US20080300305A1 - Method of purifying pravastatin - Google Patents
Method of purifying pravastatin Download PDFInfo
- Publication number
- US20080300305A1 US20080300305A1 US12/187,555 US18755508A US2008300305A1 US 20080300305 A1 US20080300305 A1 US 20080300305A1 US 18755508 A US18755508 A US 18755508A US 2008300305 A1 US2008300305 A1 US 2008300305A1
- Authority
- US
- United States
- Prior art keywords
- batch
- compactin
- pravastatin
- weight
- less
- 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.)
- Abandoned
Links
- TUZYXOIXSAXUGO-CANQTTTMSA-N [H][C@@]12C(=C[C@@H](O)C[C@@H]1OC(=O)[C@@H](C)CC)C=C[C@H](C)C2CCC(O)C[C@@H](O)CC(=O)O Chemical compound [H][C@@]12C(=C[C@@H](O)C[C@@H]1OC(=O)[C@@H](C)CC)C=C[C@H](C)C2CCC(O)C[C@@H](O)CC(=O)O TUZYXOIXSAXUGO-CANQTTTMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
-
- 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
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
Definitions
- the invention encompasses methods for isolating and purifying pravastatin from reactions conducted in aqueous fermentation broths.
- the invention encompasses the synthesis, isolation, and purification of pravastatin, such as pravastatin made by the fermentation of compactin.
- LDL low density lipoprotein
- Statin drugs are currently the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease.
- This class of drugs includes, inter alia, compactin, lovastatin, simvastatin, pravastatin and fluvastatin.
- the mechanism of action of statin drugs has been elucidated in some detail.
- the statin drugs disrupt the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoA reductase”).
- HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Consequently, HMG-CoA reductase inhibition leads to a reduction in the rate of formation of cholesterol in the liver.
- Pravastatin is the common medicinal name of the chemical compound [1S-[1 ⁇ ( ⁇ *, ⁇ *)2 ⁇ ,6 ⁇ ,8 ⁇ (R*),8a ⁇ ]]-1,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoic acid. (CAS Registry No. 81093-370.)
- the molecular structure of pravastatin in free acid form is represented by Formula (I):
- Pravastatin possesses an alkyl chain that is terminated by a carboxylic acid group closed in a lactone and that bears two hydroxyl groups, one at the ⁇ position and a second at the ⁇ position, with respect to the carboxylic acid group.
- the alkyl chain is the portion of the molecule that binds to HMG-CoA reductase.
- the carboxylic acid group and the hydroxyl group at the ⁇ position are prone to lactonize.
- Compounds that form a lactone like the statins, may exist either in the free acid form or the lactone form or in an equilibrium mixture of both forms.
- Pravastatin exhibits an important therapeutic advantage over other statins. Pravastatin selectively inhibits cholesterol synthesis in the liver and small intestine but leaves cholesterol synthesis in the peripheral cells substantially unaffected. Koga, T. et al., Biochim. Biophys. Acta, 1045, 115-120 (1990). The selectivity appears to be due, in part, to the presence of a hydroxyl group at the C-6 position of the hexahydronaphthalene nucleus. The C-6 position is occupied by a hydrogen atom in compactin and a methyl group in lovastatin. Pravastatin is less able to permeate the lipophilic membranes of peripheral cells than the other more lipophilic congeners. Serajuddin et al., J. Pharm. Sci., 80, 830-34 (1991). Also, the limited mobility of pravastatin is thought to account for its more localized action in the liver and intestine.
- pravastatin can be obtained by fermentation of compactin using a variety of microorganisms: Absidia coerulea IFO 4423 spores, Cunninghamella echinulata IFO 4445 , Streptomyces rosochromogenus NRRL 1233 , Syncephalastrum racemosum IFO 4814 and Syncephalastrum racemosum IFO 4828.
- Absidia coerulea IFO 4423 spores Cunninghamella echinulata IFO 4445 , Streptomyces rosochromogenus NRRL 1233 , Syncephalastrum racemosum IFO 4814 and Syncephalastrum racemosum IFO 4828.
- pravastatin after fermentation pravastatin was separated from the fermentation broth by acidifying the broth to a pH of 3 and extracting pravastatin and other non-hydrophilic organics with ethyl acetate, followed by washing with brine.
- the pravastatin free acid was lactonized by addition of a catalytic amount of trifluoroacetic acid, then neutralized with dilute sodium bicarbonate, dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative reverse-phase high performance liquid chromatography (“HPLC”).
- U.S. Pat. No. 5,942,423 discloses the microbial hydroxylation of compactin to pravastatin using a strain of Actinomadura .
- the pravastatin is isolated, enriched, separated, or purified, using commonly known techniques such as precipitation, extraction, and chromatography.
- HPLC is disclosed as the preferred method of isolation of pravastatin from the fermentation broth.
- U.S. Pat. No. 5,202,029 discusses a process for the purification of HMG-CoA reductase inhibitors using HPLC.
- HPLC is not an economical purification method for large-scale preparation of chemical compounds and difficulties associated with high volume purification may discourage the use of HPLC.
- the HMG-CoA reductase inhibitor is eluted from the HPLC column as a solute dissolved in the eluent. The eluent is partially evaporated and then water is added to induce crystallization of the HMG-CoA reductase inhibitor.
- U.S. Pat. No. 5,616,595 discloses a continuous process for recovering water-insoluble compounds from a fermentation broth by tangential filtration.
- the fermentation broth is cycled past a filter and becomes increasingly concentrated with each cycle because of water loss through the filter.
- the concentrated broth is slurried with a solvent in which the desired compound is soluble.
- the slurry is then cycled past the filter.
- the desired compound is collected as a filtrate and subsequently isolated from the filtrate.
- the compound may be further purified.
- the patent states that the method is applicable to a wide variety of compounds including lovastatin, pravastatin and simvastatin.
- pravastatin is by enzymatic hydroxylation of compactin at the C-6 position.
- the known methods for isolating a statin from a fermentation broth are ill-suited for isolating pure pravastatin, in particular from the pravastatin sodium salt.
- the currently employed methods do not achieve pharmaceutically acceptable levels of purity, or alternatively, require economically impractical chromatographic separation to achieve high purity.
- the invention encompasses methods of synthesizing pravastatin comprising less than about 0.1% by weight pravastatin C comprising:
- the purifying step in a) may be performed by a crystallization process comprising dissolving or suspending compactin in at least one water miscible organic solvent; adding water in a volume ratio of about 0.16 to about 0.4 to the water miscible organic solvent to the reaction mixture; cooling the reaction mixture to a temperature in which compactin crystallizes; and collecting the pure compactin crystals.
- the invention encompasses compactin prepared according to the crystallization process described above, and pharmaceutical formulations comprising thereof.
- the invention encompasses methods of synthesizing pravastatin having less than about 0.1% by weight pravastatin C comprising:
- the invention encompasses pravastatin comprising less than about 0.1% pravastatin C by weight made by a fermentation of compactin having less than 0.16% compactin C by weight, and pharmaceutical formulations comprising thereof.
- the invention encompasses methods of synthesizing pravastatin by hydroxylation of compactin, wherein the compactin contains less than about 0.16% by weight of compactin C.
- the invention provides a method for preparing a composition comprising pravastatin sodium having less than about 0.1% by weight pravastatin C.
- the method includes starting with a compactin sample comprising a sufficiently low level of compactin C.
- the amount of compactin C in the compactin sample is less than about 0.16% by weight.
- the method comprises:
- the invention provides a composition comprising pravastatin sodium having less than about 0.1% by weight pravastatin C, and pharmaceutical formulations comprising thereof.
- the invention provides compactin compositions comprising less than about 0.16% by weight compactin C and pharmaceutical formulations comprising thereof.
- the invention provides a process for purifying pravastatin which comprises dissolving pravastatin salt in water to form an aqueous solution of pravastatin; adjusting the pH of the aqueous solution of pravastatin to a pH of about 6.7 to about 10; contacting the pravastatin aqueous solution to an adsorption column bed; eluting pravastatin with an eluting solution; and collecting fractions having pure pravastatin.
- the pravastatin salt in the aqueous solution may be obtained by hydroxylation of compactin.
- the present invention provides pravastatin produced by this purification process, and pharmaceutical formulations comprising thereof.
