United States Patent 9
`Schneider
`
`[54] STORAGE-STABLE PROSTAGLANDIN
`CO
`SETIONS
`Inventor: L. Wayne Schneider, Crowley, Tex.
`
`[75]
`
`Cx.
`
`LL
`US005631287A
`(11) Patent Number:
`5,631,287
`[45] Date of Patent:
`May20, 1997
`
`
`FOREIGN PATENT DOCUMENTS
`0132027A1
`1/1985 European Pat. Off.
`.
`0407148A3
`1/1991 European Pat. Off. .
`0645145A3
`3/1995 European Pat. Off..
`0667160A2
`8/1995 European Pat. Off. .
`
`OTHER PUBLICATIONS
`
`[21] Appl. No.: 362,677
`[22] Filed:
`Dec. 22, 1994
`
` [Si] Ant.CLe a woe AGIK 31/557
`[52]:
`“WSs Clivcsiisssissecs
`.. 514/530; 514/573; 560/118
`[58] Field of Search .0....2......cccsscceseseeeee 514/530, 5733
`560/118, 121; 562/503
`
`[56]
`
`;
`References Cited
`U.S. PATENT DOCUMENTS
`
`Foster et al., “Intraocular Penetration of Miconazole in
`Rabbits,” Arch. Ophthalmol. 97/9, pp. 1703-1706 (1979)
`(abstract only).
`Primary Examiner—Robert Gerstl
`Attorney, Agent, or Firm—Patrick M. Ryan
`7]
`BBSTRACTE
`The use of polyethoxylated castor oils in prostaglandin
`compositions greatly enhancesthe prostaglandin’s chemical
`stably.
`
`5,004,752
`
`4/1991 Raduechel ......csssssssessssesenee S14/530
`
`12 Claims, 3 Drawing Sheets
`
`000001
`
`Exhibit 1103
`Exhibit 1103
`ARGENTUM
`ARGENTUM
`IPR2017-01053
`IPR2017-01053
`
`000001
`
`

`

`US. Patent
`
`May20, 1997
`
`Sheet 1 of 3
`
`5,631,287
`
`FIG.
`
`1
`
`Stability of Compound No. 2. at 65°C in pH 5.0
`Preserved Vehicle with Cremophor® EL.
`
`>bOO¢oOd
`
`
`5% Cremophor® EL /0.01% Compound No.2.
`0.5% Cremophor® EL /0.01% Compound No.2.
`0.5% Cremophor® EL /0.001% Compound No.2.
`0.05% Cremophor® EL /0.001% Compound No.2.
`
`
`
`
`
`
`
`
`100 ||
`ili
`
`
`
` ta TihZT7Are7CoCt
`
`PTPE
`
`rc
`
`
`
`ai
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`TIME (DAYS)
`
`000002
`
`000002
`
`

`

`U.S. Patent
`
`May 20, 1997
`
`Sheet 2 of 3
`
`5,631,287
`
`FIG. 2
`Stability of 0.01% Compound No. 2. at 55°C in pH 5.0
`Preserved Vehicle with the indicated Surfactant.
`
`Oo 0.5% Cremophor® EL
`4 0.5% Alkamuls® EL-620
`© Polysorbate 80
`
` PERCENTOFSTANDARD
`
`TIME (DAYS)
`
`000003
`
`000003
`
`

`

`U.S. Patent
`
`May20, 1997
`
`Sheet 3 of 3
`
`5,631,287
`
`FIG. 3
`
`Stability of 0.01% Compound No. 2. at 55°C in pH 7.4
`Preserved Vehicle with the indicated Surfactant.
`
`© 0.5% Cremophor® EL
`4 0.5% Alkamuls® EL- 620
`© 0.5% Polysorbate 80
`
`PERCENTOFSTANDARD
`
`TIME (DAYS)
`
`000004
`
`000004
`
`

