United States Patent [19]
`Crow et al.
`
`US006054486A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,054,486
`Apr. 25, 2000
`
`[54] USE OF 9-DEOXY-2',9-(X-METHANO-3-0XA-4,
`5,6-TRINOR-3,7-(1',3'-INTERPHENYLENE)-13,
`14-DIHYDRO-PROSTAGLANDIN F1 TO
`TREAT PERIPHERAL VASCULAR DISEASE
`
`[75] Inventors: James W. Crow, Chapel Hill; Shelmer
`D. Blackburn, Jr., Raleigh; Robert
`Roscigno, Chapel Hill; Michael Wade,
`Mebane; Gilles Cloutier, Chapel Hill,
`all of NC; Martine Rothblatt, Silver
`Spring, Md.
`
`[73] Assignee: United Technology Corporation,
`Washington, DC.
`
`[21] Appl. No.: 09/190,450
`[22] Filed:
`NOV. 13, 1998
`
`Related US. Application Data
`[60] Provisional application No. 60/066,049, Nov. 14, 1997.
`
`[51] Int. Cl.7 ................................................... .. A61R 31/19
`[52]
`.. 514/571
`[58] Field of Search ............................................. .. 514/571
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,306,075 12/1981 Aristoff ................................... .. 560/56
`4,490,537 12/1984 Johnson .
`4,499,085
`2/1985 Masuda .
`5,153,222 10/1992 Tadepalli et al. ..................... .. 514/571
`5,814,301
`9/1998 Klopp et al. .
`
`FOREIGN PATENT DOCUMENTS
`
`1236380 7/1996 U.S.S.R..
`
`83 04021 11/1983 WIPO .
`
`OTHER PUBLICATIONS
`
`Y. Okuda et al. Prostaglandins, vol. 52 “Acute Effect of
`Beraprost Sodium on LoWer Limb Circulation in Patients
`With
`Non—Insulin—Dependent
`Diabetes
`Melitus—Evaluation .
`.
`. Ultrasonography,” pp. 375—384
`
`(Nov. 1996).
`Patterson et al. The American Journal of Cardiology, vol. 75,
`“Acute Hemodynamic Effects of the Prostacyclin Analog
`15AU81 in Service Congestive Heart failure,” pp. 26A—33A
`(Jan. 1995).
`Mohler, Emile R. “Medical Management of Claudication,”
`pp. 1—6, (Mar. 1997).
`Mohler, Emile R. “Clinical Manifestations of Claudication,”
`pp. 1—4 (Sep. 1996).
`Neschis et al. “Surgical Indications for the Patient With Limb
`Threatening Ischemia,” pp. 1—10.
`Belch et al. Circulation, vol. 95, No. 9, “Randomized,
`Double—Blind, Placebo—Controlled Study Evaluating the the
`Efficacy and Safety of AS—013 .
`.
`. With Intermittent
`Claudication,” pp. 2298—2301 (May, 1997).
`
`Primary Examiner—James H. Reamer
`Attorney, Agent, or Firm—Foley & Lardner
`
`[57]
`
`ABSTRACT
`
`An improved treatment for peripheral vascular disease is
`described using 9-deoXy-2‘,9-ot-methano-3-oXa-4,5,6-trinor
`3,7-(1‘,3‘-interphenylene)-13,14-dihydro-prostaglandin F1.
`
`17 Claims, No Drawings
`
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`

`1
`USE OF 9-DEOXY-2',9-(X-METHANO-3-OXA-4,
`5,6-TRINOR-3,7-(1',3'-INTERPHENYLENE)-13,
`14-DIHYDRO-PROSTAGLANDIN F1 TO
`TREAT PERIPHERAL VASCULAR DISEASE
`
`This application claims the bene?t under Title 35, United
`States Code § 119(e) of US. provisional Ser. No. 60/066,
`049, ?led Nov. 14, 1997.
`
`FIELD
`
`The invention relates to the use of 9-deoXy-2‘,9-ot
`methano-3-oXa-4,5,6-trinor-3,7-(1‘,3‘-interphenylene)-13,
`14-dihydro-prostaglandin F1 (hereafter “UT-15”) to treat
`peripheral vascular disease and kits for this purpose.
