CA1323836C - Pharmaceutical compositions having good stability - Google Patents
Pharmaceutical compositions having good stabilityInfo
- Publication number
- CA1323836C CA1323836C CA000591236A CA591236A CA1323836C CA 1323836 C CA1323836 C CA 1323836C CA 000591236 A CA000591236 A CA 000591236A CA 591236 A CA591236 A CA 591236A CA 1323836 C CA1323836 C CA 1323836C
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical composition
- weight
- pravastatin
- lactose
- microcrystalline cellulose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Vending Machines For Individual Products (AREA)
- Formation And Processing Of Food Products (AREA)
Abstract
Abstract PHARMACEUTICAL COMPOSITIONS HAVING GOOD STABILITY
A pharmaceutical composition is provided which has excellent stability, when dispersed in water has a pH of at least about 9, and includes a medicament which is sensitive to a low pH
environment such as pravastatin, one or more fillers such as lactose and/or microcrystalline cellulose, one or more binders, such as microcrystalline cellulose (dry binder) or polyvinylpyrrolidone (wet binder), one or more disintegrating agents such as croscarmellose sodium, one or more lubricants such as magnesium stearate and one or more basifying agents such as magnesium oxide.
A pharmaceutical composition is provided which has excellent stability, when dispersed in water has a pH of at least about 9, and includes a medicament which is sensitive to a low pH
environment such as pravastatin, one or more fillers such as lactose and/or microcrystalline cellulose, one or more binders, such as microcrystalline cellulose (dry binder) or polyvinylpyrrolidone (wet binder), one or more disintegrating agents such as croscarmellose sodium, one or more lubricants such as magnesium stearate and one or more basifying agents such as magnesium oxide.
Description
PHARMACEUTICAL COMPOSITIONS HAVING GOOD STABILITY
The present invention relates to a pharmaceutical composition, proferably in the form of a tablet, which includes a medicament which is sen6itive to a low pH environment, such as pravastatin, yet has excellent stability.
Pharmaceutical composition~ which include a medicament which is unstable in an acidic environment will reguire a basic excipient to enhance storage stability.
Pravastatin, an HMG-CoA rcductase inhibitor disclosed in U. S. Patent No. 4,346,227 to Terahara et al and having the formula , OH
-OOC~r ' HO~J
H ~ ~H3 HO
.- ~
The present invention relates to a pharmaceutical composition, proferably in the form of a tablet, which includes a medicament which is sen6itive to a low pH environment, such as pravastatin, yet has excellent stability.
Pharmaceutical composition~ which include a medicament which is unstable in an acidic environment will reguire a basic excipient to enhance storage stability.
Pravastatin, an HMG-CoA rcductase inhibitor disclosed in U. S. Patent No. 4,346,227 to Terahara et al and having the formula , OH
-OOC~r ' HO~J
H ~ ~H3 HO
.- ~
is sensitive to a low pH environment and will degrade to form its lactone and various isomers.
In accordance with the present invention, a pharmaceutical composition is provided which has excollent storage stability even though it includes a medicament which may degrade in a low pH environment. The pharmaceutical composition of the invontion, which i8 preferably in the form of a tablet, includes a medicamont which is sensitive to a low pH environment, such as pravastatin, one or more fillers, ~uch as lactose and/or microcrystalline cellulose, one or more binders, such as mirocrystalline cellulose (dry binder) or polyvinylpyrrolidone (wet binder), one or more disintegrating agents such as croscarmellose sodium, one or more lubricants such a~ magnesium stearat~, and one or more basifying agents such as magnesium oxide to impart a pH to an aqueous disper~ion of the composition of at least about 9Ø
The invention is particularly adapted to pharmaceutical compositions containing pravastatin a- the medicament. Pravastatin, will be present in an amount within the range of from about 1 to about 60% and preferably from about 3 to about 50%
by weight of the compo~ition.
To ensure acceptable stability, the composition of the invention will include a basifying agent which will raise the p~ of an aqueous dispersion of the composition to at least 9 and preferably to a pH of at least about 9.5.
The basifying agent will be present in an amount within the rango of from about 1 to about 75% by weight and preferably from about 2 to about 70% by weight of the composition. Examples of basifying agents which may be included herein include but are not limited to magnesium oxide, aluminum oxide, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide, with magnesium oxide being preferred.
The composition of the invention will also include one or more fillers or excipients in an amount within the range of from about 5 to about 90% by weight and preferably from about 10 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose.
One or more binders will be present in addition to or in licu of the fillers in an amount within the range of from about 5 to about 35% and preferably from about 10 to about 30% by weight of tho compo~ition. Examples of such binders which are suitable for use herein include polyvinyl-pyrrolidone (molecular weight ranging from about 5000 to about 80,000 and preferably about 40,000), lactose, starches such as corn starch, modified corn starch, sugars, gum acacia and the like as well as a wax binder in finely powdered form (less than 500 microns) such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax.
