PCI‘
`
`Doc Ref. FP13
`Appl. No. 11/273,575
`
`II
`reau
`RTY ORGANIZATION
`I
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 =
`(11) International Publication Number:
`W0 93/17685
`A61K 31/549 31/40
`(43) International Publication Date:
`16 September 1993 (16.09.93:
`
`(21) International Application Number:
`PCT/US93/Ol8l3
`(22) International Filing Date:
`2 March 1993 (02.03.93)
`
`(81) Designated States: AU, BB, BG, BR, CA, CZ, F1, HU, JP
`KR, LK, MG, MN, MW, NO, NZ, PL, RO, RU, SD,
`SK, UA, European patent (AT, BE, CH, DE, DK, ES,
`FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI pa-
`tent (BF, BJ, CF, CG, CI, CM, GA, GN, M MR, SN,
`TD, TG).
`
`Published
`With international search report.
`
`(30) Priority data:
`849,554
`
`.
`11 March 1992 (11.03.92)
`
`US
`
`(71) Applicant: MERCK & CO., INC. [US/US]; 126 East Lin-
`coin Avenue, Rahway, NJ 07065 (US).
`
`(72) Inventors: KRISTIANSON, J., Krister ; Olofsgatan 13, S-
`193 00 Sigtuna (SE). WOLDOLSEN, Per ; 454-191 Pro-
`spect Avenue, West Orange, NJ 07052 (US).
`
`(74) Agent: NICHOLSON, William, H.; 126 East Lincoln Ave-
`nue, Rahway, NJ 07065 (US).
`
`
`
`(54) Title: COMBINATIONS 0F ACE INHIBITORS AND DIURETICS
`
`(57) Abstract
`
`Pharmaceutical formulations comprising as active ingredients an angiotensin converting enzyme (ACE) inhibitor at a dose
`level normally found effective as an antihypertensive and a diuretic at a dose level below its minimum effective dose, demonstrate
`greater efficacy than would be expected in returning the blood pressure of hypertensive patients to normotensive values.
`
`73
`_
`)‘3
`
`é.‘
`
`H
`
`
`
`Doc Ref. FP13
`Appl. No. 11/273,575
`
`II
`reau
`RTY ORGANIZATION
`I
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 =
`(11) International Publication Number:
`W0 93/17685
`A61K 31/549 31/40
`(43) International Publication Date:
`16 September 1993 (16.09.93:
`
`(21) International Application Number:
`PCT/US93/Ol8l3
`(22) International Filing Date:
`2 March 1993 (02.03.93)
`
`(81) Designated States: AU, BB, BG, BR, CA, CZ, F1, HU, JP
`KR, LK, MG, MN, MW, NO, NZ, PL, RO, RU, SD,
`SK, UA, European patent (AT, BE, CH, DE, DK, ES,
`FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI pa-
`tent (BF, BJ, CF, CG, CI, CM, GA, GN, M MR, SN,
`TD, TG).
`
`Published
`With international search report.
`
`(30) Priority data:
`849,554
`
`.
`11 March 1992 (11.03.92)
`
`US
`
`(71) Applicant: MERCK & CO., INC. [US/US]; 126 East Lin-
`coin Avenue, Rahway, NJ 07065 (US).
`
`(72) Inventors: KRISTIANSON, J., Krister ; Olofsgatan 13, S-
`193 00 Sigtuna (SE). WOLDOLSEN, Per ; 454-191 Pro-
`spect Avenue, West Orange, NJ 07052 (US).
`
`(74) Agent: NICHOLSON, William, H.; 126 East Lincoln Ave-
`nue, Rahway, NJ 07065 (US).
`
`
`
`(54) Title: COMBINATIONS 0F ACE INHIBITORS AND DIURETICS
`
`(57) Abstract
`
`Pharmaceutical formulations comprising as active ingredients an angiotensin converting enzyme (ACE) inhibitor at a dose
`level normally found effective as an antihypertensive and a diuretic at a dose level below its minimum effective dose, demonstrate
`greater efficacy than would be expected in returning the blood pressure of hypertensive patients to normotensive values.
`
`73
`_
`)‘3
`
`é.‘
`
`H
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`83
`BE
`BF
`BC
`3.!