`
`BACKGROUND
`
`The compound UT-15 is a knoWn compound disclosed in
`US. Pat. No. 4,306,075 in eXample 33. UT-15 is a synthetic
`analog of epoprostenol, a prostaglandin F1. The activities
`ascribed to the various compounds of this patent include
`inhibition of platelet aggregation, reduction of gastric
`secretion, and bronchodilation. It is indicated that the com
`pounds of this patent have useful application as anti
`thrombotic agents, anti-ulcer agents, and anti-asthma agents.
`US. Pat. No. 5,153,222 discloses the use of UT-15 and
`related compounds to treat pulmonary hypertension.
`Prostaglandin E1 has been found to increase Walking
`distance in a small but statistically signi?cant group of
`patients With peripheral arterial occlusive disease. HoWever,
`since this drug is rapidly inactivated in the lungs, it must be
`administered intra-arterially, Which leads to numerous harm
`ful side effects. See Belch et al., Circulation, 95(9):
`2298—2302 (1997). Belch further discloses the use of
`AS-013, a prostaglandin E1 prodrug, to treat peripheral
`arterial occlusive disease, presenting as intermittent claudi
`cation.
`Okuda et al., Prostaglandins, 52(5): 375—384 (November
`1996) shoWed that beraprost sodium, a stable analogue of
`prostaglandin I2, increased the cross-sectional area and the
`blood ?oW indeX of the dorsal pedis artery in non-insulin
`dependent diabetes patients. In addition, Okuda shoWed an
`increase in the dermal microcirculatory blood volume of
`these patients.
`Patterson et al., Amer. J. of Cardiology, 75(1995):
`26A—33A, have shoWn the vasodilator effects of UT-15 in
`patients With class III or class IV heart failure.
`
`SUMMARY
`The present inventors discovered that UT-15 is especially
`Well suited for the treatment of peripheral vascular disease
`compared to other prostaglandin-type compounds because it
`is not degraded When it passes through the lungs, it has a
`long biological half-life, it has potent peripheral vasodila
`tory properties, it is a highly potent platelet aggregation
`inhibitor, and it inhibits the release of vasoconstrictive
`substances.
`Accordingly, it is an object of the present invention to
`provide an improved treatment for peripheral vascular dis
`ease comprising administering to a subject in need thereof
`an effective amount of UT-15 and pharmaceutically accept
`able salts and acid derivatives thereof, as Well as kits for
`accomplishing this purpose.
`
`DETAILED DESCRIPTION
`
`The present invention relates to a method for treatment of
`peripheral vascular disease, including peripheral arterial
`
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`occlusive disease and intermittent claudication, comprising
`administering to a subject, preferably a human being, in
`need thereof an effective amount of UT-15 and/or its phar
`maceutically acceptable salts and acid derivatives thereof.
`The present invention also relates to kits for accomplish
`ing such treatment comprising
`an effective amount of
`UT-15, its pharmaceutically acceptable salts, and/or acid
`derivatives thereof, (ii) one or more pharmaceutically
`acceptable carriers and/or additives, and (iii) instructions for
`use in treating peripheral vascular disease.
`As used herein, the phrase “instructions for use” shall
`mean any FDA-mandated labelling, instructions, or package
`inserts that relate to the administration of UT-15 for the
`purpose of treating peripheral vascular disease. For eXample,
`instructions for use may include, but are not limited to,
`indications for peripheral vascular disease, identi?cation of
`speci?c symptoms of peripheral vascular disease that can be
`ameliorated by UT-15, and recommended dosage amounts
`for subjects suffering from peripheral vascular disease.
`The term “acid derivative” is used herein to describe
`C1—4 alkyl esters and amides, including amides Wherein the
`nitrogen is optionally substituted by one or tWo C1—4 alkyl
`groups.
`The invention also includes bioprecursors or “pro-drugs”
`of UT-15, that is, compounds Which are converted in vivo to
`UT-15 or its pharmaceutically active derivatives thereof.