In accordance with the present invention, a pharmaceutical composition is provided which has excollent storage stability even though it includes a medicament which may degrade in a low pH environment. The pharmaceutical composition of the invontion, which i8 preferably in the form of a tablet, includes a medicamont which is sensitive to a low pH environment, such as pravastatin, one or more fillers, ~uch as lactose and/or microcrystalline cellulose, one or more binders, such as mirocrystalline cellulose (dry binder) or polyvinylpyrrolidone (wet binder), one or more disintegrating agents such as croscarmellose sodium, one or more lubricants such a~ magnesium stearat~, and one or more basifying agents such as magnesium oxide to impart a pH to an aqueous disper~ion of the composition of at least about 9Ø
The invention is particularly adapted to pharmaceutical compositions containing pravastatin a- the medicament. Pravastatin, will be present in an amount within the range of from about 1 to about 60% and preferably from about 3 to about 50%
by weight of the compo~ition.
To ensure acceptable stability, the composition of the invention will include a basifying agent which will raise the p~ of an aqueous dispersion of the composition to at least 9 and preferably to a pH of at least about 9.5.
The basifying agent will be present in an amount within the rango of from about 1 to about 75% by weight and preferably from about 2 to about 70% by weight of the composition. Examples of basifying agents which may be included herein include but are not limited to magnesium oxide, aluminum oxide, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide, with magnesium oxide being preferred.
The composition of the invention will also include one or more fillers or excipients in an amount within the range of from about 5 to about 90% by weight and preferably from about 10 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose.
One or more binders will be present in addition to or in licu of the fillers in an amount within the range of from about 5 to about 35% and preferably from about 10 to about 30% by weight of tho compo~ition. Examples of such binders which are suitable for use herein include polyvinyl-pyrrolidone (molecular weight ranging from about 5000 to about 80,000 and preferably about 40,000), lactose, starches such as corn starch, modified corn starch, sugars, gum acacia and the like as well as a wax binder in finely powdered form (less than 500 microns) such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax.
Where the composition is to be in the form of a tablet, it will include one or more tablet disintegrants in an amount within the range of from about 0.5 to about 10% and preferably from about 2 to about 8% by weight of the composition such as croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch or microcrystalline cellulose as well as one or more tableting lubricants in an amount within the range of from about 0.2 to about 8% and preferably from about 0.5 to about 2% by weight of ~he composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and the like. Other conventional ingredients which may optionally be present include preservatives, stabilizers, anti-adherents or silica flow conditioners or glidants, such as Syloid brand silicon dioxide as well as FD&C colors.
Tablets of the invention may also include a coating layor which may comprise from O to about 15X by weight of the tablet composition. The coating layer which is applied over the tablet core may compriso any conventional coating formulation~ and will includo one or more film-formers or binders, such as a hydrophilic polymer lik- hydroxypropylmethyl cellulose and a hydrophobic polymer like ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, ~-pinene polymers, glyceryl ester~ of wood resins and the like and one or more plasticizers, such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthlate, castor oil and the like. Both core . .
_5_ HX13 tablets as well as coating formulations may contain aluminum lakes to provide color.
The film formers are applied from a solvent system containing one or more solvents including water, alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, or ethylmethyl ~otone, chlorinated hydrocarbons like methylene chloride, dichloroethane, and l,l,l-trichloroethane.
Where a color is employed, the color will be applied together with tho film former, pla~ticizer and solvent compositions.
A preferred tablet composition of the invention will include from about 2 to about 35%
by weight pravastatin, from about 2.5 to about 70%
by weight magnesium oxide, from about 10 to about 80% by weight lactose, from ~bout 10 to about 30%
by weight microcry~talline cellulose or polyvinylpyrrolidone, from about 2 to about 8% by weight cro~carmellose sodium and from about 0.5 to about 2X by weight magnesium stearate.
The pharmaceutical co~position of the invention may be prepared as follows. A mixture of the medicament (pravastatin), basifying agent (preferably magnesium oxide), and a fraction (less than 50%) of the filler (such as lactose), with or without color, are mixed together and passed through a #12 to #40 mesh screen. Filler-binder (such as microcrystalline cellulose), disintegrant (such as croscarmellose sodium) and the remaining lactose are added and mixed. Lubricant (such as magnesium stearate) is added with mixing until a homogeneous mixture is obtained.
The resulting mixture may then be compressed into tablets of up to 1 gram in size.
Where desired, the tablets of the invention may be formulated by a wet granulation technique wherein medicamont (pravastatin) is dissolved in warm agueous solution of binder (polyvinyl-pyrrolidone). The rcsulting solution is used to granulate a mixture of filler (lactose hydrous), basifying agont (such as magnesium oxide), fill~r-binder (microcrystalline collulo~e), and a portion of tho disintogrant (croscarmellose sodium). The granulated mixture is passed through a #4 to #10 m~sh screen and is then dried in a tray drying oven. The dried granulation i~ passed through a #12 to #20 mesh screen. The remainder of the disintegrant and the lubricant (such as magnesium stearate~ are added and the resulting granules are compressed into a tablet.
