilizing elfect of dilferent surfac~
`tants in a preserved prostaglandin formulation at pH 7.4.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Prostaglandin esters are dificult to formulate in storage-
`stable solutions as they tend to be hydrolytically unstable. In
`
`the parent acids of some prostaglandin
`some instances,
`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.
`
`10
`
`15
`
`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 (Q‘anbury,
`NJ.) under the Alkamuls® brand, and those manufactured
`by BASF (Parsippany, NJ.) under the Gemophor® brand.
`It is preferred to use the polyethoxylated caster oils classi-
`fied as PEGIS to PEG-50 castor oils. and more preferred to
`use PEG—30 to PEG»35 Castor oils. It is moet preferred to use
`those polyethoxylated castor oils known as Cremophor® EL
`and Alkamuls® 3.4320.
`
`The terms “prostaglandin” and “PG” are generally used to
`describe a class of compounds which are analogues and
`derivatives of prostanoic acid (1):
`
`9
`
`10
`
`a “OVW COOK
`\
`1
`5
`3
`
`]
`
`12
`
`ll
`
`1
`( )
`
`PG’s may be further classified, for example, according to
`their 5-membered ring structure, using a letter designation:
`
`0
`
`0
`
`O
`
`H0
`
`0 D
`
`110'
`
`Prostaglamlins of the A series (PGA‘s):
`
`Hostaglandins of the E series (PGE‘S):
`
`Prostnglandins of the C scrim (PGC‘s):
`
`Prostsglandins of the D series (PGD‘s):
`
`Prostaglandins of the E series [PGE’5):
`
`35
`
`45
`
`50
`
`55
`
`65
`
`000005
`
`000005
`
`

`

`3
`-continued
`
`anmghmfiuofmermksflXHW$
`
`Prostaglandins of the J series (PGI's):
`
`H0
`
`H0!”
`
`0
`
`PG‘s may be further classified based on the number of
`unsaturated bonds on the side chain:
`
`I’Gl's (13,14-msattn'aled):
`
`5,6312%?
`
`4
`
`16-phenoxy), which enhance selectivity of action andreduce
`biological metabolism Derivatives of these prostaglandins
`include all phannaceutically acceptable salts and esters,
`which may be attached to the 1~carboxy1 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 similarto those ofprostaglandins per
`SC.
`
`Specific samples of prostaglandins which are useful in
`the present invention include the following compounds:
`Compound No.
`1. (SZ)-(9R,l1R,15R)—9-chloro-15-cyclohexyl-11,15—
`dihydroxy-3 Hoxa- 16,17 , 18,19,20—pentanor—5—prcstenoic
`acid;
`
`10
`
`15
`
`
`
`
`1
`5
`a
`Wow}! (optimum)
`CH;
`(omega-chain)
`
`
`
`45
`
`50
`
`55
`
`60
`
`The proslaglandins which may be utilized in the present
`invention include all pharmaceutically acceptable
`[nostaglandins their din-Natives and analogues, and their
`pharmaceutically acceptable esters and salts. Such prostag-
`landins include the natural compounds: PGEI, PGEZ, PGEa,
`PGFm, PGsz PGFM. PGD2 and P612 (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 pmstaglandins include
`but are not limited to: alkyl substitutions (e.g., 15-methyl oer
`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 (eg., 2,3-didehydro, 13,14~dihydro), which confer sus-
`tained potency by reducing biological metabolism or alter
`selectivity of action; deletions or replacements (e.g.,
`ll-deoxy, 9-deoxo-9-methylene), china-o (or halogen) for
`oxygen (e.g., Qfi-cbloro), oxygen for carbon (e.g., 3-oxa),
`lower alkyl for oxygen (e.g., 9-methyl), hydrogen for oxy-
`gen (e.g., l—CHQOHJ-CHZO Acyl) which enhance chemical
`stability andlor selectivity of action; and (ii-chain modifica—
`tions (e.g., 18,19,20—trinor-17-phenyl, l7,18,19,20—tetranor-
`
`2. (52)-(9R,1 1R,15R)-9-chloro— 15-cyclohexyl—11,15-
`dihydroxy-S-ox a- 16,17,18,19,20-pentanor-5-prostenoic
`acid isopropyl ester;
`3 . (SZ)-(9R,l1R,15R)-9-chloro-lS—cyclohexyl-11,15-
`dihydroxy-3 -oxa- 16,17, 18, 19,20-pentanor—5-pro stenoic
`acid t—butyl ester;
`4.