- the methods of the present invention produce high purity pravastatin by: i) using relatively pure starting materials to synthesize pravastatin or ii) using adsorption chromatography. Therefore in one aspect of the present invention, high purity pravastatin is synthesized by using pure compactin, which is obtained by at least one step of purifying the compactin prior to pravastatin synthesis, or by selecting a batch of pure compactin.
- pravastatin The high purity and high yield pravastatin is obtained without the need for multiple extractions, or purification by HPLC. Therefore the invention is more cost effective and practical than previous methods for isolating pravastatin, meeting the need in the art for an economically practical method of preparing pravastatin on a preparative scale.
- pravastatin C refers to the pravastatin impurity having the chemical name 3S,5S-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[[(2S)-2-methylpentanoyl]oxy]-1,2,6,7,8,8a-hexahydronaphtalen-1-yl]heptanoic acid.
- compactin C refers to the compactin impurity having the chemical name pentanoic acid, 2-methyl-, 1,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester, [1S-[1 ⁇ (R*),7 ⁇ ,8 ⁇ (2S*,4S*),8a ⁇ ]].
- the register number is 159225-32-8.
- compactin batch refers to a composition consisting essentially of compactin, which composition may contain low levels of impurities, one of which may be compactin C.
- sample refers to a portion of the “compactin batch” that is taken for the purpose of measuring the compactin C level.
- the present invention provides a method for synthesizing a pravastatin composition comprising less than about 0.1% by weight pravastatin C comprising:
- the composition in a) may be purified by crystallization.
- the composition in a) is crystallized until it contains less than about 0.15% by weight compactin C.
- the pravastatin composition synthesized in b) contains less than about 0.04% by weight pravastatin C, more preferably, less than about 0.03% by weight pravastatin C, and most preferably, the composition comprises less than about 0.02% by weight pravastatin C.
- the crystallization process comprises dissolving or suspending compactin in at least one water miscible organic solvent to form a reaction mixture; adding water to the reaction mixture, in a volume of about 0.16 to about 0.4 to the water miscible organic solvent; cooling the reaction mixture to a temperature until compactin crystallizes; and collecting the pure compactin crystals.
- the crystallization process may be repeated as necessary to obtain the desired compactin purity.
- the water miscible organic solvents comprise at least one of C 3-5 ketones, nitriles, and C 1-4 alcohols. More preferably, the water miscible organic solvent is at least one of acetone, methanol, ethanol, n-propanol, isopropanol, acetonitrile, methyl-ethyl-ketone, or tetrahydrofuran. Most preferably, the water miscible organic solvent is at least one of acetone, methanol, ethanol, isopropanol, or acetonitrile.
- the volume of water miscible organic solvent necessary to dissolve or suspend the compactin can be easily determined by one of ordinary skill in the art with little or no experimentation. The volume will vary depending upon the amount of compactin and the boiling point of the water miscible organic solvent. Typically, the volume of water miscible organic solvent is sufficient to dissolve or suspend the compactin at the reflux temperature of the water miscible organic solvent. Preferably, the volume of water miscible organic solvent is about seven times the mass of compactin, and more preferably about fives times the mass of compactin.
- the amount of water added water added is about 0.17 to about 0.4 times the volume of the water miscible organic solvent.
- the reaction mixture Prior to the addition of water, the reaction mixture is heated to a temperature of about 30° C. to about reflux, and preferably to a temperature of about 20° C. to about 25° C.
- the reaction mixture should be cooled to a temperature at which compactin crystallizes.
- the appropriate temperature may easily be determined by the skilled artisan as the temperature at which crystals become visible.
- the reaction mixture of compactin is cooled to a temperature from about 0° C. to about 30° C., and preferably to a temperature of about 20° C. to about 25° C.
- the reaction mixture is typically cooled at a rate of about 1° C. to about 6° C. per hour and preferably, at a rate of about 2° C. to about 4° C. per hour.
- the reaction mixture may optionally may be heated to about 30° C. for 16 hours prior to cooling for a second time.
- the compactin crystals are then collected using any method commonly known to one of ordinary skill in the art. Such methods include, but are not limited to, centrifuge, filtration funnel, belt filtration, or press filtration. Subsequently, the compactin crystals are washed with a solution of water and water miscible organic solvent, preferably in a 1:1 volume ratio. Thereafter, the collected compactin crystals are dried using techniques commonly known to one of ordinary skill in the art. The pure compactin is then used to synthesize a high purity pravastatin composition.
- the present invention also provides compactin containing less than about 0.16% compactin C, and pharmaceutical formulations thereof.
- compactin C is present in an amount of less than about 0.15% by weight.
- the present invention further provides compactin prepared according to the above process, and pharmaceutical formulations thereof.
- One of the advantages of the present invention is that the high purity pravastatin is obtained without the need for purification by HPLC.
- Measurement of compactin C in the samples of compactin batches can be conducted by standard analytical chemistry techniques, for example reverse phase HPLC or other suitable chromatographic methods.
- the synthesis of pravastatin sodium by enzymatic hydroxylation of compactin as well as the isolation of the pure pravastatin are described in U.S. Pat. Nos. 5,942,423 and 4,346,227, hereby incorporated by reference.
- the fermentation or hydroxylation broth from which pravastatin is then isolated can be any of the aqueous broths known for industrial scale fermentation of compactin.
- the present invention provides a composition comprising pravastatin sodium and less than about 0.1% by weight pravastatin C, preferably, less than about 0.04% by weight pravastatin C, more preferably less than 0.03% by weight pravastatin C, and most preferably, less than about 0.02% by weight pravastatin C.
- the present invention provides a method for the purification of pravastatin or pravastatin salts comprising using adsorption chromatography.
- This method comprises dissolving pravastatin or its salt in water to form an aqueous solution; adjusting the pH of the aqueous solution to a pH of about 6.7 to about 10; adding the aqueous solution to an adsorption column bed, eluting pravastatin with an eluting solution; and collecting fractions having high purity pravastatin.
- the purification method may be repeated as necessary to achieve the desired pravastatin purity.
- the amount of water used should be sufficient to dissolve the pravastatin or pravastatin salt and may be easily determined by one of ordinary skill in the art as the amount may vary depending on the amount of pravastatin or salt. Typically, the amount of water used is about 8 ml of water per gram of pravastatin salt and preferably about 6 ml of water per gram.
- the pH of the aqueous solution may be adjusted using any method known in the art. Typically, the pH of the aqueous solution may be adjusted using a basic solution, such as 25% NaOH, in sufficient amount to achieve a pH of about 6.7 to about 10.
- a basic solution such as 25% NaOH
- the adsorption column bed includes resins such as polymeric adsorbents with highly porous structures whose internal surfaces can adsorb and then desorb a wide variety of different species depending on the environment in which they are used.
- resins such as polymeric adsorbents with highly porous structures whose internal surfaces can adsorb and then desorb a wide variety of different species depending on the environment in which they are used.
- the polymeric adsorbents exhibit non-polar or hydrophobic behavior and may adsorb organic species that are sparingly soluble.
- the adsorption column bed may be a reverse phase silica gel column.
- Commercially available resins include those manufactured by Rohm and Haas, Philadelphia Pa., such as AMBERLITETM XADTM 4, XADTM 7, XADTM 16, XADTM 16HP, XADTM 761, and XADTM 1180.
- resins suitable for the process of the invention include those manufactured and sold by Mitsubishi Kasei Corporation, Japan, such as DAIONTM HP 10, DAIONTM HP 20, DAIONTM HP 21, DAIONTM HP 30, DAIONTM HP 40, DAIONTM HP 50, DAIONTM SP 800, DAIONTM SP 825, DAIONTM SP 850, DAIONTM SP 875, DAIONTM SP 205, DAIONTM SP 207, DAIONTM HP1MG, and DAIONTM HP2MG.
- Reverse phase silica gels include those manufactured and sold by Merck & Co., Whitehouse Station, N.J., such as C-18, RP-2, RP-8, and RP-18.
- Eluting pravastatin or pravastatin salt with an eluting solution is carried out using techniques known to one of ordinary skill in the art.
- the eluting solution typically comprises water and at least one of acetone, acetonitrile, methanol, ethanol, or isopropanol.
- the ratio of water to acetone, acetonitrile, methanol, ethanol, or isopropanol is about 7:3 to about 9:1 by volume, and more preferably the ratio is 8:2.
