CA2150372C - Stable oral ci-981 formulation and process of preparing same - Google Patents
Stable oral ci-981 formulation and process of preparing same Download PDFInfo
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- CA2150372C CA2150372C CA002150372A CA2150372A CA2150372C CA 2150372 C CA2150372 C CA 2150372C CA 002150372 A CA002150372 A CA 002150372A CA 2150372 A CA2150372 A CA 2150372A CA 2150372 C CA2150372 C CA 2150372C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
Abstract
An oral pharmaceutical composition is provided for treating hypercholesterolemia or hyperlipidemia containing an advantageous formulation for stabilizing the HMG-CoA coenzyme A inhibitor, CI-981 Hemi-Calcium, of formula (IA) with effective amounts of calcium carbonate. A method for preparing a CI-981 stabilizing composition is described.
Description
_ ~1503°~~
AND PROCESS OF PREPARING SAME
~ 5 FIELD OF THE INVENTION
The present invention relates to stable oral pharmaceutical formulations of acid-sensitive substituted pyran ring-opened acid forms of substituted pyrrolyl carboxamides useful in the treatment of hypercholesterolemia or hyperlipidemia. A method for the preparation of such formulations is also described.
BACKGROUND OF THE INVENTION
Hypercholesterolemia and hyperlipidemia, conditions of excessively high levels of blood cholesterol and lipids, are well recognized risk factors in the onset of atherosclerosis and coronary heart disease. The blood cholesterol pool is generally dependent on dietary uptake of cholesterol from the intestine and biosynthesis of cholesterol throughout the body, especially the liver. Cholesterol is an indispensable component of virtually all cell membrane systems, as well as a precursor of a variety of steroid hormones and bile acids.
It is well known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA
reductase), an important enzyme catalyzing the intracellular synthesis of cholesterol, will bring about reduced levels of blood cholesterol, especially in terms of the low density lipoprotein form of cholesterol. Therefore, HMG-CoA reductase enzyme inhibitors are considered potentially useful as hypocholesterolemic or hypolipidemic agents.
SUBSTITUTE SHEET
AND PROCESS OF PREPARING SAME
~ 5 FIELD OF THE INVENTION
The present invention relates to stable oral pharmaceutical formulations of acid-sensitive substituted pyran ring-opened acid forms of substituted pyrrolyl carboxamides useful in the treatment of hypercholesterolemia or hyperlipidemia. A method for the preparation of such formulations is also described.
BACKGROUND OF THE INVENTION
Hypercholesterolemia and hyperlipidemia, conditions of excessively high levels of blood cholesterol and lipids, are well recognized risk factors in the onset of atherosclerosis and coronary heart disease. The blood cholesterol pool is generally dependent on dietary uptake of cholesterol from the intestine and biosynthesis of cholesterol throughout the body, especially the liver. Cholesterol is an indispensable component of virtually all cell membrane systems, as well as a precursor of a variety of steroid hormones and bile acids.
It is well known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA
reductase), an important enzyme catalyzing the intracellular synthesis of cholesterol, will bring about reduced levels of blood cholesterol, especially in terms of the low density lipoprotein form of cholesterol. Therefore, HMG-CoA reductase enzyme inhibitors are considered potentially useful as hypocholesterolemic or hypolipidemic agents.
SUBSTITUTE SHEET
Certain trans-6-(2-(3 or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and corresponding pyran ring-opened hydroxy acids derived therefrom have been described in U.S. Patent 4,681,893 to Roth as potent inhibitors of HMG-CoA
reductase. The pyran ring-opened hydroxy acids which are intermediates in the synthesis of the lactone compounds can be used as free acids or as pharmaceutically acceptable metal or amine salts. In particular, these compounds can be represented by the Formula I below:
R~
N-X C-CH2 C-CH2COOM (I) 1 o R3 wherein:
X is : -CHZ-;
-CHZCHZ-;
-CHZCH2CHZ-; or -CHZCH ( CH3 ) ;
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
'i one of RZ and R3 is -CONRSR6 where RS and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of RZ and R3 is:
hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
RQ is: alkyl of from one to six carbon atoms;
cyclopropyl;
- 3a -cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation. M may be derived from a pharmaceutically acceptable metal salt or from a pharmaceutically acceptable amine salt.
Among the stereo-specific isomers one particular compound having HMG-CoA reductase inhibitory activity, CI-981 Hemi-Calcium'r", is currently under development for the treatment of moderate to severe familial or nonfamilial hypercholesterolemia (Type IIa). This most preferred compound characterized is the ring-opened form of (2R-trans)-5-(4-fluorophenyl)-2-(1 methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, namely the enantiomer [R-(R*,R*)]-2-(4-fluorophenyl-a,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenyl-amino)carbonyl)-1H-pyrrole-1-heptanoic acid hemicalcium salt. Its chemical structure may be represented by Formula IA:
F
OH OH
I2CH2CHCH2CHCH2C02H (IA) . 1/2 Ca The specific isomer (CI-981) has been described in Canadian Patent No. 2,021,546.
reductase. The pyran ring-opened hydroxy acids which are intermediates in the synthesis of the lactone compounds can be used as free acids or as pharmaceutically acceptable metal or amine salts. In particular, these compounds can be represented by the Formula I below:
R~
N-X C-CH2 C-CH2COOM (I) 1 o R3 wherein:
X is : -CHZ-;
-CHZCHZ-;
-CHZCH2CHZ-; or -CHZCH ( CH3 ) ;
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
'i one of RZ and R3 is -CONRSR6 where RS and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of RZ and R3 is:
hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
RQ is: alkyl of from one to six carbon atoms;
cyclopropyl;
- 3a -cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation. M may be derived from a pharmaceutically acceptable metal salt or from a pharmaceutically acceptable amine salt.
Among the stereo-specific isomers one particular compound having HMG-CoA reductase inhibitory activity, CI-981 Hemi-Calcium'r", is currently under development for the treatment of moderate to severe familial or nonfamilial hypercholesterolemia (Type IIa). This most preferred compound characterized is the ring-opened form of (2R-trans)-5-(4-fluorophenyl)-2-(1 methyl-ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, namely the enantiomer [R-(R*,R*)]-2-(4-fluorophenyl-a,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenyl-amino)carbonyl)-1H-pyrrole-1-heptanoic acid hemicalcium salt. Its chemical structure may be represented by Formula IA:
F
OH OH
I2CH2CHCH2CHCH2C02H (IA) . 1/2 Ca The specific isomer (CI-981) has been described in Canadian Patent No. 2,021,546.
However, these compounds are unstable in that they are susceptible to heat, moisture, low pH environment, and light. In an acidic environment, in particular, ' the hydroxy acids will degrade to lactone. In addition, the hydroxy acids will decompose rapidly when ' exposed to W or fluorescent light.
When packaged in the form of tablets, powders, granules, or within capsules, the compounds may be further destabilized by contact.with the molecular moieties of other components. Since pharmaceutical dosage components such as binders, diluents, antiadherents, surfactants, and the like may adversely interact with the active ingredient compounds a stabilizing means is required for effective pharmaceutical dosages.
Therefore, it is an object of the present invention to provide a stable solid peroral pharmaceutical formulation comprising substituted pyrrolyl substituted pyran ring-opened hydroxy acids for therapy of hypercholesterolemia or hyperlipidemia.
More particularly, it is the object of the present invention to provide a stable solid peroral pharmaceutical formulation comprising a HMG CoA
reductase inhibitor, such as the aforedescribed CI-981 Hemi-Calcium, as active ingredient.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a pharmaceutical formulation characterized by improved .
stability of a 7-substituted pyrrolyl-3,5-dihydroxy-heptanoic acid salt as active ingredient combined with at least one pharmaceutically acceptable stabilizing additive for peroral treatment of hypercholesterolemia or hyperlipidemia.
su~sTO-ru-rE sHE~-WO 94/16693 ~ PCT/US93112471 An aspect of the present invention is to provide a stable oral pharmaceutical formulation for the ~ treatment of hypercholesterolemia or hyperlipidemia comprising as active ingredient, a HMG-CoA reductase . 5 enzyme inhibitor according to Formula I, as defined above, which is stabilized by combination. with at least one pharmaceutically acceptable metal salt additive.
Another aspect of the present invention is to provide a stable oral pharmaceutical formulation for the treatment of hypercholesterolemia or hyperlipidemia comprising, as an active ingredient, a HMG-CoA
reductase inhibitor such as CI-981 Hemi-Calcium or its enantiomer [R(R*,R*))-2-(4-fluorophenyl-/3,8-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl)]-1H-pyrrole-1-heptanoic acid, hemicalcium salt, having the proposed isomeric structural Formula IA stabilized by a combination with at least one pharmaceutically acceptable alkaline earth metal salt such as calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate or aluminum magnesium hydroxide.
Further, a preferred embodiment of the present invention provides a stable peroral pharmaceutical formulation for the treatment of hypercholesterolemia or hyperlipidemia comprising the HMG-CoA reductase inhibitor, CI-981 Hemi-Calcium, having the proposed structure according to the above-described structural Formula IA combined with calcium carbonate as stabilizing additive.
Further, a preferred embodiment of the present invention provides a stable oral pharmaceutical formulation for the treatment of hypercholesterolemia or hyperlipidemia comprising the HMG-CoA reductase inhibitor, CI-981 Hemi-Calcium, as active ingredient in a composition comprising, in addition to the stabilizing additive calcium carbonate, at least one StJBSTiTUTE SHEET
When packaged in the form of tablets, powders, granules, or within capsules, the compounds may be further destabilized by contact.with the molecular moieties of other components. Since pharmaceutical dosage components such as binders, diluents, antiadherents, surfactants, and the like may adversely interact with the active ingredient compounds a stabilizing means is required for effective pharmaceutical dosages.
Therefore, it is an object of the present invention to provide a stable solid peroral pharmaceutical formulation comprising substituted pyrrolyl substituted pyran ring-opened hydroxy acids for therapy of hypercholesterolemia or hyperlipidemia.
More particularly, it is the object of the present invention to provide a stable solid peroral pharmaceutical formulation comprising a HMG CoA
reductase inhibitor, such as the aforedescribed CI-981 Hemi-Calcium, as active ingredient.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a pharmaceutical formulation characterized by improved .
stability of a 7-substituted pyrrolyl-3,5-dihydroxy-heptanoic acid salt as active ingredient combined with at least one pharmaceutically acceptable stabilizing additive for peroral treatment of hypercholesterolemia or hyperlipidemia.
su~sTO-ru-rE sHE~-WO 94/16693 ~ PCT/US93112471 An aspect of the present invention is to provide a stable oral pharmaceutical formulation for the ~ treatment of hypercholesterolemia or hyperlipidemia comprising as active ingredient, a HMG-CoA reductase . 5 enzyme inhibitor according to Formula I, as defined above, which is stabilized by combination. with at least one pharmaceutically acceptable metal salt additive.
Another aspect of the present invention is to provide a stable oral pharmaceutical formulation for the treatment of hypercholesterolemia or hyperlipidemia comprising, as an active ingredient, a HMG-CoA
reductase inhibitor such as CI-981 Hemi-Calcium or its enantiomer [R(R*,R*))-2-(4-fluorophenyl-/3,8-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl)]-1H-pyrrole-1-heptanoic acid, hemicalcium salt, having the proposed isomeric structural Formula IA stabilized by a combination with at least one pharmaceutically acceptable alkaline earth metal salt such as calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate or aluminum magnesium hydroxide.
Further, a preferred embodiment of the present invention provides a stable peroral pharmaceutical formulation for the treatment of hypercholesterolemia or hyperlipidemia comprising the HMG-CoA reductase inhibitor, CI-981 Hemi-Calcium, having the proposed structure according to the above-described structural Formula IA combined with calcium carbonate as stabilizing additive.
Further, a preferred embodiment of the present invention provides a stable oral pharmaceutical formulation for the treatment of hypercholesterolemia or hyperlipidemia comprising the HMG-CoA reductase inhibitor, CI-981 Hemi-Calcium, as active ingredient in a composition comprising, in addition to the stabilizing additive calcium carbonate, at least one StJBSTiTUTE SHEET
other ingredient such as a binder, diluent, disintegrant, surfactant, and, optionally, antioxidant.
