Document FP4
`App]. No.: 11/273,575
`
`
`
`UK Patent Application GB 2 394 660 A
`
`(43) Date of A Publication
`
`05.05.2004
`
`
`(51)
`(NT CL7:
`(21) Application No:
`03292323
`A61K 47/00 31/404 38/05 , A61P 9/00 9/12
`
`
`17.12.2003
`(22) Date of Filing:
`
`
`
`(71) Applicant(s):
`Niche Generics Limited
`(Incorporated in the United Kingdom)
`1 The Cam Centre, Wilbury Way, HITCHIN,
`Hertfordshlre, SG4 0TW, United Kingdom
`
`(52) UK CL iEdition W )2
`A53 BJB B180 B31Y B317 B46Y B461 B47Y B471 BSOY
`8501 BSZY 8523 BSSY 8551 BS7Y 8575 362Y B626
`8828
`U1S $2415
`
`WO 2003/075842 A2
`wo 2003/028707 A1
`us 5562921 A
`us 5151433 A
`
`(55) Documents Cited:
`EP 0264887 A1
`wo zoos/059330 A1
`wo 2002/011709 A2
`us 5433951 A
`us 5005344 A
`
`(58) Field of Search:
`INT CL7 A61K
`Other: EPODOC, JAPIO, WPI
`
`Unichem Laboratories Limited
`(Incorporated in the United Kingdom)
`Mahalaxmi Chambers, 2nd Floor,
`22 Bhulabhai Desai Road,
`Mumbal- 400 026, India
`
`(72)
`
`lnventor(s):
`Jeffrey Bergman
`Pranita S Mantri
`
`
`
`
`
`
`
`
`
`
`
`
`
`(74) Agent and/or Address for Service:
`Venner Shipley & Co
`
`20 Little Britain, LONDON, EC1A 7DH,
`
`United Kingdom
`
`
`
`
`(54) Abstract Title: Stabilisation of pharmaceutical compositions comprising ACE inhibitor by absence of acidic excipients
`having large specific surface area, eg silicon dioxide
`
`(57) Stable pharmaceutical compositions comprising an ACE inhibitor (which are otherwise susceptible to degradation due
`to cyclisation, hydrolysis and oxidation) are provided. This is achieved by providing compositions substantially free of
`any acidic excipients having a large specific surface area, especially substantially free of colloidal silicon dioxide.
`The composition also comprises one or more excipients, which are preferably compatible with the ACE inhibitor.
`The ACE inhibitor is preferably perindopril or ramipril.
`The composition may be used as a medicament for the treatment or prevention of a cardiovascular disorder,
`hypertension, coronary heart disease or a cerebrovascular disease. The composition may further comprise a B—blocker,
`a diuretic, a calcium-channel blocker, a vasodilator anti- hypertensive drug, or an angiotensin II receptor antagonist.
`
`V0991768Z89
`
`Original Printed on Recycled Paper
`
`

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`

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`2394660
`
`Pharmaceutical Composition
`
`Technical field
`
`The present invention relates to a stable pharmaceutical composition comprising an
`
`ACE inhibitor.
`
`In particular,
`
`the invention relates to a composition, which
`
`comprises one or more excipients,'which are compatible with the ACE inhibitor.
`
`More specifically, the composition is substantially free of colloidal silicon dioxide.
`The composition may be for the use as a medicament for the treatment of a
`
`cardiovascular disorder, hypertension, coronary heart disease or a cerebrovascular
`
`disease.
`
`The present invention further relates to a method of preparing the pharmaceutical
`
`composition,
`
`a method of providing a
`
`stable pharmaceutical composition by
`
`providing the composition substantially free of colloidal silicon dioxide, and a use
`
`of
`
`a
`
`substantial absence of colloidal
`
`silicon dioxide
`
`to provide a
`
`stable
`
`pharmaceutical composition.
`
`Background art
`
`10
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`15
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`20
`
`ACE inhibitors, i.e. inhibitors of angiotensin converting enzymes, are drugs useful
`
`in the treatment of cardiovascular disorders, in particular hypertension and coronary
`
`heart disease.
`
`It has been widely observed that ACE inhibitors are susceptible to
`
`25
`
`degradation between the time of manufacture and the time of desired usage,
`in
`particular due to cyclization, hydrolysis and oxidation. Typical degradation products
`
`are hydrolytic degradation products formed by hydrolysis of the ACE inhibitor and
`
`diketopiperazine degradation products formed by cyclization of the ACE inhibitor.
`
`Most, if not all, known ACE inhibitors have ester (COvO), amide (CO-N), thio-
`
`}0
`
`ester (CO-S) and/or phospho-ester (PO-O) bonds. Such bonds are susceptible to
`
`hydrolysis leading to the formation of hydrolytic degradation products.
`
`

