Indian Patents. 279608:Pharmaceutical Composition comprising hemicalcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid.

Title of Invention	Pharmaceutical Composition comprising hemicalcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid.
Abstract	A chemically stable formulation of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrim idin-5-yl]-(3R, 5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically-acceptable salt thereof for oral use, such as tablets, capsules, powders, granules has been developed using the substances which stabilize against formation of degradation products: lactone and oxidation product.

Full Text	Pharmaceutical compotiUon Present invention from the field of phamiaceutics relates to pharmaceuficsd composition contaMrtng(EH44-{4-fluorophenyl)-6-l8opropyl-2Hm^^ ylK3R, 5S)-3.5-dihydrDxyhep(-6 Byyicflrpymi jnytn^p The agent is a 3-hydioxy-3-methytgtutaryi (HMG) CoA reductase InhOjitor loiown from EP 521471 and formulated into a phamnaceutical composition can be used for (manutacturnig the medicament for) treating hyperchoiesteroiemia, hyperlipidproteinemia and atherosclerosis. A mqjor issue assotiated with the bulk agent or fonnulated into a composition is that It is particularly sensHive to degradation. The major degradation products fbnned (as known from US 6548513) are the lactone (N-{4-(4^luoro-phenyl)-5H2-(4- hydroxy-«-oxo-tetrtahydropyran-2-yl)-vtnyi)-e-i8opropyHifyrimk^ methanesulfonamide) and the oxklatton product (7-[4-(4-fluoropheny()-6-isopropyl-2- [me0)yKtnethy(sulfonyi)aminoK>yrimidhvS-yl}-3-hydrox^5-oxo-hept-e«r^ add). Also, when exposed to ligM, the agent undergoes degradatkm to two diastereomeric cydk: products, described in US 2005/0187234 A1. The mentioned degradations of the agent under conditions of humkfity, acidity, oxygen and light is a challenge for tfie manufacture of a pharmaoeutk»l fonnulatkm, stable enough for ordinary storage condttions. This stabiSzation of the agent or chemtoalty simflar compounds, espedaiiy those belonging to HM6-C0A reductase inhibitorB, could be achieved by controlling pH in a formulaSon (by addition of components such as a carboruite or bicarbonate) and by adding to compo^on a stabilizing inorganic salt, particularly tribask: Mbasks caldum phosphate. AnUoxklants, such as butylated hydroxytoluene may also be used to hinder oxkiatkm of the ageint. Ararther option is to stabilize a pharmaceutteal compositkxi using an amino sugar. Pharmaceutk^l composition of the agent currently marketed under name Creator contains 5,10,20, or 40 mg of the agent, tnlMUlc cateium phosphate as the stabilizing inoiganic salt and the foltowing inactive ingredients: mkxocrystalline cellulose, lactose monohydrate, crospovklone, magnesium stearate, hypromellose. triacetin, titanium doxide. yellow fenric oxide, and red ferric oxide. Pescriatton of the figure Figure represents the comparison of the amount of the main degradation product (lactone form of the agent, as measured by IHPLC), wMch is fomned if ttie compositions corresponding to currently mar1(eted formulation and the composition in accordance with our imwntion are subjected to accelerated stability program (as proposed by ICH guidelines: 40C and 75 % relative humidity, stored in the primary padcage). The y axis represents the % of the fornied degradation product (lactone), and x axis the time in months. Disclosure of fl>e inventton in an aspect the invention provides a phannaceutical ccunposition comprising (E)-7-[4-(4- fluorophenyl)-6-isopropyi-2-{methyl(methylsulfony\|)amino}(^midin-S-yt^ 5S)-3,5- dihydroxyhept-6-enoic add or a phannaceutically-acceptable salt thereof characterized in that it contains less than 0.05% as measured by HPLC of the 7-['K4-«fuorophenyi)-6- iso(MX>pyl-2•4^)ethyl(nmthylsuifbnyOaminotByrimidilv^yl^341yd^}xy-5-oxo-h^ add. In additional aspect the invention is a phannaceutical conrqiosition comprising the agent, characterized in that it contains less than 0,5% as measured by HPLC of the hH4-(4-Fluoto- phenyl)-5-[2--vinylI^i80propyH?yrimlefin-2-yl}-h^ methyl^ethanesulfonamide and also less than 0,05% as measwed by HPLC of the 7-[4-(4- fluorophenyl>-64sopropyl-2-{tr)ettiyKnriethylsulfonyi)amlno]pyrimkiln-5-y^ hept-6-enoic acid. In a specific en^x>diment the invention is a pharmaceutical composition comprising the a^nt, characterize in that at least one of the ingredients is chosen fix>m the first group consisting of: com starch, sUidfied microcrystatNne ceHuJose, croscarmellose sodum, and hypromellose and/or from the second group consisting of com starch, mannitol, hydroxypropyl cellulose artd hypronwilose. Specific^ in an embodbnent the phanrwceutical coinposition according win coriqxise sHidfied microcrystaltine ceitulose, agent, corn starch in weight ratio 10:3-4:1-2. More specifically it will additionally comprise up to 5% of at least one lubricant which may be selected from group consisting of tsrtc and glyceryt behanate Yet more specttically the pharmaceutic^ composWon wUI comprise the agerrt, ^lidfied microaystaMne cellidose, com starch, lactose, talc, colloidal silicon cfioxide, glyceryl behariate arKl sodium stearyl fimarate h viwigM ratio 10:20-30:10-17:50^: 1-3: 0-2:0-1. The composition may film coated wherein said coating comprises HPMC, iHPC, polyethylene glycol and talc. In anc^her aspect the invention represents a process for preparing a phamtaceufical composition comprising the agent with steps: a) mixing and screening of the agent and exdpients, comprising silidfied miorocrystalllne celluiose and com starch to obtain homogeneous mixture; and b) (optional) granulation of powder mixture; and c) mixing of powder mixture (or granules) with liixicarA; and d) compressing of powder mixture (or granules) Into tablets: and e) (optional) coating of tabjets prepared in preceding steps; in specific aspect wherein the weight ratio of agent: silidfied microcrystalline ceHulose: com starch is 10:10 to 40: 2 to 20. Additionally the invention is a process for preparing a phamtaoeuticd composition comprising the hemicalcwm salt of (E)-7-{4-(4-fluorophenyl)-6-isopropyl-2- lmethyl(methylsulf6nyl)amino]pyrhnidin-5-ylH3R. 5S)-3.5-dlhydroxyhept-6-enoic add characterized in that the process comprises following steps: a) dry blending said hemicaldum salt and exdpienis mixture, wherein this mixture comprises lactose, silidfied microcrystalline cellulose and com starch; b) (optionally) mixing therein additional exdpients; c) nftixing ttierein a lubrk»nt selected from sodium steari funuurate or gl^^ specifically glyceryl behanate; d) compressing obtained powder mixture into tablets; e) (optionally) coating of tablets prepared in preceding steps, specffically in amounts strid hemicaldum salt: 5-20% wt; lactose: 40 - 60% wt; silidfied microcrystalline cellulose: 20- 30% wt; and com starch: 1 to 25 % wt relative to the weight of the composition and (optionally) film coating. Invention is embocfied in the use of the phannaceuticai composition as described above for treating hypercholesterolemia, hypertipidproteinemia and atherosclerosis and also in the use of the agent together wim sttidfied microcrystalline cellulose and com starch for manufcicturing of a medicament for treating hypercholesterolemia. hyperHpidproteinemia and atherosclerosis. In another aspect the inventions is the use of siHdfied microcrystalline celhtlose and com starch for stat>itizafion of a phannaceutical composition comprising hemicatcium salt of (E)-?- [4-(4^uorophenyl)^isoprapyl-2-(methyKmethytsulfbnyl)am-\|^^^ dihy(iroxyhept-6-enoic acid, specfficatiy wherein said siticffied microcrysta^ ceUuiose and com starch are together present in an anwunt 10 - 70% relative to the vyeight of pharmaceuticat composition. The invention is embodied in a novel phamiaceutical composition having the following advantages: the composition inhibits in long temn Thus the lack of alkaline ingredients on one hand minimizes the potential of impaired in-vivo absorption of the ^lent due to the changes of thegastrointestinai pH and on the other sMe such composition is advantageous for patient because an alkaine compositkNi wouki have adverse effects on gastric mucosa. The pl-i of the aqueous solution or dispersion of the composition in accordance with our invention will be substantia neutral, preferably between 6 and 8, as detenmined if a tablet containing 40 mg of agent is dispersed in 40 ml of water and measured by glass electrode pH meter. CompositkHis can be manufoctured by e8tat>lished technokj^cal procedures, prefers^ direct compresston or wet granulatkxi fottowed by tabletting and film coating for manufacturing of finished dosage fomi (e.g. tablet) and at the same time demonstrates suitable bk>pharmaoeutk:al properties such as comparable cNssolution and/or bioequivalence to Creator. The present invention combines in a pharmaceutical composition the agent with the ingredients that stabilize the agent. Ingredients are selected according to two stabilizing properties. In the first group are the ingredients which were found to inhibit oxidatton of the agent: com starch, siik:ified microcrystalline ceRuk>se, croscamnellose sodium, and hypromellose. In the second group are the ingredients which were found to inhibit the formation of