(12) INTERNATIONAL APPLICI
`
`Doc Ref. FP21
`
`App]. No. 11/273,575
`
`E PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`IllllllllllillllIlllllllllllllllllllllllll|||I|llllllllllllllllllllIllllllllllllllllllllllllll
`
`(10) International Publication Number
`(43) International Publication Date
`WO 2005/007130 Al
`27 January 2005 (27.01.2005)
`
`(51) International Patent Classifieation7:
`31/00, 47/22
`
`A61K 9/00,
`
`(21) International Application Number:
`PCTIEP2004/007591
`
`(22) International Filing Date:
`
`9 July 2004 (09.07.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`10/618,548
`
`11 July 2003 (11.07.2003)
`
`US
`
`(71) Applicant (for all designated States except AT, US): NO-
`VARTIS AG [CH/CH]; Lichtstrasse 35, 4056 Basel (CH).
`
`(71) Applicant (forATonly): NOVARTIS PHARMA GMBH
`[AT/AT]; Brunner Strasse 59, A-1230 Vienna (AT).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): PATEL, Ashish,
`Anilbhai [IN/US]; 20 New Road #6A, Kendall Park, NJ
`08824 (US). DAVILA, Pablo [US/US]; 130 Woods Road,
`East Windsor, NJ 08520 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, T1", TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
`SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`— with international search report
`— before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(74) Agent: GRUBB, Philip; Novartis AG, Corporate Intellec-
`tual Property, CPI-4002 Basel (CH).
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: STABLE PHARMACEUTICAL COMPOSITIONS CONTAINING AN ACE INHIBITOR
`
`
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`07130A1||||l|||||||||||ll|||l||||||l|||l|||||||||||||||||||||||||||||||||||||||||||ll||||l||||||||||||
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`c (57) Abstract: A pharmaceutical composition comprising about 1 wt. % to about 80 wt. % of an ACE inhibitor or a pharmaceu-
`R tically acceptable salt thereof, about 1 wt. % to about 70 wt. % of an alkali or alkaline earth metal carbonate, and about 1 wt. %
`c to about 80 wt. % of hydroxypropyl cellulose, wherein the weight percents are based on the total weight of the pharmaceutical
`c composition. Preferably, the pharmaceutical composition is stable, and the formation of an internal cyclization product, and/or ester
`N hydrolysis product, and/or oxidation product within the composition, has been reduced or eliminated. The ACE inhibitor is selected
`from the group consisting of quinapril, enalapril, spirapril, ramipril, perindopn'], indolapril, lisinopril, alacepril, trandolapril, benaza-
`pril, libenzapn'l, delapril, cilazapril and combinations thereof. Advantageously, the stabilized pharmaceutical compositions of the
`invention preserve the ACE inhibitor or a pharmaceutically acceptable salt thereof present in the compositions from degradation.
`
`

`

`WO 2005/007130
`
`PCT/EP2004/007591
`
`-'1 -
`
`Stable Pharmaceutical Compositions Containing an ACE Inhibitor
`
`Field of the Invention
`
`The invention relates to pharmaceutical compositions comprising an angiotensin converting
`
`enzyme (ACE) inhibitor, an alkali or alkaline earth metal carbonate, and hydroxypropyl
`
`cellulose. More particulany, the invention relates to stable pharmaceutical compositions
`wherein the formation of an internal cyclization product and/or ester hydrolysis product
`
`and/or oxidation product, has been reduced or eliminated.
`
`Background of the Invention
`
`There are a number of pharmaceutical compositions which suffer from instability problems
`
`due to the fact that the active component is susceptible to certain types of degradation,
`thereby diminishing their attractiveness and, in some cases, rendering them unsuitable from
`
`a commercial standpoint. For example, several ACE inhibitor—containing compositions suffer
`
`from this drawback since certain ACE inhibitors degrade readily in pharmaceutical dosage
`
`forms. For example, quinapril. enalapril, and spirapril degrade readily in dosage form to a
`
`diketo piperazine (the internal cyclization product) and a diacid (the ester hydrolysis product).
`
`it is believed that one or more of these types of degradation including oxidation causes the
`
`discoloration in pharmaceutical compositions containing ACE inhibitors. in addition, the
`degradation products may result in decreased drug effectiveness in such pharmaceutical
`
`compositions. Accordingly, in view of their usefulness in treating hypertension, a number of
`
`research endeavors have been directed to overcoming the instability problem associated
`
`with pharmaceutical compositions containing ACE inhibitors, with limited success.
`
`Various methods of improving the stability of certain ACE inhibitors have been disclosed.
`U.S. Patent No. 4,743,450 discloses that certain ACE inhibitors, and in particular, quinapril
`
`and its acid‘addition salts can be stabilized by making solid compositions that include an
`
`alkali or alkaline earth metal carbonate, preferably magnesium carbonate, and a saccharide,
`
`Specifically a sugar, such as mannitol or lactose. U.S. Patent No. 4,793,998 discloses that
`
`certain ACE inhibitors, and in particular, quinapril and its acid addition salts can be stabilized
`
`by making solid compositions that include ascorbic acid, and optionally one or more acids
`
`selected from citric, fumaric and maleic acids. U.S. Patent No. 4,830,853 discloses that
`
`