The tablets may also be formulated by a wet granulation technique where a mixture of the medicament (pravastatin), basifying agent (preferably magnesium oxide), filler-binder (such a~ microcrystalline cellulose), and a fraction (less than 50%) of the filler (such as lactose) with or without color, are mixed and passed through a #12 to #40 mesh screen. A portion of the disintegrant (such as croscarmellose sodium) and the remaining lactose are added and mixed. The resulting mixture is granulated using an aqueous binder solution (such as polyvinyl pyrrolidone).
The formulated wet mixture is passed thorugh a #4 to #20 mesh screen and is then dried in a tray drying oven. The dry granulation is passed through a #12 to #20 mesh screen. The remainder of the disintegrant and the lubricant (such as magnesium stearate) are added and the resulting granules are compressod into a tablet.
All mesh sizes are U.S. Standard ASTME.
_~_ The following Examples represent preferred embodiments of the present invention. All temperatures aro expressed in degrees Centigrade unless otherwise indicated and all mesh sizes are U.S.
Standard ASTME.
Example 1 A pravastatin formulation in the form of tablets having the following composition was prepared as doscribed below.
Inarodient Percent bv Weiaht Pravastatin 6.7 Lactose 67 15 Microcryotalline cellulose 20 Croscarmelloso sodium 2 Magnesium stearate Magne~ium oxide 3.3 Prava~tatin, magnosium oxide and a fraction (30%) of tho lactose wero mixed together for 2 to 10 minutos omploying a suitable mi~er. The resulting mixture wa8 pa~sed through a #12 to #40 mesh size screen.
Microcrystalline cellulose, cro~carmellose sodium and the remaining lactose were added and the mixture was mixed for 2 to 10 minutes. Thereafter, magne-ium ~tearate was added and mixing was continued for 1 to 3 minutes.
The resulting homogeneous mixture was then co~pressed into tablets each containing 5 mg, 10 mg, 20 or 40 mg pravastatin.
A dispersion of the tablets in water had a pH of about 10.
_9_ Upon subjecting the so-formed tablets to a stability study at 60C, or ~0C/75% relative humidity for 2 months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
Example 2 A pravastatin formulation in the form of tablots, each containing 5 mg, 10 mg, 20 mg or 40 mg pravastatin, having the following composition was prepared as described in Example 1, except that color was incorporated into the powder mixture containing pravastatin, magnesium oxide and a fraction of the lactose.
Inar-dient Percent bY Weiaht Pravastatin 6.7 Lactose 66.8 20 Microcrystalline cellulose 20 Croscarmollo~e sodium 2 Magne~ium stearate Maqne~ium oxide 3.3 FD6C Red #3 Lake 0.2 A dispersion of the tablets in water had a pH of about 10.
Upon ~ubjecting the so-formed tablets to a stability study at 60C, or 40C/75% relative humidity for 2 months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
~X13 Example 3 A pravastatin formulation in the ~orm of tablets, each containing 5 mg, 10 mg, 20 mg or 40 mg pravastatin, having the following composition was prepared as described below.
Inarediont Percent bY Wei~ht Pravastatin 6.7 L~ctose 71 lO Microcxystalline cellulose 15 Croscarmello~e sodium 2 Magne~ium stearate Magnesium oxide 3.3 Polyvinylpyrrolidone Pravastatin was dissolved in warm aqueous solution of polyvinylpyrrolidono. The solution wa~ used to granulate a mixture of lactose, magnefiium oxide, microcrystalline cellulose and a fraction of tho croscarmellose sodium. The formulated mixture was pas~ed through a #4 to #10 mesh screen and was then dry granulated in a tray drying oven. The dry granulation was passed through a #12 to #20 mesh screen. The remainder of the disintegrant was added to the dry granules and mixed for 2 to lO minutes. Thereafter, magnesium stearate was added and mixing was continued for 1 to 5 minutes. The resulting granulation was compressed into tablets.
A dispersion of the tablets in water had a pH of about 10.
Upon subjecting the so-formed tablets to a stability study at 60C or 40C/75%
relative humidity for 2 months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
Exam~le 4 A pravastatin formulation in the form of tablots, each containing 5 mg, 10 mg, 20 mg or 40 mg pr~vastatin, having the following composition was prepared as described in Example 3, except that color was incorporated into the powder mixture containing lactose, magnesium oxide, microcrystal-line cellulose and a fraction of the croscarmellose sodium 15 Inaredient Percent bv Weiaht Pravastatin 6.7 Lactose 70.8 Microcry~talline cellulose 15 Croscarmollose sodium 2 20 Magn ~ium stearate Magnesium oxide 3.3 FD&C #3 Lake 0.2 Polyvinylpyrrolidone A dispersion of the tablets in water had a p~ of about lO.