More specifically, the present invention provides a stable solid oral pharmaceutical composition wherein 5 the active ingredient dosage is between about 1's and about 50% by weight of the composition.
The present invention also provides a stable solid oral pharmaceutical composition containing about 5% to about 75% of the stabilizer calcium carbonate by weight 10 of the composition.
Another preferred embodiment of the present invention is a stable solid oral phax~aceutical composition comprising in addition to the active and the stabilizing ingredients, cited above, by weight, 15 between about 5k and about 75~ microcrystalline cellulose; between about 1% and about 80% of hydrous lactose; between about 1% and about 15% of croscarmellose sodium; between about 0.5% and about 6%
hydroxypropyl cellulose; between about 0.1% and about 2 0 4k Of polyoxyethylene sorbitan; between about 0.25% and about 2% of magnesium stearate; and optionally between about 0.0%
and about 3% of sodium ascorbate or butylated hydroxyanisole of the total solid composition.
The present invention is also directed to a method 25 of preparing a stable solid composition of the active ingredient according to Formula I comprising a stabilizing additive, for peroral therapy of hypercholesterolemia or hyperlipidemia.
A preferred embodiment of the present invention 30 also provides a method for preparing the solid oral composition, including stabilizing the active ingredient, CI-981 Hemi-Calcium, according to Forarula IA with calcium carbonate and admixing a binder, a diluen" a disintegrant, a surfactant, and 35 optionally an antioxidant-- 6a -Another preferred embodiment of the present invention comprises a stable pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia wherein the active ingredient is CI-981 Hemi-Calcium of formula (IA) .
F
OH OH
N-CH2CH2CHCH2CHCH2C02H (IA) NHC~CHCH3 p ~ 1/2 Ca O CHs - 6b -In a further preferred embodiment, the present invention comprises a pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture:
(A) a compound as active ingredient of structural formula I
Rt N-X C-CH2 C-CH2COOM (I) wherein:
X is: -CHZ-;
-CH2CH2-;
-CHZCHZCHZ-; or -CHZCH ( CH3 ) ;
Rl is : 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms or alkanoylalkoxy of from two to eight carbon atoms;
- 6c -one of R2 and R3 is -CONRSR6 where RS and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or 1C~ carboalkoxy of from three to eight carbon atoms; and the other o f RZ and R3 i s hydrogen;
alkyl of from one to six carbon atoms;
15 cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or 20 phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon 25 atoms;
R4 is: alkyl of from one to six carbon atoms, cyclopropyl;
cyclobutyl;
cyclopentyl;
30 cyclohexyl; or - 6d -trifluoromethyl; and M is a pharmaceutically acceptable metal cation;
(B) at least one stabilizing pharmaceutically 5~ acceptable alkaline earth metal salt additive;
(C) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising between about 0.5~ and about 6~ by weight of the total solid composition;
(D) at least one diluent selected from the group consisting of microcrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1~ and about 80~ of the total solid composition;
(E) at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about 1~ and about 15$
of the total solid composition;
(F) at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1$ and about 4~ of the total solid composition;
(G) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25$ and about 2~ of the total solid composition; and (H) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium - 6e -ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3~ of the total solid composition.
Another preferred embodiment of the present invention comprises a peroral pharmaceutical composition for treating hypercholesterolemia comprising:
(A) an effective, cholesterol synthesis inhibitory amount of the enantiomer [R- (R*, R* ) ) -2- [4-fluorophenyl ) -~3-8-~~ihydroxy-5-(1-methylethyl)-3-phenyl-9-[(phenylamino)carbonyl) -1H-pyrrole-1-heptanoic acid, hemicalcium salt stabilized by calcium carbonate, - 6f -(B) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, '. polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising by weight between about 0.5$ and about 6$ of the composition;
(C) at least one diluent selected from the group consisting of micocrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1$ and about 80$ of the composition;
(D) at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about 1$ and about 15$
of the composition;
(E) at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1$ and about 4$ of the composition;
(F) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25$ and about 2$ of the composition; and (G) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3$ of the composition, - 6g -in a dosage of solid enantiomer ranging from about 0.1 to about 8.0 mg/kg body weight per day.
A further preferred embodiment of the invention comprises a pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture:
(A) about 1$ to about 50~ by weight of the composition of a compound as active ingredient of ;structural formula I
Ri wherein:
?; is : -CHZ-;
-CH2CHZ-;
-CHZCH2CH2-; or -CH2CH ( CH3 ) ;
k1 is: 1-naphthyl;
- 6h -2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
'> phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of RZ and R3 is -CONRSR6 where RS and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of RZ and R3 is hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or 6i phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
RQ is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation; and (B) about 5~ to about 75~ by weight of the composition of calcium carbonate to stabilize the composition.
A further embodiment of the invention comprises a pharmaceutical composition comprising the hemi-calcium salt of Formula IA:
F
OH OH
r r i2CHZCHCH2CHCH2C02H (IA) i1 s ~ 1/2 Ca and a metal salt. A further embodiment comprises the use of such composition in the treatment of hypercholesterolemia or hyperlipidemia.
DETAILED DESCRIPTION OF THE INVENTION
The pyran ring-opened hydroxy acid corresponding to certain trans-6-(2-(3 or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones can be useful inhibitors of HMG-CoA reductase and may be used in their free acid form. Hoth lactone and free acid forms can be prepared in accordance with the process described in US P,~.ent 4, 681, 893. The free acid can be prepared by hydrolysis of the lactone form or by treatment of the salt with cationic exchange resin (H+ resin) and evaporating the water portion. These free acids also react to form pharmaceutically acceptable metal or amine salts. The term "pharmaceutically acceptable metal salt" contemplates sodium, potassium, lithium, calcium, magnesium, aluminum, iron, or zinc salts. The term "pharmaceutically acceptable amine salt"
contemplates salts formed by reaction with ammonium hydroxide or organic amine salt or for example methylglucamine, choline, arginine, 1-deoxy-2-(methyl-amino)-D-glucitol, and the like.
Insofar as the hydroxy acid compounds according to Formula I or metal or amine salts thereof are HMG-CoA
reductase inhibitors they may be useful in the treatment of hypercholesterolemia or hyperlipidemia.
The compound of particular interest is the HMG-CoA
reductase enzyme inhibitor, CI-981 Hemi-Calcium, Formula (IA), which is presently under development as a drug for treatment of hypercholesterolemia or hyperlipidemia.
The preferred compounds according to the present invention, especially the compound CI-981 or [ R- ( R* , R* ) ] - 2 - ( 4 - f luorophenyl ) - (3 . 6 - dihydroxy -5-(1-methylethyl)-3-phenyl-4-((phenylamino)-carbonyl]-1H_-pyrrole-1-heptanoic acid hemicalcium salt, WO 94!16693 PCT/LJS93l12471 -8_ inhibit the biosynthesis of cholesterol a9 measured in the CSI screen assay disclosed in US Patent 4,681,893, More particularly, the level of HMG-CoR reductase enzyme-activity in standard laboratory rats is increased by feeding the rats a chow diet containing 5% cholestyramine for 4 days, after which the rats are sacrificed. The rat livers are dissected and homogenized, and the incorporation of cholesterol-14C-acetate into nonsaponifiable lipid by the rat liver homogenate is measured. The micromolar concentration of compound reuuired for 50% inhibition of sterol synthesis over a 1-hour period is measured, and denoted as an ICSO value. The activity data of representative examples of the compound CI-981 Hemi-Calcium, its enantiomer and the racemate of both compounds have been disclosed in the aforementioned Canadian Patent No . 2, 021, 54 6 .
Compound ICSn (mmol/L) [R- (R*R*) ] isomer 0.0044 (CI-981 Hemi-Calcium [S-(R*R*)J isomer 0.44 Racemate 0.045 The most preferred compound of the present invention, CI-981 (stnictural Formula IA), is the enantiomer [R-(R*R*)-2-(4-fluorophenyl)-/3,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino>-carbonyl)-1H-pyrrole-1-heptanoic acid, hemicalcium salt. This chiral form can be synthesized from known starting materials or from materials prepared according to methods analogous to known processes in accordance WO 94116693 PCTlUS93/12471 _g_ with the Scheme 2 of Canadian Patent No. 2,021,546, as follows:
21~ 03'~ ~
-z0_ F
Z
' ~~~~\\\M9 ph O ~ O''~ Ph ~: ~, THF-80--90°C
1 hr O
~ N H t ~Ph Z. AcOH
PhNH i ph O
(21 F F
ph OH O Ph h OH
i ~OH 1~1 eq NaOMe N p' ~ /~CO:Me Ph MeOH. -10°C
PhNHOC Ph 16 hrs phNHOC
(3) 73% (4) 75t F
_OBu' 8 eq OH O
ph 1. BiEt)j, NaHH~
i \
-3 -- 0° \ N COzBu' 2. HZOZ
2 0 5 hrs PhNHOC
F (5) 78%
a off ph OH OH 1. NaOH
~ co;su' - -Ph ' N 2. Tol. -i-f~0 fi. ~ \N 0 O
PhNHOC ~ ~ H
PhNHOC
(6) 83%
More specifically, the present invention provides a stable solid oral pharmaceutical composition wherein 5 the active ingredient dosage is between about 1's and about 50% by weight of the composition.
The present invention also provides a stable solid oral pharmaceutical composition containing about 5% to about 75% of the stabilizer calcium carbonate by weight 10 of the composition.
Another preferred embodiment of the present invention is a stable solid oral phax~aceutical composition comprising in addition to the active and the stabilizing ingredients, cited above, by weight, 15 between about 5k and about 75~ microcrystalline cellulose; between about 1% and about 80% of hydrous lactose; between about 1% and about 15% of croscarmellose sodium; between about 0.5% and about 6%
hydroxypropyl cellulose; between about 0.1% and about 2 0 4k Of polyoxyethylene sorbitan; between about 0.25% and about 2% of magnesium stearate; and optionally between about 0.0%
and about 3% of sodium ascorbate or butylated hydroxyanisole of the total solid composition.
The present invention is also directed to a method 25 of preparing a stable solid composition of the active ingredient according to Formula I comprising a stabilizing additive, for peroral therapy of hypercholesterolemia or hyperlipidemia.
A preferred embodiment of the present invention 30 also provides a method for preparing the solid oral composition, including stabilizing the active ingredient, CI-981 Hemi-Calcium, according to Forarula IA with calcium carbonate and admixing a binder, a diluen" a disintegrant, a surfactant, and 35 optionally an antioxidant-- 6a -Another preferred embodiment of the present invention comprises a stable pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia wherein the active ingredient is CI-981 Hemi-Calcium of formula (IA) .
F
OH OH
N-CH2CH2CHCH2CHCH2C02H (IA) NHC~CHCH3 p ~ 1/2 Ca O CHs - 6b -In a further preferred embodiment, the present invention comprises a pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture:
(A) a compound as active ingredient of structural formula I
Rt N-X C-CH2 C-CH2COOM (I) wherein:
X is: -CHZ-;
-CH2CH2-;
-CHZCHZCHZ-; or -CHZCH ( CH3 ) ;
Rl is : 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms or alkanoylalkoxy of from two to eight carbon atoms;
- 6c -one of R2 and R3 is -CONRSR6 where RS and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or 1C~ carboalkoxy of from three to eight carbon atoms; and the other o f RZ and R3 i s hydrogen;
alkyl of from one to six carbon atoms;
15 cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or 20 phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon 25 atoms;
R4 is: alkyl of from one to six carbon atoms, cyclopropyl;
cyclobutyl;
cyclopentyl;
30 cyclohexyl; or - 6d -trifluoromethyl; and M is a pharmaceutically acceptable metal cation;
(B) at least one stabilizing pharmaceutically 5~ acceptable alkaline earth metal salt additive;
(C) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising between about 0.5~ and about 6~ by weight of the total solid composition;
(D) at least one diluent selected from the group consisting of microcrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1~ and about 80~ of the total solid composition;
(E) at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about 1~ and about 15$
of the total solid composition;
(F) at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1$ and about 4~ of the total solid composition;
(G) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25$ and about 2~ of the total solid composition; and (H) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium - 6e -ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3~ of the total solid composition.