the lactone form of the agent: com starch, mannitol, hydroxypropyi ceOiriose and hypromenose. The fomnation of the degradation products of the agent under the influence of light can also be addittonally hindered using phantiaceutteally acceptable pigments or colorants, for instance in a tablet coating. Preferably selection of ingredient» from tx^ groups and a protecSon from light resiAs in a pharmaceutical composition wherein the agent is stabiltzed. In such formulation, the agent stays stable witti respect to oxidation, formation of the lactone and fonnation of degradation products, preferably over a petkxl of years, more preferably moi4hs. In an emboiftnent the invention comprises a phamtaceutical composition comprising the agent, one or more ingredients from the first group (oxidation Inhibfting Ingredients), one or more ingredients from the second group (lactonization inhibiting ingredients) and one or more fillers (also known as diluents), binders, disintegrants or lubricants. Additionally, conventional excipients may be added: for example preservatives, silica flow conditioners, antiadherents and stabiKzers. It wiU be appreciated that a paiticuieH-exdpient may act different roles in a pharmaceutical composition, e.g. asafHer, a binder and a disintegraN. Typically the agent will be present in a weight amount wtthin the range of 1 to 50%, preferably 3 to 30%. Typically the combined arrraunt of stabilizing substance selected fonn the above first group and the above second group wHI be up to 90%, preferably 10 to 70%. The above stat^zing substances can also have a function of a filer (diluents), binder, or disintegrant Typically one or more additional filters may be preseiti ^ amount up to 90% by vraight, preferably 30 to 70%. Suitable additional fillers include, for example, lactose, cellulose and its derivatives (e.g. microcrystailHie celiulose, powdered oeikitose), mocfified starches, polyols, inorganic salts, or any other fillers commonly used in the art. Typically one or more binders will be present in an amount up to 90% by weight pr^erably 20 to 70%. Suitable binders include, for example, polyv&iylpynrolidone, gum acacia, girni tragacanth, guar gum, pectin, microcrystalline ceflulose, methylcellulose, carboxymethylceaulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, gelatin and sodium alginate. Suitable disintegrants include, for example, crosscannellose sodium, crospovidone, sodium starch glycollate, hydroxypropyl methylcelkitose and hydroxypropyl oeHulose. Suitable lubricants inchJde, for example, magnesium stearate, stearic acid, palmitic acid, calckim stearate. Uric, camauba wax. hytftogenated vegetable oHs, mineral oil, glyceryl behanate, polyethylene glycols and sodium stearyl fumarate. In a prefen^ embodiment a composition wilt contain from 4 to 11 % of agent; from 10 to 50%, preferably in sum around 40% of staUlizing substances selected from the first group consisting of com starch, sflidfied microctyst^ne cellulose, croscamiellose sodium, and hypromellose and second group consisting of com starch, mannitd, hydroxypropyl oeltaJlose and hypromellose. The stabilizing substances will be preferably silicified microcrystalline celtulose. com starch and sodium stech glycotate, prefen^ in weight rafio 10:1-2:0-2. The composition may aclcHtionally comprise from 20 to 80%, preferably around 40 to 60% of lactose flUer and up to 5% of lut>ricants, preferatiiy talc, gylceryl behanate and sodium stearyl fumarate. In a preferred embodiment the weight ratios of agent to silictfied microcrystaiiine ceMulose, com starch, lactose, talc, colloidal silicon dioxide, glyceryl behanate and sodium stearyl fumarate will be 10:10^: 2-20:30-70:1-10: &0.6:0-3:0-2. Most pfefertMy the above ratios will be 10:20-30:10-17:50-60:1-3:0-0.6:0-2:0-1. The phamiaceutical composition of the invention may be prepared using standard techniques and manufacturing processes generally known in the art, for example by dry blending the components. The components of the blend prior to blending, or the blend Itself, may be passed through a mesh screen. Conveniently a lubricant may also be added to the blend and bianding cor4inued until a homogeneous mixture is obtained. The mixture is then compressed into tablets. Alternatively, a wet granul^ion technique can be employed. Pharmaceutical compositions comprising (E)-7-[4-(4-auorophenyl}-6-isopropyl-2- (methyi(methylsulf6nyl)amino]pyrimidin-5-yi]-(3R, 5S)-3,5-dihydroxyhept-6-enoic add hemicak^m salt and ingrecKents finm aforesaid first group and second group ate prepared by dry blencHng the agent and all excipients (inactive