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`W0 2005/007130
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`PCT/EP2004/007591
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`- 2 .
`
`certain ACE inhibitors, and in particular. quinapril and its acid addition salts can be stabilized
`
`by making solid compositions that include ascorbic acid or a metal or ammonium ascorbate.
`
`Although each of the above patents represents an attempt to overcome the instability
`
`problems associated with pharmaceutical compositions containing an ACE inhibitor, there
`
`still exists a need for improving the stability of such pharmaceutical compositions, especially
`
`in the presence of moisture.
`
`Summam‘ of the Invention
`
`The invention provides a pharmaceutical composition comprising about 1 wt. % to about
`
`80 wt. % of an ACE inhibitor or a pharmaceutically acceptable salt thereof, about 1 wt. % to
`
`about 70 wt. % of an alkali or alkaline earth metal carbonate, and about 1 wt. % to about
`
`80 wt. % of hydroxypropyl cellulose, wherein the weight percents are based on the total
`
`weight of the pharmaceutical composition.
`
`According to another aspect, the invention provides a method of preparing a pharmaceutical
`
`composition comprising about 1 wt. % to about 80 wt. % of an ACE inhibitor or a
`
`pharmaceutically acceptable salt thereof, about 1 wt. % to about 70 wt. % of an alkali or
`
`alkaline earth metal carbonate, and about 1 wt. % to about 80 wt. % of hydroxypropyl
`
`cellulose, wherein the weight percents are based on the total weight of the pharmaceutical
`
`composition, said method comprising:
`
`(a) mixing the ACE inhibitor or a pharmaceutically acceptable salt thereof, an alkali
`
`or alkaline earth metal carbonate, hydroxypropyl cellulose, and optionally one or
`
`more excipients, to form a premix;
`
`(b) adding a solvent, and optionally one or more excipients, to the premix formed in
`
`Step (a) to form a wet granulation;
`
`(c) drying the wet granulation to form granules, and optionally milling the granules;
`
`and
`
`(d) optionally mixing one or more excipients with the granules
`
`to form a pharmaceutical composition.
`
`