`BR
`CA
`CF
`CG
`CH
`CI
`CM
`
`$C
`
`Z
`DE
`DK
`ES
`Fl
`
`Viel Nam rl‘
`
`France
`Gabon
`United Kingdom
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Democratic People's Republic
`of Korea
`'
`Republic of Korea
`Kamkhstan
`ljtxhtenslein
`Sri lanka
`Luxembourg
`Monaco
`Madagascar
`Mali
`Mongolia
`
`Auatria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Canada
`Central African Republic
`Congo
`Switzerland
`colt: d'lvoire
`Cameroon
`Czechoslovakia
`(heel: Republic
`Germany
`Denmark
`Spain
`Finland
`
`Mauritania
`Malawi
`Netherlands
`Norway -
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovak Republic
`Senegal
`Soviet Union
`Chad
`Togo
`Ukraine
`United States of America
`
`
`
`WU 93/ 17035
`
`PCT/US93/01813
`
`10
`
`ELILEJMLJEELINMENIIQH
`
`COMBINATIONS OF ACE INHIBITORS AND DIURETICS
`
`15
`
`20
`
`§ACKERQHBD;QILIHE.IHEEHIIQH
`Both diuretics and ACE-inhibitors have an
`
`effect on the renin—angiotensip-aldosterone system.
`ACE—inhibitors act by inhibiting the conversion of"
`angiotensin I to angiotensin II. Diuretics regulate
`the sodium-balance, and thereby also fluid volume.
`The decrease, both in sodium as well as volume,
`following therapy with diuretics increases plasma
`renin activity and thereby activates the
`renin-angiotensin-aldosterone system. This effect
`will to some degree counteract the blood—pressure
`lowering effect of the diuretic. When a diuretic and
`
`25
`
`an ACE—inhibitor are combined the different
`pharmacological actions of these two drugs will,
`
`30
`
`
`
`W0 93/17685
`
`PCT/US93/01813
`
`- 2 -
`
`influence the effect of the other. There is
`
`accordingly a logical rationale for combining these
`
`two pharmacological principles.
`
`It is possible to establish the highest
`non—pharmacological active dose of diuretic, i.e. a
`
`dose that is so low that it has no effect on blood
`
`pressure, and no apparent adverse effects.
`
`The
`
`highest non—effective dose of diuretic will still
`
`trigger the renin-angiotensin-aldosterone system and
`
`although it has no physiological effect of it's own,
`
`it will nonetheless have a potentiating effect on an
`ACE-inhibitor .
`
`In a recently completed study by us of the
`
`effects of different doses of HCTZ on blood pressure
`
`and various metabolic parameters, doses ranging from
`
`3 mg to 25 mg were investigated.
`
`25 mg HCTZ produced
`
`significant effects on blood pressure and the
`
`metabolic parameters.
`
`12.5 mg of HCTZ was found to
`
`be at the threshold of an effective antihypertensive
`
`response, and changes were seen in the metabolic
`
`parameters. Contrary to this,
`
`the doses of 3 and 6
`
`mg were demonstrated not to be different from placebo
`
`in effects on blood pressure and various metabolic
`
`parameters.
`
`Based on this study it can be concluded that
`
`6 mg has been established as the highest non-
`
`pharmacological dose of HCTZ.
`
`10
`
`15
`
`20
`
`25
`
`In a study by Andren et al., J;_prertsnsisn
`
`1 (suppl. 2) 384-386 (1983)) doses of 6.25, 12.5 and
`
`30
`
`25 mg of hydrochlorothiazide (HCTZ) were combined
`
`with 10 and 40 mg of enalapril reSpectively.
`
`The
`
`authors concluded that: "the five combinations were
`
`equally effective in reducing blood pressure, and
`
`when given with enalapril the dose of HCTZ can be
`
`very low". When the Andren study was performed, it
`
`
`
`wu 93/ 17085
`
`PCT/US93/01813
`
`_ 3 _
`
`was not known by him that 6.25 mg is or is close to
`
`the non—pharmacological dose.
`
`EHMMABX_QE_IEE_IHEEHI;QE
`This invention is concerned with
`pharmaceutical formulations for the treatment of
`
`essential hypertension and disorders associated
`
`therewith such as congestive heart failure which have
`
`10
`
`as active ingredients an angiotensin converting
`enzyme (ACE) inhibitor and a diuretic wherein the
`
`diuretic is at a dose level below the recognized
`.pharmacological dose.
`
`With these formulations the ACE inhibitor is
`
`.15
`
`found to have greater efficacy in reducing elevated
`blood pressure to normal levels than it would have if
`
`used at the same dose in monotherapy. At the same
`
`time the diuretic is being administered at dose
`
`levels that would be ineffective as an
`
`20
`
`antihypertensive if used alone and similarly
`ineffective in causing adverse reactions;
`
`25
`
`30
`
`DEIAILED_DE5flBIRIIQH_QE_IEE_IHYEHIIQH
`
`The novel pharmaceutical formulations of
`
`a pharmaceutical carrier;
`this invention comprise:
`an ACE inhibitor at the dose level normally employed
`in monotherapy, which is usually about 5450 mg,
`depending on the ACE inhibitor; and a diuretic at a
`dose level which is the highest non—pharmacolbgical
`dose.