Upon subjecting the so-formed tablets to a stability study at 60C or 40C/75% relative humidity for 2 months, it was found that the tablets including the pravastatin re~ained 3ubstantially stable; no lactone formation was observed.
Example 5 A pravastatin formulation in the form of tablets, each containing 10 mg pravastatin, having the following composition was prepared as described S in Example 3.
Inaredient Percent bv Weiaht Pravastatin 6.7 Lacto8e 54.5 10 Polyvinylpyrrolidone O.S
Croscarmollose sodium 4 Magnosium stoarate Magnesium oxide 33.3 A dispersion of the tablets in water had a pH of about lO.
Upon ~ubjecting the so-formed tablets to a stability study at 40C for 18 months, it was found that the tablets including the pravastatin remainod substantially stable; no lactone formation was obsorved.
E~amDle 6 A pravastatin formulation in the form of tablot~, each containing S mg, 10 mg, 20 mg and 40 mg pravastatin, having the following composition wa~ prepared as described below.
Inqredient Percent bY Weiaht Pravastatin 10 Lactose 66.7 Microcrystalline cellulose 15 5 Croscarmellose sodium 2 Magnesium stearate Magnesium oxide 3.3 Polyvinylpyrrolidone 2 Pravastatin, magnesium oxide, microcrystalline cellulose, and a fraction of the lactose were mixed for 5-10 minutes. The resulting mixture was pas~od through a #12 to #40 mesh ~creen. A portion of the croscarmellose sodium and the remaining lactose were added and mixing was continued for 5-10 minutes. The resulting mixture was granulated with an aqueous polyvinylpyrrolidone solution. The granulated wet mixture wa8 passed through a #4 to #20 mesh screen and then dried in a tray drying oven. The dry granulation was passed through a #12-#20 mesh screon. The remainder of the croscarmellose sodium was added to the granules and mixed for 5-10 minutes. The magnesium stearate was added to the resulting granule mixture and mixing was conti~ued for 1-5 minutes. The resulting formulation was compressed into tablets.
A dispersion of the tablets in water had a pH of about 10.
Upon subjecting the so-formed tablets to a stability study at 60C or 40C/75%
relative humidity for 2 months, it was fsund that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
ExamDle 7 A pravastatin formulation in the form of tablets, each containing 5 mg, 10 mg, 20 mg and 40 mg pravastatin, having the following composition was prepared as described in Example 6, except that FD&C Red #3 Lako color was mixed with pravastatin, magnesium oxide, microcrystalline celluloso and lactose.
Inaredient _ercent bY Weiaht Pravastatin 10 15 Lactose 66.5 Microcrystalline cellulose 15 Croscarmellose sodiu~ 2 Magnesium stearate Magnosium o~ide 3.3 20 FD&C ~ed #3 Lako 0.2 Polyvinylpyrrolidone 2 A dispersion of the tablets in water had a p~ of about 10.
Upon subjocting the so-formed tablets to a stability study at 60C or 40C/75% relative humidity for 2 months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
Example 8 A pravastatin formulation in the form of tablet~, each containing S mg, 10 mg, 20 mg and -15_ HX13 40 mg pravastatin, having the following composition was prepared as described in Example 6, except that all of the croscarmellose sodium was mixed with dry granules prior to addition of magnesium stearate.
Inqred ent Percent bv Weiaht Pravastatin 10 Lactose 64.7 lO Microcrystalline cellulose 15 Croscarmellose sodium 5 Magnesium stearate Magnosium oxide 3.3 Polyvinylpyrrolidone A dispersion of the tablets in water had a pH of about 10.
Upon subjecting the so-formed tablets to a stability study at 60C or 40C/75% relative humidity for 2 months, it was found that the tablet~ including the prava~tatin remained sub~tantially stable; no lactone formation was obsorved.
ExamDle 9 A pravastatin formulation in the form of tablets, having the following co~position was prepared as described in Example 8 except that FD&C Red #3 Lake color was mixed with pravastatin, magnesium oxide, microcrystalline cellulose and lactosc .
~, ...
Inaredient Percent bv Weiaht Pravastatin 10 Lactose hydrous 64.5 Microcrystalline cellulose lS
5 Polyvinylpyrrolidone Croscarmellose sodium 5 Maqnesium stearate Magnesium oxide 3.3 FD&C #3 Lake O.2 A dispersion of the tablets in water had a pH of about 10.
Upon subjecting the so-formed tablets to a stability study at 40 to 60C for several months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
Other basifying agents may be employed which will raise the pH of an agueous dispersion of the compo~ition of the invention as shown in Examples 1 to 9 to about 10. Examples of such basifying agent4 include NaOH, XOH, Ca(OH)2, Mg(OH)2 or NH40~.
. , ,
Tablets of the invention may also include a coating layor which may comprise from O to about 15X by weight of the tablet composition. The coating layer which is applied over the tablet core may compriso any conventional coating formulation~ and will includo one or more film-formers or binders, such as a hydrophilic polymer lik- hydroxypropylmethyl cellulose and a hydrophobic polymer like ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, ~-pinene polymers, glyceryl ester~ of wood resins and the like and one or more plasticizers, such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthlate, castor oil and the like. Both core . .
