`
`UK Patent Application WGB m2 411 355 A
`
`(43) Date of A Publication
`
`31.08.2005
`
`Document FP8
`Appl. No.: 11/273,575
`
`
`(51)
`INT CL7:
`(21) Application No:
`04044202
`A61K 31/403 31/405 31/4704 47/14 , A61P 9/00
`
`Date of Filing:
`
`
`27.02.2004
`
`
`(71) Applicant(s):
`Niche Generics lelted
`(Incorporated in the United Kingdom)
`1 The Cam Centre, Wilbury Way, HITCHIN,
`Hertfordshire, SG4 OTW, United Kingdom
`
`(52) UK CL (Edition X ):
`A58 BJB B170 3180 326Y B42Y B421 B423 343Y B431
`B433 B46Y 3461 3463 B47Y B471 350Y 3501 B52Y
`3523 355Y B551 357Y 3575 3576 358Y 3586 361Y
`3616 362Y 3625 3626 366Y 3666 3828
`U1S $2415
`
`
`
`
`
`
`
`
`
`
`(74) Agent and/or Address for Service:
`
`Venner Shlpley LLP
`20 Little Britain, LONDON, EC1A 7DH,
`
`United Kingdom
`
`
`(72)
`
`Inventorlsl:
`Jeffrey Bergman
`Pratibha S Pilgaonkar
`Maharukh Tehmasp Rustomlee
`Amita P Surana
`Rizwana Mulagath
`Atul A Kelkar
`
`(56) Documents Cited:
`GB 2394660 A
`WO 1995/025504 A
`US 5055483 A
`
`WO 2003/077929 A
`US 5433951 A
`
`(58) Field of Search:
`INT CL7 A61K, A61P
`Other: omune, EPODOC, WPI, JAPIO, CAS-ONLINE,
`TXTE, MEDLINE, BIOSIS.
`
`(54) Abstract Title: ACE inhibitor and glyceride containing pharmaceutical composition
`
`(57) A stable pharmaceutical composition comprising an ACE inhibitor or a pharmaceutically acceptable salt
`or derivative thereof and a C15-C28 glyceride. The preferred ACE inhibitors are susceptible to heat and/or
`mechanical stress-induced degradation, but may be stabilised using a C15-C28 glyceride. Preferred ACE
`inhibitors include ramipril, trandolapril and quinapril. The preferred glyceride is glycerol dibehenate. The
`composition may be useful for the treatment or prevention of cardiovascular disease, coronary heart
`disease, cerebrovascular disease, peripheral vascular disease, arrhythmia, hypertension, cardiac failure,
`cardiovascular death, myocardial infarction, stroke or angina. A method of preparing the pharmaceutical
`composition and a method of providing a stable pharmaceutical composition comprising an ACE
`inhibitor, or a pharmaceutically acceptable salt or derivative thereof, by incorporating a C15-C28 glyceride
`are also outlined.
`
`V998N17285)
`
`Original Printed on Recycled Paper
`
`