`(SEQ-(95 ,11R,15RHS-cyclobexyl-3-oxa—9 ,11,15-
`u-ihydroxy-16,17,18,19,20—pentan0I-5 -prostenoic acid iso-
`pronyl ester,
`5. (SZ)-(9R,11R,lSS)-9—cbloro-15-cyclohexyl-ll,15-
`dihydroxy-B-oxa—16,l7,18,19,20wpentanor-5-prostenoic
`acid isopropyl ester:
`6. (SZ)-(9R,l 111,1 5R)-9-chloro-l S—cyclohexyl- l 1,15-
`dihydroxy-B—oxa- 16,17,18, 19,20-pentanor—5 —prostenoic
`acid amide;
`7.
`(5 Z)-(9R,11R,15R)-9-chloro— 15-cydohexyl—1 1, 15-
`dihydroxy-3-oxa-16,1'l,18,19,20-pentanor-5-prostenoic
`acid N,N-dimethylamide;
`8.
`(SZ)w(9R, 1lR,15R)-9-chioro-15-cyclohexy1-11,15-
`dihydroxy-B-oxa-16,17,18,19,20-pentanor—S-prostenoic
`acid 1-methylcyclohexyl ester;
`9.
`(SZ)-(9R.l1R,15R)-9-cbloro—15-cyclohexyl-11,15-
`dihydroxy—B-oxa-16,17,18,19,20-pentanor—5-prostenoic
`acid l—methylcyclopentyl ester;
`
`000006
`
`000006
`
`

`

`5
`
`5,631,287
`
`10. (SD-(9R,11R,15R)-9-chloro- 15-cyclohexyl-1 1,15-
`dihydroxy-3-oxa-16.17,13,19,20-pentanor-5-prostenoic
`acid cyclopentyl ester;
`11. {SZ)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy—3~oxa-16.17.18,19.20-pentanor—5—prostenoic
`acid 22—dimethlen-opyl ester;
`12. (52) -(9R., 11R.15R)—9—chloro- lS-cyclohexyl-11,15-
`dihydroxy-3 -oxa- 16,17 .18, 19,20-pentanor-S -pros tenoic
`acid adamantyl ester;
`13.
`(52)-(9R,11R.15R)-9-chloro-15-cyclohexyl-11.15-
`dihy droxy-3-oxa- 16. 1'? , 18. 19,20-pen tanor-S-pro ste noic
`acid 2.6-diisopropy1phenyl ester;
`14. (SZ)-(9R.11R.15R)-9—chloro-15-cyclohexyl-11,15-
`dihy droxy-B -oxa- 16,17 , 18.19.20-pentanorw5vprostenoic
`acid 2.6-dirnethylphenyl estu;
`15. (52. 13E}(9S.11R,15R)—3-oxa-9,ll,15-ttihydroxy-
`16-(3-chlorophenoxy)-17 . 18.19.20-tetranor-5 .13-
`prostadienoic acid isopropyl ester;
`16.
`(SZ)-(9R.11R,15R)-9-chloro-15-cyclohexyl-l1-
`hydroxy-I5-methoxy—3—oxa—16,17.18.19.20-pentanor—5-
`prostenoic acid t—butyl ester;
`17.
`(52) -(9R, 1 1R,15R)-15- cyclohexyl—3 -oxa-9,11 ,15-
`tn'hydroxy—lé.17,18.19,20—pentanor—5-prostenoic acid iso-
`rmpyl ester:
`18.
`(SE)-{9R,11R, 15R)-9-chloro- 15 -cyclohexyl-l 1,15-
`dihydroxy—B—oxa—16,17,18,19,20~pentanor—S—prostenoic
`acid isopropyl ester;
`19.