_5_ HX13 tablets as well as coating formulations may contain aluminum lakes to provide color.
The film formers are applied from a solvent system containing one or more solvents including water, alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, or ethylmethyl ~otone, chlorinated hydrocarbons like methylene chloride, dichloroethane, and l,l,l-trichloroethane.
Where a color is employed, the color will be applied together with tho film former, pla~ticizer and solvent compositions.
A preferred tablet composition of the invention will include from about 2 to about 35%
by weight pravastatin, from about 2.5 to about 70%
by weight magnesium oxide, from about 10 to about 80% by weight lactose, from ~bout 10 to about 30%
by weight microcry~talline cellulose or polyvinylpyrrolidone, from about 2 to about 8% by weight cro~carmellose sodium and from about 0.5 to about 2X by weight magnesium stearate.
The pharmaceutical co~position of the invention may be prepared as follows. A mixture of the medicament (pravastatin), basifying agent (preferably magnesium oxide), and a fraction (less than 50%) of the filler (such as lactose), with or without color, are mixed together and passed through a #12 to #40 mesh screen. Filler-binder (such as microcrystalline cellulose), disintegrant (such as croscarmellose sodium) and the remaining lactose are added and mixed. Lubricant (such as magnesium stearate) is added with mixing until a homogeneous mixture is obtained.
The resulting mixture may then be compressed into tablets of up to 1 gram in size.
Where desired, the tablets of the invention may be formulated by a wet granulation technique wherein medicamont (pravastatin) is dissolved in warm agueous solution of binder (polyvinyl-pyrrolidone). The rcsulting solution is used to granulate a mixture of filler (lactose hydrous), basifying agont (such as magnesium oxide), fill~r-binder (microcrystalline collulo~e), and a portion of tho disintogrant (croscarmellose sodium). The granulated mixture is passed through a #4 to #10 m~sh screen and is then dried in a tray drying oven. The dried granulation i~ passed through a #12 to #20 mesh screen. The remainder of the disintegrant and the lubricant (such as magnesium stearate~ are added and the resulting granules are compressed into a tablet.
The tablets may also be formulated by a wet granulation technique where a mixture of the medicament (pravastatin), basifying agent (preferably magnesium oxide), filler-binder (such a~ microcrystalline cellulose), and a fraction (less than 50%) of the filler (such as lactose) with or without color, are mixed and passed through a #12 to #40 mesh screen. A portion of the disintegrant (such as croscarmellose sodium) and the remaining lactose are added and mixed. The resulting mixture is granulated using an aqueous binder solution (such as polyvinyl pyrrolidone).
The formulated wet mixture is passed thorugh a #4 to #20 mesh screen and is then dried in a tray drying oven. The dry granulation is passed through a #12 to #20 mesh screen. The remainder of the disintegrant and the lubricant (such as magnesium stearate) are added and the resulting granules are compressod into a tablet.
All mesh sizes are U.S. Standard ASTME.
_~_ The following Examples represent preferred embodiments of the present invention. All temperatures aro expressed in degrees Centigrade unless otherwise indicated and all mesh sizes are U.S.
Standard ASTME.
Example 1 A pravastatin formulation in the form of tablets having the following composition was prepared as doscribed below.
Inarodient Percent bv Weiaht Pravastatin 6.7 Lactose 67 15 Microcryotalline cellulose 20 Croscarmelloso sodium 2 Magnesium stearate Magne~ium oxide 3.3 Prava~tatin, magnosium oxide and a fraction (30%) of tho lactose wero mixed together for 2 to 10 minutos omploying a suitable mi~er. The resulting mixture wa8 pa~sed through a #12 to #40 mesh size screen.
Microcrystalline cellulose, cro~carmellose sodium and the remaining lactose were added and the mixture was mixed for 2 to 10 minutes. Thereafter, magne-ium ~tearate was added and mixing was continued for 1 to 3 minutes.
The resulting homogeneous mixture was then co~pressed into tablets each containing 5 mg, 10 mg, 20 or 40 mg pravastatin.
A dispersion of the tablets in water had a pH of about 10.
_9_ Upon subjecting the so-formed tablets to a stability study at 60C, or ~0C/75% relative humidity for 2 months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
Example 2 A pravastatin formulation in the form of tablots, each containing 5 mg, 10 mg, 20 mg or 40 mg pravastatin, having the following composition was prepared as described in Example 1, except that color was incorporated into the powder mixture containing pravastatin, magnesium oxide and a fraction of the lactose.
Inar-dient Percent bY Weiaht Pravastatin 6.7 Lactose 66.8 20 Microcrystalline cellulose 20 Croscarmollo~e sodium 2 Magne~ium stearate Maqne~ium oxide 3.3 FD6C Red #3 Lake 0.2 A dispersion of the tablets in water had a pH of about 10.