`Further aspects of the present invention are concerned
`With the use of UT-15, or a pharmaceutically acceptable salt
`or acid derivative thereof, in the manufacture of a medica
`ment for the treatment of peripheral vascular disease
`The present invention eXtends to non-physiologically
`acceptable salts of UT-15 Which may be used in the prepa
`ration of the pharmacologically active compounds of the
`invention. The physiologically acceptable salts of UT-15
`include salts derived from bases.
`Base salts include ammonium salts, alkali metal salts such
`as those of sodium and potassium, alkaline earth metal salts
`such as those of calcium and magnesium, salts With organic
`bases such as dicycloheXylamine and N-methyl-D
`glucamine, and salts With amino acids such as arginine and
`lysine.
`Quaternary ammonium salts can be formed, for eXample,
`by reaction With loWer alkyl halides, such as methyl, ethyl,
`propyl, and butyl chlorides, bromides, and iodides, With
`dialkyl sulphates, With long chain halides, such as decyl,
`lauryl, myristyl, and stearyl chlorides, bromides, and
`iodides, and With aralkyl halides, such as benZyl and phen
`ethyl bromides.
`The amount of UT-15, or a physiologically acceptable salt
`or acid derivative thereof, Which is required in a medication
`or diagnostic aid according to the invention to achieve the
`desired effect Will depend on a number of factors, in
`particular the speci?c application, the nature of the particular
`compound used, the mode of administration, and the con
`dition of the patient. In general, a daily dose per patient for
`the treatment of peripheral vascular disease is in the range 25
`rig to 250 mg; typically from 0.5 rig to 2.5 mg, preferably
`from 7 rig to 285 pg, per day per kilogram bodyWeight. For
`eXample, an intravenous dose in the range 0.5 rig to 1.5 mg
`per kilogram bodyWeight per day may conveniently be
`administered as an infusion of from 0.5 ng to 1.0 pg per
`kilogram bodyWeight per minute. A preferred dosage is 10
`ng/kg/min. Infusion ?uids suitable for this purpose contain,
`for eXample, from 10 ng to 10 pig per milliliter. Ampoules for
`injection contain, for eXample, from 0.1 pg to 1.0 mg and
`orally administrable unit dose formulations, such as tablets
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`3
`or capsules, contain, for example, from 0.1 to 100 mg,
`typically from 1 to 50 mg. For diagnostic purposes, a single
`unit dose formulation may be administered. In the case of
`physiologically acceptable salts, the Weights indicated above
`refer to the Weight of the active compound ion, that is, the
`ion derived from UT-15.
`In the manufacture of a medicament or diagnostic aid
`according to the invention, hereinafter referred to as a
`“formulation”, UT-15 and its physiologically acceptable
`salts and acid derivatives are typically admixed With, inter
`alia, an acceptable carrier. The carrier must, of course, be
`acceptable in the sense of being compatible With any other
`ingredients in the formulation and must not be deleterious to
`the patient. The carrier may be a solid or a liquid, or both,
`and is preferably formulated With the compound as a unit
`dose formulation, for example, a tablet, Which may contain
`from 0.05% to 95% by Weight of the active compound. One
`or more of UT-15 and/or its physiologically acceptable salts
`or acid derivatives may be incorporated in the formulations
`of the invention, Which may be prepared by any of the Well
`knoWn techniques of pharmacy for admixing the compo
`nents.
`In addition to UT-15, other pharmacologically active
`substances may be present in the formulations of the present
`invention Which are knoWn to be useful for treating periph
`eral vascular disease. For example, the compounds of the
`invention may be present in combination With trental, a
`substance knoWn to increase red blood cell deformability.
`The formulations of the invention include those suitable
`for oral, inhalation (in solid and liquid forms), rectal, topical,
`buccal (e.g. sub-lingual), parenteral (e.g. subcutaneous,
`intramuscular, intradermal, or intravenous) and transdermal
`administration, although the most suitable route in any given
`case Will depend on the nature and severity of the condition
`being treated and on the nature of the particular form of
`UT-15, or the physiologically acceptable salt or acid deriva
`tive thereof, Which is being used.