`

`Moreover, many known ACE inhibitors are of formula 1
`
`R‘OZC
`
`H
`N
`
`Y
`
`R2
`
`R3
`
`R5
`
`o
`
`t
`
`Nl
`
`R4
`
`0
`
`OH
`
`1
`
`wherein
`
`R‘ is H or 'c,—c, alkyl,
`
`R2 is C1-C3 alkyl optionally substituted with phenyl,
`R3 is C1-C5 alkyl optionally substituted with -NH2, or together with R4 forms
`
`an s-caprolactam derivative optionally containing a sulphur atom and/or a double
`
`bond and optionally substituted with —CH=CH-CH=CH- or -C‘H,S,
`
`R“ is indanyl, or together with R3 forms an e—caprolactarn derivative as
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`10
`
`defined above, or together with R5 forms a pyrrolidine or piperidine derivative
`
`optionally containing-another nitrogen at'om and/or a double bond and optionally
`
`substituted
`with
`-SCH2CHZS—,
`-CH2CHZCH2CH2-,
`—CH2CH2CH2-,
`-CH=CH-CH=CH~, -Cl-I=C(OCH,)-C(OCH,)=CH-, =0 or -CH,, and
`
`R5 is H, or together with R‘ forms a pyrrolidine or piperidine derivative as
`defined above,
`i
`
`75
`
`or wherein R3, R‘ and Rs together form a bicyclic ring system
`
`t5
`
`Known ACE inhibitors of formula 1 are, for example, benazepril, cilazapril, delapril,
`
`20
`
`enalapril, enalaprilat, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril,
`
`spirapril, temocapril and trandolapril.
`
`

`

`Due to their molecular structure, compounds of formula 1 are susceptible to
`
`cyclization to form the diketopiperazine degradation product of formula 2
`
`.
`
`1
`COZR o
`/l\ -
`
`N
`
`R2
`
`2
`
`R5
`
`R3
`
`N
`
`\R“
`
`0
`
`One example of an ACE inhibitor of formula 1 is perindopril erbumine, also called
`
`perindopril
`
`tert-butylamine or
`
`(28,3aS,7aS)-1-[($)-N-[(S)-1-(cthoxycarbonyl)butyl]
`
`alanyl]octahydro-1H-indole-Z-carboxylic
`erbumine is of formula 3
`
`acid tert-butylamine
`
`salt.
`
`Perindopril
`
`3
`
`HZN
`
`CH3
`
`”3c
`
`CH3
`
`O
`
`HSC
`
`H3C—\
`
`"""’COZI-l
`
`70
`
`I5
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`Perindopril erbumine is a long-acting ACE inhibitor and currently used in the
`
`treatment of hypertension, coronary heart disease and cerebrovascular disease.
`
`Commercially available formulations of perindopril erbumine are currently sold
`
`under the trade names Coversyl“, Coversumm, Aceon® and Procaptan®. All of these
`
`formulations contain perindopril erbumine as active ingredient as well as lactose,
`
`microcrystalline cellulose, colloidal
`
`silicon dioxide and magnesium stearate as
`
`inactive ingredients. Known degradation products of perindopril erbumine are
`
`shown in Figure 1, including hydrolytic degradation product B, and diketopiperazine
`
`degradation products C, D and F.
`
`

`

`Degradation of ACE inhibitors has been found to occur both in solid and in liquid
`
`states. As the degradation of an ACE inhibitor in a pharmaceutical composition-
`
`increases, the concentration of available, functional ACE inhibitor decreases. Thus
`the shelf-life of pharmaceutical compositions comprising ACE inhibitors is limited
`
`due to this degradation. Accordingly, degradation should be avoided.
`
`Various ways to minimize the degradation of ACE inhibitors in pharmaceutical
`
`compositions have been advocated. For example, it has been suggested that alkali
`
`or alkaline earth metal salts can stabilize ACE inhibitors in pharmaceutical
`
`compositions.
`
`WO 01/15724 and US-6,555,551 disclose a method of stabilizing pharmaceutical
`
`compositions comprising ACE inhibitors.
`
`The method comprises the -step of
`
`mixing an alcoholic dispersion of an ACE inhibitor with an aqueous solution or
`
`dispersion of a metal compound; .the resulting mixture may be dried. Suitable metal
`
`compounds are alkali or alkaline earth metal salts.
`
`EP-0,280,999
`
`and US-4,743,450 teach that
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`the
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`cyclization, hydrolysis
`
`and
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`discolouration of pharmaceutical compositions comprising ACE inhibitors are
`
`minimized by formulating the compositions with a metal-containing alkaline
`stabilizer. The metal-containing alkaline stabilizer is preferably an inorganic salt of
`
`an alkali or alkaline earth metal, such as magnesium, calcium or sodium borate,
`silicate or carbonate.
`
`WO 99/62560 and US-6,417,196 disclose pharmaceutical compositions comprising
`
`ACE inhibitors, which are stabilized by the presence of magnesium oxide,
`
`preferably in combination with a hydrolysis—minimizing agent. The presence of
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`magnesium oxide is also said to lend itself to favourable processing conditions
`
`during the manufacture of the ACE inhibitor-containing compositions, especially
`
`processing by wet granulation.
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`