Another preferred embodiment of the present invention comprises a peroral pharmaceutical composition for treating hypercholesterolemia comprising:
(A) an effective, cholesterol synthesis inhibitory amount of the enantiomer [R- (R*, R* ) ) -2- [4-fluorophenyl ) -~3-8-~~ihydroxy-5-(1-methylethyl)-3-phenyl-9-[(phenylamino)carbonyl) -1H-pyrrole-1-heptanoic acid, hemicalcium salt stabilized by calcium carbonate, - 6f -(B) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, '. polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising by weight between about 0.5$ and about 6$ of the composition;
(C) at least one diluent selected from the group consisting of micocrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1$ and about 80$ of the composition;
(D) at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about 1$ and about 15$
of the composition;
(E) at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1$ and about 4$ of the composition;
(F) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25$ and about 2$ of the composition; and (G) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3$ of the composition, - 6g -in a dosage of solid enantiomer ranging from about 0.1 to about 8.0 mg/kg body weight per day.
A further preferred embodiment of the invention comprises a pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture:
(A) about 1$ to about 50~ by weight of the composition of a compound as active ingredient of ;structural formula I
Ri wherein:
?; is : -CHZ-;
-CH2CHZ-;
-CHZCH2CH2-; or -CH2CH ( CH3 ) ;
k1 is: 1-naphthyl;
- 6h -2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
'> phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of RZ and R3 is -CONRSR6 where RS and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of RZ and R3 is hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or 6i phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
RQ is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation; and (B) about 5~ to about 75~ by weight of the composition of calcium carbonate to stabilize the composition.
A further embodiment of the invention comprises a pharmaceutical composition comprising the hemi-calcium salt of Formula IA:
F
OH OH
r r i2CHZCHCH2CHCH2C02H (IA) i1 s ~ 1/2 Ca and a metal salt. A further embodiment comprises the use of such composition in the treatment of hypercholesterolemia or hyperlipidemia.
DETAILED DESCRIPTION OF THE INVENTION
The pyran ring-opened hydroxy acid corresponding to certain trans-6-(2-(3 or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones can be useful inhibitors of HMG-CoA reductase and may be used in their free acid form. Hoth lactone and free acid forms can be prepared in accordance with the process described in US P,~.ent 4, 681, 893. The free acid can be prepared by hydrolysis of the lactone form or by treatment of the salt with cationic exchange resin (H+ resin) and evaporating the water portion. These free acids also react to form pharmaceutically acceptable metal or amine salts. The term "pharmaceutically acceptable metal salt" contemplates sodium, potassium, lithium, calcium, magnesium, aluminum, iron, or zinc salts. The term "pharmaceutically acceptable amine salt"
contemplates salts formed by reaction with ammonium hydroxide or organic amine salt or for example methylglucamine, choline, arginine, 1-deoxy-2-(methyl-amino)-D-glucitol, and the like.
Insofar as the hydroxy acid compounds according to Formula I or metal or amine salts thereof are HMG-CoA
reductase inhibitors they may be useful in the treatment of hypercholesterolemia or hyperlipidemia.
The compound of particular interest is the HMG-CoA
reductase enzyme inhibitor, CI-981 Hemi-Calcium, Formula (IA), which is presently under development as a drug for treatment of hypercholesterolemia or hyperlipidemia.
The preferred compounds according to the present invention, especially the compound CI-981 or [ R- ( R* , R* ) ] - 2 - ( 4 - f luorophenyl ) - (3 . 6 - dihydroxy -5-(1-methylethyl)-3-phenyl-4-((phenylamino)-carbonyl]-1H_-pyrrole-1-heptanoic acid hemicalcium salt, WO 94!16693 PCT/LJS93l12471 -8_ inhibit the biosynthesis of cholesterol a9 measured in the CSI screen assay disclosed in US Patent 4,681,893, More particularly, the level of HMG-CoR reductase enzyme-activity in standard laboratory rats is increased by feeding the rats a chow diet containing 5% cholestyramine for 4 days, after which the rats are sacrificed. The rat livers are dissected and homogenized, and the incorporation of cholesterol-14C-acetate into nonsaponifiable lipid by the rat liver homogenate is measured. The micromolar concentration of compound reuuired for 50% inhibition of sterol synthesis over a 1-hour period is measured, and denoted as an ICSO value. The activity data of representative examples of the compound CI-981 Hemi-Calcium, its enantiomer and the racemate of both compounds have been disclosed in the aforementioned Canadian Patent No . 2, 021, 54 6 .
Compound ICSn (mmol/L) [R- (R*R*) ] isomer 0.0044 (CI-981 Hemi-Calcium [S-(R*R*)J isomer 0.44 Racemate 0.045 The most preferred compound of the present invention, CI-981 (stnictural Formula IA), is the enantiomer [R-(R*R*)-2-(4-fluorophenyl)-/3,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino>-carbonyl)-1H-pyrrole-1-heptanoic acid, hemicalcium salt. This chiral form can be synthesized from known starting materials or from materials prepared according to methods analogous to known processes in accordance WO 94116693 PCTlUS93/12471 _g_ with the Scheme 2 of Canadian Patent No. 2,021,546, as follows:
21~ 03'~ ~
-z0_ F
Z
' ~~~~\\\M9 ph O ~ O''~ Ph ~: ~, THF-80--90°C
1 hr O
~ N H t ~Ph Z. AcOH
PhNH i ph O
(21 F F
ph OH O Ph h OH
i ~OH 1~1 eq NaOMe N p' ~ /~CO:Me Ph MeOH. -10°C
PhNHOC Ph 16 hrs phNHOC
(3) 73% (4) 75t F
_OBu' 8 eq OH O
ph 1. BiEt)j, NaHH~
i \
-3 -- 0° \ N COzBu' 2. HZOZ
2 0 5 hrs PhNHOC
F (5) 78%
a off ph OH OH 1. NaOH
~ co;su' - -Ph ' N 2. Tol. -i-f~0 fi. ~ \N 0 O
PhNHOC ~ ~ H
PhNHOC
(6) 83%
(7) 57t [a)19 a + 18.07 (CHC1J) D
SUBSTITUTE SHEET
WO 94/16693 PCTlUS93/12471 In addition, the pref erred chirai form can be prepared from a racemic mixture prepared by the methods described in US Patent 4,681,893, especially Examples 1 and 2.
Reference of the racemate and separation of the preferred isomer can be performed in accordance with the methodology for chiral synthesis disclosed in Canadian Patent No. 2,021,546, as illustrated in the Examples 1-5.
The present invention provides a pharmaceutical composition containing hypocholesterolemic or hypolipidemic compounds according to preferably Formula (I) or more preferably Formula (IA). The preferred effective stereoisomeric compounds of the present invention are administered to the patient at adult dosage levels of from approximately 10 to 500 mg per day, or from about 0.1 to about 8.0 mg/kg body weight per day. More-pref erred daily dosages range from about 0.5 to about 1.0 mg/kg. The unit dosage treatment embodiment provided by the present invention for oral or parenteral aaministration may be varied or adjusted from 10 to 500 mg, preferably from 20 to 100 mg depending on potency or application.
Since the hydroxy acid compounds according to Formula I are susceptible to degradation to the lactone form in an acidic environment, it has been necessary to stabilize their structural integrity in pharmaceutical formulations. Moreover, the compounds have been determined to decompose rapidly under the impact of UV
and fluorescent Light.
For the purpose of stable oral preparations of the present invention, pharmaceutically acceptable inert 35~ carriers can be either solid or liquid. The most preferred embodiment of the present invention provides _ .. . __. . .~ ~.._-- -..___._. _ _._-..~.,~,..~,...__-~..~ .____ ._. __~...~--4.~.~..,_~._ ~...~~_~._ . . ._ .
WO 94/16693 ~ ~ ~ PCT/US93/12471 ~1~
for an oral solid formulation which may include powders, tablets, dispersible granules, capsules, and cachets. A solid carrier may be one or more substances which can also act as diluents, flavoring agents, binders, or tablet disintegrating agents. , Encapsulating materials are"also within the scope of the present invention. , In powdered preparations, the carrier is preferably a solid which is finely divided in a homogeneous mixture with the finely divided active ingredient. In tablets, the active component is blended with the carrier material with binding properties that facilitate compacting, shaping and sizing as desirable. Oral powders or tablets according to the present invention are generally designed to contain between about 1~ to about 50% by weight of the active ingredient.
As is usual in the art, pharmaceutical preparations are in suitable unit dosage form, which can be a capsule, cachet or tablet, or any number thereof, as appropriate. Dosages are held to be within the skill of the art and may vary with the particular requirements and bioavailability of the active ingredient.
In practice, use of the salt form amounts to use of the acid or lactone form. Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, 1-deoxy-2-(methylamino) D-glucitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, ' ammonium hydroxide or organic amines such as N-methylglucamine, choline, arginine, and the like. ' Preferably, the lithium, calcium, magnesium, aluminum and ferrous or ferric salts are prepared from the SUBSTITUTE SHEET
WO 94/16693 , PCTIUS93/12471 sodium or potassium salt by adding the appropriate reagent to a solution of the sodium or potassium salt, i.e., addition of calcium chloride to a solution of the sodium or potassium salt of the compound of the Formula I will give the calcium salt thereof.
The active hydroxy acid metal salt ingredient of the present invention k~k~.ich may be an isomeric compound with a structure according to Formula (I) or, preferably, Formula (IA) can be prepared from sodium salt or lactone as illustrated in Example A, below.
EXAMPLE A
Calcium Salt from Sodium Salt and/or Lactone One mole lactone (540.6 g) is dissolved in 5 L of MeOH; after dissolution 1 L H20 is added. While stirring, one equivalent NaOH is added and the reaction is followed by HPLC until 2~C or less lactone and methyl ester of the diolacid remains (one cannot use an excess of NaOH, because Ca(OH)2 will form on addition of CaCl2). Usually NaOH is charged as caustic (51.3 mL, 0.98_ eq. ) or as pellets (39.1 g, 0.98 eq. ) .
SUBSTITUTE SHEET
WO 94116693 PCTlUS93l12471 The above procedure is shown as follows:
N ~~'' off \ /
Ph 'C
~N .98 eq. NaOH
H~ \
Ph MeOH, Hi0 5 . 1 m.w. = 540.6 g _ . i ~H
EtOAc, .i:exane HZO N 0 Na c Wash \ /
Ph ~ C' O N
Ph The abbreviation "Ph~ is for the term phenyl group. Upon completion of hydrolysis, 10 L H20 are added, then the product is washed at least two times with a 1:1 mixture of EtOAc/Hexane. Each wash should contain 10 L each of EtOAc/Hexane. If sodium salt is pure, 15 L of MeOH are added. If it is impure and/or contains color, 100 g of G-60* charcoal are added, the mixture is stirred far 2 hours, filtered over supercel, and washed with 15 L MeOH. An assay analysis (weight per volume, %) is performed on the reaction mixture by HPLC, to determine the exact amount of salt in solution.
Subsequently, about 1/2 equivalent or a slight excess of CaC122H20 (73.5 g) is dissolved in 20 L H20.
Both the reaction mixture and the CaCl2 solution are heated to 60°C. CaCl2 solution is added slowly, with 35~ high agitation. After complete addition, the reaction mixture is cooled slowly to 15°C and filtered. The * Trademark ~~.~037~
filter cake is washed with 5 L H20 and dried at 50°C in a vacuum oven.
The product can be recrystallized by dissolving in 4 L of EtOAc (50°C) filtering over supercel, washing with 1 L EtOAc, then charging 3 L of hexane to the 50°C
reaction solution.