bigrsdients) except hdmcant in a double cone mixer. Next a lubricant, in one embodiment glyceryl behenate, and in another embodiment sodium stearyl fumarate is added to the mixture and blended for a short period of time, such as needed to substantiany homogeniu the mixture, e.g. up to 5 miutes. The mixture is then compressed into tablets and film coated with a conventiorid coatbig composition coning of film forming polymer sudi as hypromeOose or hydroxypropyl ceflulose, film softener such as polyethylene glycol, pigments, talc. A typical composition in accordance with our invention wiH comprise (wt.) agent (hemicaicium salt) 5-20% lactose 40-60% siHcifled microcrystalHne cellulose 20 - 30% cornstarch 1-25% and further a gOdant (talc and/or o>lloidal silidum dioxide) 0,5-5% 1 a hilMlcant (sodium stearyl fumarate and/or glyceryl behanate) 0,1-3% and opHonally further sodium starch gylcolate 0-5% based film coating formulation. Coating ingredient combinations are readily avaHatrie. In an embodiment of the invention coatings contaming pigments or colorants reduce the rate of fomuition of photo degradation products of the agent Experimental part The bulk agent is subjected to stress conditions, such as elevated temperature (40C and above), elevated humldi^ (75 % or higher relative iHimicfity, dish comfitlons), oi^gen atmosphere or solutions vntti different pH. An HPLC analysis, capable of resolving the s^ent and its degradation products is then employed, to quantify the amount (given as a mass percentage relative to the agent) of degriad^ion products in the stressed samples. Good chromatographic resolution can be achieved on a C18 reversed phase column udth acidic phosphate buffer and an increasing gradient of acetonitrile and tetrahydrofuran. Degraditfon products are quantified using UV detection at 242 nm. The reporting Hmit of the (tegradatlon products has been set at 0,05 %. The % reported for HPLC analysis are in general area %. When bulk (E)-7-{4-(4^fkiorophenyl)-6-isopropyl-2-{methyt(methylsulfonyl)amino]^^ ylK3R, 5S)-3,S-dliydroxyhept-6-enok: acM hemteahdum scdt is exposed to stress conditnns the compound cheinkally degrades, showHig its instability as denwnstrated by foUomn findings: stress condition amount of lactone (%) amount of oxkiatton pro(fcjct(%) aqueous solutkm of the agerrt, buffered to pH = 5 at room temperature (24 hours) 2,30 the agent under oxygen at 60C for 14 days 0,17 0,71 The results of exposing to the same stress condition a mixture of agent and commonly used exdpients such as lactose, crosslinked cartwxymethyteelkilose sodium or crosslinked PVP are substantially similar to resists of the bulk agent subjected to the stress conditk>ns. However exposing mixtiras of agent and ttie ingredierts from ttw aforementioned first and second group, the amounts of lactone fbnned are sutistantiaHy lower then as wtth the ^jent alone, showing their stabifizing property. When a t>inary mii(ture (w 1:1) of the agent and any of the ingredients fimn the first group is stored under oxygen at 60C for 14 days, no oxidation product is fbnned compared to 0,71% fomtedon exposing the ixjik agent Two working examples of stable formulations are presented, foUowed by two reference examples (first with commonly used tableUng exdpients and second including an allcalizing excipient). WORKING EXAMPt^l The following pharmaceutical composition is a novel composition, prepared by the process as described above, using ingredients from both two groups of stabilizing ingrecfients. Ingredient Function w% The Agent (cateium salt) acHve .9,2 Lactose fHler 55,9 Silidfied Microcrystalliro Celtuk>se filler, binder, disintegrant, active stabilizer 24,4 Cornstarch filter, binder, disintegrant. active stabilizer 3,6 Sodium Starch Glycolate disMegrant, active stabilizer 2.4 Tate gridant 2,7 Glyceryl Behanate lubiteant 1.8 The pH of the fonnulatton is 6,2. The amount of lactone is only 0.50% after 14 days at 40'C and 75% relative humidity (open dish). The o}ddation product is nci formed. Ttie amount of lactone does not increase above 0.25% after 6 months at 40C in bnpemieable package. The amount of the oxkiatton product after 6 months at 40C in impermeable package is only 0,05% or below. Comparatively the amounts of lactone and oxidatton product in a phamraceutfcal composition of the agent such as the one currently marketed (Figure) are 0,51 % and 0,38 %, respectively. The tablet film coating (2.5% coating on weight of coated tabM) consisting of hyimmetlose. hydroxypropyl cellulose, polyethylene glycol, pigments and talc had no sut>stantial effect on fonnation of lactone or oxidation product.