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`EP-0,545,l94, US-S,350,582, US-5,690,962, WO 97/05881
`
`and US-5,573,780
`
`propose stabilizing enalapril maleate, an ACE inhibitor, by converting it into its
`sodium salt.
`
`It has also been suggested that certain acids can be used to stabilize ACE inhibitors
`
`in pharmaceutical compositions.
`
`EP-0,468,929, US-6,300,361 and US—6,300,362
`
`disclose the use of hydrochloric acid donors as stabilizers in pharmaceutical
`
`Suitable hydrochloric acid donors are
`compositions comprising ACE inhibitors.
`amino acid hydrochlorides, such as glycine, glutainic acid, betaine, alanine, valine,
`
`lysine, arginine and aspartic acid hydrochloride, and Lewis acid chlorides, such as
`
`ferric, zinc and aluminium chloride.
`
`- EP—0,264,888 and US-4,793,998 'suggest
`
`that
`
`the cyclization, hydrolysis and
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`oxidative discolouration of ACE inhibitors in pharmaceutical compositions can be
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`minimized by formulating them with ascorbic acid as stabilizer, optionally in
`
`combination with fumaric, citric and/ or maleic acid.
`
`Moreover,
`
`the use of protective coatings has been advocated to stabilize ACE
`
`inhibitors in pharmaceutical compositions. EP-0,317,878, US-5,151,433 and US-
`
`5,442,008 disclose pharmaceutical compositions comprising ACE inhibitors,
`
`in
`
`which the ACE inhibitors are stabilized by a polymeric protective coating and/or by
`
`a buffer which maintains the pH of the compositions between 5.5 and 8.0.
`
`WO 95/34283,
`
`EP-0,624,364
`
`and US-5,527,540
`
`disclose
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`pharmaceutical
`
`compositions comprising an alkali-sensitive active substance, such as an ACE
`
`inhibitor, and an effervescent system, such as a carbonate component. To stabilise
`the active substance, it is embedded in at least one of the following compounds: an
`
`edible organic acid,
`
`a higher alcohol,
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`a hydrocolloid,
`
`a
`
`long-chain polyvinyl
`
`pyrrolidone, and is preferably coated with at least one of said compounds. The
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`carbonate component is also preferably embedded in at least one edible organic acid
`
`and coated by the same or another acid.
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`

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`It has still further been suggested to stabilize ACE inhibitors in pharmaceutical
`
`compositions by derivatisation. For example, WO 02/03970 discloses a transdermal-
`
`therapeutic system comprising an adhesive matrix. The matrix comprises an ACE
`inhibitor derivative, which has been stabilized by derivatisation into a salt or di-
`ester.
`
`Finally an incompatibility between ACE inhibitors and certain excipients has been
`
`observed in US-S,562,921. US-5,562,921 discloses that enalapril maleate is unstable
`
`when associated with many excipients commonly used in the manufacture of
`
`pharmaceutical compositions, and teaches
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`stable pharmaceutical compositions
`
`comprising enalapril maleate, a carrier that is comprised primarily of water-soluble
`carbohydrates, and a lubricant other than magnesium stearate.
`'
`
`Despite these efforts to stabilize ACE inhibitors,
`
`there remains a long-standing
`
`need for stable pharmaceutical. compositions comprising ACE inhibitors and
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`methods of preparing the same.
`
`Surprisingly, it has now been found that the presence of colloidal silicon dioxide
`
`promotes the degradation of ACE inhibitors in pharmaceutical compositions. This
`
`is the more surprising, because in a number of prior publications the use of colloidal
`silicon dioxide is advocated for use in stable pharmaceutical compositions
`
`cOmprising ACE inhibitors; see for example EP-0,468,929, US-6,300,361 and US-
`
`6,300,361 (examples 2A—2D, 5A, SB, 5D and 8A-8D), WO 99/62560 (page 10, line
`
`30), US-6,417,196
`
`(column
`
`6,
`
`line
`
`55), WO 01/15724 and US—6,555,551
`
`(formulations I, II and V) and W0 02/ 03970 (examples 1 to 6). Moreover, at least
`
`some of the currently commercially available compositions of perindopril erbumine
`
`contain colloidal silicon dioxide as inactive ingredient. This highlights the fact that
`
`the incompatibility between colloidal silicon dioxide and ACE inhibitors has not
`
`been recognised until now.
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`