`Formulations suitable for oral administration may be
`presented in discrete units, such as capsules, cachets,
`loZenges, or tablets, each containing a predetermined
`amount of UT-15 or a physiologically acceptable salt or acid
`derivative thereof; as a poWder or granules; as a solution or
`a suspension in an aqueous or non-aqueous liquid; or as an
`oil-in-Water or Water-in-oil emulsion. Such formulations
`may be prepared by any suitable method of pharmacy Which
`includes the step of bringing into association the active
`compound and a suitable carrier (Which may contain one or
`more accessory ingredients)
`In general, the formulations of the invention are prepared
`by uniformly and intimately admixing the active compound
`With a liquid or ?nely divided solid carrier, or both, and then,
`if necessary, shaping the resulting mixture. For example, a
`tablet may be prepared by compressing or molding a poWder
`or granules containing the active compound, optionally With
`one or more accessory ingredients. Compressed tablets may
`be prepared by compressing, in a suitable machine, the
`compound in a free-?oWing form, such as a poWder or
`granules optionally mixed With a binder, lubricant, inert
`diluent, and/or surface active/dispersing agent(s). Molded
`tablets may be made by molding, in a suitable machine, the
`poWdered compound moistened With an inert liquid binder.
`Formulations suitable for buccal (sub-lingual) adminis
`tration include loZenges comprising UT-15, or a physiologi
`cally acceptable salt or acid derivative thereof, in a ?avored
`base, usually sucrose and acacia or tragacanth; and pastilles
`comprising the compound in an inert base such as gelatin
`and glycerin or sucrose and acacia.
`
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`6,054,486
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`4
`Formulations of the present invention suitable for
`parenteral administration conveniently comprise sterile
`aqueous preparations of UT-15, or a physiologically accept
`able salt or acid derivative thereof, Which preparations are
`preferably isotonic With the blood of the intended recipient.
`These preparations are preferably administered
`intravenously, although administration may also be effected
`by means of subcutaneous, intramuscular, or intradermal
`injection. Such preparations may conveniently be prepared
`by admixing the compound With Water or a glycine buffer
`and rendering the resulting solution sterile and isotonic With
`the blood. Inj ectable formulations according to the invention
`generally contain from 0.1 to 5% W/v of active compound
`and are administered at a rate of 0.1 ml/min/kg.
`Formulations suitable for rectal administration are pref
`erably presented as unit dose suppositories. These may be
`prepared by admixing UT-15, or a physiologically accept
`able salt or acid derivative thereof, With one or more
`conventional solid carriers, for example, cocoa butter, and
`then shaping the resulting mixture.
`Formulations suitable for topical application to the skin
`preferably take the form of an ointment, cream, lotion, paste,
`gel, spray, aerosol, or oil. Carriers Which may be used
`include vaseline, lanoline, polyethylene glycols, alcohols,
`and combinations of tWo or more thereof. The active com
`pound is generally present at a concentration of from 0.1 to
`15% W/W, for example, from 0.5 to 2% W/W. Formulations
`for transdermal administration may be delivered by ionto
`phoresis (see, for example, Pharmaceutical Research 3(6),
`318, (1986)) and typically take the form of an optionally
`buffered aqueous solution of UT-15 or of a salt or acid
`derivative thereof. Suitable formulations comprise citrate or
`bis/tris buffer (pH 6) or ethanol/Water and contain from 0.1
`to 0.2M active ingredient.
`The compounds of the present invention are conveniently
`prepared by methods the same as or analogous to those
`described in US. Pat. No. 4,306,075 and co-pending appli
`cation Ser. No. 08/957,726 ?led on Oct. 24, 1997.
`There are three features of UT-15’s pharmacological
`pro?le in particular Which make it Well suited for treating
`peripheral vascular disease. Those features are (1) its vasodi
`lation effect, (2) its inhibition of platelet function, and (3) its
`cytoprotective effect. In addition to having a potent vasodi
`lation effect, the present inventors believe that one important
`aspect of an effective treatment for peripheral vascular
`disease is that the active ingredient should be able to inhibit
`platelet function, Which may be an exacerbating factor in
`peripheral vascular disease. UT-15 exhibits this pharmaco
`logical pro?le.