`

`5,631,287
`
`1
`STORAGE-STABLE PROSTAGLANDIN
`COMPOSITIONS
`
`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 madeto solubi-
`lize and stabilize various prostaglandins by complexing
`them with different cyclodextrins. See, for example: EP 330
`511 A2 (Uenoet 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.
`Theuse 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.
`4,075,333 (Josse) discloses stable, intravenous emulsion
`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 etal.)
`discloses topically administrable ophthalmic formulations of
`vitamin A which are stable preparations in which a non-ionic
`surfactant is used to form an emulsion of vitamin A in an
`aqueous medium,
`Whatis needed is a commercially viable, storage-stable
`prostaglandin composition.
`SUMMARYOF THE INVENTION
`
`Thepresent inventionis 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 showsthestabilizing effect at different concentra-
`tions of a polyethoxylated castor oil in a preserved prostag-
`lJandin formulation at pH 5.0.
`FIG. 2 comparesthe stabilizing effect of different surfac-
`tants in a preserved prostaglandin formulation at pH 5.0.
`FIG. 3 compares the stabilizing effect of different surfac-
`tants in a preserved prostaglandin formulation at pH 7.4.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Prostaglandin esters are difficult to formulate in storage-
`stable solutions as they tend to be hydrolytically unstable. In
`
`45
`
`50
`
`55
`
`65
`
`2
`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.
`
`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, and those manufactured
`by BASF (Parsippany, N.J.) under the Cremophor® brand.
`It is preferred to use the polyethoxylated castor oils classi-
`fied as PEG-15 to PEG-50 castor oils, and more preferred to
`use PEG-30 to PEG-35castoroils. It is most preferred to use
`those polyethoxylated castor oils known as Cremophor® EL
`and Alkamuls® EL-620.,
`
`Theterms “prostaglandin” and “PG” are generally used to
`describe a class of compounds which are analogues and
`derivatives of prostanoic acid (1):
`
`
`
`PG’s may be furtherclassified, for example, according to
`their 5-membered ring structure, using a letter designation:
`
`Prostaglandins of the A series (PGA's):
`
`Prostaglandins of the B series (PGB's):
`
`Prostaglandins of the C series (PGC’s):
`
`o
`
`HO
`
`ProstaglandinsoftheDseries(PGD's): IoO
`ProstaglandinsoftheEseries(PGE’s): YY
`
`oO
`
`HO.
`
`000005
`
`000005
`
`

`

`5,631,287
`
`3
`-continued
`
`Prostaglandins ofthe F series (PGF's):
`
`Prostaglandins ofthe J series (PGI’s):
`
`HO
`
`HO
`
`Oo
`
`PG’s may be further classified based on the number of ©
`unsaturated bonds on the side chain:
`
`4
`16-phenoxy), which enhanceselectivity ofaction andreduce
`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
`andphysical responses similar to those ofprostaglandins per
`se.
`
`Specific examples of prostaglandins which are useful in
`the present invention include the following compounds:
`Compound No.
`1. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic
`acid;
`
`PGy's (13,14-umsaturated):
`
`
`
`The prostaglandins which may be utilized in the present
`invention include all pharmaceutically acceptable
`prostaglandins, their derivatives and analogues, and their
`pharmaceutically acceptable esters and salts. Such prostag-
`landins include the natural compounds: PGE,, PGE., PGE;,
`PGF,.., PGF2,, PGF3,,, PGD, and PGI, (prostacyclin), as
`well as analoguesand derivatives ofthese 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-dihydro), which confer sus-
`tained 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
`oxygen (e.g., 9B-chloro), oxygen for carbon (e.g., 3-oxa),
`lower alkyl for oxygen (e.g., 9-methyl), hydrogen for oxy-
`gen (e.g., 1-CH,OH,1-CH,0 Acyl) which enhance chemical
`stability and/or selectivity of action; and @-chain modifica-
`tions(€.g.,
`18,19,20-trinor-17-phenyl, 17,18,19,20-tetranor-
`
`45
`
`60
`
`65
`
`2. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic
`acid isopropyl ester;
`3. (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;
`4. (5Z)-(9S_,11R,15R)-15-cyclohexyl-3-oxa-9 ,11,15-
`trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid iso-
`ropyl ester;
`5. (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic
`acid isopropyl ester;
`6. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic
`acid amide;
`7. (5Z)-(9R,11R,15R)-9-chloro-15-cydohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic
`acid N,N-dimethylamide;
`8. (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;
`9. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic
`acid 1-methylcyclopentylester;
`
`000006
`
`000006
`
`