Full Text

Pharmaceutical compotiUon
Present invention from the field of phamiaceutics relates to pharmaceuficsd composition contaMrtng(EH44-{4-fluorophenyl)-6-l8opropyl-2Hm^^
ylK3R, 5S)-3.5-dihydrDxyhep(-6 Byyicflrpymi jnytn^p
The agent is a 3-hydioxy-3-methytgtutaryi (HMG) CoA reductase InhOjitor loiown from EP 521471 and formulated into a phamnaceutical composition can be used for (manutacturnig the medicament for) treating hyperchoiesteroiemia, hyperlipidproteinemia and atherosclerosis. A mqjor issue assotiated with the bulk agent or fonnulated into a composition is that It is particularly sensHive to degradation. The major degradation products fbnned (as known from US 6548513) are the lactone (N-{4-(4^luoro-phenyl)-5H2-(4- hydroxy-«-oxo-tetrtahydropyran-2-yl)-vtnyi)-e-i8opropyHifyrimk^ methanesulfonamide) and the oxklatton product (7-[4-(4-fluoropheny()-6-isopropyl-2- [me0)yKtnethy(sulfonyi)aminoK>yrimidhvS-yl}-3-hydrox^5-oxo-hept-e«r^ add). Also, when exposed to ligM, the agent undergoes degradatkm to two diastereomeric cydk: products, described in US 2005/0187234 A1. The mentioned degradations of the agent under conditions of humkfity, acidity, oxygen and light is a challenge for tfie manufacture of a pharmaoeutk»l fonnulatkm, stable enough for ordinary storage condttions.
This stabiSzation of the agent or chemtoalty simflar compounds, espedaiiy those belonging to HM6-C0A reductase inhibitorB, could be achieved by controlling pH in a formulaSon (by addition of components such as a carboruite or bicarbonate) and by adding to compo^on a stabilizing inorganic salt, particularly tribask: Mbasks caldum phosphate. AnUoxklants, such as butylated hydroxytoluene may also be used to hinder oxkiatkm of the ageint. Ararther option is to stabilize a pharmaceutteal compositkxi using an amino sugar. Pharmaceutk^l composition of the agent currently marketed under name Creator contains 5,10,20, or 40 mg of the agent, tnlMUlc cateium phosphate as the stabilizing inoiganic salt and the foltowing inactive ingredients: mkxocrystalline cellulose, lactose monohydrate, crospovklone,
magnesium stearate, hypromellose. triacetin, titanium doxide. yellow fenric oxide, and red ferric oxide.
Pescriatton of the figure
Figure represents the comparison of the amount of the main degradation product (lactone form of the agent, as measured by IHPLC), wMch is fomned if ttie compositions corresponding to currently mar1(eted formulation and the composition in accordance with our imwntion are subjected to accelerated stability program (as proposed by ICH guidelines: 40*C and 75 % relative humidity, stored in the primary padcage). The y axis represents the % of the fornied degradation product (lactone), and x axis the time in months.
Disclosure of fl>e inventton
in an aspect the invention provides a phannaceutical ccunposition comprising (E)-7-[4-(4- fluorophenyl)-6-isopropyi-2-{methyl(methylsulfony|)amino}(^midin-S-yt^ 5S)-3,5- dihydroxyhept-6-enoic add or a phannaceutically-acceptable salt thereof characterized in that it contains less than 0.05% as measured by HPLC of the 7-['K4-«fuorophenyi)-6- iso(MX>pyl-2•4^)ethyl(nmthylsuifbnyOaminotByrimidilv^yl^341yd^}xy-5-oxo-h^ add.
In additional aspect the invention is a phannaceutical conrqiosition comprising the agent, characterized in that it contains less than 0,5% as measured by HPLC of the hH4-(4-Fluoto- phenyl)-5-[2--vinylI^i80propyH?yrimlefin-2-yl}-h^ methyl^ethanesulfonamide and also less than 0,05% as measwed by HPLC of the 7-[4-(4- fluorophenyl>-64sopropyl-2-{tr)ettiyKnriethylsulfonyi)amlno]pyrimkiln-5-y^ hept-6-enoic acid.
In a specific en^x>diment the invention is a pharmaceutical composition comprising the a^nt, characterize in that at least one of the ingredients is chosen fix>m the first group consisting of: com starch, sUidfied microcrystatNne ceHuJose, croscarmellose sodum, and hypromellose and/or from the second group consisting of com starch, mannitol, hydroxypropyl cellulose artd hypronwilose.
Specific^ in an embodbnent the phanrwceutical coinposition according win coriqxise sHidfied microcrystaltine ceitulose, agent, corn starch in weight ratio 10:3-4:1-2. More specifically it will additionally comprise up to 5% of at least one lubricant which may be selected from group consisting of tsrtc and glyceryt behanate
Yet more specttically the pharmaceutic^ composWon wUI comprise the agerrt, ^lidfied microaystaMne cellidose, com starch, lactose, talc, colloidal silicon cfioxide, glyceryl behariate arKl sodium stearyl fimarate h viwigM ratio 10:20-30:10-17:50^: 1-3: 0-2:0-1.
The composition may film coated wherein said coating comprises HPMC, iHPC, polyethylene glycol and talc.