- the fractions with high purity pravastatin are collected, reduced in volume, and dried. See European Pharmacopoeia 4.5 (2003).
- the pravastatin produced by this method contains less than about 0.1% by weight pravastatin C.
- pravastatin contains less than about 0.1% by weight pravastatin C, more preferably less than 0.03% by weight, and most preferably, less than about 0.02% by weight.
- the present invention further provides purified pravastatin and pravastatin sodium produced by the methods of the invention, and pharmaceutical formulations comprised thereof.
- compositions of the present invention contain purified pravastatin or compactin, such as disclosed herein.
- the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g.
- Avicel® microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
- Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
- Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
- carbomer e.g. carbopol
- carboxymethylcellulose sodium, dextrin ethyl cellulose
- gelatin
- the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
- Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
- alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®
- Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
- Excipients that may function as glidants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
- a dosage form such as a tablet
- the composition is subjected to pressure from a punch and dye.
- Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
- a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
- Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
- Common flavoring agents and flavor enhancers for pharmaceutical products include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
- Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
- pravastatin of compactin in combination with any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
- Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
- Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
- Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
- a viscosity enhancing agent include, but are not limited to, acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
- Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
- Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
- a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
- a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
- the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
- the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
- the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
- Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
- the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
- the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
- compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
- a composition for tableting or capsule filling may be prepared by wet granulation.
- wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
- the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
- the granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
- a tableting composition may be prepared conventionally by dry blending.
- the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
- a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
- Direct compression produces a more uniform tablet without granules.
- Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
- a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
- PLAVDX The dosage of PLAVDX may be used as guidance.
- PLAVIX is administered orally.
- the recommended oral dose of PLAVIX is 75 mg once daily.
- the samples were prepared in 0.4 mg/ml concentrations and the impurity profile was determined as the peak area compared to the standardized sample.
- the impurity compactin C in an amount of 0.25% by weight.
- the pure compactin was then fermented into pravastatin and isolated according to the methods disclosed in U.S. Pat. No. 6,444,452.
- Analysis of the pravastatin salt by HPLC determined that the impurity pravastatin C was present in an amount of 0.12% by weight.
- the pravastatin salt from Example 1 (90 g) was dissolved in water (540 ml), thereafter, the pH was adjusted to 6.7 to 10 using 25% NaOH.
- the pravastatin salt solution was passed through a sorption resin bed (550 ml of sorption resin XADTM 1180). The column diameter was 3.2 cm and the applied flow rate was 90 ml/hour. After adsorption of pravastatin salt, the column was eluted with 4 L of water:acetone (8:2) and the fractions containing pravastatin were combined (1760 ml), reduced in volume, and pravastatin salt (64.8 g) was isolated. Impurity analysis by HPLC, as described in European Pharmacopoeia, determined that pravastatin C was present in an amount of 0.04% by weight.
- a compactin sample with compactin C present in an amount of 0.2% by weight was purified by crystallization.
- the compactin sample (30 g) was suspended in acetone (5 times by volume) and heated to reflux. Water (1.25 times by volume) was added to the heated suspension, and the solution was allowed to cool to 20° C. at a cooling rate of 2° C./hour. Upon cooling, crystals formed which were stirred for 2 hours at 20° C., and subsequently collected by filtration, washed with a water:acetone (1:1) solution, and dried. After drying, the crystalline compactin (28.2 g) was collected and analyzed by HPLC, as described in the European Pharmacopoeia. The crystalline compactin had 0.15% by weight of compactin C.
- a compactin sample with compactin C in an amount of 0.2% by weight was purified by crystallization.
- the compactin sample (30 g) was suspended in methanol (5 times by volume) and heated to reflux. Water (1.5 times by volume) was added to the heated suspension, and the solution was allowed to cool to 20° C. at a cooling rate of 2° C./hour. Thereafter, the solution was heated to 30° C. and stirred for 16 hours. Upon cooling, crystals formed which were collected by filtration, washed with a water:methanol (1:1) solution, and dried. After drying, the crystalline compactin (27.2 g) was collected and analyzed by HPLC. The crystalline compactin had 0.15% by weight of compactin C.
- pravastatin is isolated according to the methods disclosed in U.S. Pat. No. 6,444,452.
- Achievable pravastatin C level is 0.02% by weight.
- a compactin sample with compactin C in an amount of 0.2% by weight was purified by crystallization.
- the compactin sample (30 g) was suspended in isopropanol (5 times by volume) and heated to reflux. Water (1.5 times by volume) was added to the heated suspension, and the solution was allowed to cool to 25° C. at a cooling rate of 2° C./hour. Upon cooling, crystals formed which were collected by filtration, washed with a water:isopropanol (1:1) solution, and dried. After drying, the crystalline compactin (22.9 g) was collected and analyzed by HPLC. The crystalline compactin had 0.16% by weight of compactin C.
- a compactin sample with compactin C in an amount of 0.2% by weight was purified by crystallization.
- the compactin sample (30 g) was suspended in acetonitrile (5 times by volume) and heated to reflux. Water (1.5 times by volume) was added to the heated suspension, and the solution was allowed to cool to 25° C. at a cooling rate of 2° C./hour. Upon cooling, crystals formed which were collected by filtration, washed with a water:acetonitrile (1:1) solution, and dried. After drying, the crystalline compactin (24.2 g) was collected and analyzed by HPLC. The crystalline compactin had 0.15% by weight of compactin C.
- pravastatin C level is 0.02% by weight.
Abstract
The present invention provides pure pravastatin compositions and pure compactin compositions, and methods for the preparation thereof.
Description
- This application is a continuation of Ser. No. 10/996,238, filed Nov. 23, 2004, and claims the benefits of U.S. Provisional Patent Application Nos. 60/525,494, filed Nov. 24, 2003, 60/532,314, filed Dec. 22, 2003, and 60/554,165, filed Mar. 18, 2004, the contents of all of which are incorporated herein by reference.
- The invention encompasses methods for isolating and purifying pravastatin from reactions conducted in aqueous fermentation broths. In particular, the invention encompasses the synthesis, isolation, and purification of pravastatin, such as pravastatin made by the fermentation of compactin.
- Complications of cardiovascular disease, such as myocardial infarction, stroke, and peripheral vascular disease account for half of the deaths in the United States. A high level of low density lipoprotein (LDL) in the bloodstream has been linked to the formation of coronary lesions which obstruct the flow of blood and can rupture and promote thrombosis. Goodman and Gilman, T
HE PHARMACOLOGICAL BASIS OF THERAPEUTICS , p. 879 (9th ed., 1996). Reducing plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and in patients who are free of cardiovascular disease but who have hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b. - Statin drugs are currently the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease. This class of drugs includes, inter alia, compactin, lovastatin, simvastatin, pravastatin and fluvastatin. The mechanism of action of statin drugs has been elucidated in some detail. The statin drugs disrupt the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoA reductase”). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Consequently, HMG-CoA reductase inhibition leads to a reduction in the rate of formation of cholesterol in the liver.
- Pravastatin is the common medicinal name of the chemical compound [1S-[1α(β*,δ*)2α,6α,8β(R*),8aα]]-1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoic acid. (CAS Registry No. 81093-370.) The molecular structure of pravastatin in free acid form is represented by Formula (I):
- Pravastatin possesses an alkyl chain that is terminated by a carboxylic acid group closed in a lactone and that bears two hydroxyl groups, one at the β position and a second at the δ position, with respect to the carboxylic acid group. The alkyl chain is the portion of the molecule that binds to HMG-CoA reductase. The carboxylic acid group and the hydroxyl group at the δ position are prone to lactonize. Compounds that form a lactone, like the statins, may exist either in the free acid form or the lactone form or in an equilibrium mixture of both forms. Compounds that form lactones cause processing difficulties during the manufacture of statin drugs because the free acid and the lactone form of the compounds have different polarities. One method of purifying one form will remove impurities but also is likely to remove the other form thereby resulting in a lower overall yield. Consequently, great care must be exercised when handling lactonizable compounds to isolate them in high yield.