`

`WO 2005/007130
`
`PCT/EP2004/007591
`
`Preferably, the pharmaceutical composition of the invention is stable, and the formation of an
`
`internal cyclization product, and/or ester hydrolysis product, and/or oxidation product within
`
`the compositon, has been reduced or eliminated.
`
`'
`
`In a further aspect, the pharmaceutical composition of the invention comprises an ACE
`
`inhibitor which is selected from the group consisting of quinapril, enalapril, spirapril, ramipril,
`
`pen'ndopril, indolapril, lisinopril, alacepril, trandolapril, benazapril, libenzapril, delapril,
`
`cilazapril, and combinations thereof.
`
`The stabilized pharmaceutical compositions of the invention exhibit a number of advantages
`
`as follows: (i) the ACE inhibitor or a pharmaceutical acceptable salt thereof present in the
`
`compositions is preserved from degradation; (ii) the compositions exhibit extended shelf-life
`
`under normal storage conditions; (iii) the effect of moisture on the compositions is minimized;
`
`(iv) the compositions exhibit minimal, if any, discoloration over a significant period of time;
`
`and (v) the compositions exhibit minimal, if any, instability when employed in the presence of
`
`colorants.
`
`Description of the Invention
`
`The pharmaceutical composition of the invention contains an ACE inhibitor or a
`
`pharrnaceutically acceptable salt thereof, an alkali or alkaline earth metal carbonate, and
`
`hydroxypropyl cellulose. The ACE inhibitor is selected from quinapril, enalapril, spirapril,
`
`ramipril, perindopril, indolapril, lisinopril, alacepril, trandolapril, benazapril, libenzapril,
`
`delapril, and cilazapril. A combination of ACE inhibitors may also be used. Preferably, the
`
`ACE inhibitor is selected from quinapril, enalapril, and spirapril. More preferably, the ACE
`
`inhibitor is quinapril hydrochloride. It is noted that the ACE inhibitor may form a salt with
`
`various inorganic and organic acids and bases, which salts may be prepared by conventional
`
`methods.
`
`The amount of ACE inhibitor or a pharrnaceutically acceptable salt thereof in the
`
`pharmaceutical compositions is preferably from about 1 wt. % to about 80 wt. %, based on
`
`the total weight of the pharmaceutical composition. More preferably, the amount of ACE
`
`inhibitor or a pharmaceutically acceptable salt thereof is from about 5 wt. % to about
`
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`WO 2005/007130
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`PCT/EP2004/007591
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`_ 4 -
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`50 wt. %, most preferably about 10 wt. % to about 15 wt.%. As indicated above, ACE
`
`inhibitors including pharrnaceutically acceptable salts thereof are known and their usefulness
`
`in treating hypertension is also well known. Accordingly, the daily dosages at which said ACE
`
`inhibitors or pharmaceutically acceptable salts thereof are employed as well as typical unit
`dosages of said ACE inhibitors or phannaceutically acceptable salts thereof are well
`
`documented in the literature. Preferably, the ACE inhibitor or a pharrnaceutically acceptable
`
`salt thereof is present in the pharmaceutical composition in an amount of from about 1 mg to
`
`about 100 mg.
`
`The alkali or alkaline earth metal carbonate is a salt which is prepared by reacting an alkali
`
`metal or alkaline earth metal with carbonic acid. The alkali metal is selected from lithium,
`
`sodium, potassium, rubidium, caesium and francium. The alkaline earth metal is selected
`
`from magnesium, calcium, barium, strontium and radium. Magnesium, calcium and sodium
`
`are the preferred metals. Most preferably, the metal is magnesium.
`
`The amount of the alkali or alkaline earth metal carbonate in the pharmaceutical
`
`compositions is from about 1 wt. % to about 70 wt. %, based on the total weight of the
`
`pharmaceutical composition. Preferably, the amount of the alkali or alkaline earth metal
`
`carbonate is from about 10 wt. % to about 60 wt. %, more preferably about 45 wt. % to about
`
`55 wt.%.
`
`Hydroxypropyl cellulose is a partially substituted poly(hydroxypropyl) ether of cellulose.
`
`Hydroxypropyl cellulose is commercially available in a number of different grades which have
`
`different solution viscosities. The molecular weight of the hydroxypropyl cellulose ranges
`
`from about 50,000 to about 1,250,000. A preferred hydroxypropyl cellulose is available from
`
`Aqualon under the trademark KLUCEL. Suitable grades of hydroxypropyl cellulose include
`
`the following:
`
`1) KLUCEL EF having a molecular weight of about 80,000;
`
`2) KLUCEL LF having a molecular weight of about 95,000;
`
`3) KLUCEL JF having a molecular weight of about 140,000;
`
`4) KLUCEL GF having a molecular weight of about 370,000;
`
`5) KLUCEL MF having a molecular weight of about 850,000; and
`
`6) KLUCEL HF having a molecular weight of about 1,150,000.
`
`