`

`5,631,287
`
`5
`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-dimethylpropylester;
`12.
`(5Z)-(9R,11R,15R)-9-chloro-15-cyclohexy]-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic
`acid adamantylester;
`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-diisopropylphenylester;
`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-dimethylphenylester;
`15.
`(5Z, 13E)-(9S8,11R,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 iso-
`propyl ester;
`18.
`(SE)-(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)-(9S8,11R,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,1LIR,15R)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-p entanor-5-prostenol;
`23. (OR, 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,1IR,15R)-9-chloro-15-cyclohexyl-11,15-
`dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid iso-
`propyl ester;
`29.
`(5Z)-(98,11R,158)-15-cyclohexyl-9,11,15-
`trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid iso-
`propyl ester;
`30.
`(5Z, 13E)-(98,11R,15R)-9,11,15-trihydroxy-16-(3-
`chlorophenoxy)-17,18,19,20-tetranor-5, 13-prostadienoic
`acid amide;
`31. PGF.,isopropyl ester; and
`32. Fluprostenol isopropylester.
`All of the foregoing compounds are known. Preferred
`prostaglandins for use in the compositions of the present
`invention are Compounds 2-8 above. Most preferred are
`Compounds 2 and 3 above. The structures of Compounds 2
`and 3 are shown below.
`
`aoO
`
`15
`
`=]oO
`
`baA
`
`50
`
`65
`
`(2)
`
`G)
`
`HO
`
`HO
`
`The prostaglandin compositions of the present invention
`contain one or more polyethoxylated castor oils in an
`amounteffective 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 about0.5 and about 2.0
`wt %. It is preferred to use one or more prostaglandinsin 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 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 knownto 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 %. Examplesof suitable agents
`which maybeutilized 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 o table
`buffering agents include acetic acid, citric acid, carbonic
`acid, phosphoric acid, boric acid,
`the pharmaceutically
`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,
`
`000007
`
`000007
`
`

`

`8
`The stabilizing effect ofpolyethoxylated castoroils in the
`compositionsof 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) samplevials.
`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 ccscintillation vials
`with several mLs 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 temperature
`ovens and reassay periodically by HPLC. Standards are
`stored in a refrigerator.
`8. HPLC Data Analysis: Divide Sample Peak Area by
`Standard PeakArea and multiply by 100 to obtain Percent
`of Standard for each sample at each time point.
`9. Plot Percent ofStandard 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 Cremophor® EL is
`increased.
`FIG. 2 demonstrates the superior stabilizing effect of the
`polyethoxylated castor oils, Cremophor® EL and Aikam-
`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, andthe injection quantity was 25
`meL.
`The invention has been described by reference to certain
`preferred embodiments; however, it should be understood
`that it may be embodiedin 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.
`Whatis claimedis:
`1. A method of enhancing the chemical stability of an
`aqueous composition comprising a therapeutically-effective
`amountof a prostaglandin, wherein the method comprises
`adding a chemically-stabilizing amountof 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 polyethoxylated
`castor oil is present at a concentration between about 0.1 wt
`% and about 5.0 wt %.
`
`10
`
`15
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`Compound 2
`Compound 3
`Cremophor ® EL
`Sodium Acetate
`(Trihydrate)
`Tromethamine
`Boric Acid
`Mannitol
`Disodium EDTA.
`Benzalkonium
`Chloride
`NaOH and/or
`Hcl
`
`q.s. to 100% qs. to 100%Purified Water qs. to 100%
`
`0.01
`—
`05
`0.07
`
`_
`—
`4.6
`0.1
`0.01
`
`_—
`0.01
`05
`0.07
`
`_
`—
`4.6
`O01
`0.01
`
`qs. to pH 5
`
`qs. to pH 5
`
`
`
`
`
`0.01
`_—
`0.5
`_—
`
`0.12
`0.3
`4.6
`01
`0.01
`
`qs. to pH 7
`
`5,631,287
`
`7
`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.
`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 (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 accordingto the present invention,
`The frequency and amount of dosage will be determined by
`the clinician based on variousclinical 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
`
`The following topically administrable ophthalmic formu-
`lations are representative of the compositions of the present
`invention.
`
`INGREDIENT
`A
`B
`c
`
`
`FORMULATION (wt %)
`
`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 ofthe 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.
`
`000008
`
`000008
`
`