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`Summary of the invention
`
`For
`
`the purposes of
`
`the present
`
`invention,
`
`a pharmaceutical composition
`
`comprising an ACE inhibitor is considered to be “stable”, if the ACE inhibitor
`
`degrades less or more slowly than 'it does in known pharmaceutical compositions.
`
`An excipient
`
`is considered to be"‘incompatible” with an ACE inhibitor,
`
`if it
`
`promotes the degradation of the ACE inhibitor, i.e. if the ACE inhibitor degrades
`
`more or faster in the presence of the excipient when compared to the degradation
`
`of the ACE inhibitor on its own. The terms “incompatibility”, “compatible” and
`
`“compatibility” are defined accordingly.
`
`A composition is “substantially free of colloidal silicon dioxide”, if it contains less
`
`colloidal silicon dioxide than is required to cause substantial degradation of the
`
`ACE inhibitor. Preferably a composition, which is substantially free of colloidal
`
`silicon dioxide, comprises less than 0.3% by weight colloidal silicon dioxide, more
`
`preferably 0.1% by weight. The term “substantially free of any acidic excipients” is
`
`' defined accordingly. Hence a composition, which is substantially free of any acidic
`
`excipients, preferably comprises less than 0.3% by weight of any acidic excipients,
`
`more preferably 0.1% by weight.
`
`An “acidic excipient” is an excipient with a pH of 5.5 or less, or even 3.5 or less.
`
`An “excipient having a large specific surface area” is an excipient having a specific
`
`surface area of ZOOmZ/g or more, or even 400m2/g or more, when measured on a
`
`Stroehlein apparatus, single point. Alternatively, an “excipient having a large
`
`specific surface area” is an excipient having a specific surface area of 50ng or
`
`more, or even 380m2/g or more, when measured using the BET method (S.
`
`Brunauer, P. Emmett and E. Teller, “Adsorption of gases in multimolecular layers”,
`
`]. Am. Chem. 505., vol. 60, pages 309-319).
`
`A first embodiment of the present
`
`invention provides a stable pharmaceutical
`
`composition comprising an ACE inhibitor.
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`

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`Preferably the composition further comprises one or more excipients, which are»
`
`compatible with the ACE inhibitor. The composition may comprise two such
`excipients. The composition may comprise three such excipients. The composition
`
`may comprise four such excipients. The composition may comprise five such
`
`excipients. The composition may comprise six such excipients. Alternatively the
`
`composition may comprise seven or more such excipients.
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`70
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`The one or more excipients may be selected from carbonates (such as calcium
`
`carbonate,
`
`sodium carbonate or magnesium carbonate), phosphates
`
`(such as
`
`anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic
`
`calciumphosphate or sodium phosphate), sulfates (such as calcium sulfate), silicates
`
`(such as kaolin,
`
`talc, magnesium aluminium silicate, magnesium silicate or
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`magnesium trisilicate), carbohydrates
`
`(such as dextrates, dextrin, maltodextrin,
`
`dextrose, polydextrose,
`
`fructose,
`
`sucrose,
`
`sugar
`
`spheres, compressible
`
`sugar,
`
`confectioner’s sugar, maltose, mannitol, lactose, lactitol, maltitol, sorbitol, sodium
`
`alginate, alginic acid or liquid glucose), starches (such as starch, pregelatinized
`
`starch, maize starch, corn starch or sodium starch glycolate), celluloses (such as
`
`carboxymethylcellulose
`
`calcium,
`
`carboxymethylcellulose
`
`sodium,
`
`cross-linked
`
`carboxymethylcellulose sodium, microcrystalline cellulose, silicified microcrystalline
`cellulose, powdered cellulose,
`cellulose
`acetate,
`cellulose
`acetate phthalate,
`
`methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, low-
`
`substituted
`
`hydroxypropyl
`
`cellulose
`
`or
`
`hydroxypropyl methylcellulose),
`
`polyvinylpyrrolidones (such as povidone or crospovidone), fatty acids or fatty acid
`
`derivatives (such as hydrogenated vegetable oil, hydrogenated castor oil, mineral oil,
`
`light mineral oil, hydrogenated vegetable oil, cottonseed oil,
`
`a medium-chain
`
`triglyceride,
`
`glyceryl palmitostearate,
`
`calcium stearate,
`
`stearic
`
`acid,
`
`glyceryl
`
`monostearate, magnesium stearate, polyoxyethylene stearate, zinc stearate, sodium
`
`stearyl fumarate or glyceryl behenate), gums (such as tragacanth gum, guar gum or
`
`acacia), magnesium oxide, sodium chloride, polymethacrylate, polacrilin potassium,
`
`sodium lauryl
`
`sulfate,
`
`a poloxamer, polyethylene glycol,
`
`sodium benzoate,
`
`a
`
`carbomcr, ccratonia, gelatin, polyethylene oxide,
`
`zein, and mixtures
`
`thereof.
`
`Preferably,
`
`the one or more excipients are selected from phosphates (preferably
`
`