Upon ~ubjecting the so-formed tablets to a stability study at 60C, or 40C/75% relative humidity for 2 months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
~X13 Example 3 A pravastatin formulation in the ~orm of tablets, each containing 5 mg, 10 mg, 20 mg or 40 mg pravastatin, having the following composition was prepared as described below.
Inarediont Percent bY Wei~ht Pravastatin 6.7 L~ctose 71 lO Microcxystalline cellulose 15 Croscarmello~e sodium 2 Magne~ium stearate Magnesium oxide 3.3 Polyvinylpyrrolidone Pravastatin was dissolved in warm aqueous solution of polyvinylpyrrolidono. The solution wa~ used to granulate a mixture of lactose, magnefiium oxide, microcrystalline cellulose and a fraction of tho croscarmellose sodium. The formulated mixture was pas~ed through a #4 to #10 mesh screen and was then dry granulated in a tray drying oven. The dry granulation was passed through a #12 to #20 mesh screen. The remainder of the disintegrant was added to the dry granules and mixed for 2 to lO minutes. Thereafter, magnesium stearate was added and mixing was continued for 1 to 5 minutes. The resulting granulation was compressed into tablets.
A dispersion of the tablets in water had a pH of about 10.
Upon subjecting the so-formed tablets to a stability study at 60C or 40C/75%
relative humidity for 2 months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
Exam~le 4 A pravastatin formulation in the form of tablots, each containing 5 mg, 10 mg, 20 mg or 40 mg pr~vastatin, having the following composition was prepared as described in Example 3, except that color was incorporated into the powder mixture containing lactose, magnesium oxide, microcrystal-line cellulose and a fraction of the croscarmellose sodium 15 Inaredient Percent bv Weiaht Pravastatin 6.7 Lactose 70.8 Microcry~talline cellulose 15 Croscarmollose sodium 2 20 Magn ~ium stearate Magnesium oxide 3.3 FD&C #3 Lake 0.2 Polyvinylpyrrolidone A dispersion of the tablets in water had a p~ of about lO.
Upon subjecting the so-formed tablets to a stability study at 60C or 40C/75% relative humidity for 2 months, it was found that the tablets including the pravastatin re~ained 3ubstantially stable; no lactone formation was observed.
Example 5 A pravastatin formulation in the form of tablets, each containing 10 mg pravastatin, having the following composition was prepared as described S in Example 3.
Inaredient Percent bv Weiaht Pravastatin 6.7 Lacto8e 54.5 10 Polyvinylpyrrolidone O.S
Croscarmollose sodium 4 Magnosium stoarate Magnesium oxide 33.3 A dispersion of the tablets in water had a pH of about lO.
Upon ~ubjecting the so-formed tablets to a stability study at 40C for 18 months, it was found that the tablets including the pravastatin remainod substantially stable; no lactone formation was obsorved.
E~amDle 6 A pravastatin formulation in the form of tablot~, each containing S mg, 10 mg, 20 mg and 40 mg pravastatin, having the following composition wa~ prepared as described below.
Inqredient Percent bY Weiaht Pravastatin 10 Lactose 66.7 Microcrystalline cellulose 15 5 Croscarmellose sodium 2 Magnesium stearate Magnesium oxide 3.3 Polyvinylpyrrolidone 2 Pravastatin, magnesium oxide, microcrystalline cellulose, and a fraction of the lactose were mixed for 5-10 minutes. The resulting mixture was pas~od through a #12 to #40 mesh ~creen. A portion of the croscarmellose sodium and the remaining lactose were added and mixing was continued for 5-10 minutes. The resulting mixture was granulated with an aqueous polyvinylpyrrolidone solution. The granulated wet mixture wa8 passed through a #4 to #20 mesh screen and then dried in a tray drying oven. The dry granulation was passed through a #12-#20 mesh screon. The remainder of the croscarmellose sodium was added to the granules and mixed for 5-10 minutes. The magnesium stearate was added to the resulting granule mixture and mixing was conti~ued for 1-5 minutes. The resulting formulation was compressed into tablets.
A dispersion of the tablets in water had a pH of about 10.
Upon subjecting the so-formed tablets to a stability study at 60C or 40C/75%
relative humidity for 2 months, it was fsund that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
ExamDle 7 A pravastatin formulation in the form of tablets, each containing 5 mg, 10 mg, 20 mg and 40 mg pravastatin, having the following composition was prepared as described in Example 6, except that FD&C Red #3 Lako color was mixed with pravastatin, magnesium oxide, microcrystalline celluloso and lactose.
Inaredient _ercent bY Weiaht Pravastatin 10 15 Lactose 66.5 Microcrystalline cellulose 15 Croscarmellose sodiu~ 2 Magnesium stearate Magnosium o~ide 3.3 20 FD&C ~ed #3 Lako 0.2 Polyvinylpyrrolidone 2 A dispersion of the tablets in water had a p~ of about 10.