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`-1-
`
`2411355
`
`Pharmaceutical Composition
`
`Technical field
`
`The present invention relates to a stable pharmaceutical composition comprising an
`
`ACE inhibitor or a pharmaceutically acceptable salt or derivative thereof.
`
`In
`
`particular, the 1nvention relates to a pharmaceutical composmon, which comprises
`
`an ACE inhibitor, or a pharmaceutically acceptable salt or derivative thereof, and a
`
`Cw—C28 glyceride. ACE inhibitors useful in the present invention are susceptible to
`
`heat and/or mechanical stress-induced degradation. Preferred ACE inhibitors are
`
`ramipril, trandolapril, quinapril and pharmaceutically acceptable salts and derivatives
`
`thereof. The composition of the present invention may be for use as a medicament
`
`for the treatment or prevention of a cardiovascular disease, a coronary heart disease,
`
`a cerebrovascular disease, a peripheral vascular disease, arrhythmia, hypertenSion,
`
`cardiac failure, cardiovascular death, myocardial infarction, stroke or angina.
`
`The present invention further relates to a method of preparing the pharmaceutical
`
`composmon of the present invention. The present
`
`invention also relates to a
`
`method of prOViding a stable pharmaceutical composition comprismg an ACE
`
`inhibitor, or
`
`a
`
`pharmaceutically
`
`acceptable
`
`salt
`
`or derivative
`
`thereof,
`
`by
`
`incorporating a CNS-C28 glyceridc into the composition. The present
`
`invention
`
`further relates to a use of a Clo-C23 glyceride to provide a stable pharmaceutical
`
`composmon comprismg an ACE inhibitor or a pharmaceutically acceptable salt or
`
`derivative thereof.
`
`Background art
`
`ACE inhibitors, i.e. inhibitors of angiotensm 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
`
`degradation between the time of manufacture and the time of desired usage,
`
`in
`
`particular due to cyclization, hydrolySis and ox1dation. Typical degradation products
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`-2-
`
`are hydrolyuc degradation products formed by hydrolysm of the ACE inhibitor and
`
`diketopiperazme degradation products formed by cyclizauon of the ACE inhibitor.
`
`Ramlpril,
`
`also
`
`called
`
`(25,3a5,6a5)-1-[(25)-[[(1D-(ethoxycarbonyl)-3—
`
`phenylpropyl]amino]-1-oxopropyl]—octahydrocyclopenta[b]pyrrole—2-carboxyhc
`
`acid,
`
`is an ACE inhibitor of formula 1. Trandolapril, also called (25,3aR,7a5)-l-[(25)—
`
`[[(1D-(ethoxycarbonyl)-3-phenylpropyl]amino]-l-oxopropyl]-octahydro-lH-indole-
`
`2-carboxylic acxd,
`
`is an ACE inhibitor of formula 2. Qumaprrl, also called (3.9-2-
`
`[(25)-[[(15)-(ethoxycarbonyl)-3-phenylpropyl]amino]-‘l-oxopropyl]-1,2,3,4-tetra-
`
`10
`
`hydrorsoquinohne-3-carboxyhc ac1d, IS an ACE inhibitor of formula 3.
`
`H3c—\
`
`0
`
`
` ""”’COZH
`
`:IIln-n
`
`ACE inhibitors such as ramipril, trandolapnl or qulnaprll, are used in the treatment
`
`or prevention of cardiovascular diseases, coronary heart diseases, peripheral
`
`75
`
`vascular diseases, arrhythmias, hypertension, cardiac failure, cardiovascular death,
`
`myocardial infarction, stroke or angina.
`
`

`

`Currently commercmlly available
`
`formulations of ramipril contain as
`
`inactive
`
`ingredients one or more of
`
`the following excipients: hydroxypropylcellulose,
`
`hydroxypropylmethylcellulose, microcrystalline
`
`cellulose, pregelatinized starch,
`
`maize starch, sodium stearyl
`
`fumarate, gelatin, anhydrous lactose, polyethylene
`
`glycol, polyoxyl hydrogenated castor oil, propyl gallate, sodium aluminium silicate,
`
`paraffin, and/or colouring agents (such as, black, red and/or yellow ferric oxide
`
`E172, titanium dioxide E171, and/or indigo carmine E132).
`
`70
`
`75
`
`20
`
`25
`
`30
`
`Currently commercrally available formulations of trandolapril contain as inactive
`
`ingredients one or more of the followmg eXCipients: corn starch, lactose, povidone,
`
`and/or sodium stearyl fumarate.
`
`Currently commercially available formulations of quinapril contain as
`
`inactive
`
`ingredients one or more of the followmg exc1pients: magneSium carbonate, lactose,
`
`hydrous lactose, gelatin, povidone, crospovrdone, magneSium stearate, candelilla
`
`wax, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol,
`
`maize starch, talc, and/or colouring agents (such as red and/or yellow ferric oxide
`
`E172, titanium dioxide E171 , and/or indigotine E132).
`
`Many ACE inhibitors, including ramipril, trandolapril and quinapril, have an ester
`
`(CO-O) and/or an amide (CO-N) bond. Such bonds are susceptible to hydrolysis
`
`leading to the formation of hydrolytic degradation products. Moreover, due to their
`
`molecular structure many ACE inhibitors,
`
`including ramipri],
`
`trandolapril and
`
`quinapril, are susceptible to cyclization to form diketopiperazme degradation
`
`products. Some known degradation products of ramipril are shown in Figure 1,
`
`including hydrolytic
`
`degradation products E and
`
`F,
`
`and diketopiperazine
`
`degradation products D, K and L.
`
`The 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
`
`composmon increases,
`
`the concentration of available,
`
`functional ACE inhibitor
`
`decreases. Thus the shelf-life of pharmaceutical composmons comprismg the ACE
`
`