`

`anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate or
`
`tribasic calcium phosphate), silicates (preferably kaolin, talc, magnesium aluminium
`
`silicate, magnesium silicate or magnesium trisilicate), carbohydrates (preferably
`
`dextrates, maltodextrin, dextrose, polydextrose, fructose, sucrose, sugar spheres,
`compressible
`sugar, confectioner’s
`sugar, maltose, mannitol,
`lactose,
`lactitol,
`
`maltitol, sorbitol or sodium alginate), starches (preferably starch, pregelatinized
`starch, maize starch, corn starch or' sodium starch glycolate), celluloses' (preferably
`
`carboxymethylcellulose
`carboxymethylcellulose
`
`calcium,
`carboxymethylcellulose
`sodium,
`cross-linked
`sodium, microcrystalline' cellulose, powdered cellulose,
`
`cellulose
`
`acetate,
`
`cellulose
`
`acetate phthalate, methylcellulose,
`
`ethylcellulose,
`
`hydroxyethyl
`
`cellulose, hydroxypropyl cellulose,
`
`low-substituted hydroxypropyl
`
`cellulose or hydroxypropyl methylcellulose), polyvinylpyrrolidones
`povidone or crospovidone),
`fatty acids or
`fatty acid derivatives
`
`(preferably
`(preferably
`
`hydrogenated vegetable oil, glyceryl palmitostearate, calcium stearate, stearic acid,
`
`glyceryl monostearate, magnesium stearate, zinc stearate, sodium stearyl fumarate or
`
`glyceryl behenate), gums (preferably guar gum), sodium chloride, polymethacrylate,
`
`sodium lauryl
`
`sulfate,
`
`a poloxamer, polyethylene glycol,
`
`sodium benzoate,
`
`a
`
`‘ carbomer, ceratonia, polyethylene oxide, zein, and mixtures thereof. Preferably the
`
`one or more excipients are selected from lactose, microcrystalline cellulose,
`
`mannitol,
`
`dibasic
`
`calcium phosphate, maize
`
`starch,
`
`pregelatinised
`
`starch,
`
`polyvinylpyrrolidone, talc and magnesium stearate.
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`70
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`Preferably the composition further comprises a glidan‘t, which is substantially free
`
`of colloidal silicon dioxide.
`
`Preferably the composition is substantially free of
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`25
`
`colloidal silicon dioxide.
`
`A further embodiment of
`
`the present
`
`invention provides
`
`a pharmaceutical
`
`composition comprising an ACE inhibitor, wherein the composition is substantially
`
`free of any acidic excipients having a large specific surface area. Preferably the
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`30
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`composition is stable.
`
`A further embodiment of
`
`the present
`
`invention provides
`
`a pharmaceutical
`
`composition comprising an ACE inhibitor, a diluent, a disintegrant, a glidant and a
`
`