`
`Administration Of UT-15 To Humans Suffering
`From Peripheral Vascular Disease
`Eight patients With moderate to severe peripheral vascular
`disease (Fontaine Stage IIb—III) Were dosed With placebo for
`a minimum of 30 minutes and then With increasing doses of
`UT-15 (one hour of dosing at each dose step) until the
`maximum tolerated dose. Safety Was assessed by adverse
`experience monitoring and clinical laboratory tests.
`Common side effects at peak dose Were expected and
`included headache and nausea. No serious adverse events
`Were noted during hospitaliZation. The most common main
`tenance dosing level Was 10 ng/kg/min. Unaudited data
`summariZed beloW compare blood ?oW velocity at baseline
`and the end of the maintenance dosing period, and include
`all arteries for Which data Were available at both time points
`(up to 12 loWer limb arteries in each patient). The data shoW
`
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`6,054,486
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`5
`that blood ?oW velocity Was increased signi?cantly. Acute
`intravenous UT-15 administration Was Well-tolerated in
`patients With moderate to severe peripheral vascular disease.
`Potentially clinically signi?cant improvement in loWer limb
`blood How Was observed When UT-15 Was administered
`actutely at a maXimum tolerated dose. The results are
`presented beloW in Tables 1 and 2:
`
`TABLE 1
`
`LoWer Limb Blood FloW Velocity After Acute
`Treatment
`
`Baseline
`
`End of Treatment
`
`% Change from Baseline
`
`64:8
`
`78:9
`
`14:6(2319)
`
`Mean in cm/s : standard error. N = 8 patients.
`
`TABLE 2
`
`Summary Of LoWer Limb Blood FloW Velocity (BFV)
`Changes After Acute Treatment
`
`Arteries W/Increase
`In BFV
`
`Arteries W/Decrease
`In BFV
`
`p (sign test)
`
`56
`
`19
`
`<.OOOOOO1
`
`25
`
`Administration Of UT-15 To AnesthetiZed Dogs
`
`Tests have been performed Which support the use of
`UT-15 to treat peripheral vascular disease. In anesthetiZed
`dogs, intravenous boluses (0.32—3.2 pig/kg) and 10-minute
`infusions of UT-15 produced dose-dependent decreases in
`mean arterial blood pressure. Also, in anesthetiZed dogs,
`intravenous infusions of UT-15 (0.1—3.0 pg/kg/min) for four
`hours produced dose-dependent decreases in mean total
`peripheral vascular resistance.
`
`35
`
`Administration of UT-15 To AnesthetiZed Piglets
`
`Another set of tests has been performed in anesthetiZed
`neWborn piglets. Intravenous boluses of UT-15 (6 and 12
`pig/kg) Were shoWn to abolish hypoXia-induced increases in
`pulmonary vascular resistance in anesthetiZed neWborn pig
`lets.
`It Will be apparent to those skilled in the art that various
`modi?cations and variations can be made to the composi
`tions and processes of this invention. Thus, it is intended that
`the present invention cover such modi?cations and
`variations, provided they come Within the scope of the
`appended claims and their equivalents.
`The disclosure of all publications cited above are
`eXpressly incorporated herein by reference in their entireties
`to the same eXtent as if each Were incorporated by reference
`individually.
`What is claimed is:
`1. A method for treatment of peripheral vascular disease
`comprising administering to a subject in need thereof an
`effective amount of 9-deoXy-2‘,9-ot-methano-3-oXa-4,5,6
`trinor-3,7-(1‘,3‘-interphenylene)-13,14-dihydro
`
`45
`
`55
`
`6
`prostaglandin F1, its pharmaceutically acceptable salts, and/
`or acid derivatives thereof.
`2. The method as claimed in claim 1, Wherein a pharma
`ceutically acceptable salt of 9-deoXy-2‘,9-ot-methano-3-oXa
`4,5,6-trinor-3,7-(1‘,3‘-interphenylene)-13,14-dihydro
`prostaglandin F1 is administered.