`

`inhibitor is limited due to this degradation. Accordingly, degradation should be
`
`aVOided.
`
`Various ways to minimize the degradation of ACE inhibitors in pharmaceutical
`
`composruons have been advocated. For example, it has been suggested that alkali
`
`or alkaline-earth metal
`
`salts can stabilise ACE inhibitors and their
`
`salts and
`
`derivatives in pharmaceutical composmons.
`
`WO 01/15724 and US-6,555,551 disclose a method of stabilising pharmaceutical
`
`compositions
`
`comprismg ACE inhibitors
`
`such as
`
`ramipril hydrochloride or
`
`quinapril hydrochloride. The method comprises the step of mixing an alcoholic
`
`disperSion of an ACE inhibitor With an aqueous solution or dispersmn of a metal
`
`compound; the resulting mixture may be dried. Snitable metal compounds are alkali
`or alkaline-earth metal salts.
`
`EP-O,280,999
`
`and US-4,743,450 teach
`
`that
`
`the
`
`cyclization,
`
`hydrolysis
`
`and
`
`discolouration of pharmaceutical composrtions, comprising quinapril, enalapril,
`
`indolapril or structurally-related ACE inhibitors, are minimized by formulating the
`
`composrtions 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.
`
`W0 03/059388 discloses that
`
`the cyclization, hydrolysrs and discolouration of
`
`pharmaceutical
`
`compositions,
`
`comprismg ramipril, quinapril,
`
`trandolapril or
`
`structurally—related ACE inhibitors, are minimized by formulating the compOSitions
`
`With a basic compound and a filler. The basic compound is preferably an alkali or
`
`alkaline-earth metal carbonate, such as magnesium carbonate, sodium carbonate or
`
`sodium hydrogen carbonate. The filler is preferably an insoluble alkaline—earth
`
`metal hydrogen phosphate, such as calcium hydrogen phosphate.
`
`WO 02/11709 discloses stable pharmaceutical compositions comprising ramipril
`
`and an effervescent system. The effervescent system comprises an alkali or alkaline-
`
`earth metal carbonate or bicarbonate, such as sodium, calcium or magnesmm
`
`10
`
`I5
`
`20
`
`25
`
`30
`
`

`

`carbonate or bicarbonate, and at least one acid, such as Citric acid, monosodium
`
`Citrate, ascorbic aCid, gluconic acid, lactic acid, malic acid or tartaric acid. The ratio
`
`of and to (bi)carbonate is said to be between 0.6 and 1.3, and the ratio of ramipril
`
`to effervescent system is said to be between 0.004 and 0.013, for the pharmaceutical
`
`composmons to be stable.
`
`WO 99/62560 and US-6,4]7,196 disclose pharmaceutical compositions, comprismg
`
`qumapril, enalapril,
`
`indolapril or structurally~related ACE inhibitors, which are
`
`stabilised by the presence of magneSium oxide, preferably in combination with a
`
`hydrolysis-minimizing agent. The presence of magnesmm 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.
`
`It has also been suggested that certain ac1ds can be used to stabilise ACE inhibitors
`
`in pharmaceutical composttions.
`
`EP-0,468,929,
`
`[ls-6,300,361 and US-6,300,362
`
`disclose the use of hydrochloric ac1d donors as stabilizers in pharmaceutical
`
`composmons comprismg ACE inhibitors such as quinapril, enalapril, spirapril,
`
`spiraprilate,
`
`ramipril, perindopril,
`
`indolapril,
`
`lismopril,
`
`alacepril,
`
`trandolapril,
`
`benazepril, libenzapril, delapril or Cilazapril. Suitable hydrochloric acid donors are
`
`amino ac1d hydrochlorides, such as glycme, glutamic aCid, betaine, alanine, valine,
`
`lysme, arginine or aspartic acid hydrochloride, and Lewis acid chlorides, such as
`
`ferric, Zinc or aluminium chloride.
`
`Furthermore,
`
`it has been suggested that certain compounds such as
`
`lactose
`
`monohydrate can be used to stabilise ACE inhibitors
`
`such as
`
`ramipril
`
`in
`
`pharmaceutical
`
`composuions.
`
`W0
`
`03/028707
`
`discloses
`
`pharmaceutical
`
`composntions comprismg ramipril and lactose monohydrate as diluent. The lactose
`
`monohydrate was
`
`found to stabilise the ramipril
`
`in the compositions.
`
`The
`
`composmons may further optionally comprise a lubricant, such as magnesium, zinc
`
`10
`
`I5
`
`20
`
`25
`
`30
`
`or calcium stearate.
`
`Moreover,
`
`the use of protective coatings has been advocated to stabilise ACE
`
`inhibitors in pharmaceutical composnions. EP-0,317,878, US—S,151,433 and US—
`
`