`

`-10-
`
`lubricant, wherein the diluent, disintegrant, glidant and lubricant are compatible
`
`with the ACE inhibitor, and wherein the composition is substantially free of-
`
`colloidal silicon dioxide. The present
`invention also provides a pharmaceutical
`composition comprising an ACE inhibit-013‘s diluent, a disintegrant, a glidant and a
`
`lubricant, wherein the diluent, disintegrant, glidant and lubricant are compatible
`
`with the ACE inhibitor, and wherein the composition is substantially free of any
`
`acidic excipients having a large specific surface area.
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`The diluent may be a carbonate (such as calcium carbonate, sodium carbonate or
`
`magnesium carbonate), a phosphate (such as anhydrous dibasic calcium phosphate,
`
`dibasic calcium phosphate dihydrate,
`
`tribasic calcium phosphate or
`
`sodium
`
`phosphate), a sulfate (such as calcium sulfate), a silicate (such as kaolin or talc), a
`
`carbohydrate (such as dextrates, dextrin, maltodexttin, dextrose, fructose, sucrose,
`
`sugar spheres, compressible sugar, confectioner’s sugar, maltose, mannitol, lactose,
`
`lactitol, maltitol, sorbitol or sodium alginate), a starch (such as starch, pregelatinized
`starch or maize starch),
`a cellulose
`(such as carboxymethylcellulose calcium,
`cellulose acetate, micrdcrystalline cellulose, silicified'microcrystalline cellulose or
`powdered cellulose), a polyvinylpyrrolidone (such as povidone), a fatty acid or fatty
`
`acid derivative (such as hydrogenated vegetable 'oil or glyceryl palmitostearate), a
`
`gum (such
`as
`tragacanth
`gum), magnesium oxide,
`sodium chloride,
`polymethacrylate, or a mixture thereof.
`Preferably the diluent
`is a phosphate
`
`calcium phosphate, dibasic calcium phosphate
`(preferably anhydrous dibasic
`dihydrate or tribasic calcium phosphate), a silicate (preferably kaolin or talc), a
`
`carbohydrate (preferably dextrates, maltodexttin, dextrose, fructose, sucrose, sugar
`
`spheres, compressible sugar, confectioner’s
`
`sugar, maltose, mannitol,
`
`lactose,
`
`lactitol, maltitol,
`
`sorbitol or
`
`sodium alginate),
`
`a
`
`starch (preferably starch,
`
`pregelatinized starch or maize starch), a cellulose (preferably carboxymethylcellulose
`
`calcium, cellulose acetate, microcrystalline cellulose or powdered cellulose),
`
`a
`
`polyvinylpyrrolidone (preferably povidone), a fatty acid or fatty acid derivative
`
`(preferably hydrogenated vegetable oil or glyceryl palmitostearatc), sodium chloride,
`
`polymethacrylate, or a mixture thereof.
`
`Preferably the diluent
`
`is a cellulose, a
`
`carbohydrate,
`
`a phosphate or
`
`talc.
`
`If present, preferably the cellulose is
`
`