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`WO 2005/007130
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`PCT/EP2004/007591
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`- 5 -
`
`Preferably, the hydroxypropyl cellulose is a low-substituted hydroxypropyl cellulose. The low-
`
`substituted hydroxypropyl cellulose (L-HPC) useful in the pharmaceutical compositions of the
`
`invention is available in a number of different grades which have different particle sizes and
`substitution levels, and which are classified on the basis of their % hydroxypropoxy content.
`
`When dried at 105 °C for 1 hour, the L-HPC contains from about 5% to about 16% of
`
`hydroxypropoxy groups, preferably from about 10% to about 13% of hydroxypropoxy groups.
`
`Suitable grades of L-HPC include the following:
`
`,.
`
`1) LH-11 having a hydroxypropoxy content of 11% and an average particle size of
`
`50 microns;
`
`2) LH-21 having a hydroxypropoxy content of 11% and an average particle size of
`
`40 microns;
`
`3) LH-31 having a hydroxypropoxy content of 11% and an average particle size of
`
`25 microns;
`
`4) LH-22 having a hydroxypropoxy content of 8% and an average particle size of
`
`40 microns;
`
`5) LH-32 having a hydroxypropoxy content of 8% and an average particle size of i
`
`25 microns;
`
`6) LH-20 having a hydroxypropoxy content of 13%, and an average particle size of
`
`40 microns; and
`
`7) LH-30 having a hydroxypropoxy content of 13%, and an average particle size of
`
`25 microns.
`
`Preferred L-HPCs are commercially available from Shin-Etsu Chemical Company under the
`
`trade designation L-HPC Grade LH-21 and LH-11.
`
`The amount of hydroxypropyl cellulose in the pharmaceutical compositions is from about
`
`1 wt. % to about 80 wt. %, based on the total weight of the pharmaceutical composition.
`
`Preferably, the amount of hydroxypropyl cellulose is from about 10 wt. % to about 50 wt. %,
`
`more preferably about 30 wt. % to about 40 wt. %.
`
`The pharmaceutical compositions of the invention may also contain one or more excipients
`
`that are normally employed in pharmaceutical formulations, the only qualification being that
`
`they must not deleteriously affect the stability of the pharmaceutical compositions. Examples
`
`of such excipients are surfactants, diluents, binders, amino acids, solubilizers, disintegrants,
`
`

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`PCT/EP2004/007591
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`- 6 -
`
`fillers, lubricants, buffers, stabilizers, colorants, dyes, anti-oxidants, anti-adherents,
`
`preservatives and glidants. A combination of excipients may also be used. Such excipients
`are known to those skilled in the art, and thus, only a limited number will be specifically
`referenced.
`
`Examples of fillers include microcrystalline cellulose, dibasic calcium phosphate dihydrate,
`
`calcium sulfate trihydrate and calcium sulfate dehydrate. A combination of fillers may also be
`
`used. Preferably, the pharmaceutical composition of the invention does not contain a
`
`saccharide, specifically a sugar. such as lactose or mannitol. in addition, preferably the
`
`pharmaceutical composition of the invention does not contain starch.
`
`Examples of lubricants include magnesium stearate, sodium stearate, calcium stearate, zinc
`
`stearate, talc, propylene glycol, PEG, stearic acid, vegetable oil, sodium benzoate, sodium
`
`lauryl sulfate, magnesium lauryl sulfate, mineral oil and polyoxyethylene monostearate. A
`
`combination of lubricants may also be used. A preferred lubricant is magnesium stearate.
`
`Examples of binders include gums, such as gum tragacanth, acacia gum and gelatin;
`
`.microcrystalline cellulose, e.g., products known under the registered trademarks Avicel,
`
`Filtrak, Heweten or Pharmacel, hydroxyethyl cellulose and hydroxypropylmethyl cellulose;
`
`and polyvinyl pyrrclidone, e.g., Povidone.
`
`Examples of glidants include silica, magnesium trisilicate, powdered cellulose, talc, calcium
`
`silicate, and tribasic calcium phosphate. Colloidal silica, e.g., Aerosil, is particularly preferred.
`
`Examples of disintegrants include:
`
`(i) cross-linked polyvinylpyrrolidones, e.g., crospovidones, such as Polyplasdone® XL
`
`and Komdon® CL;
`
`'
`
`(ii) alglnic acid and sodium alginate;
`
`(iii) methacrylic acid-divinylbenzene co-polymer salts, e.g., Amberlite® lRP-88; and
`
`(iv) cross-linked sodium carboxymethylcellulose, available as, e.g., Ac-di-sol‘”,
`
`Primellose®, Pharmacel® XL, Explocel® and Nymcel® zsx.
`
`