`

`5,442,008 disclose pharmaceutical composmons comprismg ACE inhibitors such as
`
`ramipril,
`
`enalapril,
`
`perindopril,
`
`indolapril,
`
`lismopril,
`
`qumapril,
`
`alacepril
`
`or
`
`trandolapril,
`
`in which the ACE inhibitors are stabilised 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-5,527,54O disclose
`
`pharmaceutical
`
`composttions comprising an alkali-sensitive active substance, such as captopril,
`
`ramipril, perindopril erbumine or enalapril, and an effervescent system, such as a
`
`10
`
`carbonate component. To stabilise the active substance, it is embedded in at least
`
`one of the following compounds: an edible organic and, a higher alcohol, a
`
`hydrocollmd, a long-chain polyvinylpyrrolidone, and is preferably coated with at
`
`least one of said compounds.
`
`The carbonate component
`
`is also preferably
`
`embedded in at least one edible organic and and coated by the same or another
`
`15
`
`acid.
`
`Furthermore,
`
`in W0 03/059330 it has been suggested that mechanical stress-
`
`induccd degradation of ACE inhibitors
`
`such as
`
`ramipril,
`
`spirapril,
`
`lismopril,
`
`enalapril, quinapril, benazepril or
`
`structurally-related ACE inhibitors, can be
`
`avoided by coating a core of diluents and other formulating agents with a layer of
`
`the ACE inhibitor. The core is compressed prior to coating with the ACE inhibitor,
`
`thereby av01ding the need to compress the ACE inhibitor and thus avoiding
`
`mechanical stress-induced degradation.
`
`It has still further been suggested to stabilise ACE inhibitors by derivatisatjon. For
`
`example, WO 02/03970 discloses a transdermal therapeutic system comprising an
`
`adhesive matrix. The matrix comprises a derivative of an ACE inhibitor such as
`
`ramipril or trandolapril, which has been stabilised by derivatisation into a salt or
`diester.
`
`20
`
`25
`
`30
`
`Despite these efforts to stabilise ACE inhibitors, there remains a long-standing need
`
`for
`
`stable pharmaceutical
`
`compositions
`
`comprising an ACE inhibitor or
`
`a
`
`

`

`pharmaceutically acceptable salt or derivative thereof, and methods of preparing the
`same.
`
`Surprisingly, it has now been found that the presence of a Cm-C28 glyceride reduces
`
`or slows the degradation of ACE inhibitors such as ramipril, trandolapril, quinapril,
`
`or their salts or derivatives in pharmaceutical composmons. Astonishingly, until
`
`now Cm—Cza glycerides such as glycerol dibchcnate, a common pharmaceutical
`
`exc1pient, have not been used in pharmaceutical composttions comprismg ramipril,
`
`trandolapril, quinapril, or their salts or derivatives either in the published prior art
`
`or in commercmlly available composmons.
`
`Summary of the invention
`
`For the purposes of the present invention, a “Cw—C28 glyceridc" is a mono-, di— or
`
`tri—glyceride comprising one,
`
`two or
`
`three Cm—Cza acyl mOieties
`
`respectively.
`
`Preferably each Clo-C23 acyl mOiety is independently of the formula -CO—R, wherein
`
`R is a saturated or unsaturated hydrocarbon, which contains from 16 to 28 carbon
`
`atoms, and which is straight—chained or branched.
`
`Preferably R is a saturated
`
`hydrocarbon. Preferably R is a straight-chained hydrocarbon. The acyl mOieties
`
`may be derived from naturally occurring or synthetic fatty acids. The terms “Cm-C26
`
`glyceride”, “Cw-C24 glyceride” and “sz glyceride” are defined accordingly. Glycerol
`
`dibehenate comprises mainly C22 diglyceride comprismg two C22 acyl moreties of the
`
`formula ~CO—(CHon-CH3.
`
`A pharmaceutical composition comprising an ACE inhibitor, or a pharmaceutically
`
`acceptable salt or derivative thereof,
`
`is considered to be “stable”,
`
`if the ACE
`
`inhibitor, or its salt or derivative, in the pharmaceutical composition degrades less
`
`or more slowly than it does in known pharmaceutical compositions. The term
`
`“unstable” is defined accordingly.
`
`An excrpient
`
`is considered to be “compatible” With an ACE inhibitor, or
`
`a
`
`pharmaceutically acceptable salt or derivative thereof, if it does not promote the
`
`degradation of the ACE inhibitor, or its salt or derivative, i.e. if the ACE inhibitor,
`
`10
`
`I5
`
`20
`
`25
`
`30
`
`