`(SZ)-(9R.llR)—9—chloro-15-cyclohexyl-ll-hydroxy-
`3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostenoic acid
`tertbutyl ester;
`20.
`(52)~(9S,l1R.15R)-3-oxa-l'7—phenyl—9,11,15-
`trihydroxy—ls.19,20trinor—5-prostenoic acid is0pr0py1
`ester;
`
`(52.)-(9R,11R.15R)-9-chloro-15-cyclohexyl-l-
`21.
`(dimethylamino)-3-oxa-16.17,18.19.20-pentanor-5-
`prostene—llJS-diol;
`22.
`(SZ)—(9R,1 1R,15R)—9—chloro— 15—cyclohexy1~11,15—
`dihydroxy—B-oxa-16,17,18.19.20~p entanta—S—prostenol;
`23. (9R.11R.15R)—9-chloro-15-cyclohexyl-11—hydroxy—3—
`t11ia-16.17.18,19.20-pentanor—B-prostynoic acid;
`24. Latanoprost (PhXAAl);
`25. Cloprostenol isopropyl ester;
`26.
`(SZ)-(9S,11R_. 15R)- 1-decarboxy-l-(pivaloyloxy)
`methyl-9.1 1,15-t1ihydroxy-16-[(3 -chlorophenyl)oxy}-17 ,
`18.19.20-tetranor-5-prostenoic acid;
`27.
`(52)—(98,11R,15R)-l-decarboxy-l-(pivaloyloxy)
`methyl~9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]—l? ,
`13.19.20-tetranoe5,13—prostadienoic acid;
`28.
`(SZ)-(9R_. 11R.15R)-9- chloro— lS-cyclohexyl- 11 .15-
`dihydroxy-16.1?,18.19.20-pentanm-5-prostenoic acid iso-
`propyl ester;
`29.
`(SZ)-(98_.11R,lSS)-15—cyclohexyl-9_.11,15—
`trihydroxy-lfi.17,18.19.20-penmnoe5-prostenoic acid is}
`propyl ester;
`30. (52, 13E)-(93.11R,15R)-9,11.15-trihydroxy-16-(3-
`chlorophenoxy)-17_.18, 19,20-tetranor-5, 13 -pro stadienoic
`acid amide;
`31. PGFmisopropyl ester; and
`32. Huprcstenol isopropyl ester.
`All of the foregoing compounds are known. Preferred
`prostaglandins for use in the compositions of the {resent
`invention are Compounds 2—8 above. Most preferred are
`Compounds 2 and 3 above. The structures of Compounds 2
`and 3 are shown below.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`(2)
`
`(3)
`
`The prostaglandin compositions of the present invention
`contain one or more poiyethoxylated caster oils in an
`amount effective to enhance the stability of the prostaglan-
`din. As FIG. 1 illustrates the stabilizing efl’ect of the poly-
`etihoxylated 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 polyetboxylated 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.
`The compositions of the present invention may be admin-
`istered to the body in a variety of ways. The compositions
`may be administered by month, 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 buifers.
`Examples of suitable antimicrobial preservatives include:
`benzalltonium 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 ‘36. 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 0 table
`bufl'ering agents include acetic acid. citric acid, carbonic
`acid, phosphoric acid, boric acid.
`the phannaoeutically
`acceptable salts of the foregoing, and trometbamine. 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 andlor
`comfort. Such components include high molecular weight.
`
`000007
`
`000007
`
`

`

`7
`
`5,631,287
`
`8
`
`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% wlv prostaglandin
`ethanolic stock solution into 1.5 mL high perfcsmance
`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 prostaglandin.
`5. Run initial HPLC assays.
`6. Place the HPLC sample vials into 20 cc scintillation vials
`with several m1.s of deionized water and cap tightly.
`(Note: This prevents loss due to evaporation.) Standards
`are stored with HPLC mobile phase in the scintillation
`vial.
`
`10
`
`15
`
`’7- Place the vials in the appropriate controlled temperature
`ovens and reassay periodically by HPLC. Standards 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 semilogarithmic
`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-
`cal stability of a given concentration of prostaglandin is
`increased as the concentration of Gramophor® EL is
`increased.