In anc^her aspect the invention represents a process for preparing a phamtaceufical composition comprising the agent with steps: a) mixing and screening of the agent and exdpients, comprising silidfied miorocrystalllne celluiose and com starch to obtain homogeneous mixture; and b) (optional) granulation of powder mixture; and c) mixing of powder mixture (or granules) with liixicarA; and d) compressing of powder mixture (or granules) Into tablets: and e) (optional) coating of tabjets prepared in preceding steps; in specific aspect wherein the weight ratio of agent: silidfied microcrystalline ceHulose: com starch is 10:10 to 40: 2 to 20.
Additionally the invention is a process for preparing a phamtaoeuticd composition comprising the hemicalcwm salt of (E)-7-{4-(4-fluorophenyl)-6-isopropyl-2- lmethyl(methylsulf6nyl)amino]pyrhnidin-5-ylH3R. 5S)-3.5-dlhydroxyhept-6-enoic add characterized in that the process comprises following steps: a) dry blending said hemicaldum salt and exdpienis mixture, wherein this mixture comprises lactose, silidfied microcrystalline cellulose and com starch; b) (optionally) mixing therein additional exdpients; c) nftixing ttierein a lubrk»nt selected from sodium steari funuurate or gl^^ specifically glyceryl behanate; d) compressing obtained powder mixture into tablets; e) (optionally) coating of tablets prepared in preceding steps, specffically in amounts strid hemicaldum salt: 5-20% wt; lactose: 40 - 60% wt; silidfied microcrystalline cellulose: 20- 30% wt; and com starch: 1 to 25 % wt relative to the weight of the composition and (optionally) film coating.
Invention is embocfied in the use of the phannaceuticai composition as described above for treating hypercholesterolemia, hypertipidproteinemia and atherosclerosis and also in the use of the agent together wim sttidfied microcrystalline cellulose and com starch for manufcicturing of a medicament for treating hypercholesterolemia. hyperHpidproteinemia and atherosclerosis.
In another aspect the inventions is the use of siHdfied microcrystalline celhtlose and com starch for stat>itizafion of a phannaceutical composition comprising hemicatcium salt of (E)-?- [4-(4^uorophenyl)^isoprapyl-2-(methyKmethytsulfbnyl)am-|^^^ dihy(iroxyhept-6-enoic acid, specfficatiy wherein said siticffied microcrysta^ ceUuiose and com starch are together present in an anwunt 10 - 70% relative to the vyeight of pharmaceuticat composition.
The invention is embodied in a novel phamiaceutical composition having the following advantages: the composition inhibits in long temn Thus the lack of alkaline ingredients on one hand minimizes the potential of impaired in-vivo absorption of the ^lent due to the changes of thegastrointestinai pH and on the other sMe such composition is advantageous for patient because an alkaine compositkNi wouki have adverse effects on gastric mucosa. The pl-i of the aqueous solution or dispersion of the composition in accordance with our invention will be substantia neutral, preferably between 6 and 8, as detenmined if a tablet containing 40 mg of agent is dispersed in 40 ml of water and measured by glass electrode pH meter. CompositkHis can be manufoctured by e8tat>lished technokj^cal procedures, prefers^ direct compresston or wet granulatkxi fottowed by tabletting and film coating for manufacturing of finished dosage fomi (e.g. tablet) and at the same time demonstrates suitable bk>pharmaoeutk:al properties such as comparable cNssolution and/or bioequivalence to Creator.
The present invention combines in a pharmaceutical composition the agent with the ingredients that stabilize the agent. Ingredients are selected according to two stabilizing properties. In the first group are the ingredients which were found to inhibit oxidatton of the agent: com starch, siik:ified microcrystalline ceRuk>se, croscamnellose sodium, and hypromellose. In the second group are the ingredients which were found to inhibit the formation of the lactone form of the agent: com starch, mannitol, hydroxypropyi ceOiriose and hypromenose. The fomnation of the degradation products of the agent under the influence of light can also be addittonally hindered using phantiaceutteally acceptable pigments or colorants, for instance in a tablet coating.
Preferably selection of ingredient» from tx^ groups and a protecSon from light resiAs in a pharmaceutical composition wherein the agent is stabiltzed. In such formulation, the agent stays stable witti respect to oxidation, formation of the lactone and fonnation of degradation products, preferably over a petkxl of years, more preferably moi4hs.