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`WO 2005/007130
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`PCT/EP2004/007591
`
`- 7 -
`
`'
`
`Additional disintegrants also include hydroxypropylmethyl cellulose, croscarmellose sodium,
`
`polacrillln potassium, polyacrylates, such as Carbopol®, magnesium aluminium silicate and
`
`bentonite.
`
`The pharmaceutical compositions of the invention can be prepared by any of the
`
`conventionally employed processing techniques such as dry granulation or wet granulation
`
`process. Wet granulation is preferably chosen to ensure a homogeneous distribution of the
`
`ACE, alkali or alkaline earth metal carbonate, and low-substituted hydroxypropyl cellulose.
`
`in one embodiment of the invention, the pharmaceutical composition is prepared by a
`
`process comprising:
`
`(a) mixing the ACE inhibitor or a pharrnaceutically acceptable salt thereof, an alkali
`
`or alkaline earth metal carbonate, hydroxypropyl cellulose, and optionally one or more
`
`excipients, to form a premix;
`
`(b) adding a solvent, and optionally one or more excipients, to the premix formed in
`
`Step (a) to form a wet granulation;
`
`(c) drying the wet granulation to form granules, and optionally milling the granules;
`
`and
`
`(d) optionally mixing one or more excipients with the granules
`
`to form a pharmaceutical composition.
`
`Examples of solvents to be used in the wet granulation process include water, methanol,
`
`ethanol, isopropanol, acetone and ethylene chloride. A combination of solvents may also be
`
`used. Preferably, the solvent is water.
`
`Drying techniques useful for drying the granulation include spray-drying, fluid bed, flash
`
`drying, ring drying, micron drying, tray drying, vacuum drying, radio-frequency drying and
`
`microwave drying.
`
`‘
`
`The pharmaceutical compositions of the invention may be in the form of a capsule, caplet,
`bar, block, powder, disc or tablet, or in the form of granules. In a preferred embodiment, the
`
`pharmaceutical compositions are in the form of a tablet.
`
`

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`WO 2005/007130
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`PCT/EP2004/007591
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`The following non-limiting examples illustrate further aspects of the invention.
`
`The L-HPC used in the examples is commercially available from Shin-Etsu Chemical
`
`Company under the trade designation L-HPC Grade LH-21.
`
`Example 1
`
`Preparation of Quinapril Hydrochloride 40 mg Tablets.
`
`
`
`Item #
`Ingredients
`mgltablet
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`Quinapril Hydrochloride
`
`Magnesium Carbonate
`
`Microcrystalline Cellulose pH 102
`
`L-HPC
`
`Crospovidone
`
`Magnesium Stearate
`
`Methocel E15 LV
`
`Triethyl Citrate
`
`Opadry Beige YS—1 -2718
`
`Purified Water
`
`43.33
`
`200.0
`
`0.0
`
`136.67
`
`16.0
`
`4.0
`
`8.0
`
`0.8
`
`8.0
`
`q.s.
`
`
`
`Total 416.8
`
`The tablet composition is prepared by:
`
`' (a) mixing quinapril hydrochloride, magnesium carbonate. and L-HPC to form a
`
`premix;
`
`(b) adding water to the premix formed in Step (a) to form a wet granulation under
`
`high shear granulation conditions;
`
`(c) drying the wet granulation in a fluid bed, and co-milling the dried granules;
`
`(d) V-blending the crospovidone and magnesium stearate with the granules to form
`
`a composition which is compressed on a Manesty Beta Press to form tablets; and
`
`(e) coating the tablets formed in Step (d) with Methocel and triethyl citrate using a
`
`Accela Cota; and
`
`(f) color coating the tablets formed in Step (e) with Opadry Beige using an Accela
`
`Cota.
`
`

`

`WO 2005/007130
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`PCT/EP2004/007591
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`' Examgle 2
`
`Preparation of Quinapril Hydrochloride 40 mg Tablets.
`
`
`
`Item #
`Ingredients
`mgltablet
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`Quinapril Hydrochloride
`
`Magnesium Carbonate
`
`Microcrystalline Cellulose pH 102
`
`L-HPC
`
`Crospovidone
`
`Magnesium Stearate
`
`Methocel E15 LV
`
`Triethyl Citrate
`
`Opadry Beige YS-1-2718
`
`Purified Water
`
`43.33
`
`200.0
`
`136.67
`
`0.0
`
`16.0
`
`4.0
`
`8.0
`
`0.8
`
`8.0
`
`q.s.
`
`
`
`Total 416.8
`
`The quinapril tablets are prepared according to the procedure set forth in Example 1.
`
`Examgle 3
`
`Preparation of Quinapril Hydrochloride 40 mg Tablets.
`
`
`
` item # Ingredients mgltablet
`
`
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`Quinapril Hydrochloride
`
`Magnesium Carbonate
`
`Microcrystalline Cellulose pH 102
`
`L-HPC
`
`Crospovidone
`
`Magnesium Stearate
`
`Methocei E15 LV
`
`Triethyl Citrate
`
`Opadry Beige YS-1-2718
`
`Purified Water
`
`,
`
`43.33
`
`200.0
`
`68.34
`
`68.33
`
`16.0
`
`4.0
`
`8.0
`
`0.8
`
`8.0
`
`q.s.
`
`
`
`Total 416.8
`
`The quinapril tablets are prepared according to the procedure set forth in Example 1.
`
`