`
`The formulation is designed for oral
`
`administration and is presented as tablets, capsules,
`ge1.caps, caplets or as a sustained release
`
`formulation.
`
`It may also be designed as an elixir
`
`
`
`W0 93/17685
`
`PCT/US93/01813
`
`_ 4 -
`
`for oral administration, or a suppository for rectal
`
`administration.
`
`Illustrative of the excipients which can be
`
`incorporated in tablets, capsules and the like are:
`a binder such as gum tragacanth, acacia, corn starch
`
`or gelatin; an excipient such as microcrystalline
`
`cellulose; a disintegrating agent such as corn
`
`starch, pregelatinized starch, alginic acid and the
`
`like; a lubricant such as magnesium stearate; a
`
`10
`
`sweetening agent such as sucrose,
`
`lactose or
`
`saccharin; a flavoring agent such as peppermint,
`
`oil of wintergreen or cherry. When the unit dosage
`
`form is a capsule, it may contain,
`
`in addition to
`
`materials of the above type, a liquid carrier such as
`
`15
`
`fatty oil. Various other materials may be present as
`
`coatings or to otherwise modify the physical form of
`
`the dosage unit.
`
`For instance, tablets may be coated
`
`with shellac, sugar or both.
`
`A syrup or elixir may
`
`contain the active compound, sucrose as a sweetening
`
`20'
`
`agent, methyl and propyl parabens as preservatives, a
`
`dye and a flavoring such as cherry or orange flavor.
`
`The novel formulations of this invention are
`
`useful in the treatment of essential hypertension,
`
`and congestive heart failure.
`
`25
`
`30
`
`
`
`'WU 93/ l 7685
`
`-
`
`PCT/US93/0181 3 .
`
`_ 5 _
`
`The ACE inhibitors useful in the novel
`
`formulation and method of treatment of this invention
`
`'are enalapril,
`
`lisin0pri1, captopril alacipril,
`
`benazapril, cilazapril, delapril, fosinopril,
`perindopril, quinapril, ramipril, moveltipril,
`spirapril, ceronapril,
`imidapril,
`temocapril,
`trandolopril, utilbapril, zofenopril, CV5975, EMD—
`
`56855, libenzapril, zalicipril, HOEO65, MDL 27088,
`A347, DU 1777, MDL 27467A, Equatennh Prentylnh
`Synecorna and Y23785.
`
`Preferred ACE inhibitors are enalapril,
`lisinopril, captopril, perindopril, benzapril,
`quinapril, and cilazapril, especially enalapril.
`The diuretics useful in the novel
`
`formulation and method of treatment of this invention
`are: hydrochlorothiazide (HCTZ), furosemide,
`altizide, trichlormethazide, triflumethazide,
`" bemetizide, cyclothiazide, methylchlothiazide,
`azosemide, chlorothiazide, butizide,
`
`10
`
`15
`
`20
`
`bendroflumethazide, cyclopenthiazide,
`
`benzclortriazide, polythiazide, hydroflumethazide,
`benzthiazide, ethiazide, penflutazide.
`
`Preferred diuretics for incorporation in the
`novel formulation of this invention are
`
`25
`
`hydrochlorothiazide,
`
`trichlormethazide, furosemide
`
`and altizide, especially hydrochlorothiazide.
`‘In the specification and claims hereof,
`naming of an ACE inhibitor or diuretic such as
`
`the
`
`3O
`
`enalapril or hydrochlorothiazide respectfully is
`meant to include salts thereof such as enalapril
`maleate.
`.
`
`The novel method of treatment of this
`invention comprises the administration of a unit dose
`of the novel pharmaceutical formulation, one to three
`
`
`
`
`
`W0 93/17685
`
`PCI'/US93/01813
`
`-5-
`
`times a day depending on the patient and the severity
`of the indication being treated. Usually once or
`
`'twice a day is adequate.
`
`EXAMZLE_l
`
`Qommnent
`
`We).