In an emboiftnent the invention comprises a phamtaceutical composition comprising the agent, one or more ingredients from the first group (oxidation Inhibfting Ingredients), one or more ingredients from the second group (lactonization inhibiting ingredients) and one or more fillers (also known as diluents), binders, disintegrants or lubricants. Additionally, conventional excipients may be added: for example preservatives, silica flow conditioners, antiadherents and stabiKzers. It wiU be appreciated that a paiticuieH-exdpient may act different roles in a pharmaceutical composition, e.g. asafHer, a binder and a disintegraN.
Typically the agent will be present in a weight amount wtthin the range of 1 to 50%, preferably 3 to 30%. Typically the combined arrraunt of stabilizing substance selected fonn the above first group and the above second group wHI be up to 90%, preferably 10 to 70%. The above stat^zing substances can also have a function of a filer (diluents), binder, or disintegrant Typically one or more additional filters may be preseiti ^ amount up to 90% by vraight, preferably 30 to 70%. Suitable additional fillers include, for example, lactose, cellulose and its derivatives (e.g. microcrystailHie celiulose, powdered oeikitose), mocfified starches, polyols, inorganic salts, or any other fillers commonly used in the art. Typically one or more binders will be present in an amount up to 90% by weight pr^erably 20 to 70%. Suitable binders include, for example, polyv&iylpynrolidone, gum acacia, girni tragacanth, guar gum, pectin, microcrystalline ceflulose, methylcellulose, carboxymethylceaulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, gelatin and sodium alginate. Suitable disintegrants include, for example, crosscannellose sodium, crospovidone, sodium starch glycollate, hydroxypropyl methylcelkitose and hydroxypropyl oeHulose. Suitable lubricants inchJde, for example, magnesium stearate, stearic acid, palmitic acid, calckim stearate. Uric, camauba wax. hytftogenated vegetable oHs, mineral oil, glyceryl behanate, polyethylene glycols and sodium stearyl fumarate.
In a prefen^ embodiment a composition wilt contain from 4 to 11 % of agent; from 10 to 50%, preferably in sum around 40% of staUlizing substances selected from the first group consisting of com starch, sflidfied microctyst^ne cellulose, croscamiellose sodium, and hypromellose and second group consisting of com starch, mannitd, hydroxypropyl oeltaJlose and hypromellose. The stabilizing substances will be preferably silicified microcrystalline celtulose. com starch and sodium stech glycotate, prefen^ in weight rafio 10:1-2:0-2. The composition may aclcHtionally comprise from 20 to 80%, preferably around 40 to 60% of lactose flUer and up to 5% of lut>ricants, preferatiiy talc, gylceryl behanate and sodium stearyl fumarate.
In a preferred embodiment the weight ratios of agent to silictfied microcrystaiiine ceMulose, com starch, lactose, talc, colloidal silicon dioxide, glyceryl behanate and sodium stearyl fumarate will be 10:10^: 2-20:30-70:1-10: &0.6:0-3:0-2. Most pfefertMy the above ratios will be 10:20-30:10-17:50-60:1-3:0-0.6:0-2:0-1.
The phamiaceutical composition of the invention may be prepared using standard techniques and manufacturing processes generally known in the art, for example by dry blending the components. The components of the blend prior to blending, or the blend Itself, may be passed through a mesh screen. Conveniently a lubricant may also be added to the blend and bianding cor4inued until a homogeneous mixture is obtained. The mixture is then compressed into tablets. Alternatively, a wet granul^ion technique can be employed.
Pharmaceutical compositions comprising (E)-7-[4-(4-auorophenyl}-6-isopropyl-2- (methyi(methylsulf6nyl)amino]pyrimidin-5-yi]-(3R, 5S)-3,5-dihydroxyhept-6-enoic add hemicak^m salt and ingrecKents finm aforesaid first group and second group ate prepared by dry blencHng the agent and all excipients (inactive bigrsdients) except hdmcant in a double cone mixer. Next a lubricant, in one embodiment glyceryl behenate, and in another embodiment sodium stearyl fumarate is added to the mixture and blended for a short period of time, such as needed to substantiany homogeniu the mixture, e.g. up to 5 miutes. The mixture is then compressed into tablets and film coated with a conventiorid coatbig composition coning of film forming polymer sudi as hypromeOose or hydroxypropyl ceflulose, film softener such as polyethylene glycol, pigments, talc.
A typical composition in accordance with our invention wiH comprise (wt.)
agent (hemicaicium salt) 5-20%
lactose 40-60%
siHcifled microcrystalHne cellulose 20 - 30%
cornstarch 1-25%
and further
a gOdant (talc and/or o>lloidal silidum dioxide) 0,5-5%