`

`-8-
`
`or its salt or derivative, does not degrades more or faster in the presence of the
`
`exc1pient compared to the degradation of the ACE inhibitor, or its salt or derivative,
`
`on its own. The terms “compatibility”, “incompatible” and “incompatibility” are
`
`defined accordingly.
`
`An ACE inhibitor, or a pharmaceutically acceptable salt or derivative thereof, is
`
`conSidered
`
`to
`
`be
`
`“susceptible
`
`to
`
`heat
`
`and/or mechanical
`
`stress-induced
`
`degradation”,
`
`if it degrades more or faster when it
`
`is subjected to heat and/or
`
`mechanical stress such as, for example, due to pressure and heat exerted during
`
`compression of a powder blend into tablets, than it does when it is not subjected to
`
`heat and/or mechanical stress.
`
`A drug, such as an ACE inhibitor or a pharmaceutically acceptable salt or derivative
`
`thereof, and an exc1pient, such as glycerol dibehenate, are conSidered to form a
`
`“mixture”,
`
`if the drug and the excrpient are blended together. Thus, if a first
`
`eXCipient is solely used to coat a drug or a drug/second exc1pient blend, then the
`
`first exCipient 15 not conSidered to form a mixture with the drug or the drug/second
`
`exc1pient blend. However, if an exupient is blended together with a drug and is
`
`10
`
`15
`
`also used to coat the drug/excipient blend, then the exc1pient is conSJdered to form
`a mixture With the drug. A mixture or blend of a drug and an eXCipient
`is
`
`20
`
`considered to form an “intimate mixture or blend”, if the mixture or blend is
`
`substantially uniform.
`
`25
`
`30
`
`A first embodiment of the present invention prov1des a pharmaceutical composition
`
`comprismg an ACE inhibitor, or a pharmaceutically acceptable salt or derivative
`
`thereof, and a Cm—C28 glyceride.
`
`Preferably the pharmaceutical composition
`
`comprises 5-30% by weight Cm-CZB glyceride, more preferably 5-20% by weight,
`
`even more preferably 10-15% by weight of the total composition.
`
`Preferably the glyceride comprises one, two or three Cm-C28 acyl moieties, wherein
`
`each Cm—Cza acyl mOiety is independently of the formula —CO-R, wherein R is a
`
`saturated or unsaturated hydrocarbon, which contains from 16 to 28 carbon atoms,
`
`and which is straight-chained or branched. Preferably R is a saturated hydrocarbon
`
`

`

`-9.
`
`and/or R is a straight-chained hydrocarbon. Preferably the glyceride IS a Cm-Cz6
`
`glyceride, more preferably a Clo—C24 glyceride, even more preferably a C22 glyceride.
`
`Preferably the glyceride comprises at least 50% diglyceride, more preferably at least
`
`60% diglyceride, even more preferably at
`
`least 70% diglyceride.
`
`In the most
`
`preferred embodiment of the present invention, the glyceride is glycerol dibehenate.
`
`Preferably the ACE inhibitor, or the pharmaceutically acceptable salt or derivative
`
`thereof, is susceptible to heat and/or mechanical stress-induced degradation. More
`
`preferably the ACE inhibitor, or the pharmaceutically acceptable salt or derivative
`
`thereof, is ramipril, trandolapril, quinapril, or a pharmaceutically acceptable salt or
`
`derivative thereof.
`
`In the most preferred embodiment of the present invention, the
`
`ACE inhibitor, or the pharmaceutically acceptable salt or derivative thereof,
`
`is
`
`ramipril or a pharmaceutically acceptable salt or derivative thereof.
`
`Preferably the pharmaceutical composition comprises one or more
`
`further
`
`exc1pients, which are compatible with the ACE inhibitor or the pharmaceutically
`
`acceptable salt or derivative thereof.
`
`The one or more further excipients may be selected from carbonates (such as
`
`calcium carbonate, sodium carbonate or magneSium carbonate), phosphates (such as
`
`anhydrous dibasrc calcmm phosphate, dibasie calcium phosphate dihydrate, tribaSic
`
`calcium phosphate or sodium phosphate), sulfates (such as calcium sulfate), silicates
`
`(such as kaolin,
`
`talc, sodium aluminium Silicate, magnesium aluminium silicate,
`
`magneSium silicate or magnesium trisilicate), carbohydrates (such as dextrates,
`
`dextrin, maltodextrin, dextrose, polydextrose,
`
`fructose, sucrose,
`
`sugar spheres,
`
`compressible sugar, confectioner’s sugar, maltose, mannitol,
`
`lactose, anhydrous
`
`lactose, hydrous lactose, lactitol, maltitol, sorbitol, sodium alginate, alginic and 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, srlicified microerystalline cellulose, powdered
`
`cellulose,
`
`cellulose
`
`acetate,
`
`cellulose
`
`acetate
`
`phthalate, methylcellulose,
`
`cthylcellulose,
`
`hydroxyethylcellulose,
`
`hydroxypropylcellulose,
`
`low-substituted
`
`70
`
`15
`
`20
`
`25
`
`30
`
`