`

`-11-
`
`microcrystalline cellulose.
`
`If present, preferably the carbohydrate is lactose or
`
`mannitol. If present, preferably the phosphate is dibasic calcium phosphate.
`
`The disintegrant may be a silicate '(such as magnesium aluminium silicate), a
`
`carbohydrate (such as sodium alginate or alginic acid), a starch (such as starch,
`
`pregclatinized starch, maize starch, corn starch or sodium starch glycolate), a
`cellulose
`(such
`as
`carbOxymethylcellulose
`calcium,
`cross-linked
`
`carboxymethylcellulose sodium, carboxymethylcellulose sodium, microcrystalline
`
`cellulose,
`
`powdered
`
`cellulose,
`
`low-substituted
`
`hydroxypropyl. cellulose
`
`or
`
`methylcellulose), a polyvinylpyrrolidone (such as povidone or crospovidone), a gum
`
`(such as guar gum), polacrilin potassium, or a mixture thereof.
`
`Preferably the
`
`disintegrant is a silicate (preferably magnesium aluminium silicate), a carbohydrate
`
`(preferably sodium alginate), a starch (preferably starch, pregelatinized starch, maize
`
`starch,
`
`corn
`
`starch
`
`or
`
`sodium starch
`
`glycolate),
`
`a
`
`cellulose
`
`(preferably
`
`carboxymethylcellulose
`
`calcium,
`
`cross-linked
`
`carboxymethylcellulose
`
`sodium,
`
`carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, low-
`
`substituted' hydroxypropyl cellulose or methylcellulose), a polyvinylpyrrolidone
`
`' (preferably povidone or crospovidone), a gum (preferably guar gum), or a mixture
`
`thereof. Preferably the disintegrant is a starch.
`
`If present, preferably the starch is
`
`maize starch or pregelatinised starch.
`
`The glidant may be a phosphate (such as tribasic calcium phosphate), a silicate (such
`
`as magnesium silicate, magnesium trisilicate or tale), a starch (such as starch,
`
`pregelatinized starch or maize starch), a cellulose (such as powdered cellulose), a
`
`fatty acid or fatty acid derivative (such as calcium stearate), or a mixture thereof.
`
`Preferably the glidant is tribasic calcium phosphate, magnesium silicate, magnesium
`
`trisilicate,
`
`talc, pregelatinized starch, maize starch, powdered cellulose, calcium
`
`stearate, or a mixture thereof. Preferably the glidant is a starch or talc.
`
`If present,
`
`preferably the starch is maize starch or pregelatinised starch.
`
`The lubricant may be a silicate (such as talc), a cellulose (such as microcrystalline
`
`cellulose), a fatty acid or fatty acid derivative (such as hydrogenated castor oil,
`
`mineral oil,
`
`light mineral oil, hydrogenated vegetable oil, stearic acid, calcium
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`-12-
`
`stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate,
`
`polyoxyethylene stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate or‘
`
`a medium-chain triglyceride), sodium Ilauryl sulfate,
`
`a poloxamer, polyethylene
`
`glycol, sodium benzoate, sodium chloride, or a mixture thereof.
`
`Preferably the.
`
`lubricant
`
`is a
`
`silicate (preferably talc), a cellulose (preferably microcrystalline
`
`cellulose), a fatty acid or fatty acid derivative (preferably hydrogenated vegetable oil,
`
`stearic acid, calcium stearate, glyceryl monostearate, glyceryl palmitostearate‘,
`
`magnesium stearate, zinc stearate, sodium stearyl fumarate or glyceryl behenate),
`
`sodium lauryl sulfate, a poloxamer, polyethylene glycol, sodium benzoate, sodium
`
`chloride, or a mixture thereof. Preferably the lubricant is an alkali or earth alkaline
`
`metal salt of a saturated C1“, carboxylic acid.
`acid salt is magnesium stearate.
`‘
`
`If present, preferably the carboxylic
`
`Preferably the composition further comprises a binder. The binder may be a silicate
`
`(such as magnesium aluminium silicate), a carbohydrate (such as dextrates, dextrin,
`
`liquid glucose, sucrose, compressible sugar,
`maltodextrin, dextrose, polydextrose,
`confectioner’s sugar, sorbitol, sodium alginate or alginic acid), a starch (such as
`
`starch,
`
`pregelatinized
`
`starch
`
`or maize
`
`starch),
`
`a
`
`cellulose
`
`(such
`
`as
`
`carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose acetate
`
`phthalate, microcrystalline
`
`cellulose,
`
`powdered
`
`cellulose, methylcellulose,
`
`ethylcellulose, hydroxyethyl
`
`cellulose, hydroxypropyl
`
`cellulose,
`
`low-substituted
`
`hydroxypropyl cellulose or hydroxypropyl methylcellulose), a polyvinylpyrrolidone
`
`(such as povidone), a fatty acid or fatty acid derivative (such as cottonseed oil,
`
`hydrogenated vegetable oil, stearic acid or glyceryl behenate), a gum (such as guar
`
`gum or acacia), polymethacrylate, a carbomer, a poloxamer, ceratonia, gelatin,
`
`polyethylene oxide, zein, or a mixture thereof.
`
`If present, preferably the binder is. a
`
`silicate
`
`(preferably magnesium aluminium silicate),
`
`a carbohydrate (preferably
`
`dextrates, maltodextrin, dextrose, polydextrose,
`
`sucrose,
`
`compressible
`
`sugar,
`
`confectioner’s sugar, sorbitol or sodium alginate),
`
`a starch (preferably starch,
`
`pregelatinized starch or maize starch), a cellulose (preferably carboxymethylcellulose
`
`calcium, carboxymethylcellulose sodium, cellulose acetate phthalate, microcrystalline
`
`cellulose, powdered cellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose,
`
`hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose or hydroxypropyl
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`methylcellulose), a polyvinylpyrrolidone (preferably povidone), a fatty acid or fatty
`
`acid derivative (preferably hydrogenated vegetable oil, stearic acid or glyceryl
`
`behenate), a gum (preferably guar gum), polymethacrylate, a carbomer, a poloxamer,
`
`If present, preferably the
`ceratonia, polyethylene oxide, zein, or a mixture thereof.
`binder is a starch or polyvinylpyrrolidone.
`If present, preferably the starch is maize
`
`5
`
`. starch or pregelatinised starch.
`
`10
`
`15
`
`20
`
`a pharmaceutical
`invention provides
`the present
`A further embodiment of
`composition comprising an ACE inhibitor and four or more excipients selected
`
`from lactose, microcrystalline cellulose, mannitol, dibasic calcium phosphate, maize
`
`starch, pregelatinised starch, polyvinylpyrrolidone,
`
`talc and magnesium stearate,
`
`wherein the composition is substantially free of colloidal silicon dioxide.
`
`The
`
`composition may
`
`comprise
`
`five
`
`excipients
`
`selected
`
`from lactose,
`
`microcrystalline cellulose, mannitol, dibasic calcium phosphate, maize starch,
`
`pregelatinised starch, polyvinylpyrrolidone,
`
`talc and magnesium stearate.
`
`The
`
`composition may comprise six such excipients. Alternatively the composition may
`
`comprise seven or more such excipients.
`
`In any of the above pharmaceutical compositions, the ACE inhibitor preferably has
`
`an ester (CO—O), amide (CO-N), thio-ester (CO-S) and/or phospho-ester (PO—O)
`
`bond. Preferably the ACE inhibitor is of formula 1
`
`o
`
`R5
`
`1
`R 02C
`
`H
`N
`
`\I/
`
`R2
`
`R3
`
`OH
`
`N|
`
`R4
`
`o
`
`1
`
`,
`
`wherein
`
`25
`
`R' is H or Cl—C3 alkyl,
`
`R2 is Cl-C3 alkyl optionally substituted with phenyl,
`
`R3 is CI—C5 alkyl optionally substituted with -NH2, or together with R‘ forms
`
`an s-caprolactam derivative optionally containing a sulphur atom and/or a double
`
`bond and optionally substituted with -CI-l=CH-CH=CH- or —C,H_,S,
`
`