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`WO 2005/007130
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`-10-
`
`Example 4
`
`Preparation of Quinapn’l Hydrochloride 40 mg Tablets.
`
`
`
` Item # Ingredients mgltablet
`
`
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`Quinapril Hydrochloride
`
`Magnesium Carbonate
`
`Microcrystalline Cellulose pH 102
`
`L-HPC
`
`Crospovidone
`
`Magnesium Stearate
`
`Methocel E15 LV
`
`Triethyl Citrate
`
`Opadry Beige YS-1-2718
`
`Purified Water
`
`43.33
`
`200.0
`
`100.0
`
`36.67
`
`16.0
`
`4.0
`
`8.0
`
`0.8
`
`8.0
`
`q.s.
`
`
`
`Total 416.8
`
`The quinapril tablets are prepared according to the procedure set forth in Example 1.
`
`Example 5
`
`The stability of the tablets prepared in Examples 1-4 is determined by the amount of
`
`degradation products according at 40 °C and 75% relative humidity.
`
`Table 1.
`
`
`Tablet
`
`Degradation
`Degradation
`Product DKP
`Product
`Quinaprilate
`(wt. %)
`
`(wt. %)
`
`Quinapril (%)
`
`Example 1
`
`Example 2
`
`Example 3
`
`99.9
`
`91.5
`
`92.7
`
`0.733
`
`2.281
`
`1.421
`
`0.173
`
`0.132
`
`0.138
`
`
`
`Example 4 0.140 96.8 0.924
`
`
`
`
`
`The test results in Table 1 clearly show that Example 2 which is prepared with magnesium
`
`carbonate but without hydroxypropyl cellulose has a significantly high level of degradation
`
`product quinaprilate.
`
`Degradation product DKP is understood to mean the diketo piperazine degradation product
`as herein mentioned.
`
`

`

`wo 2005/007130
`
`PCT/EP2004/007591
`
`-11-
`
`While the invention has been described with particular reference to certain embodiments
`
`thereof, it will be understood that changes and modifications may be made by those of
`
`ordinary skill within the scope and spirit of the following claims:
`
`

`

`W0 2005/007130
`
`PCT/EP2004/007591
`
`- 12 -
`
`WHAT IS CLAIMED IS:
`
`1.
`
`A pharmaceutical composition comprising about 1 wt. % to about 80 wt. % of an ACE
`
`inhibitor or a pharmaceutically acceptable salt thereof, about 1 wt. % to about 70 wt. %
`
`of an alkali or alkaline earth metal carbonate, and about 1 wt. % to about 80 wt. % of
`
`hydroxypropyl cellulose, wherein the weight percents are based on the total weight of
`
`the pharmaceutical composition.
`
`2.
`
`A pharmaceutical composition according to claim 1 which is stable, and wherein the
`
`formation of an internal cyclization product, and/or ester hydrolysis product, and/or
`
`oxidation product, has been reduced or eliminated.
`
`3.
`
`The composition according to claim 1 or 2 wherein the ACE inhibitor is selected from
`
`the group consisting of quinapril, enalapril, spirapril. ramipril, perindopril, indolapril,
`
`lisinopril, alacepril. trandolapril, benazapril, Iibenzapril, delapril, cilazapril and
`
`combinations thereof.
`
`4.
`
`The composition according to any of claims 1 to 3, wherein the ACE inhibitor is
`
`selected from the group consisting of quinapril, enalapril and spirapril.
`
`5.
`
`The composition according to any preceding claim, wherein the ACE inhibitor is
`
`quinapril hydrochloride.
`
`6.
`
`The composition according to any preceding claim, wherein the amount of the ACE
`
`inhibitor or a pharmaceutically acceptable salt thereof is from about 5 wt. % to about
`
`50 wt. %, based on the total weight of the pharmaceutical composition.
`
`7.
`
`The composition according to claim 6, wherein the amount of the ACE inhibitor or a
`
`pharmaceutically acceptable salt thereof is from about 10 wt. % to about 15 wt. %,
`
`based on the total weight of the pharmaceutical composition.
`
`8.
`
`The Composition according to any preceding claim, wherein the alkali metal is selected
`
`from the group consisting of lithium, sodium, potassium, rubidium, caesium and
`
`francium.
`
`