`
`FIG. 2 demonstrates the superior stabilizing elfcct of the
`polyethoxylated castor oils, Ctemophor® EL and Alham-
`uls® EL-620, over Polysorbate 80 in a type A Fonnnlation
`(pH=5.0).
`FIG. 3 demonstrates the superior stabilizing effect of the
`polyethoxylated castor oils. Cremophor® EL and Alkam~
`uls® E1r620, over Polysorbate 80 in a type C fornmlation
`(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 5050
`acetoniuile10.1% phosphoric acid at pH 3 with NaOH, 5
`mM tenabutylammonium hydroxide, and 5 mM sodium
`dodecylsulfate. The flow rate was 2 leminnte, the detec—
`tion was 190—192 nm UV, and the injection quantity was 25
`mcL.
`
`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. A method of enhancing the chemical stability of an
`aqueous composition comprising a tlierapeutically-eifective
`amount of a prostaglandin, wherein the method comprises
`adding a chemically-stabilizing amount of a polyethoxylated
`castor oil to the composition.
`2. The method of claim 1 wherein the polyethoxylated
`castor oil is present at: a concentration between about 0.02 wt
`% and about 20.0 wt %.
`
`3. The method of claim 2 wherein the polyethcrtylated
`castor oil is present at a concentration between about 0.1 wt
`% and about 5.0 wt %.
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`anionic mucomimetic polymers and gelling
`polysaccharides, such as those described in US. Pat. No.
`4,861,760 (Mazuel et a1). U.S. Pat. No. 4,911,920 (Jani et
`al.), and in commonly assigned U.S. Ser. No. 08008324
`(Lang et al.). The contents of these patents and patent
`applications relating to the polymers cited above are incor-
`porated herein by reference.
`As will be appreciated by those skilled in the art, the
`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 (mOsmlkg).
`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 etfective
`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 fonn, to the ati‘ected eye one to two times per
`day.
`
`EXALIPLE
`
`The following topically administrahle ophthalmic formu-
`lations are representative of the compositions of the present
`invention.
`
`1 F
`
`INGREDIENT
`
`A
`
`B
`
`C
`
`ORhflmON (wt 95)
`
`0.01
`—
`05
`0.01r
`
`—
`—
`4.6
`0.1
`0.01
`
`—
`0.01
`05
`0.01I
`
`—
`—
`4.6
`0.1
`0.01
`
`0.01
`—
`05
`—
`
`0.12
`0.3
`4.6
`0.1
`0.01
`
`Compound 2
`Compound 3
`QummkrEEL
`Sodium Acetate
`(William)
`Tromethamhe
`Doric Acid
`Mini
`Disodinm EDTA.
`Benzalkcnium
`Chloride
`NaOI-I acdior
`[fill
`
`qe. to 100% :15. to 100%Purified Water (1.5. to 100%
`
`qs. to pH 5
`
`(1.5. to pH 5
`
`q.s. to pH ”I
`
`
`
`
`
`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 andt‘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.
`
`000008
`
`000008
`
`

`

`5,631,287
`
`9
`4. The method of claim 3 wherein the pelyethoxylated
`caster oil is present at a concentration between about 0.5 wt
`as and about 2.0 wt %.
`
`5. The method of claim 1 wherein the polyethoxylated
`castor oil is selected from the group consisting of: PEG-2 to
`PEG-200 caster oils and PEG-5 to PEG-200 hydrogenated
`caster eiis.
`
`6. The method of claim 5 wherein the polyethoxylated
`castor oil is selected from the group consisting of: PEG-15
`to PEG-50 caster oils.
`
`7. The method of claim 6 wherein the polyethoxylated
`castor oil is selected from the group consisting of: PEG—30
`to PEG-35 caster oils.