`

`-10-
`
`hydroxypropylcellulose
`
`or hydroxypropylmethylcellulose), polyvmylpyrrolidones
`
`(such as povrdone or crospovxdone), fatty aCids or fatty acid derivatives (such as
`
`hydrogenated vegetable oil, hydrogenated castor Oil, polyoxyl hydrogenated castor
`
`oil, mineral oil,
`
`light mineral orl, cottonseed 011, a medium-chain triglyceride,
`
`glyceryl palmitostearate,
`
`calcium stearate,
`
`stearic acrd, glyceryl monostearate,
`
`magneSium stearate,
`
`polyoxyethylene
`
`stearate, Zinc
`
`stearate,
`
`sodium stearyl
`
`fumarate, candelilla wax or glycerol dibehenate), gums (such as tragacanth gum, guar
`
`gum or acacia), colouring agents (such as black, red or yellow ferric ox1de, titanium
`
`dioxide or indigotine), magnesmm oxide, sodium chloride, polymethacrylate, propyl
`
`gallate, collordal
`
`silicon dioxide, polacrilin potasSium, sodium lauryl sulfate, a
`
`poloxamer, polyethylene glycol, sodium benzoate, a carbomer, ceratonia, gelatin,
`
`paraffin, polyethylene ox1de, zein, or a i-ruxture thereof.
`
`Preferably,
`
`the one or more further excipients are selected from carbonates
`
`(preferably magnesmm carbonate), phosphates
`
`(preferably anhydrous dibasic
`
`calCium phosphate, dibaSic calcium phosphate dihydrate or
`
`tribasic calcrum
`
`phosphate), silicates (preferably kaolin, talc, sodium aluminium Silicate, magnesium
`
`aluminium Silicate, magneSium Silicate or magnesrum trisilicate), carbohydrates
`
`(preferably dextrates, maltodextrin, dextrose, polydextrose, fructose, sucrose, sugar
`
`spheres,
`
`compreSSible
`
`sugar, confectioner’s
`
`sugar, maltose, mannitol,
`
`lactose,
`
`anhydrous lactose, hydrous lactose, lactitol, maltitol, sorbitol or sodium alginate),
`
`starches (preferably starch, pregelatinized starch, maize starch, corn starch or
`
`sodium starch glycolate), celluloses
`
`(preferably carboxymethylcellulose calcium,
`
`carboxymethylcellulose
`
`sodium,
`
`cross-linked
`
`carboxymethylcellulose
`
`sodium,
`
`microcrystalline cellulose, powdered cellulose, cellulose acetate, cellulose acetate
`
`phthalate,
`
`methylcellulose,
`
`ethylcellulose,
`
`hydroxyethylcellulose,
`
`hydroxypropylcellulose,
`
`low-substituted
`
`hydroxypropylcellulose
`
`hydroxypropylmethylcellulose),
`
`polyvinylpyrrolidones
`
`(preferably
`
`povidone
`
`or
`
`or
`
`crospowdone),
`
`fatty acids or
`
`fatty actd derivatives
`
`(preferably hydrogenated
`
`vegetable orl, hydrogenated castor oil, polyoxyl hydrogenated castor oil, glyceryl
`
`palmitostearate, calcrum stearate, stearic acid, glyceryl monostearate, magnesium
`
`stearate,
`
`zinc
`
`stearate,
`
`sodium stearyl
`
`fumarate,
`
`candelilla wax or glycerol
`
`dibehenate), gums (preferably guar gum), colouring agents (preferably black, red or
`
`70
`
`15
`
`20
`
`25
`
`30
`
`