`

`-14-
`
`R‘
`
`is indanyl, or together with R3 forms an s-caprolactam derivative as
`
`defined above, or together with R5 forms a pyrrolidine or piperidine derivative'
`
`optionally containing another nitrogen atom and/ or a double bond and optionally
`
`substituted
`
`with
`
`-SCH2CHZS-,
`
`-CH2CH2CH2CH2-,
`
`-CH2CH2CH2-,
`
`-CH=CH-CH=CH-, -CH=C(OCH3)-C(OCH,)=CH—, =0 or -CH,, and
`
`R5 is H, or together with R“ forms a pyrrolidine or piperidine derivative as
`defined above,
`.
`
`or wherein R3, R‘I and RS together form a bicyclic ring system
`
`10
`
`The ACE inhibitor may be alacepril, benazepril, captopril, ceronapril, cilazapril,
`delapril, enalapril, enalaprilat, fosinopril, irnidapril, libenzapril, lisinopril, moexipril,
`moveltipril,
`pentopril,_ perindopril;
`quinapril,
`ramipril,
`rentiapril,
`spirapril,
`
`sosinopril, temocapril, trandolapril or zofenopril, or a pharmaceutically acceptable
`salt or derivative thereof.
`
`15
`
`20
`
`25
`
`The ACE inhibitor may be alacepril, benazepril, captopril, ceronapril, cilazapril,
`
`delapril, fosinopril, imidapril, libenzapril, lisinopril, moexipril, moveltipril, pentopril,
`
`perindopril,
`
`quinapril,
`
`ramipril,
`
`rentiapril,
`
`spirapril,
`
`sosinopril,
`
`temocapril,
`
`trandolapril or zofenopril, or
`
`a pharmaceutically acceptable salt or derivative
`
`thereof.
`
`The ACE inhibitor may be benazepril, cilazapril, delapril, fosinopril,
`imidapril,
`moexipril, perindopril, quinapril, ramipril, spirapril, trandolapril or zofenopril,~ or a
`
`pharmaceutically acceptable salt or derivative thereof. The ACE inhibitor may be
`
`benazepril, cilazapril, delapril, fosinopril, imidapril, moexipril, perindopril, ramipril,
`
`spirapril,
`
`trandolapril or zofenopril, or
`
`a pharmaceutically acceptable salt or
`
`derivative thereof.
`
`

`

`-15-
`
`Optionally the ACE inhibitor is not enalapril or enalaprilat or a pharmaceutically
`
`acceptable salt or derivative thereof. Optionally the ACE inhibitor is not lisinopril
`
`or a pharmaceutically acceptable salt or derivative thereof. Optionally the ACE
`
`inhibitor is not quinapril or a pharmaceutically acceptable salt or derivative thereof.
`
`Preferably the ACE inhibitor is benazepril or a pharmaceutically acceptable salt or
`derivative thereof. Preferably the ACE inhibitor is cilazapril or a pharmaceutically
`
`acceptable salt or derivative thereof. Preferably the ACE inhibitor is delapril or a
`
`pharmaceutically acceptable salt or derivative thereof. Preferably the ACE inhibitor
`
`is fosinopril or a pharmaceutically acceptable salt or derivative thereof. Preferably
`
`the ACE inhibitor is imidapril or a pharmaceutically acceptable salt-or derivative
`
`thereof. Preferably the ACE inhibitor is moexiprilpr a pharmaceutically acceptable
`
`salt or derivative thereof.
`
`Preferably the ACE inhibitor
`
`is quinapril or
`
`a
`
`pharmaceutically acceptable salt or derivative thereof. Preferably the ACE inhibitor
`
`is ramipril or a pharmaceutically acceptable salt or derivative thereof. Preferably the
`
`ACE inhibitor is spirapril or a pharmaceutically acceptable salt or derivative thereof.
`
`Preferably the ACE inhibitor is trandolapril or a pharmaceutically acceptable salt or
`
`' derivative thereof. Preferably the ACE inhibitor is zofenopril or a pharmaceutically
`
`acceptable salt or derivative thereof. More preferably the ACE inhibitor
`
`is
`
`perindopril or
`
`a pharmaceutically acceptable salt or. derivative thereof. Most
`
`preferably the ACE inhibitor is perindopril erbumine.
`
`The composition may preferably comprise:
`
`2-8°/o by weight perindopril erbumine,
`
`20-75% by weight l