`
`8. The method of claim 1 wherein the prostaglandin is
`selected from the group consisting of: (SZ)—(9R.11R.15R}
`9-chlero-15-cyclohexyl-l1,15-dihydroxy-3-exa-16,17.18,
`19,20—pentanor—5-prostenoic acid;
`(SZ)-(9R,11R,15R)-9-
`chlere-15~cyclohexyl-11.15-dihydroxy-3—oxa—16,17,18,19,
`20-pentanor-5-prestenoic acid isepropyl ester; (SD-(9R,
`11R.15R)-9-chloro-15-cyclohexyl—11,15-clihydroxy—3-oxa—
`16,17.18,19,20—pentanor—5—prostenoic acid t—butyl ester;
`(SZ)-(QS,11R,15R)— lS~cyclohexyl-3-oxa-9,11, 15-
`trihydroxy—l6,1?,18,19,20—pentancx—5—[Iostenoic acid iso—
`propyl ester; (52}(912.l1R,15$)-9-ch10ro-15-cyclohexyl-
`11,15-dihydrexy-3-exa-16,17,18,19,20-pentaner-5-
`prostenoic acid isopropyl ester;
`(SZ)—(9R,11R,15R)-
`9-chloro-15-cyclehexyl-I1,15-dihydroxy-3-oxa-16.17.18,
`19,20—pentanor—S-prostenoic acid amide;
`(52)—(9R,11R,
`15R)-9-chlore-15-cyclohexyl-11,15-dlhydroxy-3-oxa-16,
`1?,18.19,20-pentanor-5-prosteneic acid N,N-
`dimethylamide;
`(SZ)—(9R,11R,15R)—9—chloro—15—
`cyclohexyl-ll,15-dihydroxy-3-oxa-16,17,18,19,20-
`pentanor—S —prostenoic acid l—methylcyclohexyl ester; (52)—
`(9R,11R,ISR)—9—chloro-lS-cyclohexyl-ll,15-dihydroxy—3-
`oxa- 16,17, 1 8, I9,20-pentanor-S-prestenoic acid
`l-methylcyclopentyl ester; (SZ)-(9R,11R,15R)-9-chlero-15-
`cyclehexyl-11.15-dihydroxy-3-oxa-16,17.18,19,20—
`penmnor-S-prestenoic acid cyclepentyl ester; (52)-(9R,11R.
`15R)-9-chloro~15~cyclohexyl—11,15-dihydroxy-3-oxa—16,
`17,18,1920pentaner-5-prestenoic acid 2.2—dimethylpropyl
`ester;
`(5Z)~(9R.l1R,15R}9~chloro-15~cyclehexyl-11.15-
`dLhydroxy—B—oxa—16,17,l8.19,20—pentanor—S—prostenoic
`acid adamantyl ester;
`(SZ)-(9R_.11R,15R)-9-chlere-15—
`cyclohexyl-11_.15-dihydrexy-3-exa-16,17,13, 19.20-
`pentaner—S-prostenoic acid 2.6-diisopropylphenyl ester;
`(Sm-(911.1111,15R)-9-chloro-ls-cydehexyl-11,15-
`dihydrexy-3 -oxa-16,17 , 18,19,20—pentanor—5-prestenoic
`acid 2,6-dimethylphenyl ester; (52. 13E)~(QS,11R,15R}3—
`era-9.11,15-lrihydrexy-16-(3-chlorephenoxy)-17.18.l9,20-
`ten-anor—SJB—p'estadieneic acid isopropyl ester; (SQ—(9R,
`11R, lSR)—9-chloro— 15-cyclohexyl-ll—hydroxy—lS-rnethoxy—
`3-oxa-16,17.18. 19.20-pentance—5-prostenoic acid t-butyl
`ester;
`(5Z)—(9R,1lR,15R)-15-cyclohexy1—3-oxa-9,l1,15-
`nihydroxy-16,17,18,1920—pentanor-5-[n'ostenoic acid iso-
`propyl ester; (5E)-(9R,11R,15R)—9-chlero-15-cyclohexyl-
`11,15-dihydroxy-3-oxa-16,17,18,19,20-pentaner-5-
`
`1'0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`10
`
`prosteneic acid isopropyl ester; (SZ)-(9R,11R)-9-chlere-15-
`cyclehexyl- ll-dihydrexy-B-exa-IS -oxe-16, 17,18,19,20-
`pentanor-S-prostenoic acid tertbotyl ester; (SZHQSJIR,
`15R)—3—oxa-l’i'-phenyl—9_.11,15-n'ihydroxy-18,19,20-u'iner-