The above procedure is shown as follows:
OH OH O
OH OH O
y ~0 Na F ~ \ / 1/2 eq.CaCl2 ~ 2H;0 F ~ N O Ca"
Ph ~C' H 0 O Ph ,C' iN O
H \Ph H/N\ph m.w. - 580.6 g m.w. - 1155.4 q The present invention provides a preferred composition for stabilizing the active ingredient such as, e.g., CI-981 Hemi-Calcium, using basic inorganic pharmaceutically acceptable salts of calcium such as calcium carbonate and calcium hydroxide or basic inorganic pharmaceutically acceptable salts of magnesium such as magnesium carbonate, magnesium hydroxide, magnesium -silicate, magnesium aluminate, and aluminum magnesium hydroxide, or basic inorganic pharmaceutically acceptable salts of lithium such as lithium hydroxide and similar lithium compounds or other similarly suitable alkaline earth metals. The basic inorganic salts of calcium, lithium or magnesium can be utilized in a weight ratio ranging between about 0.1 to 1 and about 50 to 1 of salt compound to active ingredient.
Stabilized solid' oral pharmaceutical formulations of the present invention are designed to protect the antihypercholesterolemia or anti-hyperlipidemia drug, SUBSTITUTE SHEET
e.g., CI-981 Hemi-Calcium, of Formula IA (as defined above), from any degrading or_processing environment, as well as preserve it from photochemical decomposition during storage. Specifically, the most preferred 5 active chemical ingredient is the compound CI-981 Hemi-Calcium of Foranila (IA). The solid formulation according to the present invention also includes, in addition to a stabilizing metal or alkaline earth metal salt, several additives which are known as suitable 10 agents in the art comprising combinations and concentrations as further described below.
The present invention without limiting further provides for diluent additives such as microcrystalline cellulose, hydrous lactose, corn starch, sucrose, 15 silicic anhydride, or polysaccharides (as are known as suitable in the art); binders such as methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, or starch; disintegrants such as 20 carboxymethylcellulose calcium, croscarmellose sodium, or starch; and surfactants such as Tween* 80(polyoxyethylene sorbitan) or polyoxyethylene-polyoxypropylene copolymer.
Antioxidants can also be incorporated with the foxznulations in order to prevent any oxidation of the 25 drug compound. For example, antioxidants that could be used are butylated hydroxanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid and ascorbic acid.
The most preferred embodiment of the present 30 invention is directed to a solid oral cosaposition including CI-981 Hemi-Calcium as active ingredient, calcium carbonate as the stabilizing component, and other additives.
The basic exciDient, calcium carbonate, has been 35 found to provide effective control of the microenvironment of the coaroosition. Further to the * trade-mark present invention, microcrystalline cellulose, and hydrous lactose are applied as suitable diluents. In addition, the inventive composition contains a suitable amount of croscazmellose sodium as functional 5 disintegrant. The non-ionic detergent Tween 80*is used we a surfactant. The composition also contains hydroxypropyl cellulose as binder selected from among several applicable substances such as, i.e.,..
polyethylene glycol, polyvinylpyrrolidone, polyvinyl 10 alcohol, hydroxymethylcellulose or hydroxypropylmethylcellulose. As anti-oxidants, reagents such as butylated hydroxyanisole, sodium ascorbate, ascorbic acid or others may optionally be incorporated in the composition. Magnesium stearate 15 can be selected frown a group including other substances such as stearic acid, palmitic acid, talc or similar lubricating compounds.
Other possible and supplemental ingredients such as preservatives, driers, glidants, or colorants known 20 as conventional by those skilled in the art may be included optionally in the inventive formulation.
In accordance with the preferred embodiment of the present invention, the formulations provide for the following concentration ranges of ingredients by 25 weight: the active ingredient or drug concentration is in the range from about 1% to about 50%; calcium carbonate from about 5% to about 75%; microcrystalline cellulose from about 5% to about 75%; hydrous lactose from about 1% to about 80%; croscarmellose sodium from 30 about 1% to about 15%; hydroxypropylcellulose from about 0.5~ to about 6$; Tween* 80 (polyoxyethylene sorbitan) from about 0.1~ to about 4~; magnesium stearate from about 0.25 to about 2~; and sodium ascorbate (or ascorbic acid) from about 0.0~ to about 3~.
35 The more preferred composition formulated according to the present invention includes the trade-mark following approximate concentrations of ingredients by weight: 6.91 of the drug; 22k of calcium carbonate;
40~ microcrystalline cellulose; 22.19 hydrous lactose;
6k croscarmellose sodium; 2~ hydroxypropyl cellulose;
5 0.4~ 'I~reen'~ 80 (polyoxyethylene sorbitan) ; and 0. 5$
magnesium stearate; in addition, optionally 0.02$ of an antioxidant such as sodium ascorbate.
In particular, CI-981 Hemi-Calcium degrades rapidly in compositions prepared by the wet-granulation 10 method. It has therefore been a surprising discovery that, by adding calcium carbonate, solid formulations for this dnig can be prepared by the wet granulation method without compromising the stability of the drug.
15 Method-of Preparation of Pharmaceutical Composition:
The method for preparing a solid pharmaceutical composition according to the present invention includes (a) milling an excess of the drug, which can be a compound of Fotmula I or Formula IA (CI-981 20 Hemi-Calcium); (b) dissolving at least one binder additive in aqueous surfactant solution; (c) blending the milled drug with at least one drug-stabilizing additive and at least one diluent additive with the drug-stabilizing additive and one-half of a 25 disintegrant additive in a rotary mixing vessel equipped with a chopping device; (d) granulating the blended dnig ingredient mixture of step (c) with the surfactant/binder solution of step (b) in gradual increments in the chopper equipped mixing vessel;
30 (e) drying the granulated drug mixture overnight at about 50°C; (f) sieving the dried granulated drug mixture; (g) tumble blending the sieved drug mixture with the remaining amount of the disintegrant additive;
(h) mixing separately an aliquot of the drug mixture of 35 step (g) with magnesium stearate, sieving same, and retux-ning same to the drug mixture of step (g) and * trade-mark _1g'_ tumble blending the eatire drug mixture; and compzessing aliquots of the drug mixture of step (h) into tablet having suitable drug strength.
More particularly, the preferred embodiments of 5 the present imrention can be prepared in accordance with the batch procedure given in the e~camples below.
ALE 1 (PROTOCOL) 10 In order to produce 1.5 kg of the composition formulated for peroral therapy, the following steps are taken:
(a) An excess of about 5~ by weight of CI-981 Hemi-Calcium is passed through a Model D Fitzmill, 15 which is equipped with a Number 0 RH screen (0.027~). The mill is run at a high speed with impact forward. Exactly 103.65 g of the milled drug is weighed for Step (c).
(b) Tween*80 in an appropriate amount (6.0 g) is 20 dissolved in 100 mL of purified water heated to about 50°C and mixed for approximately 5 minutes;
similarly the hydzoxypropyl cellulose (30.0 g) is dispersed in the warm Tween*80 solution and mixed for about S minutes; the remaining purified water 25 (500 mL) is added, and the entire mixture is then allowed to hydrate for at least 4 hours.
(c) Thereafter, the milled dnig, CI-981 Hemi-Calcium (103.65 g), calcium carbonate (330.0 g), microcrystalline cellulose (600.0 g), hydrous 30 lactose (332.85 g), and 50~ of the croscarmellose soc~.ium (45.0 g) are mixed in the 10 liter-Collette Gral*for about 5 minutes with the mixer running at 300 rpm and chopper speed Z.
(d) The blended preparation of Step (c) is granulated 35 with the solution of Step (b) by adding the solution over 30 to 60 seconds with only the mixer trade-mark running at 300 rpm; then the mixing is continued up to a total of 3 minutes with the mixer speed of 300 rpm and the chopper speed set at 1; the bowl is now lowered and material scraped from the blades and the top of the mixing apparatus.
Subsequently, the preparation is remixed for another 3 minutes with the mixer running 300 rpm and the chopper speed setting at 1, with additional amounts of purified water and 3 minutes time increments of mixing, as necessary to obtain adequate granular consistency.
(e) The granulated preparation is spread on paper-lined trays, dried at 50°C overnight to a LOD of approximately 2%.
(f) The dried granulation is passed through a ~uadromill* (Comill) which is equipped with a 0.032" screen.
(g) Approximately half the milled granulation is transferred to a 4 qt. twin shell blender, followed by the remaining 50~ (w/w) of the croscarmellose sodium (45.0 g) and finally the remaining milled granulation; the entire mixture is tumble blended for 10 minutes.
(h) Approximately 50 g of the blend resulting from step (g) is removed and mixed with magnesium stearate (7.50 g); this side mixture is passed through a #40 mesh screen and returned to the 4 qt. twin shell blender, and the entire mixture is tumble blended for 5 minutes.
(i) Finally, an appropriate aliquot of the final mixture is compressed to -obtain a tablet weight containing the desired drug st=znqth.
* Trademark fi%ANIPLE 2 All steps in this Example 2 are the same as in Example 1 except for Step (b) which proceeds as follows:
5 (2b) Firstly, Tween*80 (6.0 g) is dissolved in 100 mL
of purified water which has been heated to 5°C;
secondly, after about 5 minutes of mechanical stirring, the hydroxypropyl cellulose (30.0 g) is dispersed in the Tween*80 solution and further 10 mixed for about 5 minutes; thirdly (and optionally) sodium ascorbate (0.3 g) is dissolved in the remaining volume of purified water and added to the Tween*80-hydroxypropyl cellulose mixture. Thereupon the mixture is allowed to 15 hydrate for at east 4 hours.
All steps of this alternative embodiment are as described in Example 1 with the exception of process 20 Step (b); however, Step (b) is as follows:
Firstly, Tween"80 is dissolved in 100 mL of purified water which has been heated to 50°C.
Secondly, butylated hydroxyanisole is dissolved in 10 mL of ethanol; which solution is 25 then stirred into the 'Ilaee~ 80 mixture and agitated for S minutes. Thirdly, the hydroxypropyl cellulose is dispersed in the above mixture and stirred for approximately 5 minutes.
The remaining purified water is added to the 30 mixture which is then allowed to hydrate for at least 4 hours.
The tablets as prepared in all the Examples are film-coated to about a 3% weight increase.
The comparative stability of the preferred 35 antihypercholesterolemia or antihyperlipidemia formulations containing CI-981 was tested under highly ~E trade-mark WO 94116693 2 ~ ~ p 3'~ 2 ' ~ ' PCT/US93/12471 accelerated stress conditions at elevated temperatures.
In particular, the stability of a CI-981 formulation was tested by comparing a powder blend prepared according to the method of Example 3, at 2.5 mg active ingredient dosage in the presence (Example 4) or the absence (Example 5) of calcium carbonate. The samples were stored in duplicate for 2 and 4 weeks at either 45°C or 60°C and then analyzed by reverse phase high performance liquid chromatography ("HPLC"). The HPLC
assay procedure employs a Zorbax~ Reliance C18 column (8 cm long, 5-~c bead) and a mobile phase of acetonitrile in aqueous buffer (35:65) containing triethylamine, sodium acetate adjusted to pH 4Ø A
detection wavelength of 244 nm was used.
The results showed that the calcium carbonate containing preparation of Example 4 incurred no detectable losses of the drug CI-981 after 2 weeks at 60°C and only negligible losses of about 0.25% by weight after 4 weeks at 45°C and about one-half percent by weight at 60°C. In contrast, the formulation of Example 5, lacking calcium carbonate, lost by weight about 2.45% ingredient after 4 weeks storage at 45°C, about 4.12% of CI-981 after only 2 weeks and about 5.3%
at 60°C (see Table I).
TABLE I. Stability of CI-981 Formulations:
A Powder Hlend With (Example 4) and Without (Example 5) Calcium Carbonate Percent Drug Remaining Time g~ple 4 fixaamle 5 (weeks) 45°C 60°C 45°C 60°C
2 ND 100 100 95.88 4 99.75 99.48 97.55 94.7 The second set of comparative data (see Table II) concerns the formulations of Examples 6 and 7 prepared in accord with the protocol of Example 3, wherein the SUBSTITUTE SHEET
~ ~ 2lrD~~~
WO 94/16693 PCTlUS93112471 composition was packaged in a capsule at 2.5 mg strength with calcium carbonate (Example 6) and without calcium carbonate (Example 7). The formulation of Example 6, when measured by HPLC, lost about one-half a ' S percent by weight of CI-981 after 4 weeks at 45°C and about 2.2% after 2 weeks at 60°C. The capsule preparation of Example 7 had a CI-981 content which was diminished by about 4.4% after 4 weeks at 45°C. After 2 weeks at 60°C, about 14% of CI-981 Hemi-Calcium was lost, as measured by HPLC.