1 a hilMlcant (sodium stearyl fumarate and/or glyceryl behanate) 0,1-3%
and opHonally further
sodium starch gylcolate 0-5%

based film coating formulation. Coating ingredient combinations are readily avaHatrie. In an embodiment of the invention coatings contaming pigments or colorants reduce the rate of fomuition of photo degradation products of the agent
Experimental part
The bulk agent is subjected to stress conditions, such as elevated temperature (40*C and above), elevated humldi^ (75 % or higher relative iHimicfity, dish comfitlons), oi^gen atmosphere or solutions vntti different pH. An HPLC analysis, capable of resolving the s^ent and its degradation products is then employed, to quantify the amount (given as a mass percentage relative to the agent) of degriad^ion products in the stressed samples. Good chromatographic resolution can be achieved on a C18 reversed phase column udth acidic phosphate buffer and an increasing gradient of acetonitrile and tetrahydrofuran. Degraditfon products are quantified using UV detection at 242 nm. The reporting Hmit of the (tegradatlon products has been set at 0,05 %. The % reported for HPLC analysis are in general area %.
When bulk (E)-7-{4-(4^fkiorophenyl)-6-isopropyl-2-{methyt(methylsulfonyl)amino]^^ ylK3R, 5S)-3,S-dliydroxyhept-6-enok: acM hemteahdum scdt is exposed to stress conditnns the compound cheinkally degrades, showHig its instability as denwnstrated by foUomn findings:
stress condition amount of lactone (%) amount of oxkiatton pro(fcjct(%)
aqueous solutkm of the agerrt, buffered to pH = 5 at room temperature (24 hours) 2,30 the agent under oxygen at 60*C for 14 days 0,17 0,71

The results of exposing to the same stress condition a mixture of agent and commonly used exdpients such as lactose, crosslinked cartwxymethyteelkilose sodium or crosslinked PVP are substantially similar to resists of the bulk agent subjected to the stress conditk>ns.
However exposing mixtiras of agent and ttie ingredierts from ttw aforementioned first and second group, the amounts of lactone fbnned are sutistantiaHy lower then as wtth the ^jent alone, showing their stabifizing property.
When a t>inary mii(ture (w 1:1) of the agent and any of the ingredients fimn the first group is stored under oxygen at 60*C for 14 days, no oxidation product is fbnned compared to 0,71% fomtedon exposing the ixjik agent
Two working examples of stable formulations are presented, foUowed by two reference examples (first with commonly used tableUng exdpients and second including an allcalizing excipient).
WORKING EXAMPt^l
The following pharmaceutical composition is a novel composition, prepared by the process as described above, using ingredients from both two groups of stabilizing ingrecfients.
Ingredient Function w%
The Agent (cateium salt) acHve .9,2
Lactose fHler 55,9
Silidfied Microcrystalliro Celtuk>se filler, binder, disintegrant, active stabilizer 24,4
Cornstarch filter, binder, disintegrant. active stabilizer 3,6
Sodium Starch Glycolate disMegrant, active stabilizer 2.4
Tate gridant 2,7
Glyceryl Behanate lubiteant 1.8

The pH of the fonnulatton is 6,2. The amount of lactone is only 0.50% after 14 days at 40'C and 75% relative humidity (open dish). The o}ddation product is nci formed.
Ttie amount of lactone does not increase above 0.25% after 6 months at 40*C in bnpemieable package. The amount of the oxkiatton product after 6 months at 40*C in impermeable package is only 0,05% or below. Comparatively the amounts of lactone and oxidatton product in a phamraceutfcal composition of the agent such as the one currently marketed (Figure) are 0,51 % and 0,38 %, respectively.
The tablet film coating (2.5% coating on weight of coated tabM) consisting of hyimmetlose. hydroxypropyl cellulose, polyethylene glycol, pigments and talc had no sut>stantial effect on fonnation of lactone or oxidation product.

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Patent Number

279608

Indian Patent Application Number

3076/CHENP/2008

PG Journal Number

05/2017

Publication Date

03-Feb-2017

Grant Date

27-Jan-2017

Date of Filing

19-Jun-2008

Name of Patentee

LEK PHARMACEUTICALS D.D.,

Applicant Address

VEROVSKOVA 57, 1526 LJUBLJANA, SLOVENIA;

Inventors:

#	Inventor's Name	Inventor's Address
1	JAKLIC MIHA, TOMAZ,	BRINJE 15, 1262 DOL PRI LJUBLJANAI,
2	NAVERSNIK, KLEMEN,	DRENOV GRIC 140, 1360 VRHNIKA,

PCT International Classification Number

A61K31/505

PCT International Application Number

PCT/EP06/12180

PCT International Filing date

2006-12-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	P200500344	2005-12-20	Slovenia