`

`WO 2005/007130
`
`PCT/EP2004/007591
`
`-13-
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`The composition according to any preceding claim, wherein the alkaline earth metal is
`
`selected from the group consisting of magnesium, calcium, barium, strontium and
`
`radium.
`
`The composition according to claim 9, wherein the alkaline earth metal is magnesium.
`
`The composition according to any preceding claim, wherein the amount of the alkali or
`
`alkaline earth metal carbonate is from about 10 wt. % to about 60 wt. %, based on the
`
`total weight of the pharmaceutical composition.
`
`The composition according to claim 11, wherein the amount of the alkali or alkaline
`
`earth metal carbonate is from about 45 wt. % to about 55 wt. %, based on the total
`
`weight of the pharmaceutical composition.
`
`The composition according to any preceding claim, wherein the hydroxypropyl
`
`cellulose has a molecular weight of from about 50,000 to about 1,250,000.
`
`The composition according to claim 13 wherein the hydroxypropyl cellulose has a
`
`molecular weight of from about 80,000 to about 1,150,000.
`
`The composition according to any preceding claim, wherein the hydroxypropyl
`
`cellulose is a low-substituted hydroxypropyl cellulose (L—HPC).
`
`The composition according to claim 15, wherein the low-substituted hydroxypropyl
`
`cellulose when dried at 105 °C for 1 hour contains 5-1 6% of hydroxypropoxy groups. .
`
`The composition according to claim 16, wherein the' low-substituted hydroxypropyl
`
`cellulose when dried at 105 °C for 1 hour contains 10—13% of hydroxypropoxy groups.
`
`The composition according to any of claims 15 to 17, wherein the low-substituted
`
`hydroxypropyl cellulose is selected from the group consisting of: LH-11 having a
`
`hydroxypropoxy content of 11% and an average particle size of 50 microns; LH—21
`
`having a hydroxypropoxy content of 11% and an average particle size of 40 microns;
`
`LH-31 having a hydroxypropoxy content of 11%, and an average particle size of
`
`

`

`W0 2005/007130
`
`PCT/EP2004/007591
`
`-14-
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`25 microns; LH-22 having a hydroxypropoxy content of 8%, and an average particle
`
`size of 40 microns; LH-32 having a hydroxypropoxy content of 8%, and an average
`
`particle size of 25 microns; LH-20 having a hydroxypropoxy content of 13%, and an
`
`average particle size of 40 microns; and LH-30 having a hydroxypropoxy content of
`
`13%. and an average particle size of 25 microns.
`
`The composition according to claim 18, wherein the L-HPC is LH-21 or LH-11.
`
`The composition according to any preceding claim, wherein the hydroxypropyl
`
`cellulose is present in an amount of from about 10 wt. % to about 50 wt. %.
`
`The composition according to claim 20. wherein the hydroxypropyl cellulose is present
`in an amount of from about 30 wt. % to about 40 wt. %.
`
`The composition according to any preceding claim, which is in the form selected from
`
`the group consisting of a tablet, bar, block, disc, capsule, caplet, powder and granules.
`
`A method of preparing a pharmaceutical composition according to any of claims 1 to 3,
`
`said method comprising:
`
`(a) mixing the ACE inhibitor or a phannaceutically acceptable salt thereof, an
`
`alkali or alkaline earth metal carbonate, hydroxypropyl cellulose, and optionally
`
`one or more excipients, to form a premix;
`
`(b) adding a solvent, and optionally one or more excipients, to the premix formed
`
`in Step (a) to form a wet granulation;
`
`(c) drying the wet granulation to form granules, and optionally milling the
`
`granules;
`
`and
`
`(d) optionally mixing one or more excipients with the granules
`
`to form a pharmaceutical composition.
`
`