TABLE II. Stability of CI-981 Formulations:
A Capsule With (Example 6) and Without (Example 7) Calcium Carbonate Percent Drug Remaining Time g~ple 6 Example 7 (Weeks) 45°C 60°C 45°C 60°C
2 ND 97.81 ND 86 2 0 4 99.75 ND 95.6 ND
Finally, the stability of the preferred formulation according to the present invention was tested in the form of a coated tablet (Example 8) containing calcium carbonate (see Table III). In particular, the preparation of Example 8 was stored for 4 weeks at 45°C and lost about 0.5% by weight of CI-981. After 2 weeks at 60°C, the composition (Example 8) contained-about 0.9% less by weight active ingredient and after 4 weeks at 60°C about 1.7% less by weight active ingredient. Clearly, the formulation according to the preferred embodiment containing calcium carbonate effectively protects the integrity of the active compounds during both the wet granulation step of the process of preparing the stable solid SUBSTITUTE SHEET
WO 94/16693 ~ ~,~ o ~" PCT/US93/12471 r composition and the subsequent storage in the form of a powder blend, capsule or coated tablet.
TABLE III. Stability of CI-981 Formulations:
A Coated Tablet With Calcium Carbonate (Example 8).
Time Percent Drug Remaining (Weeks) 45°C 60°C
99.11 4 99.47 98.30 ND = Not determined Consequently, any variations of the invention described above are not to be regarded as a departure from the spirit and scope of the invention as claimed.
suBST~TU-rE sHE~
SUBSTITUTE SHEET
WO 94/16693 PCTlUS93/12471 In addition, the pref erred chirai form can be prepared from a racemic mixture prepared by the methods described in US Patent 4,681,893, especially Examples 1 and 2.
Reference of the racemate and separation of the preferred isomer can be performed in accordance with the methodology for chiral synthesis disclosed in Canadian Patent No. 2,021,546, as illustrated in the Examples 1-5.
The present invention provides a pharmaceutical composition containing hypocholesterolemic or hypolipidemic compounds according to preferably Formula (I) or more preferably Formula (IA). The preferred effective stereoisomeric compounds of the present invention are administered to the patient at adult dosage levels of from approximately 10 to 500 mg per day, or from about 0.1 to about 8.0 mg/kg body weight per day. More-pref erred daily dosages range from about 0.5 to about 1.0 mg/kg. The unit dosage treatment embodiment provided by the present invention for oral or parenteral aaministration may be varied or adjusted from 10 to 500 mg, preferably from 20 to 100 mg depending on potency or application.
Since the hydroxy acid compounds according to Formula I are susceptible to degradation to the lactone form in an acidic environment, it has been necessary to stabilize their structural integrity in pharmaceutical formulations. Moreover, the compounds have been determined to decompose rapidly under the impact of UV
and fluorescent Light.
For the purpose of stable oral preparations of the present invention, pharmaceutically acceptable inert 35~ carriers can be either solid or liquid. The most preferred embodiment of the present invention provides _ .. . __. . .~ ~.._-- -..___._. _ _._-..~.,~,..~,...__-~..~ .____ ._. __~...~--4.~.~..,_~._ ~...~~_~._ . . ._ .
WO 94/16693 ~ ~ ~ PCT/US93/12471 ~1~
for an oral solid formulation which may include powders, tablets, dispersible granules, capsules, and cachets. A solid carrier may be one or more substances which can also act as diluents, flavoring agents, binders, or tablet disintegrating agents. , Encapsulating materials are"also within the scope of the present invention. , In powdered preparations, the carrier is preferably a solid which is finely divided in a homogeneous mixture with the finely divided active ingredient. In tablets, the active component is blended with the carrier material with binding properties that facilitate compacting, shaping and sizing as desirable. Oral powders or tablets according to the present invention are generally designed to contain between about 1~ to about 50% by weight of the active ingredient.
As is usual in the art, pharmaceutical preparations are in suitable unit dosage form, which can be a capsule, cachet or tablet, or any number thereof, as appropriate. Dosages are held to be within the skill of the art and may vary with the particular requirements and bioavailability of the active ingredient.
In practice, use of the salt form amounts to use of the acid or lactone form. Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, 1-deoxy-2-(methylamino) D-glucitol, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, ' ammonium hydroxide or organic amines such as N-methylglucamine, choline, arginine, and the like. ' Preferably, the lithium, calcium, magnesium, aluminum and ferrous or ferric salts are prepared from the SUBSTITUTE SHEET
WO 94/16693 , PCTIUS93/12471 sodium or potassium salt by adding the appropriate reagent to a solution of the sodium or potassium salt, i.e., addition of calcium chloride to a solution of the sodium or potassium salt of the compound of the Formula I will give the calcium salt thereof.
The active hydroxy acid metal salt ingredient of the present invention k~k~.ich may be an isomeric compound with a structure according to Formula (I) or, preferably, Formula (IA) can be prepared from sodium salt or lactone as illustrated in Example A, below.
EXAMPLE A
Calcium Salt from Sodium Salt and/or Lactone One mole lactone (540.6 g) is dissolved in 5 L of MeOH; after dissolution 1 L H20 is added. While stirring, one equivalent NaOH is added and the reaction is followed by HPLC until 2~C or less lactone and methyl ester of the diolacid remains (one cannot use an excess of NaOH, because Ca(OH)2 will form on addition of CaCl2). Usually NaOH is charged as caustic (51.3 mL, 0.98_ eq. ) or as pellets (39.1 g, 0.98 eq. ) .
SUBSTITUTE SHEET
WO 94116693 PCTlUS93l12471 The above procedure is shown as follows:
N ~~'' off \ /
Ph 'C
~N .98 eq. NaOH
H~ \
Ph MeOH, Hi0 5 . 1 m.w. = 540.6 g _ . i ~H
EtOAc, .i:exane HZO N 0 Na c Wash \ /
Ph ~ C' O N
Ph The abbreviation "Ph~ is for the term phenyl group. Upon completion of hydrolysis, 10 L H20 are added, then the product is washed at least two times with a 1:1 mixture of EtOAc/Hexane. Each wash should contain 10 L each of EtOAc/Hexane. If sodium salt is pure, 15 L of MeOH are added. If it is impure and/or contains color, 100 g of G-60* charcoal are added, the mixture is stirred far 2 hours, filtered over supercel, and washed with 15 L MeOH. An assay analysis (weight per volume, %) is performed on the reaction mixture by HPLC, to determine the exact amount of salt in solution.
Subsequently, about 1/2 equivalent or a slight excess of CaC122H20 (73.5 g) is dissolved in 20 L H20.
Both the reaction mixture and the CaCl2 solution are heated to 60°C. CaCl2 solution is added slowly, with 35~ high agitation. After complete addition, the reaction mixture is cooled slowly to 15°C and filtered. The * Trademark ~~.~037~
filter cake is washed with 5 L H20 and dried at 50°C in a vacuum oven.
The product can be recrystallized by dissolving in 4 L of EtOAc (50°C) filtering over supercel, washing with 1 L EtOAc, then charging 3 L of hexane to the 50°C
reaction solution.
The above procedure is shown as follows:
OH OH O
OH OH O
y ~0 Na F ~ \ / 1/2 eq.CaCl2 ~ 2H;0 F ~ N O Ca"
Ph ~C' H 0 O Ph ,C' iN O
H \Ph H/N\ph m.w. - 580.6 g m.w. - 1155.4 q The present invention provides a preferred composition for stabilizing the active ingredient such as, e.g., CI-981 Hemi-Calcium, using basic inorganic pharmaceutically acceptable salts of calcium such as calcium carbonate and calcium hydroxide or basic inorganic pharmaceutically acceptable salts of magnesium such as magnesium carbonate, magnesium hydroxide, magnesium -silicate, magnesium aluminate, and aluminum magnesium hydroxide, or basic inorganic pharmaceutically acceptable salts of lithium such as lithium hydroxide and similar lithium compounds or other similarly suitable alkaline earth metals. The basic inorganic salts of calcium, lithium or magnesium can be utilized in a weight ratio ranging between about 0.1 to 1 and about 50 to 1 of salt compound to active ingredient.
Stabilized solid' oral pharmaceutical formulations of the present invention are designed to protect the antihypercholesterolemia or anti-hyperlipidemia drug, SUBSTITUTE SHEET
e.g., CI-981 Hemi-Calcium, of Formula IA (as defined above), from any degrading or_processing environment, as well as preserve it from photochemical decomposition during storage. Specifically, the most preferred 5 active chemical ingredient is the compound CI-981 Hemi-Calcium of Foranila (IA). The solid formulation according to the present invention also includes, in addition to a stabilizing metal or alkaline earth metal salt, several additives which are known as suitable 10 agents in the art comprising combinations and concentrations as further described below.
The present invention without limiting further provides for diluent additives such as microcrystalline cellulose, hydrous lactose, corn starch, sucrose, 15 silicic anhydride, or polysaccharides (as are known as suitable in the art); binders such as methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, or starch; disintegrants such as 20 carboxymethylcellulose calcium, croscarmellose sodium, or starch; and surfactants such as Tween* 80(polyoxyethylene sorbitan) or polyoxyethylene-polyoxypropylene copolymer.
Antioxidants can also be incorporated with the foxznulations in order to prevent any oxidation of the 25 drug compound. For example, antioxidants that could be used are butylated hydroxanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid and ascorbic acid.
The most preferred embodiment of the present 30 invention is directed to a solid oral cosaposition including CI-981 Hemi-Calcium as active ingredient, calcium carbonate as the stabilizing component, and other additives.
The basic exciDient, calcium carbonate, has been 35 found to provide effective control of the microenvironment of the coaroosition. Further to the * trade-mark present invention, microcrystalline cellulose, and hydrous lactose are applied as suitable diluents. In addition, the inventive composition contains a suitable amount of croscazmellose sodium as functional 5 disintegrant. The non-ionic detergent Tween 80*is used we a surfactant. The composition also contains hydroxypropyl cellulose as binder selected from among several applicable substances such as, i.e.,..
polyethylene glycol, polyvinylpyrrolidone, polyvinyl 10 alcohol, hydroxymethylcellulose or hydroxypropylmethylcellulose. As anti-oxidants, reagents such as butylated hydroxyanisole, sodium ascorbate, ascorbic acid or others may optionally be incorporated in the composition. Magnesium stearate 15 can be selected frown a group including other substances such as stearic acid, palmitic acid, talc or similar lubricating compounds.
Other possible and supplemental ingredients such as preservatives, driers, glidants, or colorants known 20 as conventional by those skilled in the art may be included optionally in the inventive formulation.
In accordance with the preferred embodiment of the present invention, the formulations provide for the following concentration ranges of ingredients by 25 weight: the active ingredient or drug concentration is in the range from about 1% to about 50%; calcium carbonate from about 5% to about 75%; microcrystalline cellulose from about 5% to about 75%; hydrous lactose from about 1% to about 80%; croscarmellose sodium from 30 about 1% to about 15%; hydroxypropylcellulose from about 0.5~ to about 6$; Tween* 80 (polyoxyethylene sorbitan) from about 0.1~ to about 4~; magnesium stearate from about 0.25 to about 2~; and sodium ascorbate (or ascorbic acid) from about 0.0~ to about 3~.
35 The more preferred composition formulated according to the present invention includes the trade-mark following approximate concentrations of ingredients by weight: 6.91 of the drug; 22k of calcium carbonate;
40~ microcrystalline cellulose; 22.19 hydrous lactose;
6k croscarmellose sodium; 2~ hydroxypropyl cellulose;
5 0.4~ 'I~reen'~ 80 (polyoxyethylene sorbitan) ; and 0. 5$
magnesium stearate; in addition, optionally 0.02$ of an antioxidant such as sodium ascorbate.
In particular, CI-981 Hemi-Calcium degrades rapidly in compositions prepared by the wet-granulation 10 method. It has therefore been a surprising discovery that, by adding calcium carbonate, solid formulations for this dnig can be prepared by the wet granulation method without compromising the stability of the drug.