`

`-1]-
`
`yellow ferric
`
`ox1de,
`
`titanium dioxide
`
`or
`
`indigotine),
`
`sodium chloride,
`
`polymethacrylate, propyl gallate, colloidal silicon diox1de, sodium lauryl sulfate, a
`
`poloxamcr, polyethylene glycol, sodium benzoate, a carbomer, ceratonia, gelatin,
`
`paraffin, polyethylene ox1de, zein, or a mixture thereof.
`
`More preferably,
`
`the
`
`one
`
`or more
`
`further
`
`exc1pients
`
`are
`
`selected
`
`from
`
`hydroxypropylmethylcellulose, pregelaunised
`
`starch, microcrystalline
`
`cellulose,
`
`lactose, sodium starch glycolate, sodium stearyl
`
`fumarate, red ferric mode and
`
`yellow ferric oxide.
`
`Preferably the pharmaceutical composmon comprises:
`
`1-8% by weight ACE inhibitor, preferably 2-6% by weight;
`
`5-20°/o by weight Cm—C28 glyceride, preferably 10-15% by weight;
`
`60—80% by weight lactose anhydrous, preferably 65-75% by weight;
`
`5-20% by weight sodium starch glycolate, preferably 10-15% by weight;
`
`0.5-4 by weight sodium stearyl fumarate, preferably 0.5-2°/o by weight;
`
`0—0.4°/o by weight yellow ferric oxide; and
`
`0-0.1°/o by weight red ferric oxide.
`
`Preferably the pharmaceutical comp05ition of the present invention is stable.
`
`Preferably the pharmaceutical composition of the present invention is suitable for
`
`direct compression into tablets.
`
`Preferably the ACE inhibitor, or the pharmaceutically acceptable salt or derivative
`
`thereof, and the CM-Cu glyceride form a mixture, preferably an intimate mixture, in
`
`the pharmaceutical composmon of the present invention.
`
`If one or more further
`
`exapients are present
`
`in the composmon, preferably the ACE inhibitor, or the
`
`pharmaceutically acceptable salt or derivative thereof, the Cm-C23 glyceride and one
`
`or more of the one or more further excipients form a mixture, preferably an
`
`intimate mixture, in the pharmaceutical composmon. Preferably the mixture or the
`
`intimate mixture is suitable for direct compression into tablets.
`
`10
`
`I5
`
`20
`
`25
`
`30
`
`

`

`-12-
`
`Optionally the pharmaceutical composnion of the present
`
`invention comprises
`
`granules or particles comprising the ACE inhibitor, or
`
`the pharmaceutically
`
`acceptable salt or derivative thereof, wherein the granules or particles comprise a
`
`coating comprisrng the C,(,—C28 glyceride. The granules or particles may optionally
`
`further comprise one or more exc1pients.
`
`70
`
`15
`
`20
`
`25
`
`30
`
`Preferably the composition is a solid composition, more preferably it
`
`is a non-
`
`effervescent comp051tion.
`
`Optionally the pharmaceutical composmon of the present invention may further
`
`comprise a B-blocker, a diuretic, a caICium-channel blocker, a vasodilator anti-
`
`hypertensive drug, or an angiotensm II receptor antagonist.
`
`Typically, the pharmaceutical composition of the present invention is suitable for
`
`oral, parental,
`
`transdermal,
`
`airway,
`
`rectal, vaginal or
`
`topical administration.
`
`Preferably the composition is suitable for oral administration.
`
`A composmon suitable for oral administration may be in unit dosage form
`
`comprismg
`
`1—20mg,
`
`preferably
`
`1-]Omg,
`
`of
`
`the ACE inhibitor
`
`or
`
`the
`
`pharmaceutically acceptable salt or derivative thereof. A composition suitable for
`
`oral administration is typically prowded in the form of tablets, capsules, caplets,
`
`troches, lozenges, dragées, powder, granules or particles. Optionally the tablets,
`
`capsules, caplets, troches, lozenges, dragées, powder, granules or particles not only
`
`contain the Clo-C2,, glyceride, but also comprise a coating comprismg the Cw-C28
`
`glyceride. Preferably the composition is provided in the form of tablets. Preferably
`
`the tablets have a dismtegration time of not more than 10 minutes, more preferably
`
`of not more than 5 minutes,
`
`in water at 36-38°C. Preferably the tablets have a
`
`shelf-life of at least 18 months, preferably of at least 24 months, more preferably of
`
`at least 4 or 5 years.
`
`Preferably the composition is for use as a medicament, typically for the treatment or
`
`prevention of a cardiovascular disease, a coronary heart disease, a cerebrovascular
`
`