- Pravastatin exhibits an important therapeutic advantage over other statins. Pravastatin selectively inhibits cholesterol synthesis in the liver and small intestine but leaves cholesterol synthesis in the peripheral cells substantially unaffected. Koga, T. et al., Biochim. Biophys. Acta, 1045, 115-120 (1990). The selectivity appears to be due, in part, to the presence of a hydroxyl group at the C-6 position of the hexahydronaphthalene nucleus. The C-6 position is occupied by a hydrogen atom in compactin and a methyl group in lovastatin. Pravastatin is less able to permeate the lipophilic membranes of peripheral cells than the other more lipophilic congeners. Serajuddin et al., J. Pharm. Sci., 80, 830-34 (1991). Also, the limited mobility of pravastatin is thought to account for its more localized action in the liver and intestine.
- According to the U.S. Pat. No. 4,346,227 patent, pravastatin can be obtained by fermentation of compactin using a variety of microorganisms: Absidia coerulea IFO 4423 spores, Cunninghamella echinulata IFO 4445, Streptomyces rosochromogenus NRRL 1233, Syncephalastrum racemosum IFO 4814 and Syncephalastrum racemosum IFO 4828. In example 1 of the '227 patent, after fermentation pravastatin was separated from the fermentation broth by acidifying the broth to a pH of 3 and extracting pravastatin and other non-hydrophilic organics with ethyl acetate, followed by washing with brine. The pravastatin free acid was lactonized by addition of a catalytic amount of trifluoroacetic acid, then neutralized with dilute sodium bicarbonate, dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative reverse-phase high performance liquid chromatography (“HPLC”).
- U.S. Pat. No. 5,942,423 discloses the microbial hydroxylation of compactin to pravastatin using a strain of Actinomadura. In the preferred embodiments, the pravastatin is isolated, enriched, separated, or purified, using commonly known techniques such as precipitation, extraction, and chromatography. HPLC is disclosed as the preferred method of isolation of pravastatin from the fermentation broth.
- U.S. Pat. No. 5,202,029 discusses a process for the purification of HMG-CoA reductase inhibitors using HPLC. One skilled in the art will recognize that HPLC is not an economical purification method for large-scale preparation of chemical compounds and difficulties associated with high volume purification may discourage the use of HPLC. After impurity separation on the HPLC column, the HMG-CoA reductase inhibitor is eluted from the HPLC column as a solute dissolved in the eluent. The eluent is partially evaporated and then water is added to induce crystallization of the HMG-CoA reductase inhibitor.
- U.S. Pat. No. 5,616,595 discloses a continuous process for recovering water-insoluble compounds from a fermentation broth by tangential filtration. The fermentation broth is cycled past a filter and becomes increasingly concentrated with each cycle because of water loss through the filter. Once a desired concentration is reached, the concentrated broth is slurried with a solvent in which the desired compound is soluble. The slurry is then cycled past the filter. The desired compound is collected as a filtrate and subsequently isolated from the filtrate. Optionally, the compound may be further purified. The patent states that the method is applicable to a wide variety of compounds including lovastatin, pravastatin and simvastatin.
- Presently, the most economically feasible method of making pravastatin is by enzymatic hydroxylation of compactin at the C-6 position. The known methods for isolating a statin from a fermentation broth, however, are ill-suited for isolating pure pravastatin, in particular from the pravastatin sodium salt. Moreover, the currently employed methods do not achieve pharmaceutically acceptable levels of purity, or alternatively, require economically impractical chromatographic separation to achieve high purity.
- The invention encompasses methods of synthesizing pravastatin comprising less than about 0.1% by weight pravastatin C comprising:
-
- a) purifying compactin containing compactin C until the amount of compactin C is less than about 0.16% by weight, and
- b) synthesizing pravastatin using the compactin from a).
- The purifying step in a) may be performed by a crystallization process comprising dissolving or suspending compactin in at least one water miscible organic solvent; adding water in a volume ratio of about 0.16 to about 0.4 to the water miscible organic solvent to the reaction mixture; cooling the reaction mixture to a temperature in which compactin crystallizes; and collecting the pure compactin crystals.
- In another embodiment, the invention encompasses compactin prepared according to the crystallization process described above, and pharmaceutical formulations comprising thereof.
- In one embodiment, the invention encompasses methods of synthesizing pravastatin having less than about 0.1% by weight pravastatin C comprising:
-
- a) dissolving or suspending a composition comprising compactin and compactin C in at least one water miscible organic solvent;
- b) adding water in a volume ratio of about 0.16 to about 0.4 to the water miscible organic solvent;
- c) cooling the reaction mixture;
- d) isolating a sample of the composition comprising compactin and compactin C resulting from c);
- e) measuring the quantity of compactin C in the isolated sample from d);
- f) determining whether or not the quantity of compactin C in e) is less than about 0.16% by weight; and
- g) purifying by crystallization the composition resulting from d) if the quantity of compactin C measured in e) is about 0.16% by weight or more until the quantity of compactin C is less than about 0.16% by weight, and synthesizing a pravastatin composition from the composition so purified; or,
- h) if the quantity of compactin C measured in e) is less than about 0.16% by weight, synthesizing a pravastatin composition from the composition of step d).
- In another embodiment, the invention encompasses pravastatin comprising less than about 0.1% pravastatin C by weight made by a fermentation of compactin having less than 0.16% compactin C by weight, and pharmaceutical formulations comprising thereof.
- In yet another embodiment, the invention encompasses methods of synthesizing pravastatin by hydroxylation of compactin, wherein the compactin contains less than about 0.16% by weight of compactin C.
- In one embodiment, the invention provides a method for preparing a composition comprising pravastatin sodium having less than about 0.1% by weight pravastatin C. The method includes starting with a compactin sample comprising a sufficiently low level of compactin C. Preferably, the amount of compactin C in the compactin sample is less than about 0.16% by weight. The method comprises:
-
- a) obtaining at least one sample of at least one compactin batch;
- b) measuring the level of compactin C in the sample of a);
- c) selecting the compactin batch comprising less than about 0.16% compactin C by weight, based on the measurement or measurements conducted in b); and
- d) using the batch selected in c) to synthesize pravastatin sodium.
- In another embodiment, the invention provides a composition comprising pravastatin sodium having less than about 0.1% by weight pravastatin C, and pharmaceutical formulations comprising thereof.
- In yet another embodiment, the invention provides compactin compositions comprising less than about 0.16% by weight compactin C and pharmaceutical formulations comprising thereof.
- In one embodiment, the invention provides a process for purifying pravastatin which comprises dissolving pravastatin salt in water to form an aqueous solution of pravastatin; adjusting the pH of the aqueous solution of pravastatin to a pH of about 6.7 to about 10; contacting the pravastatin aqueous solution to an adsorption column bed; eluting pravastatin with an eluting solution; and collecting fractions having pure pravastatin. The pravastatin salt in the aqueous solution may be obtained by hydroxylation of compactin.
- In another embodiment, the present invention provides pravastatin produced by this purification process, and pharmaceutical formulations comprising thereof.
- The methods of the present invention produce high purity pravastatin by: i) using relatively pure starting materials to synthesize pravastatin or ii) using adsorption chromatography. Therefore in one aspect of the present invention, high purity pravastatin is synthesized by using pure compactin, which is obtained by at least one step of purifying the compactin prior to pravastatin synthesis, or by selecting a batch of pure compactin.
- The high purity and high yield pravastatin is obtained without the need for multiple extractions, or purification by HPLC. Therefore the invention is more cost effective and practical than previous methods for isolating pravastatin, meeting the need in the art for an economically practical method of preparing pravastatin on a preparative scale.
- As used herein, the term “pravastatin C” (used also in the European Pharmacopoeia) refers to the pravastatin impurity having the chemical name 3S,5S-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[[(2S)-2-methylpentanoyl]oxy]-1,2,6,7,8,8a-hexahydronaphtalen-1-yl]heptanoic acid.
- As used herein, the term “compactin C” refers to the compactin impurity having the chemical name pentanoic acid, 2-methyl-, 1,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester, [1S-[1α(R*),7β,8β(2S*,4S*),8aβ]]. The register number is 159225-32-8.
- As used herein, the term “compactin batch” refers to a composition consisting essentially of compactin, which composition may contain low levels of impurities, one of which may be compactin C. As used herein relative to a compactin batch, the term “sample” refers to a portion of the “compactin batch” that is taken for the purpose of measuring the compactin C level.