15 Method-of Preparation of Pharmaceutical Composition:
The method for preparing a solid pharmaceutical composition according to the present invention includes (a) milling an excess of the drug, which can be a compound of Fotmula I or Formula IA (CI-981 20 Hemi-Calcium); (b) dissolving at least one binder additive in aqueous surfactant solution; (c) blending the milled drug with at least one drug-stabilizing additive and at least one diluent additive with the drug-stabilizing additive and one-half of a 25 disintegrant additive in a rotary mixing vessel equipped with a chopping device; (d) granulating the blended dnig ingredient mixture of step (c) with the surfactant/binder solution of step (b) in gradual increments in the chopper equipped mixing vessel;
30 (e) drying the granulated drug mixture overnight at about 50°C; (f) sieving the dried granulated drug mixture; (g) tumble blending the sieved drug mixture with the remaining amount of the disintegrant additive;
(h) mixing separately an aliquot of the drug mixture of 35 step (g) with magnesium stearate, sieving same, and retux-ning same to the drug mixture of step (g) and * trade-mark _1g'_ tumble blending the eatire drug mixture; and compzessing aliquots of the drug mixture of step (h) into tablet having suitable drug strength.
More particularly, the preferred embodiments of 5 the present imrention can be prepared in accordance with the batch procedure given in the e~camples below.
ALE 1 (PROTOCOL) 10 In order to produce 1.5 kg of the composition formulated for peroral therapy, the following steps are taken:
(a) An excess of about 5~ by weight of CI-981 Hemi-Calcium is passed through a Model D Fitzmill, 15 which is equipped with a Number 0 RH screen (0.027~). The mill is run at a high speed with impact forward. Exactly 103.65 g of the milled drug is weighed for Step (c).
(b) Tween*80 in an appropriate amount (6.0 g) is 20 dissolved in 100 mL of purified water heated to about 50°C and mixed for approximately 5 minutes;
similarly the hydzoxypropyl cellulose (30.0 g) is dispersed in the warm Tween*80 solution and mixed for about S minutes; the remaining purified water 25 (500 mL) is added, and the entire mixture is then allowed to hydrate for at least 4 hours.
(c) Thereafter, the milled dnig, CI-981 Hemi-Calcium (103.65 g), calcium carbonate (330.0 g), microcrystalline cellulose (600.0 g), hydrous 30 lactose (332.85 g), and 50~ of the croscarmellose soc~.ium (45.0 g) are mixed in the 10 liter-Collette Gral*for about 5 minutes with the mixer running at 300 rpm and chopper speed Z.
(d) The blended preparation of Step (c) is granulated 35 with the solution of Step (b) by adding the solution over 30 to 60 seconds with only the mixer trade-mark running at 300 rpm; then the mixing is continued up to a total of 3 minutes with the mixer speed of 300 rpm and the chopper speed set at 1; the bowl is now lowered and material scraped from the blades and the top of the mixing apparatus.
Subsequently, the preparation is remixed for another 3 minutes with the mixer running 300 rpm and the chopper speed setting at 1, with additional amounts of purified water and 3 minutes time increments of mixing, as necessary to obtain adequate granular consistency.
(e) The granulated preparation is spread on paper-lined trays, dried at 50°C overnight to a LOD of approximately 2%.
(f) The dried granulation is passed through a ~uadromill* (Comill) which is equipped with a 0.032" screen.
(g) Approximately half the milled granulation is transferred to a 4 qt. twin shell blender, followed by the remaining 50~ (w/w) of the croscarmellose sodium (45.0 g) and finally the remaining milled granulation; the entire mixture is tumble blended for 10 minutes.
(h) Approximately 50 g of the blend resulting from step (g) is removed and mixed with magnesium stearate (7.50 g); this side mixture is passed through a #40 mesh screen and returned to the 4 qt. twin shell blender, and the entire mixture is tumble blended for 5 minutes.
(i) Finally, an appropriate aliquot of the final mixture is compressed to -obtain a tablet weight containing the desired drug st=znqth.
* Trademark fi%ANIPLE 2 All steps in this Example 2 are the same as in Example 1 except for Step (b) which proceeds as follows:
5 (2b) Firstly, Tween*80 (6.0 g) is dissolved in 100 mL
of purified water which has been heated to 5°C;
secondly, after about 5 minutes of mechanical stirring, the hydroxypropyl cellulose (30.0 g) is dispersed in the Tween*80 solution and further 10 mixed for about 5 minutes; thirdly (and optionally) sodium ascorbate (0.3 g) is dissolved in the remaining volume of purified water and added to the Tween*80-hydroxypropyl cellulose mixture. Thereupon the mixture is allowed to 15 hydrate for at east 4 hours.
All steps of this alternative embodiment are as described in Example 1 with the exception of process 20 Step (b); however, Step (b) is as follows:
Firstly, Tween"80 is dissolved in 100 mL of purified water which has been heated to 50°C.
Secondly, butylated hydroxyanisole is dissolved in 10 mL of ethanol; which solution is 25 then stirred into the 'Ilaee~ 80 mixture and agitated for S minutes. Thirdly, the hydroxypropyl cellulose is dispersed in the above mixture and stirred for approximately 5 minutes.
The remaining purified water is added to the 30 mixture which is then allowed to hydrate for at least 4 hours.
The tablets as prepared in all the Examples are film-coated to about a 3% weight increase.
The comparative stability of the preferred 35 antihypercholesterolemia or antihyperlipidemia formulations containing CI-981 was tested under highly ~E trade-mark WO 94116693 2 ~ ~ p 3'~ 2 ' ~ ' PCT/US93/12471 accelerated stress conditions at elevated temperatures.
In particular, the stability of a CI-981 formulation was tested by comparing a powder blend prepared according to the method of Example 3, at 2.5 mg active ingredient dosage in the presence (Example 4) or the absence (Example 5) of calcium carbonate. The samples were stored in duplicate for 2 and 4 weeks at either 45°C or 60°C and then analyzed by reverse phase high performance liquid chromatography ("HPLC"). The HPLC
assay procedure employs a Zorbax~ Reliance C18 column (8 cm long, 5-~c bead) and a mobile phase of acetonitrile in aqueous buffer (35:65) containing triethylamine, sodium acetate adjusted to pH 4Ø A
detection wavelength of 244 nm was used.
The results showed that the calcium carbonate containing preparation of Example 4 incurred no detectable losses of the drug CI-981 after 2 weeks at 60°C and only negligible losses of about 0.25% by weight after 4 weeks at 45°C and about one-half percent by weight at 60°C. In contrast, the formulation of Example 5, lacking calcium carbonate, lost by weight about 2.45% ingredient after 4 weeks storage at 45°C, about 4.12% of CI-981 after only 2 weeks and about 5.3%
at 60°C (see Table I).
TABLE I. Stability of CI-981 Formulations:
A Powder Hlend With (Example 4) and Without (Example 5) Calcium Carbonate Percent Drug Remaining Time g~ple 4 fixaamle 5 (weeks) 45°C 60°C 45°C 60°C
2 ND 100 100 95.88 4 99.75 99.48 97.55 94.7 The second set of comparative data (see Table II) concerns the formulations of Examples 6 and 7 prepared in accord with the protocol of Example 3, wherein the SUBSTITUTE SHEET
~ ~ 2lrD~~~
WO 94/16693 PCTlUS93112471 composition was packaged in a capsule at 2.5 mg strength with calcium carbonate (Example 6) and without calcium carbonate (Example 7). The formulation of Example 6, when measured by HPLC, lost about one-half a ' S percent by weight of CI-981 after 4 weeks at 45°C and about 2.2% after 2 weeks at 60°C. The capsule preparation of Example 7 had a CI-981 content which was diminished by about 4.4% after 4 weeks at 45°C. After 2 weeks at 60°C, about 14% of CI-981 Hemi-Calcium was lost, as measured by HPLC.
TABLE II. Stability of CI-981 Formulations:
A Capsule With (Example 6) and Without (Example 7) Calcium Carbonate Percent Drug Remaining Time g~ple 6 Example 7 (Weeks) 45°C 60°C 45°C 60°C
2 ND 97.81 ND 86 2 0 4 99.75 ND 95.6 ND
Finally, the stability of the preferred formulation according to the present invention was tested in the form of a coated tablet (Example 8) containing calcium carbonate (see Table III). In particular, the preparation of Example 8 was stored for 4 weeks at 45°C and lost about 0.5% by weight of CI-981. After 2 weeks at 60°C, the composition (Example 8) contained-about 0.9% less by weight active ingredient and after 4 weeks at 60°C about 1.7% less by weight active ingredient. Clearly, the formulation according to the preferred embodiment containing calcium carbonate effectively protects the integrity of the active compounds during both the wet granulation step of the process of preparing the stable solid SUBSTITUTE SHEET
WO 94/16693 ~ ~,~ o ~" PCT/US93/12471 r composition and the subsequent storage in the form of a powder blend, capsule or coated tablet.
TABLE III. Stability of CI-981 Formulations:
A Coated Tablet With Calcium Carbonate (Example 8).
Time Percent Drug Remaining (Weeks) 45°C 60°C
99.11 4 99.47 98.30 ND = Not determined Consequently, any variations of the invention described above are not to be regarded as a departure from the spirit and scope of the invention as claimed.
suBST~TU-rE sHE~
Claims (66)
1. A pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture, (A) a compound as active ingredient of structural formula I
wherein:
X is : -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R5 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of R2 and R3 is:
hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation; and (B) at least one stabilizing basic inorganic pharmaceutically acceptable salt of calcium, magnesium or lithium.
wherein:
X is : -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R5 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of R2 and R3 is:
hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation; and (B) at least one stabilizing basic inorganic pharmaceutically acceptable salt of calcium, magnesium or lithium.
2. The stable pharmaceutical composition of claim 1 wherein the active ingredient is a pharmaceutically acceptable metal salt of [R-(R*, R*)] -2- (4-fluorophenyl-.beta., .delta.-dihydroxy-5-(1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid.
3. The stable pharmaceutical composition of Claim 1, wherein M is a pharmaceutically acceptable alkaline earth metal cation.
4. The stable pharmaceutical composition of Claim 2, wherein the pharmaceutically acceptable metal salt of said acid is an alkaline earth metal salt.
5. The stable pharmaceutical composition of Claim 1, wherein said at least one stabilizing basic inorganic pharmaceutically acceptable salt of calcium or magnesium is selected from the group consisting of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide.
6. The stable pharmaceutical composition of any one of Claims 1 to 5 wherein said at least one stabilizing basic inorganic pharmaceutically acceptable salt is calcium carbonate.
7. The stable pharmaceutical composition of Claim 1 wherein said at least one stabilizing basic inorganic pharmaceutically acceptable salt is lithium hydroxide.
8. The stable pharmaceutical composition of Claim 2, wherein the active ingredient is CI-981 Hemi-Calcium of Formula (IA):
and wherein said at least one stabilizing basic inorganic pharmaceutically acceptable salt is calcium carbonate.
and wherein said at least one stabilizing basic inorganic pharmaceutically acceptable salt is calcium carbonate.
9. The stable pharmaceutical composition of any one of Claims 1 to 8 further comprising one or more other ingredients selected from the group consisting of a binder, a diluent, a disintegrant, a surfactant, a lubricant, and an antioxidant.
10. The stable pharmaceutical composition of Claim 1, 2, 7 or 8, wherein the active ingredient dosage is between 1% and 50% by weight of the composition.
11. The stable pharmaceutical composition of Claim 6 or 8 wherein said calcium carbonate is in the range from 5%
to 75% by weight of the composition.
to 75% by weight of the composition.
12. The stable pharmaceutical composition of Claim 9 wherein said other ingredients comprise by weight between 5% and 75% microcrystalline cellulose; between 1% and 80%
of hydrous lactose; between 1% and 15% of croscarmellose sodium; between 0.5% and 6% hydroxypropyl cellulose;
between 0.1% and 4% of polyoxyethylene sorbitan; between 0.25% and 2% of magnesium stearate; and up to 3% of sodium ascorbate or butylated hydroxyanisole of the total solid composition.
of hydrous lactose; between 1% and 15% of croscarmellose sodium; between 0.5% and 6% hydroxypropyl cellulose;
between 0.1% and 4% of polyoxyethylene sorbitan; between 0.25% and 2% of magnesium stearate; and up to 3% of sodium ascorbate or butylated hydroxyanisole of the total solid composition.