`

`-13-
`
`disease,
`
`a peripheral vascular disease, arrhythmia, hypertension, cardiac failure,
`
`cardiovascular death, myocardial infarction, stroke or angina.
`
`A further embodiment of the present invention provides a method of treating or
`
`preventing a cardiovascular disease, a coronary heart disease, a cerebrovascular
`
`disease,
`
`a peripheral vascular disease, arrhythmia, hypertenSion, cardiac failure,
`
`cardiovascular
`
`death, myocardial
`
`infarction,
`
`stroke
`
`or
`
`angina,
`
`comprising
`
`administering an effective amount of a pharmaceutical composnion of the present
`
`invention to a patient in need thereof.
`
`A further embodiment of the present invention provides a use of a pharmaceutical
`
`composmon of the present invention in the manufacture of a medicament for the
`
`treatment or prevention of a cardiovascular disease, a coronary heart disease, a
`
`cerebrovascular disease, a peripheral vascular disease, arrhythmia, hypertension,
`
`cardiac failure, cardiovascular death, myocardial infarction, stroke or angina.
`
`A further embodiment of the present invention prov1des a method of preparing a
`
`pharmaceutical composrtion of the present
`
`invention, comprismg the step of
`
`blending the ACE inhibitor, or the pharmaceutically acceptable salt or derivative
`
`thereof, With the Cm-Cza glyceride and optionally one or more further eXCipients.
`
`Preferably the method comprises the steps of blending the ACE inhibitor, or the
`
`pharmaceutically acceptable salt or derivative thereof, with the Cm-Cz,l glyceride to
`
`form a pie—mix, and then blending the pre-mix with one or more further exc1pients.
`
`Preferably the ACE inhibitor, or the pharmaceutically acceptable salt or derivative
`
`thereof,
`
`the Cm-CZB glyceride and optionally one or more further eXCipients are
`
`blended to form an intimate mixture. Preferably the method further comprises the
`
`step of compressing the blend of the ACE inhibitor, or
`
`the pharmaceutically
`
`acceptable salt or derivative thereof, and the excipient(s) into tablets by direct
`
`compressron. Optionally the tablets, comprisrng a Cm-Czs glyceride, may also be
`
`prov1ded With a coating comprising a Cm—C23 glyceride.
`
`Alternatively, a method of preparing a pharmaceutical composmon of the present
`
`invention may comprise the steps of preparing granules or particles comprising the
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`-14.
`
`ACE inhibitor, or the pharmaceutically acceptable salt or derivative thereof, and
`
`optionally one or more eXCipients, and providing the granules or particles With a
`
`coating comprising the CM-C2a glyceride.
`
`The composmon may be prepared by the methods of the present
`
`invention in
`
`batches of 5-150kg, preferably in batches of 5-100kg.
`
`A further embodiment of the present invention provides a method of providing a
`stable
`pharmaceutical
`composnion
`comprismg
`an ACE inhibitor,
`or
`a
`
`the method comprising
`pharmaceutically acceptable salt or derivative thereof,
`incorporating a CWC23 glyceride into the composmon. Preferably the method of
`
`prov1ding a stable pharmaceutical composition comprises incorporating the CNS-C28
`
`glyceride into the composition in a mixture, preferably an intimate mixture, with the
`
`ACE inhibitor or
`
`the pharmaceutically acceptable salt or derivative thereof.
`
`Preferably the pharmaceutical composmon is stabilised to minimize the degradation
`of the ACE inhibitor or the pharmaceutically acceptable salt or derivative thereof.
`
`Preferably the ACE inhibitor, or the pharmaceutically acceptable salt or derivative
`
`thereof, is susceptible to heat and/or mechanical stressoinduced degradation. More
`
`preferably the ACE inhibitor, or the pharmaceutically acceptable salt or derivative
`
`thereof, is rainipril, trandolapril, quinapril, or a pharmaceutically acceptable salt or
`derivative thereof.
`In the most preferred embodiment of the present invention, the
`
`ACE inhibitor, or the pharmaceutically acceptable salt or derivative thereof,
`
`is
`
`ramipril or a pharmaceutically acceptable salt or derivative thereof. Preferably the
`pharmaceutical composition comprises 5-30°/o by weight Cm-C28 glyceride, more
`
`preferably 5-20% by weight, even more preferably 10-15% by weight of the total
`
`composttion. Preferably the glyceride is a CWC26 glyceride, more preferably a C20-
`C2,, glyceride, even more preferably a C22 glyceride.
`Preferably the glyceride
`comprises at least 50% diglyceride, more preferably at least 60% diglyceride, even
`
`more preferably at least 70% diglyceride.
`
`In the most preferred embodiment of the
`
`present invention, the glyceride is glycerol dibehenate.
`
`10
`
`75
`
`20
`
`25
`
`30
`
`The present invention further prOVides a use of a Cm-C23 glyceride to prOVide a
`stable
`pharmaceutical
`composition
`comprising
`an ACE inhibitor
`or
`a
`
`

`

`-15-
`
`pharmaceutically
`
`acceptable
`
`salt
`
`or
`
`derivative
`
`thereof.
`
`Preferably
`
`the
`
`pharmaceutical composmon is stabilised to minimize the degradation of the ACE
`
`inhibitor or the pharmaceutically acceptable salt or derivative thereof. Preferably
`
`the ACE inhibitor, or the pharmaceutically acceptable salt or derivative thereof, is
`
`susceptible to heat and/or mechanical stress-induced degradation. More preferably
`
`the ACE inhibitor, or the pharmaceutically acceptable salt or derivative thereof, is
`
`ramipril, trandolapril, qui