`S—prosteneic acid isopropyl ester;
`(SZ)-(9R.11R,15R)-9—
`chloro— 15-cyclohexy1 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—dihydroxyv3-oxa-16,17,13,
`19,20—pentanor—S-prestenol; 9R,11R,15R)-9—chlero-15—
`cyclohexyl-11-dihydroxy—3-thia—16JT,18,19,20—pentaner—
`13-prostynoic acid;
`latanoprost (PhXA41); cloprostenol
`isoprepyl ester;
`(52)-(9$,11R,15R)—1-decarboxy-1-
`(pival oyloxy) methylw9, 11,15—trihydroxy-16-[(3-
`chlorophenyl)oxy]-17,18.19,20-tetranor-5-prostenoic acid;
`(SZ)-(QS.11R.15R)l-decarboxy-1-(pivaloyloxy)methy1—9,
`11.15-trihydroxy— 16—[(3—chlerophenyl)oxy]47,18,19,20-
`ten'anor-S,13-prostadienoic acid;
`(SZ)—(9R,11R,15R)-9-
`chloro- lS-cyclohexyl—l 1 , lS-dihydroxy- 16,17,18, 19,20-
`pentanor—S—prostenoic acid isepropyl ester; (SZ)-(98,11R,
`lSS)—15—cyclohexy—9,11,15-trihydroxy~ 16,17,18.19.20—
`pentaner—S-prosteneic acid isepropyl ester; (52. 13E)-(98,
`11R,15R)—9,11.l5«trihydroxy-16-(3-chlorophenexy}17,l8,
`19.20-tetranor-5,13—prostadienoic acid amide;
`PGFmisopropyl ester; and fluprostenol isopropyl ester.
`9. The method of claim 8 wherein the prostaglandin is
`selected from the group consisting of: (SZ)—(9R,11R,15R}-
`9-chloro- 15-cyclohexyl-11 .15-dihydroxy-3-exa—16,17,18,
`19.20-pentanor—Swprostenoic acid isopropyl ester; (SD-(9R,
`11R.15R)-9-chloro-15-cyclehexyl—11,15-dihydroxy—3-oxa-
`16.17,18,19.20~pentanor—5-prostenoic acid t—butyi ester;
`(SZHQS,11R,15R)-lS-cyclohexyl-3-exa-9.11,15~
`trihydroxy—lfi,17,18,1920—pentanm—5-txostenoic acid iso~
`propyl ester;
`(SD-(911,11R,lSS)-9-chloro—15—cyclehexyl—
`11,15-dihydroxy~3-oxa—16,17,18,19,20-pentaner—5-
`prostenoic acid isopropyl ester; (52)-(9R,11R,15R)-9—
`chloro- lS-cyclohexyLllJS -dihydroxy—3 -oxa- 16, 17,18,19,
`20-pentanor—5-prestenoic acid amide; (52}(9R,11R.15R)—
`9-chlore-15-cyclohexyl-ll,15-dihydroxy-3-exa-16,17,18,
`19,20-peManor-5-presteneic acid NN-dimemylamide; and
`(SZ)-(9R,11R.15R)-9-chlero-15-cydehexyl-11.15-
`dihydroxy—3—oxa-16,17,18.19,20—pentanor—5—prostenoic
`acid l-methylcyclohexyl ester.
`10. The method of claim 9 wherein the prostaglandin is
`selected from the group consisting of (52}(9R,11R.15R)—
`9—ch10ro—15~cyclohexy1—11,l5-dihydroxy-3-oxa-16.17,18,
`19,20-pentanor-5-prostenoic acid isoFopyl ester and (52)-
`(9R,11R.15R)-9rchloro~15*cyclohexyl-l1,15-dihydrexy—3-
`oxa-16,17.18,19,20—pentanor—S-presteneic acid t—butyl ester.
`11. The method of claim 1 wherein the [rostaglandin is
`present at a concentration between about 00001 wt % and
`about 0.1 wt %.
`12. The method of claim 1 wherein the composition is a
`topically adminislrable ophthalmic composition.
`
`000009
`
`000009
`
`