13. A stabilized solid pharmaceutical composition for peroral treatment of hypercholesterolemia or hyperlipidemia comprising in solid unit dosage form [R-(R*, R*) ] -2-(4-fluorophenyl) -.beta.-.delta.-dihydroxy-5-(1-methylethyl) -3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemicalcium salt and a stabilizer selected from the group consisting of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide and lithium hydroxide.
14. A method for preparing a stable pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia comprising a step of mixing thoroughly 1% to 95% by weight of the active ingredient of Claim 1, 2, or 8 with 5% to 99% by weight of at least one stabilizing basic inorganic pharmaceutically acceptable salt of calcium, magnesium or lithium.
15. A method for preparing a stable pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia comprising:
(i) a step of mixing thoroughly 1% to 50% by weight of the active ingredient of Claim 1, 2, or 8 with 5% to 75%
by weight of at least one stabilizing basic inorganic pharmaceutically acceptable salt of calcium, magnesium or lithium, and (ii) a step of adding at least one additive selected from the group consisting of a binder, a diluent, a disintegrant, a surfactant, a lubricant and an antioxidant.
(i) a step of mixing thoroughly 1% to 50% by weight of the active ingredient of Claim 1, 2, or 8 with 5% to 75%
by weight of at least one stabilizing basic inorganic pharmaceutically acceptable salt of calcium, magnesium or lithium, and (ii) a step of adding at least one additive selected from the group consisting of a binder, a diluent, a disintegrant, a surfactant, a lubricant and an antioxidant.
16. A method for preparing a stabilized pharmaceutical composition formulated for peroral therapy of hypercholesterolemia or hyperlipidemia comprising:
(a) milling an excess of the drug, CI-981 Hemi-Calcium of the formula IA:
(b) dissolving at least one binder additive in aqueous surfactant solution;
(c) blending the milled drug with at least one drug-stabilizing alkaline earth metal salt additive and at least one diluent additive ingredient with the drug-stabilizing additive and one half of a disintegrant additive in a rotary mixing vessel equipped with a chopping device;
(d) granulating the blended drug mixture of step (c) with the surfactant/binder solution of step (b) in gradual increments in the chopper equipped mixing vessel;
(e) drying the granulated drug mixture overnight at about 50°C.;
(f) sieving the dried granulated drug mixture;
(g) tumble blending the sieved drug mixture with the remaining amount of the disintegrant additive;
(h) mixing separately an aliquot of the step (g) drug mixture with magnesium stearate, sieving same, and returning same to the drug mixture of step (g) and tumble blending the entire drug mixture; and (i) compressing aliquots of the step (h) drug mixture into tablets having suitable drug strength.
(a) milling an excess of the drug, CI-981 Hemi-Calcium of the formula IA:
(b) dissolving at least one binder additive in aqueous surfactant solution;
(c) blending the milled drug with at least one drug-stabilizing alkaline earth metal salt additive and at least one diluent additive ingredient with the drug-stabilizing additive and one half of a disintegrant additive in a rotary mixing vessel equipped with a chopping device;
(d) granulating the blended drug mixture of step (c) with the surfactant/binder solution of step (b) in gradual increments in the chopper equipped mixing vessel;
(e) drying the granulated drug mixture overnight at about 50°C.;
(f) sieving the dried granulated drug mixture;
(g) tumble blending the sieved drug mixture with the remaining amount of the disintegrant additive;
(h) mixing separately an aliquot of the step (g) drug mixture with magnesium stearate, sieving same, and returning same to the drug mixture of step (g) and tumble blending the entire drug mixture; and (i) compressing aliquots of the step (h) drug mixture into tablets having suitable drug strength.
17. The method claimed in Claim 16, wherein in step (c) the drug stabilizing additive comprises basic inorganic pharmaceutically acceptable salts of calcium or magnesium or lithium and the diluent additive comprises microcrystalline cellulose, hydrous lactose, corn starch, sucrose, silicic anhydride or polysaccharides.
18. The method claimed in Claim 16, wherein in Step (b) the binder additive comprises methyl cellulose, carboxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol or starch; and the surfactant comprises polyoxyethylene sorbitan or polyoxyethylene-polyoxypropylene copolymer.
19. The method of Claim 16, wherein in Step (c) the disintegrant additive comprises croscarmellose sodium, carboxymethyl cellulose calcium or starch.
20. A peroral pharmaceutical composition for treating hypercholesterolemia comprising an effective, cholesterol synthesis inhibitory amount of the enantiomer [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.-,.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, hemicalcium salt; stabilized by calcium carbonate, in a dosage ranging from 0.1 to 8.0 mg/kg body weight per day.
21. A pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture:
(A) a compound as active ingredient of structural formula I
wherein:
X is : -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms; and the other of R2 and R3 is:
hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms, cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation;
(B) at least one stabilizing pharmaceutically acceptable alkaline earth metal salt additive;
(C) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising between about 0.5% and about 6% by weight of the total solid composition;
(D) at least one diluent selected from the group consisting of microcrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about to and about 80% of the total solid composition;
(E) at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about to and about 15%
of the total solid composition;
(F) at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1% and about 4% of the total solid composition;
(G) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25% and about 2% of the total solid composition; and (H) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3% of the total solid composition.
(A) a compound as active ingredient of structural formula I
wherein:
X is : -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms; and the other of R2 and R3 is:
hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms, cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation;
(B) at least one stabilizing pharmaceutically acceptable alkaline earth metal salt additive;
(C) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising between about 0.5% and about 6% by weight of the total solid composition;
(D) at least one diluent selected from the group consisting of microcrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about to and about 80% of the total solid composition;
(E) at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about to and about 15%
of the total solid composition;
(F) at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1% and about 4% of the total solid composition;
(G) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25% and about 2% of the total solid composition; and (H) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3% of the total solid composition.
22. The stable pharmaceutical composition of claim 21 wherein the active ingredient is a pharmaceutically acceptable metal salt of [R-(R*,R*)]-2-(4-fluorophenyl-.beta., .delta.-dihydroxy-5(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid.
23. The stable pharmaceutical composition of claim 22, wherein the pharmaceutically acceptable metal salt of said acid is an alkaline earth metal salt.
24. The stable pharmaceutical composition of claim 22, wherein the active ingredient is CI-981 Hemi-Calcium of Formula (IA):
and wherein the stabilizing pharmaceutically acceptable alkaline earth metal salt additive is calcium carbonate.
and wherein the stabilizing pharmaceutically acceptable alkaline earth metal salt additive is calcium carbonate.
25. The stable pharmaceutical composition of claim 21, 22 or 24, wherein the active ingredient dosage is between about to and about 50% by weight of the composition.
26. A method for preparing a stable pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia comprising a step of mixing thoroughly about 1% to about 50% by weight of the active ingredient of claim 21, claim 22 or claim 24 with about 5% to about 75% by weight of said stabilizing pharmaceutically acceptable alkaline earth metal salt additive.
27. The stable pharmaceutical composition of claim 21, wherein M is a pharmaceutically acceptable alkaline earth metal cation.
28. The stable pharmaceutical composition of claim 21, wherein said at least one stabilizing pharmaceutically acceptable alkaline earth metal salt additive is selected from the group consisting of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate and aluminum magnesium hydroxide.
29. The stable pharmaceutical composition of claim 21, wherein said at least one stabilizing pharmaceutically acceptable alkaline earth metal salt additive is calcium carbonate.
30. The stable pharmaceutical composition of claim 29 wherein said calcium carbonate is in the range from about 5% to about 75% by weight of the composition.
31. The stable pharmaceutical composition of claim 21, comprising an antioxidant.
32. The stable pharmaceutical composition of claim 31 wherein the composition comprises by weight between about 5% and about 75% microcrystalline cellulose; between about 1% and about 80% of hydrous lactose; between about 1% and about 15% of croscarmellose sodium; between about 0.5% and about 6% hydroxypropyl cellulose; between about 0.1% and about 4% of polyoxyethylene sorbitan; between about 0.25%
and about 2% of magnesium stearate; and up to about 3% of sodium ascorbate or butylated hydroxyanisole of the total solid composition.
and about 2% of magnesium stearate; and up to about 3% of sodium ascorbate or butylated hydroxyanisole of the total solid composition.
33. A stabilized solid pharmaceutical composition for peroral treatment of hypercholesterolemia or hyperlipidemia comprising in solid unit dosage form:
(A) [R-(R*, R*)]-2-(4-fluorophenyl) -.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt;
(B) a stabilizer selected from the group consisting of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide comprising by weight about 5% to about 75% of the total solid composition;
(C) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising by weight between about 0.5% and about 6% of the total solid composition;
(D) at least one diluent selected from the group consisting of microcrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1% and about 80% of the total solid composition;
(E) at least one disintegrant selected from the group consisting of carboxymethylcelluose, croscarmellose and starch comprising by weight between about 1% and about 15%
of the total solid composition;
(F) at least one surfactant selected from the group consisting of polyoxyethylelene sorbitan and polyoxythylene-polyoxypropylene copolymer comprising by weight between about 0.1% and about 4% of the total solid composition;
(G) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25% and about 2% of the total solid composition; and (H) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3% of the total solid composition.
(A) [R-(R*, R*)]-2-(4-fluorophenyl) -.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] -1H-pyrrole-1-heptanoic acid hemicalcium salt;
(B) a stabilizer selected from the group consisting of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide comprising by weight about 5% to about 75% of the total solid composition;
(C) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising by weight between about 0.5% and about 6% of the total solid composition;
(D) at least one diluent selected from the group consisting of microcrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1% and about 80% of the total solid composition;
(E) at least one disintegrant selected from the group consisting of carboxymethylcelluose, croscarmellose and starch comprising by weight between about 1% and about 15%
of the total solid composition;
(F) at least one surfactant selected from the group consisting of polyoxyethylelene sorbitan and polyoxythylene-polyoxypropylene copolymer comprising by weight between about 0.1% and about 4% of the total solid composition;
(G) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25% and about 2% of the total solid composition; and (H) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3% of the total solid composition.
34. A method for preparing a stabilized pharmaceutical composition formulated for peroral therapy of hypercholesterolemia or hyperlipidemia comprising:
(a) milling an excess of the drug, CI-981 Hemi-Calcium of the formula IA:
(b) dissolving at least one binder additive in aqueous surfactant solution;
(c) blending the milled drug with at least one drug-stabilizing alkaline earth metal salt additive and at least one diluent additive ingredient with the drug-stabilizing additive and one half of a disintegrant additive in a rotary mixing vessel equipped with a chopping device;
(d) granulating the blended drug mixture of step (c) with the surfactant/binder solution of step (b) in gradual increments in the chopper mixing vessel;
(e) drying the granulated drug mixture overnight at about 50° C.;
(f) sieving the dried granulated drug mixture;
(g) tumble blending the sieved drug mixture with the remaining amount of the disintegrant additive;
(h) mixing separately an aliquot of the step (g) drug mixture with magnesium stearate, sieving same, and returning same to the drug mixture of step (g) and tumble blending the entire drug mixture; and (i) compressing aliquots of the step (h) drug mixture into tablets.
(a) milling an excess of the drug, CI-981 Hemi-Calcium of the formula IA:
(b) dissolving at least one binder additive in aqueous surfactant solution;
(c) blending the milled drug with at least one drug-stabilizing alkaline earth metal salt additive and at least one diluent additive ingredient with the drug-stabilizing additive and one half of a disintegrant additive in a rotary mixing vessel equipped with a chopping device;
(d) granulating the blended drug mixture of step (c) with the surfactant/binder solution of step (b) in gradual increments in the chopper mixing vessel;
(e) drying the granulated drug mixture overnight at about 50° C.;
(f) sieving the dried granulated drug mixture;
(g) tumble blending the sieved drug mixture with the remaining amount of the disintegrant additive;
(h) mixing separately an aliquot of the step (g) drug mixture with magnesium stearate, sieving same, and returning same to the drug mixture of step (g) and tumble blending the entire drug mixture; and (i) compressing aliquots of the step (h) drug mixture into tablets.