`
`enalapril maleate
`
`10
`
`hydrochlorothiazide
`
`sodium bicarbonate
`
`lactose
`
`starch NF
`
`,
`
`pregelatinized starch NF
`
`A
`
`20
`
`6
`
`10
`
`154
`
`22
`
`2.2
`
`15
`
`magnesium stearate
`
`_ 1.1
`
`B
`
`10
`
`6
`
`‘5
`
`Q
`
`5
`
`6
`
`2.5
`
`164.1
`
`198.1
`
`22
`
`22.77
`
`2.2
`
`1.0
`
`5.06
`
`0.90
`
`The excipients shown in Example 1 are
`
`exemplary of the substituents used in each of the
`
`other examples that follow.
`
`20
`
`EXAMELE_Z
`
`when;
`
`M
`
`25
`
`lisinopril
`
`hydrochlorothiazide
`
`l
`
`20
`
`6
`
`2.
`
`10
`
`6
`
`1
`
`5
`
`6
`
`3O
`
`(i
`
`g1.
`
`
`
`wu 95/ 17085
`
`PCT/US93/01813
`
`_ 7 _
`
`EXAMELE_3
`
`Cgmpgngn;
`
`'
`
`5
`
`Captopril
`
`hydrochlorothiazide
`
`AQQQBL_1E31
`
`1
`
`50,
`
`6
`
`Z
`
`25
`
`6
`
`3
`
`12.5
`
`6
`
`EXAMELE_§
`
`' 9mm:
`
`Benazapril
`
`.
`
`hydrochlorothiazide
`
`Alumni-4mg).
`
`1
`
`40
`
`6
`
`Z
`
`20
`
`6
`
`3
`
`10
`
`6
`
`EXAMELE_§
`
`mm-
`
`Quinapril
`
`hydrochlorothiazide
`
`mm
`1
`z
`20
`10
`
`6
`
`6
`
`3
`5
`
`6
`
`EXAMELE_§
`
`10
`
`15
`
`20
`
`25
`
`9.99m
`
`Cilazapril
`
`30
`
`hydrochlorothiazide
`
`W
`l
`2
`50
`25
`
`6
`
`6
`
`' 3
`12.5
`
`6
`
`
`
`W0 93/17685
`
`PCI'IUS93/01813
`
`EEAI_l§_§LAlHED_I§;
`
`l.
`
`A pharmaceutical formulation comprising
`
`a pharmaceutical carrier; about 5-50 mg of an
`
`5
`
`angiotensin converting enzyme inhibitor; and a non-
`
`pharmacological dose of a diuretic.
`
`2.
`
`The pharmaceutical formulation of Claim
`
`1, wherein the angiotensin converting enzyme
`
`10
`
`inhibitor is selected from enalapril,
`
`lisin0pri1,
`
`captopril alacipril, benazapril, cilazapril,
`
`delapril, fosinopril, perindopril, quinapril,
`
`ramipril, moveltipril, Spirapril, ceronapril,
`
`15
`
`temocapril, trandolopril, utilbapril,
`imidapril,
`zofenopril. cv5975, mm 56855, libenzapril,
`zalicipril, HOEOSS, MDL 27088, A347, DU 1777, MDL
`
`27467A, Equatenfi”, Prentyifi", Synecornu, and
`
`Y23785; and the diuretic is selected from
`
`hydrochlorothiazide (HCTZ), furosemide, altizide,
`
`20
`
`trichlormethazide, triflumethazide, bemetizide,
`
`cyclothiazide, methylchlothiazide, azosemide,
`
`chlorothiazide, butizide, bendroflumethazide,
`
`cyclopenthiazide, benzclortriazide, polythiazide,
`
`hydroflumethazide, benzthiazide, ethiazide,
`
`25
`
`penflutazide.
`
`3.
`
`The formulation of Claim 2, wherein the
`
`angiotensin converting enzyme inhibitor is selected
`
`from enalapril, lisinopril, captopril, perindopril,
`
`30
`
`benazapril, quinapril, and cilazapril; and the
`
`diuretic is selected from hydrochlorothiazide,
`
`-trichlormethazide, furosemide and altizide.
`
`
`
`wu 9.91 17053
`
`PCT/US93/018-13
`
`_ 9 _
`
`4.
`
`The formulation of Claim 3, wherein the
`
`angiotensin converting enzyme inhibitor is enalapril,
`and the diuretic is hydrochlorothiazide;
`
`The formulation of Claim 4 comprising
`5.
`5, 10 or 20 mg of enalapril and 6 mg of
`
`hydrochlorothiazide.
`
`10
`
`congestive heart failure, which comprises the
`
`6.