`

`5,631,287
`
`9
`4. The method of claim 3 wherein the polyethoxylated
`castor oil is present at a concentration between about 0.5 wt
`% 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 castor oils and PEG-5 to PEG-200 hydrogenated
`castor oils.
`6. The method of claim 5 wherein the polyethoxylated
`castor oil is selected from the group consisting of: PEG-15
`to PEG-50 castoroils.
`7. The method of claim 6 wherein the polyethoxylated
`castor oil is selected from the group consisting of: PEG-30
`to PEG-35 castoroils.
`8. The method of claim 1 wherein the prostaglandin is
`selected from the group consisting of: (SZ)-(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-
`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)-(9S8,11R,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; (57)-(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-methylcyclopentylester; (5Z)-(9R,11R,15R)-9-chloro-15-
`eyclohexyl-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-16,
`17,18,19,20-pentanor-5-prostenoic acid 2,2-dimethylpropyl
`ester;
`(5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11.15-
`dLhydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic
`acid adamantyl 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-diisopropylphenyl ester;
`(5Z)-(9R,11R,15R)-9-chloro-15-cydohexyl-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-ll-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-
`tihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid iso-
`propyl ester; (SE)-(9R,11R,15R)-9-chloro-15-cyclohexyl-
`11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-
`
`10
`prostenoic acid isopropyl ester; (5Z)-(9R,11R)-9-chloro-15-
`eyclohexyl-11-dihydroxy-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-cyclohexyl1-(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-dihydroxy-3-thia-16,17,18,19,20-pentanor-
`13-prostynoic acid;
`latanoprost (PhXA41); cloprostenol
`isopropyl ester;
`(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;
`(5Z)-(95,11R,15R)1-decarboxy-1-(pivaloyloxy)methy1-9,
`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-cyclohexy-9,11,15-trihydroxy-16,17,18,19,20-
`pentanor-5-prostenoic acid isopropyl ester; (5Z, 13E)-(95,
`11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,
`19,20-tetranor-5,13-prostadienoic acid amide;
`PGF,,isopropyl ester; and fluprostenol isopropylester.
`9. The method of claim 8 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 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; (SZ)-(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; and
`(5Z)-(9R,11R,15R)-9-chloro-15-cydohexyl-11,15-
`dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic
`acid 1-methylcyclohexyl ester.
`10. The method of claim 9 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 isopropyl ester and (5Z)-
`(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-
`oxa-16,17,18,19,20-pentanor-5-prostenoicacid t-butyl ester.
`11. The method of claim 1 wherein the prostaglandin is
`present at a concentration between about 0.0001 wt % and
`about 0.1 wt %.
`12. The method of claim 1 wherein the composition is a
`topically administrable ophthalmic composition.
`
`35
`
`40
`
`000009
`
`000009
`
`