35. The method claimed in claim 34, wherein in step (c) the drug stabilizing additive comprises a basic inorganic salt of calcium or magnesium.
36. The method claimed in claim 34, wherein in step (b) the binder additive comprises methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol or starch; and the surfactant comprises polyoxyethylene sorbitan or polyoxyethylene-polyoxypropylene copolymer.
37. The method of claim 34 wherein in step (c) the disintegrant additive comprises croscarmellose sodium, carboxymethyl cellulose calcium or starch.
38. The method claimed in claim 34 wherein in step (c) the diluent additive is selected from the group consisting of microcrystalline cellulose, hydrous lactose, corn starch, sucrose, silicic anhydride and mixtures thereof.
39. The method claimed in claim 34 wherein the diluent additive is at least one polysaccharide.
40. A peroral pharmaceutical composition for treating hypercholesterolemia comprising:
(A) an effective, cholesterol synthesis inhibitory amount of the enantiomer [R-(R*,R*)]-2-[4-fluorophenyl)-.beta.-.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] -1H-pyrrole-1-heptanoic acid, hemicalcium salt stabilized by calcium carbonate, (B) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising by weight between about 0.5% and about 6% of the composition;
(C) at least one diluent selected from the group consisting of micocrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1% and about 80% of the composition;
(D) at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about 1% and about 15%
of the composition;
(E) at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1% and about 4% of the composition;
(F) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25% and about 2% of the composition; and (G) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3% of the composition, in a dosage of solid enantiomer ranging from about 0.1 to about 8.0 mg/kg body weight per day.
(A) an effective, cholesterol synthesis inhibitory amount of the enantiomer [R-(R*,R*)]-2-[4-fluorophenyl)-.beta.-.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] -1H-pyrrole-1-heptanoic acid, hemicalcium salt stabilized by calcium carbonate, (B) at least one binder selected from the group consisting of methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, starch, and hydroxymethylcellulose comprising by weight between about 0.5% and about 6% of the composition;
(C) at least one diluent selected from the group consisting of micocrystalline cellulose, hydrous lactose, cornstarch, sucrose, and silicic anhydride comprising by weight between about 1% and about 80% of the composition;
(D) at least one disintegrant selected from the group consisting of carboxymethylcellulose, croscarmellose and starch comprising by weight between about 1% and about 15%
of the composition;
(E) at least one surfactant selected from the group consisting of polyoxyethylene sorbitan and polyoxyethylene-polyoxypropylene copolymer comprising by weight between about 0.1% and about 4% of the composition;
(F) at least one lubricant selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, and talc comprising by weight between about 0.25% and about 2% of the composition; and (G) optionally at least one antioxidant selected from the group consisting of butylated hydroxyanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, and ascorbic acid comprising by weight up to about 3% of the composition, in a dosage of solid enantiomer ranging from about 0.1 to about 8.0 mg/kg body weight per day.
41. The use of a peroral pharmaceutical composition of claim 40 in the form of a tablet or capsule in the treatment of hypercholesterolemia.
42. A pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture, (A) about 1% to about 50% by weight of the composition of a compound as active ingredient of structural formula I
wherein:
X is: -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of R2 and R3 is hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation; and (B) about 5% to about 75% by weight of the composition of calcium carbonate to stabilize the composition.
wherein:
X is: -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of R2 and R3 is hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation; and (B) about 5% to about 75% by weight of the composition of calcium carbonate to stabilize the composition.
43. The stable pharmaceutical composition of claim 42, wherein M is a pharmaceutically acceptable alkaline earth metal cation.
44. A pharmaceutical composition characterized by improved stability comprising in a mixture, about 1% to about 50% by weight of the composition of a pharmaceutically acceptable metal salt of [R-(R*,R*)]-2-(4-fluorophenyl-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid; and about 5% to about 75% by weight of the composition of calcium carbonate to stabilize the composition.
45. The stable pharmaceutical composition of claim 44, wherein the pharmaceutically acceptable metal salt of said acid is an alkaline earth metal salt.
46. The stable pharmaceutical composition of claim 45, wherein the alkaline earth metal salt is a calcium salt.
47. A pharmaceutical composition characterized by improved stability comprising in a mixture, (A) the Hemi-Calcium salt represented by Formula (IA):
and (B) a stabilizing amount of calcium carbonate.
and (B) a stabilizing amount of calcium carbonate.
48. A method of improving the stability of a pharmaceutical composition containing a compound having the structural formula I
wherein:
X is: -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of R2 and R3 is:
hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation;
said method comprising the step of adding a stabilizing amount of an alkaline earth metal salt to the composition.
wherein:
X is: -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of R2 and R3 is:
hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation;
said method comprising the step of adding a stabilizing amount of an alkaline earth metal salt to the composition.
49. The method of claim 48, wherein the alkaline earth metal salt is selected from the group consisting of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate and aluminum magnesium hydroxide.
50. The method of claim 49, wherein the alkaline earth metal salt is calcium carbonate.
51. The method of claim 48, wherein M is a pharmaceutically acceptable alkaline earth metal cation.
52. The method of claim 51, wherein the alkaline earth metal salt is selected from the group consisting of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate and aluminum magnesium hydroxide.
53. A method of improving the stability of a pharmaceutical compound comprising a pharmaceutically acceptable metal salt of [R-(R*,R*)]-2-(4-fluorophenyl-.beta., .delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1 heptanoic acid wherein said method comprises the step of adding a stabilizing amount of calcium carbonate to said pharmaceutical compound.
54. The method of claim 53, wherein the pharmaceutically acceptable metal salt of said acid is an alkaline earth metal salt.
55. A method of improving the stability of a pharmaceutical compound wherein said pharmaceutical compound is the Hemi-Calcium salt represented by Formula (IA):
said method comprising the addition of a stabilizing amount of calcium carbonate.
said method comprising the addition of a stabilizing amount of calcium carbonate.
56. A pharmaceutical composition for the peroral treatment of hypercholesterolemia or hyperlipidemia characterized by improved stability comprising in a mixture, (A) about 1% to about 50% by weight of the composition of a compound as active ingredient of structural formula I
wherein:
X is: -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of R2 and R3 is hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation; and (B) about 50% to about 99% by weight of the composition of at least one stabilizing pharmaceutically acceptable calcium or lithium salt additive.
wherein:
X is: -CH2-;
-CH2CH2-;
-CH2CH2CH2-; or -CH2CH(CH3);
R1 is: 1-naphthyl;
2-naphthyl;
cyclohexyl;
norbornenyl;
2-, 3-,or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of from two to eight carbon atoms;
one of R2 and R3 is -CONR5R6 where R5 and R6 are independently:
hydrogen;
alkyl of from one to six carbon atoms;
2-, 3-, or 4-pyridinyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy of from three to eight carbon atoms;
and the other of R2 and R3 is hydrogen;
alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl;
phenyl; or phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms;
R4 is: alkyl of from one to six carbon atoms;
cyclopropyl;
cyclobutyl;
cyclopentyl;
cyclohexyl; or trifluoromethyl; and M is a pharmaceutically acceptable metal cation; and (B) about 50% to about 99% by weight of the composition of at least one stabilizing pharmaceutically acceptable calcium or lithium salt additive.
57. The stable pharmaceutical composition of claim 56 wherein the active ingredient is a pharmaceutically acceptable metal salt of [R-(R*,R*)]-2-(4-fluorophenyl-.beta.-.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid.
58. The stable pharmaceutical composition of claim 56 or 57 wherein the stabilizing pharmaceutically acceptable additive is a calcium salt.
59. A pharmaceutical composition comprising (i) the Hemi-Calcium salt of Formula (1A):
and (ii) a metal salt.
and (ii) a metal salt.
60. A pharmaceutical composition according to claim 59, wherein said metal salt (ii) is an alkali metal or alkaline earth metal salt.
61. A pharmaceutical composition according to claim 60, wherein said alkali metal or alkaline earth metal salt is a lithium, magnesium or calcium salt.
62. A pharmaceutical composition according to claim 59, wherein said metal salt (ii) is an alkaline earth metal salt.
63. A pharmaceutical composition according to claim 62, wherein said alkaline earth metal salt is a calcium or magnesium salt.
64. A pharmaceutical composition according to claim 63, wherein said alkaline earth metal salt is a calcium salt.
65. A pharmaceutical composition according to claim 64, wherein said calcium salt is calcium carbonate.
66. The use of a composition of any of claims 59 to 65 in the treatment of hypercholesterolemia or hyperlipidemia.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US570893A | 1993-01-19 | 1993-01-19 | |
| US005,708 | 1993-01-19 | ||
| PCT/US1993/012471 WO1994016693A1 (en) | 1993-01-19 | 1993-12-20 | Stable oral ci-981 formulation and process of preparing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2150372A1 CA2150372A1 (en) | 1994-08-04 |
| CA2150372C true CA2150372C (en) | 2002-08-20 |
Family
ID=21717295
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002150372A Expired - Lifetime CA2150372C (en) | 1993-01-19 | 1993-12-20 | Stable oral ci-981 formulation and process of preparing same |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US5686104A (en) |
| EP (1) | EP0680320B1 (en) |
| JP (1) | JP3254219B2 (en) |
| AT (1) | ATE178794T1 (en) |
| CA (1) | CA2150372C (en) |
| CY (1) | CY2128B1 (en) |
| DE (1) | DE69324504T2 (en) |
| DK (1) | DK0680320T3 (en) |
| ES (1) | ES2133158T3 (en) |
| GR (1) | GR3030359T3 (en) |
| MX (1) | MX9400281A (en) |
| SA (1) | SA01220291A (en) |
| SG (1) | SG45369A1 (en) |
| WO (1) | WO1994016693A1 (en) |
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1993
- 1993-12-20 AT AT94904881T patent/ATE178794T1/en not_active IP Right Cessation
- 1993-12-20 DE DE69324504T patent/DE69324504T2/en not_active Expired - Lifetime
- 1993-12-20 ES ES94904881T patent/ES2133158T3/en not_active Expired - Lifetime
- 1993-12-20 WO PCT/US1993/012471 patent/WO1994016693A1/en active IP Right Grant
- 1993-12-20 CA CA002150372A patent/CA2150372C/en not_active Expired - Lifetime
- 1993-12-20 JP JP51701594A patent/JP3254219B2/en not_active Expired - Lifetime
- 1993-12-20 DK DK94904881T patent/DK0680320T3/en active
- 1993-12-20 SG SG1996005027A patent/SG45369A1/en unknown
- 1993-12-20 EP EP94904881A patent/EP0680320B1/en not_active Expired - Lifetime
-
1994
- 1994-01-05 MX MX9400281A patent/MX9400281A/en not_active IP Right Cessation
- 1994-05-20 US US08/246,919 patent/US5686104A/en not_active Expired - Lifetime
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1997
- 1997-07-02 US US08/886,982 patent/US6126971A/en not_active Expired - Lifetime
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1999
- 1999-05-27 GR GR990401451T patent/GR3030359T3/en unknown
- 1999-05-28 CY CY9900012A patent/CY2128B1/en unknown
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2001
- 2001-08-19 SA SA01220291A patent/SA01220291A/en unknown
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| CY2128B1 (en) | 2002-06-21 |
| CA2150372A1 (en) | 1994-08-04 |
| DE69324504D1 (en) | 1999-05-20 |
| ATE178794T1 (en) | 1999-04-15 |
| SG45369A1 (en) | 1998-10-16 |
| SA01220291A (en) | 2005-12-03 |
| GR3030359T3 (en) | 1999-09-30 |
| JP3254219B2 (en) | 2002-02-04 |
| US5686104A (en) | 1997-11-11 |
| ES2133158T3 (en) | 1999-09-01 |
| DE69324504T2 (en) | 1999-08-26 |
| US6126971A (en) | 2000-10-03 |
| EP0680320B1 (en) | 1999-04-14 |
| WO1994016693A1 (en) | 1994-08-04 |
| MX9400281A (en) | 1994-07-29 |
| JPH08505640A (en) | 1996-06-18 |
| EP0680320A1 (en) | 1995-11-08 |
| DK0680320T3 (en) | 1999-10-25 |
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