`
`A method of treating hypertension and
`
`administration to a patient in need of such treatment
`
`of a pharmaceutical formulation comprising a
`pharmaceutical carrier; about 5-50 mg of an
`
`angiotensin converting enzyme inhibitor; and a non—
`
`15
`
`pharmacological dose of a diuretic.
`
`20
`
`25
`
`7.
`
`The method of Claim 6, wherein the
`
`angiotensin converting enzyme inhibitor is selected
`
`from-enalapril. lisinopril, captopri1.a1acipri1,
`benazapril, cilazapril, delapril, fosinopril,
`perindOpril, quinapril, ramipril, moveltipril,
`spirapril. ceronapril,
`imidapril,
`temocapril,
`trandolopril, utilbapril, zofenopril, CV5975, EMD
`
`56855, libenzapril. zalicipril, nonoes, MDL 27088,
`A347, DU 1777, MDL 27467A3 Equatennh Prentylnfi
`Synecornh and Y23785; and the diuretic is selected
`
`from hydrochlorothiazide (HCTZ), furosemide,
`
`altizide,
`
`trichlormethazide, triflumethazide,
`
`bemetizide, cyclothiazide, methylchlothiazide,
`
`3O
`
`.azosemide, chlorothiazide, butizide,
`
`in:
`
`bendroflumethazide, cyc10penthiazide,‘
`
`benzclortriazide, polythiazide, hydroflumethazide,
`
`benzthiazide, ethiazide, penflutazide.
`
`
`
`W0 93/l 7685
`
`PCT/US93/01813
`
`_ 10 -
`
`8.
`
`The method of Claim 7 wherein the
`
`angiotensin converting enzyme inhibitor is selected
`
`from enalapril, lisinopril, captoPIil perindopril,
`
`benazapril, quinapril, and cilazapril; and the
`
`diuretic is selected from hydrochlorothiazide,
`
`taichlormethazide, furosemide and altizide.
`
`9.
`
`The method of Claim 8 wherein the
`
`angiotension converting enzyme inhibitor is enalapril
`and the diuretic is hydrochlorothiazide.
`
`10.
`
`The method of Claim 9 comprising 5, 10
`
`or 20 mg of enalapril and 6 mg of hydrochlorothiazide.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`g. v -n‘- ‘s-Onvo w mm m VI.“
`
`“mow l‘ppufluon "on
`
`PCT/US93/01813
`
`CLASSIFICATION 01' SUBJECT MATTER
`A.
`lPC(5)
`:A61K31I54.31140,
`USCL :514’2235,423 - ‘
`According to Internstionll Pstent Classification (lPC) or to both-muons] classification and IPC
`B.
`FIELDS SEARCHED
`
`Minimum doeumentstion searched (clsssificstion system followed by clsssificstion symbols)
`U.S.
`:
`
`Electronicdsnbucmmuhddufingmehtaufiomsweh(nsmeofdmbueand,wbmpncfieebb,sesnchtcrmsused)
`APS and Css OnlinczACE inhibitors, diuretic. hypertension, heart, candid, enslspril, hydrochlorothiszide
`
`C.
`
`'DOCUMEN'IS CONSIDERED TO BE RELEVANT
`
`Citation ofdomwithindicstion, wheresppropristemftherclevmtpussges
`
`Journal of Hypertension, 1983, Andren et al., Enalapril with either
`a ’verylow’ or ’low’ dose of hydrochlorothiazide is equally effective
`in essential hpertension, pages 384-386.
`
`Chemical Abstract, volume 111, no. 9, Becker et al.; "Loop
`dinnetics combined with an ACE inhibitor
`for treatment of
`hypertension: a study with furosemide, piretanide, and ramipil in
`spontaneously
`hypertensive
`rats',
`70668h,
`J.
`' Cardiovasc. Pharma 001., 1989, 13 (Suppl. 3), p. 535-539.
`
`
`
`”Mytudshbmfilh‘dleorpfimity
`“duhmflhvibhmuchdtnuduudh
`Wuwmbm
`
`waMwma-mmmu
`WMwthbmum-q
`mum's-Inst.
`
`map-m muchhdhvafinmbc
`W to Evolve - m ta) Ilka the dean '-
`wmmwmohnfimmm
`beh'cbviu-bnmfilldEOem
`
`“Mythhhiflflinlfilq’ unme-
`
`Dste ofthcacualcompletion ofthe internstionslseereh
`
`01 MAY 1993
`
`Name and Insiling address of the ISAIUS
`Weffimand'rmm
`NW 13.6. 2023!
`Facsimile No. NOT APPLICABLE
`Fm-m PCT/ISAHIA lemma .t...nn..lu swan
`
`x W
`
`
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