Upon subjocting the so-formed tablets to a stability study at 60C or 40C/75% relative humidity for 2 months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
Example 8 A pravastatin formulation in the form of tablet~, each containing S mg, 10 mg, 20 mg and -15_ HX13 40 mg pravastatin, having the following composition was prepared as described in Example 6, except that all of the croscarmellose sodium was mixed with dry granules prior to addition of magnesium stearate.
Inqred ent Percent bv Weiaht Pravastatin 10 Lactose 64.7 lO Microcrystalline cellulose 15 Croscarmellose sodium 5 Magnesium stearate Magnosium oxide 3.3 Polyvinylpyrrolidone A dispersion of the tablets in water had a pH of about 10.
Upon subjecting the so-formed tablets to a stability study at 60C or 40C/75% relative humidity for 2 months, it was found that the tablet~ including the prava~tatin remained sub~tantially stable; no lactone formation was obsorved.
ExamDle 9 A pravastatin formulation in the form of tablets, having the following co~position was prepared as described in Example 8 except that FD&C Red #3 Lake color was mixed with pravastatin, magnesium oxide, microcrystalline cellulose and lactosc .
~, ...
Inaredient Percent bv Weiaht Pravastatin 10 Lactose hydrous 64.5 Microcrystalline cellulose lS
5 Polyvinylpyrrolidone Croscarmellose sodium 5 Maqnesium stearate Magnesium oxide 3.3 FD&C #3 Lake O.2 A dispersion of the tablets in water had a pH of about 10.
Upon subjecting the so-formed tablets to a stability study at 40 to 60C for several months, it was found that the tablets including the pravastatin remained substantially stable; no lactone formation was observed.
Other basifying agents may be employed which will raise the pH of an agueous dispersion of the compo~ition of the invention as shown in Examples 1 to 9 to about 10. Examples of such basifying agent4 include NaOH, XOH, Ca(OH)2, Mg(OH)2 or NH40~.
. , ,
Claims (14)
1. A pharmaceutical composition which has enhanced stability comprising medicament which is sensitive to a low pH environment, one or more fillers, one or more binders, one or more disintegrants, one or more lubricants and one or more basifying agents to impart a desired pH of at least 9 to an aqueous dispersion of said composition.
2. The pharmaceutical composition as defined in Claim 1 wherein said medicament is present in an amount within the range of from about 1 to about 60% by weight of the composition.
3. The pharmaceutical composition as defined in Claim 1 wherein the medicament is pravastatin.
4. The pharmaceutical composition as defined in Claim 1 wherein the basifying agent is present in an amount within the range of from about 1 to about 75% by weight of the composition.
5. The pharmaceutical composition as defined in Claim 1 wherein the basifying agent is an alkali metal hydroxide, an alkaline earth metal hydroxide or ammonium hydroxide.
6. The pharmaceutical composition as defined in Claim 5 wherein the basifying agent is MgO, Mg(OH)2, Ca(OH)2, NaOH, KOH, LiOH, NH4OH, Al(OH)3 or magaldrate.
7. The pharmaceutical composition as defined in Claim 1 wherein the filler is present in an amount within the range of from about 5 to about 90% by weight.
8. The pharmaceutical composition as defined in Claim 7 wherein the filler is lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, wood cellulose, microcrystalline cellulose, calcium carbonate or mixtures thereof.
9. The pharmaceutical composition as defined in Claim 1 wherein the binder is present in an amount within the range of from about S to about 35% by weight.
10. The pharmaceutical composition as defined in Claim 9 wherein the binder is microcrystalline cellulose, polyvinylpyrrolidone, lactose, corn starch, modified corn starch, sugars, gum acacia, carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax.
11. The pharmaceutical composition as defined in Claim l wherein the disintegrant is present in an amount within the range of from about 0.5 to about 101% by weight.
12. The pharmaceutical composition as defined in Claim 11 wherein the disintegrant is croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch or microcrystalline cellulose.
13. The pharmaceutical composition as defined in Claim 1 having the following formulation:
from about 3 to about 50% by weight pravastatin, from about 2 to about 70% by weight magnesium oxide, to impart a pH of at least about 9.5, from about 1 to about 85% by weight lactose, from about 10 to about 30% by weight microcrystalline cellulose or polyvinylpyrrolidone, from about 2 to about 8% by weight of croscarmellose sodium; and from about 0.5 to about 2% by weight magnesium stearate.
from about 3 to about 50% by weight pravastatin, from about 2 to about 70% by weight magnesium oxide, to impart a pH of at least about 9.5, from about 1 to about 85% by weight lactose, from about 10 to about 30% by weight microcrystalline cellulose or polyvinylpyrrolidone, from about 2 to about 8% by weight of croscarmellose sodium; and from about 0.5 to about 2% by weight magnesium stearate.
14. The pharmaceutical composition as defined in Claim 1 having a pH in water of at about 10.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/176,127 US5030447A (en) | 1988-03-31 | 1988-03-31 | Pharmaceutical compositions having good stability |
| US176,127 | 1988-03-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1323836C true CA1323836C (en) | 1993-11-02 |
Family
ID=22643088
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000591236A Expired - Lifetime CA1323836C (en) | 1988-03-31 | 1989-02-16 | Pharmaceutical compositions having good stability |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5030447A (en) |
| EP (1) | EP0336298B1 (en) |
| CN (1) | CN1026861C (en) |
| AT (1) | ATE79030T1 (en) |
| AU (1) | AU624117B2 (en) |
| CA (1) | CA1323836C (en) |
| CY (1) | CY1675A (en) |
| DE (1) | DE68902344T2 (en) |
| DK (1) | DK173862B1 (en) |
| HK (1) | HK40093A (en) |
| IE (1) | IE62956B1 (en) |
| NZ (1) | NZ228076A (en) |
| SG (1) | SG107292G (en) |
| ZA (1) | ZA891424B (en) |
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| US3865935A (en) * | 1972-08-10 | 1975-02-11 | Abbott Lab | Tableting of erythromycin base |
| US3891755A (en) * | 1973-07-11 | 1975-06-24 | Abbott Lab | Dosage formulation for erythromycin cetyl sulfate |
| US4342767A (en) * | 1980-01-23 | 1982-08-03 | Merck & Co., Inc. | Hypocholesteremic fermentation products |
| MX7065E (en) * | 1980-06-06 | 1987-04-10 | Sankyo Co | A MICROBIOLOGICAL PROCEDURE FOR PREPARING DERIVATIVES OF ML-236B |
| US4609675A (en) * | 1984-08-17 | 1986-09-02 | The Upjohn Company | Stable, high dose, high bulk density ibuprofen granulations for tablet and capsule manufacturing |
| US4681759A (en) * | 1985-05-08 | 1987-07-21 | Ortho Pharmaceutical Corporation | Rioprostil-PVP complex |
| DE3524572A1 (en) * | 1985-07-10 | 1987-01-15 | Thomae Gmbh Dr K | SOLID PHARMACEUTICAL FORMS FOR PERORAL USE CONTAINING 9-DEOXO-11-DEOXY-9,11- (IMINO (2- (2-METHOXYETHOXY) ETHYLIDEN) -OXY) - (9S) -ERYTHROMYCIN AND METHOD FOR THE PRODUCTION THEREOF |
| GB2189699A (en) * | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated acid-labile medicaments |
-
1988
- 1988-03-31 US US07/176,127 patent/US5030447A/en not_active Expired - Lifetime
-
1989
- 1989-02-16 CA CA000591236A patent/CA1323836C/en not_active Expired - Lifetime
- 1989-02-21 NZ NZ228076A patent/NZ228076A/en unknown
- 1989-02-23 AU AU30276/89A patent/AU624117B2/en not_active Expired
- 1989-02-23 ZA ZA891424A patent/ZA891424B/en unknown
- 1989-03-23 IE IE92989A patent/IE62956B1/en not_active IP Right Cessation
- 1989-03-30 EP EP89105625A patent/EP0336298B1/en not_active Expired - Lifetime
- 1989-03-30 DK DK198901556A patent/DK173862B1/en not_active IP Right Cessation
- 1989-03-30 DE DE8989105625T patent/DE68902344T2/en not_active Expired - Lifetime
- 1989-03-30 AT AT89105625T patent/ATE79030T1/en not_active IP Right Cessation
- 1989-03-31 CN CN89101911A patent/CN1026861C/en not_active Expired - Lifetime
-
1992
- 1992-10-14 SG SG1072/92A patent/SG107292G/en unknown
-
1993
- 1993-04-22 HK HK400/93A patent/HK40093A/en not_active IP Right Cessation
- 1993-10-10 CY CY1675A patent/CY1675A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2935220B2 (en) | 1999-08-16 |
| CN1026861C (en) | 1994-12-07 |
| DK155689A (en) | 1989-10-01 |
| AU624117B2 (en) | 1992-06-04 |
| JPH026406A (en) | 1990-01-10 |
| DE68902344D1 (en) | 1992-09-10 |
| DE68902344T2 (en) | 1993-01-07 |
| ZA891424B (en) | 1989-10-25 |
| IE890929L (en) | 1989-09-30 |
| EP0336298B1 (en) | 1992-08-05 |
| US5030447A (en) | 1991-07-09 |
| CN1036508A (en) | 1989-10-25 |
| CY1675A (en) | 1993-10-10 |
| SG107292G (en) | 1992-12-24 |
| EP0336298A1 (en) | 1989-10-11 |
| AU3027689A (en) | 1989-10-05 |
| DK173862B1 (en) | 2002-01-07 |
| DK155689D0 (en) | 1989-03-30 |
| IE62956B1 (en) | 1995-03-08 |
| HK40093A (en) | 1993-04-30 |
| NZ228076A (en) | 1991-04-26 |
| ATE79030T1 (en) | 1992-08-15 |
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