`

`ACLASSlFICATlON OF SUBJECT MATTER
`IPC 7
`A61K9/00
`A61K31/00
`
`A61K47/22
`
`M/Eono4/oo7591
`
`Amording to intemationai Patent Classification (iPC) or to both national classification and lPC
`B. FIELDS SEARCHED
`
`Minimum documentation searched (classification system ioitowed by classification symbols)
`IPC 7
`A61K
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
`
`EPO-Internai, PAJ, WPI Data, MEDLINE, BIOSIS
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category “ Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`EP 0 280 999 A (WARNER LAMBERT CO)
`7 September 1988 (1988—09—07)
`claims 1—10; examples A—D
`
`US 4 584 299 A (EVANS DALE B
`22 April 1986 (1986-04—22)
`claims 1-7
`
`ET AL)
`
`US 5 151 433 A (STAMMBERGER NILLI
`29 September 1992 (1992—09-29)
`column 6 — column 7, line 50
`
`ET AL)
`
`EP 0 288 732 A (SQUIBB & SONS INC)
`’2 November 1988 (1988—11—02)
`page 9; claims 1—21
`
`../__
`
`
`
`Further documents are listed In the continuation of box C.
`
`Patent family members are listed in annex.
`
`° Special categories oi cited documents:
`
`'A' document defining the general state of the art which is not
`considered to be of particular relevance
`'E' earlier document but published on or afterthe intemaiional
`filing date
`'L' document which may throw doubts on priority ciaim(s) or
`which is cited to establish the pubfimtlon date of another
`citation or other special reason (as specified)
`'0‘ document referring to an oral disclosure. use, exhibition or
`other means
`
`'P' document publishedprior to the intemational filing date but
`later than the prioritydate claimed
`Date of the actual completion of the international search
`
`23 November 2004
`
`Name and mailing address of the ISA
`European Patent Office. PB. 5818 Pateniiaan 2
`ML - 2280 HV Rijswiik
`TeL (+31—70) 340—2040, Tx. 31 651 epo ni.
`Fax: (+31—70) 3404016
`
`Form PCTIiSAI210 (secmd sheet) (January 2004)
`
`'T'
`
`later document published after the international filing date
`or priority date and not in conflict with the application but
`ven Ion
`filed to understand the principle or theory underlying the
`'X' document of particular relevance; the claimed invention
`cannot be considered novel or cannot be considered to
`Involve an inventive step when the document is taken alone
`'Y' document of particular relevance; the claimed invention
`cannot be considered to involve an inventive step when the
`document is combined with one or more other such docu—
`ments, such combination being obvious to a person skilled
`in the art
`
`'&' document member or the same patent tamiiy
`
`Date oi mailing of the international search report
`
`03/12/2004
`Authorized officer
`
`Kardas—Liorens, E
`
`

`

`C.(Cont|nuatlon) DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document, with indication, where appropriate, of The reIevant passages
`
`
`
`
`
`
`M/Eono4/oo7591
`
`
`
`
`
`Relevant to claim N0.
`
`
`
`
`US 5 298 497 A (TSCHOLLAR HERNER
`29 March 1994 (1994-03-29)
`column 16, Tine 17 - Tine 23; claim 1;
`exampTes 7,13
`
`ET AL)
`
`ANGIOTENSIN—CONVERTING ENZYME INHIBITOR,
`MOEXIPRIL HYDROCHLORIDE: DRY POWDER VS NET
`GRANULATION"
`
`PHARMACEUTICAL RESEARCH, NEW YORK, NY, US,
`v01. 7, no. 4, 1990, pages 379-383,
`XP009009003
`ISSN: 0724—8741
`
`page 381 - page 383
`
`
`
`
`
`NO 94/01093 A (MERCK & CO INC ; RORK
`GERALD s (US); HASLAM JOHN L (us))
`
`
`20 January 1994 (1994—01-20)
`page 5 — page 10; c1aims 1,15,19
`
`
`
`GU L ET AL:
`"DRUG—EXCIPIENT
`INCOMPATIBILITY STUDIES OF THE DIPEPTIDE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`AL—OMARI M M ET AL:
`
`"Effect of the
`
`
`
`
`
`
`
`
`drug—matrix on the stability of'enaTapril
`maTeate in tabTet formuTations"
`JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL
`
`ANALYSIS, NEH YORK, NY, US,
`v01. 25, no. 5-6, JuTy 2001 (2001—07),
`pages 893—902, XP002241568
`ISSN: 0731—7085
`
`page 898 — page 900
`
`
`
`
`
`
`
`
`
`
`Fan-n PCTnsA/21o (continuation 0! second sheet) (January 2004)
`
`

`

`uuvlulauvll vu Pawns Iaullly "Imam:
`
`
`
`Patent document
`cited In search report
`
`Publication
`date
`
`M/Eono4/oo7591
`Publication
`date
`
`Patent family
`member(s)
`
`EP 0280999
`
`07-09—1988
`
`4743450 A
`10—05-1988
`84210 T
`15—01-1993
`597471 82
`31-05-1990
`1130588 A
`25—08-1988
`1300510 C
`12—05-1992
`3877226 01
`18-02-1993
`29—04-1993
`3877226 T2
`94088 A
`25-08-19