`3. The method as claimed in claim 1, Wherein the subject
`is a human being.
`4. The method as claimed in claim 1, Wherein the
`9-deoXy-2‘,9-ot-methano-3-oXa-4,5,6-trinor-3,7-(1‘,3‘
`interphenylene)-13,14-dihydro-prostaglandin F1 is adminis
`tered in an orally available form selected from the group
`consisting of tablets and capsules.
`5. The method as claimed in claim 1, Wherein the
`9-deoXy-2‘,9-ot-methano-3-oXa-4,5,6-trinor-3,7-(1‘,3‘
`interphenylene)-13,14-dihydro-prostaglandin F1 is adminis
`tered by inhalation.
`6. The method as claimed in claim 1, Wherein the
`9-deoXy-2‘,9-ot-methano-3-oXa-4,5,6-trinor-3,7-(1‘,3‘
`interphenylene)-13,14-dihydro-prostaglandin F1 is adminis
`tered subcutaneously.
`7. The method as claimed in claim 1, Wherein the periph
`eral vascular disease is peripheral arterial occlusive disease.
`8. The method as claimed in claim 1, Wherein the periph
`eral vascular disease is intermittent claudication.
`9. The method as claimed in claim 1, Wherein the effective
`amount is 10 ng/kg of body Weight/min.
`10. A kit for treatment of peripheral vascular disease
`comprising
`an effective amount of 9-deoXy-2‘,9-ot
`methano-3-oXa-4,5,6-trinor-3,7-(1‘,3‘-interphenylene)-13,
`14-dihydro-prostaglandin F1, its pharmaceutically accept
`able salts, and/or acid derivatives thereof, (ii) one or more
`pharmaceutically acceptable carriers and/or additives, and
`(iii) instructions for use in treating peripheral vascular
`disease.
`11. The kit as claimed in claim 10, Wherein component
`is a pharmaceutically acceptable salt of 9-deoXy-2‘,9-ot
`methano-3-oXa-4,5,6-trinor-3,7-(1‘,3‘-interphenylene)-13,
`14-dihydro-prostaglandin F1.
`12. The kit as claimed in claim 10, Wherein component is 9-deoXy-2‘,9-ot-methano-3-oXa-4,5,6-trinor-3,7-(1‘,3‘
`
`interphenylene)-13,14-dihydro-prostaglandin F1 in an orally
`available form selected from the group consisting of tablets
`and capsules.
`
`13. The kit as claimed in claim 10, Wherein component is 9-deoXy-2‘,9-ot-methano-3-oXa-4,5,6-trinor-3,7-(1‘,3‘
`
`interphenylene)-13,14-dihydro-prostaglandin F1 in a form
`suitable for inhalation.
`
`14. The kit as claimed in claim 10, Wherein component is 9-deoXy-2‘,9-ot-methano-3-oXa-4,5,6-trinor-3,7-(1‘,3‘
`
`interphenylene)-13,14-dihydro-prostaglandin F1 in a form
`suitable for subcutaneous administration.
`15. The kit as claimed in claim 10, Wherein the peripheral
`vascular disease is peripheral arterial occlusive disease.
`16. The kit as claimed in claim 10, Wherein the peripheral
`vascular disease is intermittent claudication.
`17. The kit as claimed in claim 10, Wherein the effective
`amount is 10 ng/kg of body Weight/min.
`
`*
`
`*
`
`*
`
`*
`
`*
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO. 1 6 054 486
`DATED
`1 April 25, 2000
`INVENTOWS) 1 James Crow et al.
`
`It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby
`corrected as shown below:
`
`Cover page, line [731' Assignee: United Technology Corporation
`should be -—United Therapeutics Corporation--.
`
`Signed and Sealed this
`
`Fifteenth Day of May, 2001
`
`Afl‘éSfi'lg O?ifé‘l’
`
`Acting Director (If The United Strum Parent and Trademark Office
`
`NICHOLAS P. GODICI
`
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