- The present invention provides a method for synthesizing a pravastatin composition comprising less than about 0.1% by weight pravastatin C comprising:
-
- a) purifying a composition comprising compactin and compactin C until a composition comprising less than about 0.16% compactin C by weight is obtained, and
- b) using the composition resulting from a) to synthesize a pravastatin composition.
- The composition in a) may be purified by crystallization. Preferably, the composition in a) is crystallized until it contains less than about 0.15% by weight compactin C. Preferably, the pravastatin composition synthesized in b) contains less than about 0.04% by weight pravastatin C, more preferably, less than about 0.03% by weight pravastatin C, and most preferably, the composition comprises less than about 0.02% by weight pravastatin C.
- The crystallization process comprises dissolving or suspending compactin in at least one water miscible organic solvent to form a reaction mixture; adding water to the reaction mixture, in a volume of about 0.16 to about 0.4 to the water miscible organic solvent; cooling the reaction mixture to a temperature until compactin crystallizes; and collecting the pure compactin crystals. Optionally, the crystallization process may be repeated as necessary to obtain the desired compactin purity.
- Preferably, the water miscible organic solvents comprise at least one of C3-5 ketones, nitriles, and C1-4 alcohols. More preferably, the water miscible organic solvent is at least one of acetone, methanol, ethanol, n-propanol, isopropanol, acetonitrile, methyl-ethyl-ketone, or tetrahydrofuran. Most preferably, the water miscible organic solvent is at least one of acetone, methanol, ethanol, isopropanol, or acetonitrile.
- The volume of water miscible organic solvent necessary to dissolve or suspend the compactin can be easily determined by one of ordinary skill in the art with little or no experimentation. The volume will vary depending upon the amount of compactin and the boiling point of the water miscible organic solvent. Typically, the volume of water miscible organic solvent is sufficient to dissolve or suspend the compactin at the reflux temperature of the water miscible organic solvent. Preferably, the volume of water miscible organic solvent is about seven times the mass of compactin, and more preferably about fives times the mass of compactin.
- Preferably, the amount of water added water added is about 0.17 to about 0.4 times the volume of the water miscible organic solvent. Prior to the addition of water, the reaction mixture is heated to a temperature of about 30° C. to about reflux, and preferably to a temperature of about 20° C. to about 25° C.
- The reaction mixture should be cooled to a temperature at which compactin crystallizes. The appropriate temperature may easily be determined by the skilled artisan as the temperature at which crystals become visible. Typically, the reaction mixture of compactin is cooled to a temperature from about 0° C. to about 30° C., and preferably to a temperature of about 20° C. to about 25° C. The reaction mixture is typically cooled at a rate of about 1° C. to about 6° C. per hour and preferably, at a rate of about 2° C. to about 4° C. per hour. After cooling, the reaction mixture may optionally may be heated to about 30° C. for 16 hours prior to cooling for a second time.
- The compactin crystals are then collected using any method commonly known to one of ordinary skill in the art. Such methods include, but are not limited to, centrifuge, filtration funnel, belt filtration, or press filtration. Subsequently, the compactin crystals are washed with a solution of water and water miscible organic solvent, preferably in a 1:1 volume ratio. Thereafter, the collected compactin crystals are dried using techniques commonly known to one of ordinary skill in the art. The pure compactin is then used to synthesize a high purity pravastatin composition.
- The present invention also provides compactin containing less than about 0.16% compactin C, and pharmaceutical formulations thereof. Preferably, compactin C is present in an amount of less than about 0.15% by weight.
- The present invention further provides compactin prepared according to the above process, and pharmaceutical formulations thereof.
- Another method for obtaining a pravastatin composition comprising less than about 0.1% pravastatin C comprises measuring the compactin C in samples of manufactured compactin batches. The method comprises selecting those compactin batches containing less than about 0.16% by weight compactin C, and synthesizing the pravastatin composition from the selected batches. If the compactin batch contains about 0.16% by weight compactin C or more, the compactin batch may be purified by crystallization, according to a method such as described above. One of the advantages of the present invention is that the high purity pravastatin is obtained without the need for purification by HPLC.
- Measurement of compactin C in the samples of compactin batches can be conducted by standard analytical chemistry techniques, for example reverse phase HPLC or other suitable chromatographic methods. The synthesis of pravastatin sodium by enzymatic hydroxylation of compactin as well as the isolation of the pure pravastatin are described in U.S. Pat. Nos. 5,942,423 and 4,346,227, hereby incorporated by reference. The fermentation or hydroxylation broth from which pravastatin is then isolated can be any of the aqueous broths known for industrial scale fermentation of compactin.
- The present invention provides a composition comprising pravastatin sodium and less than about 0.1% by weight pravastatin C, preferably, less than about 0.04% by weight pravastatin C, more preferably less than 0.03% by weight pravastatin C, and most preferably, less than about 0.02% by weight pravastatin C.
- The present invention provides a method for the purification of pravastatin or pravastatin salts comprising using adsorption chromatography. This method comprises dissolving pravastatin or its salt in water to form an aqueous solution; adjusting the pH of the aqueous solution to a pH of about 6.7 to about 10; adding the aqueous solution to an adsorption column bed, eluting pravastatin with an eluting solution; and collecting fractions having high purity pravastatin. The purification method may be repeated as necessary to achieve the desired pravastatin purity.
- The amount of water used should be sufficient to dissolve the pravastatin or pravastatin salt and may be easily determined by one of ordinary skill in the art as the amount may vary depending on the amount of pravastatin or salt. Typically, the amount of water used is about 8 ml of water per gram of pravastatin salt and preferably about 6 ml of water per gram.
- The pH of the aqueous solution may be adjusted using any method known in the art. Typically, the pH of the aqueous solution may be adjusted using a basic solution, such as 25% NaOH, in sufficient amount to achieve a pH of about 6.7 to about 10.
- Generally, the adsorption column bed includes resins such as polymeric adsorbents with highly porous structures whose internal surfaces can adsorb and then desorb a wide variety of different species depending on the environment in which they are used. In this case, with polar solvents such as water, the polymeric adsorbents exhibit non-polar or hydrophobic behavior and may adsorb organic species that are sparingly soluble. In one embodiment, the adsorption column bed may be a reverse phase silica gel column. Commercially available resins include those manufactured by Rohm and Haas, Philadelphia Pa., such as AMBERLITE™ XAD™ 4, XAD™ 7, XAD™ 16, XAD™ 16HP, XAD™ 761, and XAD™ 1180. Other resins suitable for the process of the invention include those manufactured and sold by Mitsubishi Kasei Corporation, Japan, such as DAION™ HP 10, DAION™ HP 20, DAION™ HP 21, DAION™ HP 30, DAION™ HP 40, DAION™ HP 50, DAION™ SP 800, DAION™ SP 825, DAION™ SP 850, DAION™ SP 875, DAION™ SP 205, DAION™ SP 207, DAION™ HP1MG, and DAION™ HP2MG. Reverse phase silica gels include those manufactured and sold by Merck & Co., Whitehouse Station, N.J., such as C-18, RP-2, RP-8, and RP-18.
- Eluting pravastatin or pravastatin salt with an eluting solution is carried out using techniques known to one of ordinary skill in the art. The eluting solution typically comprises water and at least one of acetone, acetonitrile, methanol, ethanol, or isopropanol. Preferably, the ratio of water to acetone, acetonitrile, methanol, ethanol, or isopropanol is about 7:3 to about 9:1 by volume, and more preferably the ratio is 8:2. Thereafter, the fractions with high purity pravastatin are collected, reduced in volume, and dried. See European Pharmacopoeia 4.5 (2003).
- The pravastatin produced by this method contains less than about 0.1% by weight pravastatin C. Preferably, pravastatin contains less than about 0.1% by weight pravastatin C, more preferably less than 0.03% by weight, and most preferably, less than about 0.02% by weight.
- The present invention further provides purified pravastatin and pravastatin sodium produced by the methods of the invention, and pharmaceutical formulations comprised thereof.
- Pharmaceutical formulations of the present invention contain purified pravastatin or compactin, such as disclosed herein. In addition to the active ingredient(s), the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
- Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
- The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
- Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
- When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
- Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
- In liquid pharmaceutical compositions of the present invention, pravastatin of compactin, in combination with any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
- Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
- Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include, but are not limited to, acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
- Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
- Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
- According to the present invention, a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
- The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
- Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
- The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
- The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
- A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
- A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
- As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
- A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
- The dosage of PLAVDX may be used as guidance. PLAVIX is administered orally. The recommended oral dose of PLAVIX is 75 mg once daily.
- Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
- The fermentation and recovery of pravastatin was carried out using methods commonly known to one skilled in the art, such as those described in U.S. Pat. No. 6,444,452, hereby incorporated by reference.
- Analysis of the starting compactin by HPLC using a Waters column RP-18 (5 m, 2.1×150 mm) with a mobile phase of (a) 0.1% phosphoric acid and the pH adjusted with 25% NaOH and (b) a mixture of distilled water and acetonitrile (1:9). The column was run for 50 min at 40° C. using a detection wavelength of 240 nm. The amount of compactin was determined using a standardized solution of 10 mg of compactin and 10 mg compactin ammonium salt.
-
TABLE 1 HPLC compactin analysis Time (min) % of solution (a) % of solution (b) 0 70 30 7 70 30 18 55 45 33 30 70 42 10 90 42.1 70 30 50 70 30 - The samples were prepared in 0.4 mg/ml concentrations and the impurity profile was determined as the peak area compared to the standardized sample. For this sample, the impurity compactin C in an amount of 0.25% by weight.
- The pure compactin was then fermented into pravastatin and isolated according to the methods disclosed in U.S. Pat. No. 6,444,452. Analysis of the pravastatin salt by HPLC determined that the impurity pravastatin C was present in an amount of 0.12% by weight.
- The pravastatin salt from Example 1 (90 g) was dissolved in water (540 ml), thereafter, the pH was adjusted to 6.7 to 10 using 25% NaOH. The pravastatin salt solution was passed through a sorption resin bed (550 ml of sorption resin XAD™ 1180). The column diameter was 3.2 cm and the applied flow rate was 90 ml/hour. After adsorption of pravastatin salt, the column was eluted with 4 L of water:acetone (8:2) and the fractions containing pravastatin were combined (1760 ml), reduced in volume, and pravastatin salt (64.8 g) was isolated. Impurity analysis by HPLC, as described in European Pharmacopoeia, determined that pravastatin C was present in an amount of 0.04% by weight.
- A compactin sample with compactin C present in an amount of 0.2% by weight was purified by crystallization. The compactin sample (30 g) was suspended in acetone (5 times by volume) and heated to reflux. Water (1.25 times by volume) was added to the heated suspension, and the solution was allowed to cool to 20° C. at a cooling rate of 2° C./hour. Upon cooling, crystals formed which were stirred for 2 hours at 20° C., and subsequently collected by filtration, washed with a water:acetone (1:1) solution, and dried. After drying, the crystalline compactin (28.2 g) was collected and analyzed by HPLC, as described in the European Pharmacopoeia. The crystalline compactin had 0.15% by weight of compactin C.
- A compactin sample with compactin C in an amount of 0.2% by weight was purified by crystallization. The compactin sample (30 g) was suspended in methanol (5 times by volume) and heated to reflux. Water (1.5 times by volume) was added to the heated suspension, and the solution was allowed to cool to 20° C. at a cooling rate of 2° C./hour. Thereafter, the solution was heated to 30° C. and stirred for 16 hours. Upon cooling, crystals formed which were collected by filtration, washed with a water:methanol (1:1) solution, and dried. After drying, the crystalline compactin (27.2 g) was collected and analyzed by HPLC. The crystalline compactin had 0.15% by weight of compactin C.
- The pure compactin is then fermented into pravastatin and pravastatin is isolated according to the methods disclosed in U.S. Pat. No. 6,444,452. Achievable pravastatin C level is 0.02% by weight.
- A compactin sample with compactin C in an amount of 0.2% by weight was purified by crystallization. The compactin sample (30 g) was suspended in isopropanol (5 times by volume) and heated to reflux. Water (1.5 times by volume) was added to the heated suspension, and the solution was allowed to cool to 25° C. at a cooling rate of 2° C./hour. Upon cooling, crystals formed which were collected by filtration, washed with a water:isopropanol (1:1) solution, and dried. After drying, the crystalline compactin (22.9 g) was collected and analyzed by HPLC. The crystalline compactin had 0.16% by weight of compactin C.
- The pure compactin is then fermented into pravastatin and isolated according to the methods disclosed in U.S. Pat. No. 6,444,452. Achievable pravastatin C level is 0.03% by weight.
- A compactin sample with compactin C in an amount of 0.2% by weight was purified by crystallization. The compactin sample (30 g) was suspended in acetonitrile (5 times by volume) and heated to reflux. Water (1.5 times by volume) was added to the heated suspension, and the solution was allowed to cool to 25° C. at a cooling rate of 2° C./hour. Upon cooling, crystals formed which were collected by filtration, washed with a water:acetonitrile (1:1) solution, and dried. After drying, the crystalline compactin (24.2 g) was collected and analyzed by HPLC. The crystalline compactin had 0.15% by weight of compactin C.
- The pure compactin is then fermented into pravastatin and isolated according to the methods disclosed in U.S. Pat. No. 6,444,452. Achievable pravastatin C level is 0.02% by weight.
Claims (23)
1-48. (canceled)
49. A method of synthesizing a pravastatin batch comprising:
(a) determining the level of compactin C in at least one batch of compactin that contains compactin C;
(b) selecting a compactin batch that contains compactin C in an amount that is about 0.16% or less by weight of the batch; and
(c) hydroxylating the selected compactin batch to synthesize a pravastatin batch.
50. The method of claim 49 , wherein the selected compactin batch from step (b) contains compactin C in an amount of about 0.15% to about 0.16% by weight of the batch.
51. The method of claim 49 , wherein the pravastatin batch is synthesized by fermentation of the compactin batch.
52. The method of claim 49 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.1% or less by weight of the batch.
53. The method of claim 52 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.02% to about 0.1% by weight of the batch.
54. The method of claim 52 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.04% or less by weight of the batch.
55. The method of claim 54 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.02% to about 0.04% by weight of the batch.
56. The method of claim 54 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.03% or less by weight of the batch.
57. The method of claim 56 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.02% or less by weight of the batch.
58. A method of synthesizing a pravastatin batch comprising:
a) purifying a compactin batch containing compactin C to obtain a compactin batch containing compactin C in an amount that is about 0.16% or less by weight of the composition; and
b) hydroxylating the compactin batch resulting from step a) to synthesize a pravastatin batch.
59. The method of claim 58 , wherein the purification in step a) comprises:
i) dissolving or suspending the starting compactin batch in at least one water miscible organic solvent;
ii) adding water to the solution or suspension formed in step i) to obtain a mixture, wherein the volume ratio between the water and the water miscible organic solvent is about 0.16:1 to about 0.4:1; and
iii) precipitating the compactin batch containing compactin C in an amount that is about 0.16% or less by weight of the batch.
60. A method of synthesizing a pravastatin batch comprising:
a) dissolving or suspending a compactin batch containing compactin C in at least one water miscible organic solvent;
b) adding water to the solution or suspension formed in a) to obtain a mixture, wherein the volume ratio between the water and the water miscible organic solvent is about 0.16:1 to about 0.4:1;
c) precipitating the compactin batch;
d) determining the quantity of compactin C in the precipitated compactin batch from step c); and
if the quantity of compactin C determined in step d) is greater than 0.16% by weight of the batch, then:
e1) purifying, by crystallization, the precipitated compactin batch until the quantity of compactin C is 0.16% or less by weight of the batch; and
f) hydroxylating the purified compactin batch from step e1) to synthesize pravastatin batch; or,
if the quantity of compactin C determined in step d) is 0.16% or less by weight of the batch, then:
e2) hydroxylating the precipitated compactin batch to synthesize a pravastatin batch.
61. The method of claim 60 , wherein in step e1) the compactin batch is purified until the quantity of compactin C is about 0.15% or less by weight of the batch.
62. The method of claim 60 , wherein the pravastatin batch is synthesized by fermentation of the compactin batch.
63. The method of claim 60 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.1% or less by weight of the batch.
64. The method of claim 63 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.02% to about 0.1% by weight of the batch.
65. The method of claim 63 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.04% or less by weight of the batch.
66. The method of claim 65 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.02% to about 0.04% by weight of the batch.
67. The method of claim 65 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.03% or less by weight of the batch.
68. The method of claim 57 , wherein the synthesized pravastatin batch contains pravastatin C in an amount that is about 0.02% or less by weight of the batch.
69. A method comprising: providing a compactin batch containing compactin C in an amount that is about 0.16% or less by weight of the batch; and hydroxylating the compactin batch, thereby forming a pure pravastatin batch.
70. A method comprising: hydroxylating a compactin batch containing compactin C in an amount that is about 0.16% or less by weight of the batch, thereby forming a pure pravastatin batch.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/187,555 US20080300305A1 (en) | 2003-11-24 | 2008-08-07 | Method of purifying pravastatin |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52549403P | 2003-11-24 | 2003-11-24 | |
US53231403P | 2003-12-22 | 2003-12-22 | |
US55416504P | 2004-03-18 | 2004-03-18 | |
US10/996,238 US7425644B2 (en) | 2003-11-24 | 2004-11-23 | Method of purifying pravastatin |
US12/187,555 US20080300305A1 (en) | 2003-11-24 | 2008-08-07 | Method of purifying pravastatin |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/996,238 Continuation US7425644B2 (en) | 2003-11-24 | 2004-11-23 | Method of purifying pravastatin |
Publications (1)
Publication Number | Publication Date |
---|---|
US20080300305A1 true US20080300305A1 (en) | 2008-12-04 |
Family
ID=34637188
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/996,238 Expired - Fee Related US7425644B2 (en) | 2003-11-24 | 2004-11-23 | Method of purifying pravastatin |
US12/187,555 Abandoned US20080300305A1 (en) | 2003-11-24 | 2008-08-07 | Method of purifying pravastatin |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/996,238 Expired - Fee Related US7425644B2 (en) | 2003-11-24 | 2004-11-23 | Method of purifying pravastatin |
Country Status (12)
Country | Link |
---|---|
US (2) | US7425644B2 (en) |
EP (2) | EP2033636A1 (en) |
JP (2) | JP2007512366A (en) |
AT (1) | ATE412409T1 (en) |
CA (1) | CA2546377A1 (en) |
DE (3) | DE602004017461D1 (en) |
ES (1) | ES2251894T3 (en) |
HR (1) | HRP20080686T3 (en) |
PL (1) | PL1641447T3 (en) |
PT (1) | PT1641447E (en) |
TW (1) | TWI319707B (en) |
WO (1) | WO2005051372A2 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005121062A2 (en) * | 2004-06-09 | 2005-12-22 | Ranbaxy Laboratories Limited | Process for the preparation of pravastatin |
JP4775727B1 (en) * | 2010-08-17 | 2011-09-21 | 貞宏 平山 | Authenticity judgment method that can be easily done by ordinary people with minute marks on printed matter |
JP6218287B2 (en) * | 2013-01-29 | 2017-10-25 | 学校法人産業医科大学 | Use of HMG-CoA reductase inhibitors for the treatment of cisplatin resistant cancer |
Citations (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4319039A (en) * | 1979-06-15 | 1982-03-09 | Merck & Co., Inc. | Preparation of ammonium salt of hypocholesteremic fermentation product |
US4346227A (en) * | 1980-06-06 | 1982-08-24 | Sankyo Company, Limited | ML-236B Derivatives and their preparation |
US4857522A (en) * | 1988-03-21 | 1989-08-15 | E. R. Squibb & Sons, Inc. | Derivatives of pravastatin for inhibiting cholesterol biosynthesis |
US4857547A (en) * | 1988-01-07 | 1989-08-15 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
US5099035A (en) * | 1989-02-27 | 1992-03-24 | E. R. Squibb & Sons, Inc. | Mevinic acid derivatives useful as antihypercholesterolemic agents and method for preparing same |
US5140012A (en) * | 1990-05-31 | 1992-08-18 | E. R. Squibb & Sons, Inc. | Method for preventing onset of restenosis after angioplasty employing pravastatin |
US5153124A (en) * | 1985-09-13 | 1992-10-06 | Sankyo Company Limited | Hydroxyl-ml-236b derivatives, their preparation and use |
US5157025A (en) * | 1991-04-01 | 1992-10-20 | E. R. Squibb & Sons, Inc. | Method for lowering serum cholesterol employing a phosphorus containing ace inhibitor alone or in combination with a cholesterol lowering drug |
US5180589A (en) * | 1988-03-31 | 1993-01-19 | E. R. Squibb & Sons, Inc. | Pravastatin pharmaceuatical compositions having good stability |
US5202029A (en) * | 1991-03-13 | 1993-04-13 | Caron Kabushiki Kaisha | Process for purification of hmg-coa reductase inhibitors |
US5616595A (en) * | 1995-06-07 | 1997-04-01 | Abbott Laboratories | Process for recovering water insoluble compounds from a fermentation broth |
US5712130A (en) * | 1993-06-08 | 1998-01-27 | Krka Tovarna Zdravil, P.O | Process for the isolation of lovastatin |
US5883109A (en) * | 1996-07-24 | 1999-03-16 | Bristol-Myers Squibb Company | Method for lowering serum lipid levels employing an MTP inhibitor in combination with another cholesterol lowering drug |
US5942423A (en) * | 1995-06-07 | 1999-08-24 | Massachusetts Institute Of Technology | Conversion of compactin to pravastatin by actinomadura |
US6444452B1 (en) * | 1999-11-30 | 2002-09-03 | Biogal Gyogyszergyar Rt. | Process for recovering statin compounds from a fermentation broth |
US6682913B1 (en) * | 1999-02-03 | 2004-01-27 | Institute For Drug Research Ltd. | Microbial process for preparing pravastatin |
US6695969B1 (en) * | 1998-09-18 | 2004-02-24 | Lek Pharmaceuticals D.D. | Process for obtaining HMG-CoA reductase inhibitors of high purity |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4346277A (en) * | 1979-10-29 | 1982-08-24 | Eaton Corporation | Packaged electrical heating element |
WO1993023424A1 (en) | 1992-05-20 | 1993-11-25 | Basf Aktiengesellschaft | Derivatives of dolastatin |
NZ250609A (en) | 1992-12-28 | 1995-07-26 | Sankyo Co | Hexahydronaphthalene esters and ring closed lactones; preparation and medicaments |
IL112639A0 (en) | 1994-03-11 | 1995-05-26 | Bristol Myers Squibb Co | A pharmaceutical composition containing pravastin |
ATE189804T1 (en) | 1995-08-03 | 2000-03-15 | Dsm Nv | SELECTIVE PROCESS FOR DEACYLATION OF ACYL COMPOUNDS |
WO1998037220A1 (en) | 1997-02-20 | 1998-08-27 | Dsm N.V. | Nitrogen feed in statin fermentation |
KR100210482B1 (en) | 1997-04-10 | 1999-07-15 | 김종인 | Streptomyces exfoliatus yj-118 and process of pravastatin sodium |
AU9264598A (en) | 1997-08-22 | 1999-03-16 | Gist-Brocades B.V. | Statin production by fermentation |
SI9800046A (en) | 1998-02-18 | 1999-08-31 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Process for obtaining of HMG-CoA reductase inhibitors of high purity |
JP2931971B1 (en) | 1998-02-23 | 1999-08-09 | 利夫 佐藤 | How to make pravastatin |
SI20305A (en) | 1999-08-06 | 2001-02-28 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Pravastatin sodium salt crystals |
HUP0200650A3 (en) | 1999-02-03 | 2008-03-28 | Inst Drug Res Ltd | Microbial process for preparing pravastatin |
HUP9902352A1 (en) | 1999-07-12 | 2000-09-28 | Gyógyszerkutató Intézet Kft. | Process for producing pravastatin by microbiological way |
WO2001081611A1 (en) | 2000-04-27 | 2001-11-01 | Biocon India Limited | A novel process for the manufacture and purification of compactin |
CZ20031166A3 (en) | 2000-10-05 | 2004-04-14 | Biogal Gyogyszergyar Rt | Pravastatin sodium salt that is substantially free of pravastatin lactone and epi-pravastatin as well as composition based thereon |
JP3463881B2 (en) * | 2002-08-06 | 2003-11-05 | 三共株式会社 | Method for isolation and purification of pravastatin or a pharmacologically acceptable salt thereof |
TW589178B (en) * | 2003-02-21 | 2004-06-01 | China Chemical & Pharmaceutica | A novel industrial process to obtain pravastatin sodium of high purity |
-
2004
- 2004-11-23 TW TW093135997A patent/TWI319707B/en not_active IP Right Cessation
- 2004-11-23 AT AT04811862T patent/ATE412409T1/en active
- 2004-11-23 EP EP08018298A patent/EP2033636A1/en not_active Withdrawn
- 2004-11-23 JP JP2006541621A patent/JP2007512366A/en active Pending
- 2004-11-23 WO PCT/US2004/039217 patent/WO2005051372A2/en not_active Application Discontinuation
- 2004-11-23 PT PT04811862T patent/PT1641447E/en unknown
- 2004-11-23 DE DE602004017461T patent/DE602004017461D1/en active Active
- 2004-11-23 EP EP04811862A patent/EP1641447B1/en active Active
- 2004-11-23 US US10/996,238 patent/US7425644B2/en not_active Expired - Fee Related
- 2004-11-23 DE DE04811862T patent/DE04811862T1/en active Pending
- 2004-11-23 DE DE202004020671U patent/DE202004020671U1/en not_active Expired - Lifetime
- 2004-11-23 CA CA002546377A patent/CA2546377A1/en not_active Abandoned
- 2004-11-23 ES ES04811862T patent/ES2251894T3/en active Active
- 2004-11-23 PL PL04811862T patent/PL1641447T3/en unknown
-
2008
- 2008-08-07 US US12/187,555 patent/US20080300305A1/en not_active Abandoned
- 2008-12-30 HR HR20080686T patent/HRP20080686T3/en unknown
-
2009
- 2009-02-04 JP JP2009024212A patent/JP2009161542A/en active Pending
Patent Citations (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4319039A (en) * | 1979-06-15 | 1982-03-09 | Merck & Co., Inc. | Preparation of ammonium salt of hypocholesteremic fermentation product |
US4346227A (en) * | 1980-06-06 | 1982-08-24 | Sankyo Company, Limited | ML-236B Derivatives and their preparation |
US4410629A (en) * | 1980-06-06 | 1983-10-18 | Sankyo Company Limited | ML-236B Derivatives and their preparation |
US5153124A (en) * | 1985-09-13 | 1992-10-06 | Sankyo Company Limited | Hydroxyl-ml-236b derivatives, their preparation and use |
US4857547A (en) * | 1988-01-07 | 1989-08-15 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
US4857522A (en) * | 1988-03-21 | 1989-08-15 | E. R. Squibb & Sons, Inc. | Derivatives of pravastatin for inhibiting cholesterol biosynthesis |
US5180589A (en) * | 1988-03-31 | 1993-01-19 | E. R. Squibb & Sons, Inc. | Pravastatin pharmaceuatical compositions having good stability |
US5099035A (en) * | 1989-02-27 | 1992-03-24 | E. R. Squibb & Sons, Inc. | Mevinic acid derivatives useful as antihypercholesterolemic agents and method for preparing same |
US5140012A (en) * | 1990-05-31 | 1992-08-18 | E. R. Squibb & Sons, Inc. | Method for preventing onset of restenosis after angioplasty employing pravastatin |
US5202029A (en) * | 1991-03-13 | 1993-04-13 | Caron Kabushiki Kaisha | Process for purification of hmg-coa reductase inhibitors |
US5157025A (en) * | 1991-04-01 | 1992-10-20 | E. R. Squibb & Sons, Inc. | Method for lowering serum cholesterol employing a phosphorus containing ace inhibitor alone or in combination with a cholesterol lowering drug |
US5712130A (en) * | 1993-06-08 | 1998-01-27 | Krka Tovarna Zdravil, P.O | Process for the isolation of lovastatin |
US5616595A (en) * | 1995-06-07 | 1997-04-01 | Abbott Laboratories | Process for recovering water insoluble compounds from a fermentation broth |
US5942423A (en) * | 1995-06-07 | 1999-08-24 | Massachusetts Institute Of Technology | Conversion of compactin to pravastatin by actinomadura |
US5883109A (en) * | 1996-07-24 | 1999-03-16 | Bristol-Myers Squibb Company | Method for lowering serum lipid levels employing an MTP inhibitor in combination with another cholesterol lowering drug |
US6695969B1 (en) * | 1998-09-18 | 2004-02-24 | Lek Pharmaceuticals D.D. | Process for obtaining HMG-CoA reductase inhibitors of high purity |
US6682913B1 (en) * | 1999-02-03 | 2004-01-27 | Institute For Drug Research Ltd. | Microbial process for preparing pravastatin |
US6696599B2 (en) * | 1999-02-03 | 2004-02-24 | Institute For Drug Research, Ltd. | Microbial process for preparing pravastatin |
US20040039225A1 (en) * | 1999-02-03 | 2004-02-26 | Antonia Jekkel | Microbial process for preparing pravastatin |
US6750366B2 (en) * | 1999-02-03 | 2004-06-15 | Institute For Drug Research Ltd. | Microbial process for preparing pravastatin |
US6444452B1 (en) * | 1999-11-30 | 2002-09-03 | Biogal Gyogyszergyar Rt. | Process for recovering statin compounds from a fermentation broth |
Also Published As
Publication number | Publication date |
---|---|
ES2251894T1 (en) | 2006-05-16 |
ES2251894T3 (en) | 2009-04-01 |
WO2005051372A3 (en) | 2005-08-11 |
JP2007512366A (en) | 2007-05-17 |
CA2546377A1 (en) | 2005-06-09 |
EP1641447B1 (en) | 2008-10-29 |
US20050113446A1 (en) | 2005-05-26 |
DE602004017461D1 (en) | 2008-12-11 |
HRP20080686T3 (en) | 2009-03-31 |
DE202004020671U1 (en) | 2005-12-08 |
US7425644B2 (en) | 2008-09-16 |
PL1641447T3 (en) | 2009-04-30 |
EP2033636A1 (en) | 2009-03-11 |
DE04811862T1 (en) | 2006-03-02 |
ATE412409T1 (en) | 2008-11-15 |
JP2009161542A (en) | 2009-07-23 |
TW200518745A (en) | 2005-06-16 |
TWI319707B (en) | 2010-01-21 |
EP1641447A2 (en) | 2006-04-05 |
WO2005051372A2 (en) | 2005-06-09 |
PT1641447E (en) | 2008-12-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7683188B2 (en) | Process for preparation of mycophenolic acid and ester derivatives thereof | |
US20050250773A1 (en) | Process for preparation of mycophenolate mofetil and other esters of mycophenolic acid | |
EP1265604B1 (en) | Process for recovering statin compounds from a fermentation broth | |
JP2008526897A (en) | Diastereomeric purification of rosuvastatin | |
KR20070092993A (en) | Fluvastatin sodium crystal forms xiv, lxxiii, lxxix, lxxx and lxxxvii, processes for preparing them, compositions containing them and methods of using them | |
CZ20022779A3 (en) | Purification process of fermentation broth | |
JP2003506424A (en) | Crystals of pravastatin sodium | |
IL226616A (en) | Chemically pure polymorph of nor-udca, methods of preparation thereof and uses thereof for the treatment of liver disease | |
US20140155371A1 (en) | Multicomponent crystalline system of ezetimibe and proline | |
US20080300305A1 (en) | Method of purifying pravastatin | |
SK2172003A3 (en) | Highly purified simvastatin compositions | |
JP2007507497A (en) | Method for preparing fluvastatin sodium polymorph | |
JP2006522142A (en) | Amorphous simvastatin calcium and process for producing the same | |
MXPA06005819A (en) | Method of purifying pravastatin | |
US20080280977A1 (en) | Process for preparation of mycophenolate mofetil and other esters of mycophenolic acid | |
CA2425882A1 (en) | Method of purifying pravastatin or its pharmacologically acceptable salt | |
WO2006035295A1 (en) | Process for the purification of lovastatin | |
WO2006046130A2 (en) | Process for the preparation of pravastatin | |
EP1798214A1 (en) | Process for recovering statin compounds from a fermentation broth |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: TEVA GYOGYSZERGYAR ZARTKORUEN MUKODO RESZVENYTARSA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KERI, VILMOS;MELCZER, ISTVAN;REEL/FRAME:022519/0630;SIGNING DATES FROM 20090331 TO 20090401 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |