EP1161236A1 - Acide ouvert en dihydroxy et sels d'inhibiteurs de la hmg-co-a reductase - Google Patents

Acide ouvert en dihydroxy et sels d'inhibiteurs de la hmg-co-a reductase

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Publication number
EP1161236A1
EP1161236A1 EP00907111A EP00907111A EP1161236A1 EP 1161236 A1 EP1161236 A1 EP 1161236A1 EP 00907111 A EP00907111 A EP 00907111A EP 00907111 A EP00907111 A EP 00907111A EP 1161236 A1 EP1161236 A1 EP 1161236A1
Authority
EP
European Patent Office
Prior art keywords
dihydroxy open
open acid
statin
compound
pharmaceutically acceptable
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.)
Withdrawn
Application number
EP00907111A
Other languages
German (de)
English (en)
Inventor
Richard D. Tillyer
Paul J. Reider
Edward J. J. Grabowski
Feng Xu
Jose M. Vega
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1161236A1 publication Critical patent/EP1161236A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the instant invention relates to the use of dihydroxy open acid statins and salts and esters thereof, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, in such a way so as to minimize their in vivo lactonization, and to a particular crystalline hydrated form of the calcium salt of dihydroxy open acid simvastatin referred to herein as compound I.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • mevastatin and lovastatin there are now a variety of semi-synthetic and totally synthetic HMG-CoA reductase inhibitors, including simvastatin (ZOCOR®; see US Patent No. 4,444,784), pravastatin sodium salt (PRAVACHOL®; see US Patent No. 4,346,227), fluvastatin sodium salt (LESCOL®; see US Patent No. 5,354,772), atorvastatin calcium salt (LIPITOR®; see US Patent No. 5,273,995) and cerivastatin sodium salt (also known as rivastatin; see US Patent No. 5,177,080).
  • HMG-CoA reductase inhibitors The structural formulas of these and additional HMG-CoA reductase inhibitors, are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996).
  • the HMG-CoA reductase inhibitors described above belong to a structural class of compounds which contain a moiety which can exist as either a 3-hydroxy lactone ring or as the corresponding ring opened dihydroxy open-acid, and are often referred to as "statins.” An illustration of the lactone portion of a statin and its corresponding open- acid form is shown below.
  • Salts of the dihydroxy open-acid can be prepared, and in fact, as noted above, several of the marketed statins are administered as the dihydroxy open acid salt forms.
  • Lovastatin and simvastatin are marketed worldwide in their lactonized form. Lovastatin is shown as structural formula II, and simvastatin is shown as structural formula III, below.
  • statins are not active inhibitors of HMG- CoA reductase, but the dihydroxy open acid forms are. It is known that condensation of the dihydroxy open acid form of statins to the corresponding lactonized form occurs under acidic conditions, that is at about pH 4 or under. Therefore, due to the low gastric pH of the stomach, a statin conventionally administered by oral dosing in its lactone form will remain largely in its lactone form in the stomach. The vast majority of the drug will still be in the lactone form at the time of absorption from the intestine following oral dosing with the lactone.
  • the lactone After absorption, the lactone enters the liver and it is in the hepatocytes that the lactone can be metabolized to the active open acid form, a reaction catalyzed by two hepatic esterases or "lactonases," one which is in the cytosolic and the other in the microsomal fraction.
  • lactone Once in the blood there is an additional plasma esterase which can also hydrolyze the lactone to the open acid.
  • a statin conventionally administered by oral dosing in its dihydroxy open acid form or a pharmaceutically acceptable salt or ester thereof will tend to convert to its lactone form in the acidic environment of the stomach, so that a mixture of the open ring and the corresponding closed ring forms will co-exist there.
  • M.J. Kaufman International Journal of Pharmaceutics, 1990, 66(Dec 1), p. 97-106, which provides hydrolysis data that are used to simulate the extent of drug degradation that occurs in acidic gastric fluids following oral administration of several structurally related hypocholesterolemic agents, including simvastatin and lovastatin, and also see A.S. Kearney, et al., Pharmaceutical Research, 1993, 10(10), p.
  • 4,820,850 describes a process for making simvastatin which involves opening the lactone ring of lovastatin and forming an alkyl-amide at the resulting carboxy acid, followed by protection of the two hydroxy groups and methylation of the 8' acyl sidechain. After the methylation step, the hydroxy protecting groups are removed, the amide is hydrolyzed to the free acid and an ammonium salt of the free acid is formed, followed by a step to re-lactonize the ring.
  • the 8'-acyl sidechain of lovastatin is removed and the lactone ring opened in the first step, followed by re-lactonization of the ring and protection of its hydroxy group.
  • the 8' position is acylated to introduce the simvastatin sidechain and a deprotection step is performed to obtain the simvastatin final product.
  • the potassium salt of the ring opened form of lovastatin is methylated at the 8' acyl sidechain, the free acid is then re-generated, and the dihydroxy open acid moiety is re- lactonized.
  • One object of this invention is to minimize or eliminate the in vivo lactonization of a dihydroxy open-acid statin.
  • the dihydroxy open-acid statin or a pharmaceutically acceptable salt or ester thereof is to be administered so as to minimize formation of lactonized statin and thereby minimize the amount of lactonized statin that is absorbed from the intestine while maximizing the amount of dihydroxy open-acid statin that is absorbed from the intestine.
  • this invention involves a method of inhibiting HMG-CoA reductase with an effective inhibitory amount of an orally dosed statin comprising delivering at least 90% of the dosed statin in its dihydroxy open acid form to the intestinal mucosa of a patient in need of such treatment.
  • the instant invention further provides a method for inhibiting HMG- CoA reductase, as well as for treating and/or reducing the risk for diseases and conditions affected by inhibition of HMG-CoA reductase, comprising orally administering a therapeutically effective amount of a compound selected from a dihydroxy open acid statin and a pharmaceutically acceptable salt or ester thereof in a delayed-release pharmaceutical dosage form to a patient in need of such treatment wherein substantial release of the compound from the dosage form is delayed until after passage of the dosage form through the stomach.
  • One embodiment of the first object is to provide the above-described method wherein the delayed-release pharmaceutical dosage form is a gel extrusion module (GEM) drug delivery device.
  • GEM gel extrusion module
  • Another embodiment of the first object is to provide the above- described method wherein the delayed-release pharmaceutical dosage form is an enterically coated pharmaceutical dosage form.
  • An additional aspect of this embodiment is to provide the above-described method wherein the delayed-release pharmaceutical dosage form is selected from an enterically coated rapid-release pharmaceutical dosage form and an enterically coated time controlled-release pharmaceutical dosage form.
  • Yet another aspect of this embodiment is to provide the above-described method wherein the delayed-release pharmaceutical dosage form is an enterically coated gel extrusion module (GEM) drug delivery device.
  • GEM enterically coated gel extrusion module
  • the compound used for the above-described object and embodiments may particularly be dihydroxy open acid simvastatin and the pharmaceutically acceptable salts thereof, and more particularly a pharmaceutically acceptable salt thereof.
  • a second object of the instant invention is to provide novel HMG-CoA reductase inhibitors which are crystalline hydrated forms of the calcium salt of dihydroxy open acid simvastatin, and particularly the compound referred to herein as compound I.
  • Additional objects are to provide the use of the crystalline hydrated forms of the calcium salt of dihydroxy open acid simvastatin, particularly compound I, for inhibiting HMG-CoA reductase, as well as for treating and/or reducing the risk for diseases and conditions affected by inhibition of HMG-CoA reductase, and also to provide pharmaceutical formulations, including conventional rapid-release, delayed- release and time controlled-release formulations, including the GEM drug delivery device and enterically coated dosage forms, that can be used with the compounds.
  • a further object is to provide a process for making compound I. Additional objects will be evident from the following detailed description.
  • Figure 1 is a thermogravimetry (TG) weight loss curve for compound I obtained under a nitrogen flow at a heating rate of 10°C/minute.
  • Figure 2 is a differential scanning calorimetry (DSC) curve for compound I obtained under a nitrogen flow bubbled through 16.0°C water at a heating rate of 10°C/minute in an open cup.
  • DSC differential scanning calorimetry
  • Figure 3 is an x-ray powder diffraction (XRPD) pattern for compound I.
  • the XRPD pattern was obtained using CuK ⁇ radiation.
  • the ordinate or Y-axis is x-ray intensity (cpm) and the abscissa or X-axis is the angle two-theta (20) in degrees.
  • Figure 4 is a solid-state l 3 C nuclear magnetic resonance spectrum for
  • dihydroxy open acid statins may be less reliant on CYP3A4 metabolism than their closed ring lactonized counterparts.
  • the instant invention involves methods and pharmaceutical compositions for orally administering open-ring dihydroxy open acid statins and salts and esters thereof, which are HMG-CoA reductase inhibitors, in such a way so as to minimize conversion to their lactonized counterparts.
  • This allows for delivery of a dihydroxy open acid statin without its lactone counterpart directly to the absorptive mucosa of the small intestine thus allowing for absorption of the open acid statin into the portal circulation, penetration by active open acid statin into hepatocytes to achieve enhanced efficacy, and systemic exposure consisting of open acid moieties.
  • delayed-release of an orally administered dihydroxy open acid statin or a pharmaceutically acceptable salt or ester thereof, for example dihydroxy open acid simvastatin or a salt thereof, until after passage through the stomach reduces the amount of lactone formed and absorbed in the body.
  • Maintaining the statin in its open acid form in the body thereby reduces the potential for drug interactions between statins whose metabolism is CYP3A4-mediated and other active agents which inhibit the CYP3A4 enzymatic pathway, and also can provide enhanced efficacy.
  • maintaining the statin in its open acid form in the body may have additional clinical benefits for all statins, even for those statins that are not significantly metabolized by the CYP3A4 enzymatic pathway.
  • a novel crystalline hydrated form of the calcium salt of dihydroxy open acid simvastatin has now been discovered to be a pharmaceutically suitable salt form having desirable physical properties for formulation into an anti- hypercholesterolemic drug composition.
  • statin(s) as used herein is intended to be defined as inhibitors of HMG-CoA reductase which belong to a structural class of compounds that contain a moiety which can exist as either a 3-hydroxy lactone ring or as the corresponding ring opened dihydroxy open acid, wherein the lactone portion of the statin and its corresponding dihydroxy open-acid form is shown below.
  • HMG-CoA reductase inhibitors having the above-described lactone/dihydroxy open acid moiety are included within the scope of the term "statin(s)”.
  • Pharmaceutically acceptable salts and esters of the dihydroxy open-acid statins are included within the scope of the term "statin(s)”.
  • Statins inhibit HMG-CoA reductase in their dihydroxy open acid form.
  • dihydroxy open acid statin(s) is intended to be defined as statins which contain the dihydroxy open acid moiety, including pharmaceutically acceptable salts and esters thereof.
  • dihydroxy open acid statin(s) and “dihydroxy open acid statin(s) and the pharmaceutically acceptable salts and esters thereof are used interchangeably herein and are both intended to encompass the open acid and salt and ester forms of the open acid of the statin, unless otherwise indicated. All hydrates, solvates and polymorphic crystalline forms are encompassed within the the scope of the term “dihydroxy open acid statin(s)."
  • any dihydroxy open acid statin or a pharmaceutically acceptable salt or ester thereof may be used with the present invention.
  • dihydroxy open acid statins that may be used with the present invention include but are not limited to the dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof of: lovastatin (see US Patent No. 4,342,767); simvastatin (see US Patent No.
  • pravastatin particularly the sodium salt thereof
  • fluvastatin particularly the sodium salt thereof
  • atorvastatin particularly the calcium salt thereof
  • cerivastatin particularly the sodium salt thereof, nisvastatin also referred to as NK-104 (see PCT international publication number WO 97/23200) and ZD-4522 (see US Patent No. 5,260,440, and Drugs of the Future, 1999, 24(5), pp. 511-513).
  • any dihydroxy open acid statin or a pharmaceutically acceptable salt or ester thereof may be used with the present invention, such as those listed above, provided the statin is not pravastatin or fluvastatin.
  • the open acid statin includes dihydroxy open acid lovastatin, simvastatin, atorvastatin, cerivastatin, nisvastatin and pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts of dihydroxy open acid simvastatin, particularly the ammonium and calcium salt forms thereof, are preferred for use in the methods and compositions of this invention.
  • the calcium salt of dihydroxy open acid simvastatin includes the crystalline hydrated forms of the calcium salt of dihydroxy open acid simvastatin, and more particularly the hydrated calcium salt of dihydroxy open acid simvastatin referred to herein as compound I.
  • the term "pharmaceutically acceptable salts” shall mean non- toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-pyrrolidine-l '-yl- methylbenzimidazole, diethylamine, piperazine, morpholine, 2,4,4-trimethyl-2- pentamine and tris(hydroxymethyl)aminomethane.
  • a suitable organic or inorganic base particularly those formed
  • esters at the carboxylic acid group can be made by treating a dihydroxy open acid statin with an alcohol.
  • examples of pharmaceutically acceptable esters of dihydroxy open acid statins include, but are not limited to, -Ci-4 alkyl and - C ⁇ _4 alkyl substituted with phenyl-, dimethylamino-, and acetylamino.
  • "Ci-4 alkyl” herein includes straight or branched aliphatic chains containing from 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, n-butyl, wo-propyl, sec-butyl and tert-butyl.
  • the instant invention involves methods and pharmaceutical compositions for orally administering open-ring dihydroxy open acid statins and salts and esters thereof, which are HMG-CoA reductase inhibitors, in such a way so as to minimize conversion to their lactonized counterparts.
  • This allows for delivery of a dihydroxy open acid statin without its lactone counterpart directly to the absorptive mucosa of the small intestine thus allowing for absorption of the open acid statin into the portal circulation, penetration by active open acid statin into hepatocytes to achieve enhanced efficacy, and systemic exposure consisting of open acid moieties.
  • delayed-release of an orally administered dihydroxy open acid statin or a pharmaceutically acceptable salt or ester thereof, for example dihydroxy open acid simvastatin or a salt thereof, until after passage through the stomach reduces the amount of lactone formed and absorbed in the body. Maintaining the statin in its open acid form in the body thereby reduces the potential for drug interactions between statins whose metabolism is CYP3A4-mediated and other active agents which inhibit the CYP3A4 enzymatic pathway, and also can provide enhanced efficacy.
  • Administering a statin in its open acid form in such a way so as to minimize conversion to its lactonized counterpart, for example by using an oral delayed release dosage form, should reduce the potential for drug interaction compared to the conventional administration of an open acid statin or its lactonized counterpart, for example by using an oral rapid release dosage form.
  • An object of this invention is to provide methods for reducing the amount of lactonized statin formed and absorbed in the body after oral administration of a dihydroxy open acid statin in order to achieve enhanced clinical benefits.
  • a way to achieve this is to administer the dihydroxy open acid statin in a delayed-release pharmaceutical dosage form.
  • a delayed-release pharmaceutical dosage form as defined herein is an orally administerable pharmaceutical dosage form or device that does not release a substantial amount of the active compound, i.e., the dihydroxy open-acid statin, until after the dosage form has passed through the stomach. Therefore, substantial release of the active compound would initially occur after entry into the duodenum.
  • substantially release it is intended that 90% or more by weight of the active compound in the delayed-release dosage form is released after entry into the duodenum, and that 10% or less by weight of the active compound in the delayed-release dosage form is released in the stomach, i.e., the geometric mean ratio of the plasma AUC (area under the curve) of active vs. total HMG-CoA reductase inhibitory activity will be greater than or equal to 90%.
  • the amount of active compound released in the stomach before entry into the duodenum is 5% or less by weight, i.e., the geometric mean ratio of the plasma AUC of active vs.
  • total HMG-CoA reductase inhibitory activity will be greater than or equal to 95%, and more particularly the amount of active compound released in the stomach before entry into the duodenum is 1% or less by weight, i.e., the geometric mean ratio of the plasma AUC of active vs. total HMG-CoA reductase inhibitory activity will be greater than or equal to 99%.
  • metabolism of the dihydroxy open acid statins will occur, primarily in the liver, after orally dosing in a delayed-release dosage form.
  • lactonization of the dihydroxy open acid statin would have been substantially avoided by use of a delayed release dosage form, the active and inactive metabolites that are formed will also be in the dihydroxy open acid form.
  • the dihydroxy open acid statin is administered in a delayed release dosage form, the internal exposure to lactonized parent compound and also to lactonized active and inactive metabolites will be minimized.
  • a suitable delayed-release dosage form is a pH-dependent enterically coated dosage form.
  • the enteric coating will not dissolve in the acidic gastric environment, but will dissolve in the higher pH environment of the duodenum.
  • An enterically coated dosage form will therefore not permit release of any significant amount of the active compound from the dosage form in the stomach, but once the enteric coating dissolves in the duodenum, the active compound will be released.
  • Suitable compositions for enteric coatings that can be used with the present invention are known to those of ordinary skill in the pharmaceutical arts; for example, see L. Lachman, The Theory and Practice of Industrial Pharmacy, 3rd Ed., H. Liebermann and J. Kanig contributors (Lea & Febiger, 1986).
  • An example of a suitable enteric coating includes but is not limited to SURETERIC WHITE sold by Colorcon which is composed of polyvinyl acetate phthalate, titanium dioxide, talc, colloidal silicon dioxide, triethyl acetate, polyethylene glycol, sodium bicarbonate, purified stearic acid, and sodium alginate.
  • SURETERIC WHITE sold by Colorcon which is composed of polyvinyl acetate phthalate, titanium dioxide, talc, colloidal silicon dioxide, triethyl acetate, polyethylene glycol, sodium bicarbonate, purified stearic acid, and sodium alginate.
  • Many other suitable enteric coating materials are commercially available and are known in the art. Additional coatings employed in the preparation of the dosage form, such as those used to provide an elegant, aesthetically pleasing final product or for other purposes, may be applied before or after, or before and after, application of the enteric coating.
  • Suitable enterically coated pharmaceutical dosage forms for use with this invention include enterically coated conventional rapid-release (also referred to as immediate-release) pharmaceutical dosage forms wherein the drug is relatively rapidly released once the enteric coating is breached, and enterically coated time- controlled release dosage forms such as but not limited to an enterically coated GEM delivery device, described below.
  • Time controlled-release dosage forms are also well known in the pharmaceutical art, and are designed so as to slowly release the active compound in the body over a period of time, for example over a period of from about 6 to 24 hours.
  • Use of an enteric coated time controlled-release dosage form is preferred with more potent dosage amounts of a dihydroxy open acid statin so as to lower the systemic exposure to the active statin.
  • the enteric coating will prevent release of any substantial amount of the active compound from the dosage form in the stomach.
  • Enterically coated pharmaceutical dosage forms also include but are not limited to those wherein the dosage form or unit is comprised of the dihydroxy open acid statin in a tablet, capsule or the like that is surrounded by an enteric overcoating, and those wherein the dosage form or unit is a tablet, capsule or the like comprised of enterically coated granules of the dihydroxy open acid statin. Where the dosage form is surrounded by an enteric overcoat, the enteric coating may be the outer-most external coating on the dosage form, or there may be one or more additional finish coatings applied over the enteric coat.
  • the drug when the delayed-release dosage unit contains enterically coated granules of the drug, the drug is selected from the dihydroxy open-acid form of lovastatin and simvastatin and the pharmaceutically acceptable salt and ester forms thereof, and is more preferably a salt of dihydroxy open acid simvastatin, and most preferably the calcium or ammonium salt thereof.
  • any dihydroxy open acid statin or pharmaceutically acceptable salt or ester thereof may be used with the present invention, such as those described herein, provided that the statin is not dosed in a single pharmaceutical dosage form or unit comprised of enteric coated granules of the statin and enteric coated or non-enteric coated granules of aspirin.
  • the controlled-release drug delivery device described in U.S Patent No. 5,366,738 is known as a gel extrusion module (GEM) delivery device.
  • GEM gel extrusion module
  • the GEM device is a drug delivery device for the controlled in situ production and release of a dispersion containing a beneficial agent such as a pharmaceutical drug comprising: (A) a compressed core prepared from an admixture comprising:
  • a therapeutically effective amount of the beneficial agent (i) a therapeutically effective amount of the beneficial agent; and (ii) a polymer which upon hydration forms gelatinous microscopic particles; and (B) a water insoluble, water impermeable polymeric coating comprising a polymer and a plasticizer, which surrounds and adheres to the core, the coating having a plurality of formed apertures exposing between about 1 and about 75% of the core surface; and wherein the release rate of the beneficial agent from the device is a function of the number and size of the apertures.
  • the polymer inside the compressed core is preferably selected from sodium polyacrylate, carboxypolymethylenes and the pharmaceutically acceptable salts thereof such as a sodium salt, wherein the carboxypolymethylenes are prepared from acrylic acid crosslinked with allylethers of sucrose or pentaerythritol, and more preferably it is selected from carboxypolymethylenes prepared from acrylic acid crosslinked with allylethers of sucrose or pentaerythritol, and the pharmaceutically acceptable salts thereof.
  • CARBOPOL® 974P and pharmaceutically acceptable salts thereof, particularly the sodium salt is used as the polymer inside the compressed core.
  • the compressed core may also contain one or more polymer hydration modulating agents, anti-oxidants, lubricants, fillers and excipients.
  • An optional subcoating may be applied to the compressed core prior to application of the water insoluble coating as an aid in the manufacturing process.
  • the subcoating may be comprised of, for example, hydroxypropyl cellulose and hydroxypropylmethylcellulose. Additional coatings may be applied for aesthetic or functional purposes.
  • the water insoluble, water impermeable polymeric coating is preferably comprised of (1) a polymer selected from polyvinyl chloride, cellulose acetate, cellulose acetate butyrate, ethylcellulose and combinations of these polymers; and (2) a plasticizer selected from diethylphthalate, dibutylsebacate and triethylcitrate. More preferably, the polymeric coating is comprised of cellulose acetate butyrate and triethyl citrate.
  • the GEM device does not function as an osmotic drug delivery device, hence the release function of the device depends on passage of fluids from the external environment of the body to the internal environment of the compressed core through the formed apertures.
  • water insoluble, water impermeable used to describe the polymeric coating define a coating which is essentially water insoluble and water impermeable, meaning that the polymeric coating allows minimal to no passage of water through the coating from the external environment of the body to the internal environment of the compressed core, except for the fluid passage that occurs through the drilled apertures, during the period of time the drug is being released from the GEM device in the body.
  • Any minimal amount of water that does pass through the water insoluble, water impermeable polymeric coating is insubstantial and does not significantly contribute to the function of the GEM device, i.e. the release rate of the drug through the apertures. Rather the release rate of the drug from the GEM device is primarily a function of the number and size of the apertures on the device.
  • an outter finish coat may finally be applied to the GEM delivery device containing colorants, waxes, and the like.
  • the GEM device can also be enterically coated, either before or after the application of additional finish coatings. Even without enteric coating, extrusion of the polymer which carries the drug out from inside the compressed core of the GEM device does not occur to a substantial extent in the acidic pH of the stomach, therefore substantial release of the drug should not occur in the stomach. Further details and examples of the GEM delivery device are described in US Patent No. 5,366,738.
  • the compound employed with the GEM device may particularly be a pharmaceutically acceptable salt of dihydroxy open acid simvastatin, and more particularly the ammonium salt of dihydroxy open acid simvastatin.
  • patient includes mammals, especially humans, who use the instant active agents for the prevention or treatment of a medical condition.
  • Administering of the drug to the patient includes both self-administration and administration to the patient by another person.
  • the patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions affected by inhibition of HMG-CoA reductase.
  • the term "therapeutically effective amount” is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the term “prophylactically effective amount” is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • the dosage a patient receives can be selected so as to achieve the amount of LDL (low density lipoprotein) cholesterol lowering desired; the dosage a patient receives may also be titrated over time in order to reach a target LDL level.
  • the dosage regimen utilizing a dihydroxy open acid statin is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition.
  • novel compounds of this invention are the crystalline hydrated forms of the calcium salt of dihydroxy open acid simvastatin.
  • a particular crystalline hydrated calcium salt of dihydroxy open acid simvastatin is the one having an x-ray powder diffraction (XRPD) pattern obtained using CuK ⁇ radiation characterized by refelections at d-spacings of 30.7, 24.6, 15.9, 11.2, 8.58, 7.31 , 6.74, 6.06, 5.35, 5.09, 4.93, 4.60, 3.93, 3.84, 3.67, 3.51 and 3.28N.
  • XRPD x-ray powder diffraction
  • the crystalline hydrated form of the calcium salt of dihydroxy open acid simvastatin having the above-defined XRPD pattern will also be referred to herein as compound I.
  • Compound I can be represented two-dimensionally as a hydrated form of the following structural formula la: la
  • compound I of the instant invention is further characterized by the thermogravimetry (TG) curve shown in Figure I.
  • TG curve for compound I was obtained under a nitrogen flow at a heating rate of 10°C/minute and is characterized by a 6.3% weight loss from ambient room temperature to a stable weight loss plateau at about 175°C. Additional weight losses due to the onset of decomposition of the compound are observed above about 190°C.
  • DSC differential scanning calorimetry
  • the DSC curve for compound I was obtained under a nitrogen flow bubbled through 16.0°C water at a heating rate of 10°C/minute in an open cup, and is characterized by three lower temperature endo herms with peak temperatures of 52, 77 and 100°C and associated heats of 48, 90 and 21 J/g, respectively, and two higher temperature endofherms due to decomposition with peak temperatures of 222 and 241 °C and associated heats of 163 and 92 J/g.
  • Compound I of the instant invention is still further characterized by the ⁇ nuclear magnetic resonance (NMR) spectral data, 3 C NMR and mass spectral (MS) data as given in Example 1 herein.
  • NMR nuclear magnetic resonance
  • MS mass spectral
  • Compound I is also characterized by the solid-state 13C nuclear magnetic resonance spectrum shown in Figure 4, which was completed using a Bruker DSX 400 WB NMR system operating at 100.6 MHz for 3C and 400.1 MHz for lH using a Bruker MAS 400WB BL7 double-resonance probe with a spinning module housing a 7 mm zirconia rotor with Kel-f end caps.
  • the solid-state 13c nuclear magnetic resonance (NMR) spectrum was acquired using cross polarization (CP), magic-angle spinning (MAS), and high-power ( ⁇ 59 kHz) decoupling with variable- amplitude cross-polarization and total sideband suppression. Proton and carbon 90° pulse widths were 4.25 ⁇ sec with a contact time of 2.0 msec.
  • the compound employed is a pharmaceutically acceptable salt of a dihydroxy open acid statin, more preferably it is a pharmaceutically acceptable salt of dihydroxy open acid simvastatin such as an ammonium salt or calcium salt, and particularly a crystalline hydrated form of the calcium salt of dihydroxy open acid simvastatin such as compound I.
  • All hydrates, solvates and polymorphic crystalline forms of the above- described compounds and their use are encompassed within scope of the instant invention.
  • the instant invention provides methods for inhibiting HMG-CoA reductase, and for treating lipid disorders including hypercholesterolemia, hypertriglyceridemia and combined hyperlipidemia, comprising administering a therapeutically effective amount of a dihydroxy open acid statin to a person in need of such treatment.
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease including restenosis following revascularization procedures coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and pe ⁇ pheral vessel disease including erectile dysfunction are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms “atherosclerosis” and "atherosclerotic disease "
  • a dihydroxy open acid statin may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease event, a cerebrovascular event, and/or intermittent claudication
  • Coronary heart disease events are intended to include CHD death, myocardial infarction (1 e , a heart attack), and coronary revascula ⁇ zation procedures
  • Cerebrovascular events are intended to include lschemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient lschemic attacks
  • Intermittent claudication is a clinical manifestation of pe ⁇ pheral vessel disease
  • the term "atherosclerotic disease event" as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication It is intended that persons who have previousl) expe ⁇ enced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists
  • the instant invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event comp ⁇ sing the administration of a prophylactically effective amount of a dihydroxy open acid statin to a patient at risk for such an event
  • the patient may or may not have atherosclerotic disease at the time of administration, or may be at ⁇ sk for developing it
  • the instant invention also provides a method for preventing and/or treating inflammatory diseases or disorders alone or in conjunction with the treatment of conditions desc ⁇ bed above, comp ⁇ sing the administration of a dihydroxy open- acid statin to a patient m need of such treatment
  • This includes, for example, the treatment of inflammatory conditions susceptible to treatment with a non-steroidal anti-inflammatory agent, arth ⁇ tis including rheumatoid arth ⁇ tis, and degenerative joint diseases (osteoarth ⁇ tis), dementia, Alzheimer's disease, multiple sclerosis, inflammatory bowel disease, asthma, psoriasis, systemic lupus erythematosis, vascuhtis, gout, adrenoleukodystrophy, diabetic retmopathy, nephropathy and diabetes melhtus type II
  • Persons to be treated with the instant therapy include those at risk of developing atherosclerotic disease and of having an atherosclerotic disease event
  • Standard atherosclerotic disease ⁇ sk factors are known to the average physician practicing in the relevant fields of medicine
  • risk factors include but are not limited to hypertension, smoking, diabetes, low levels of high density lipoprotein (HDL) cholesterol, and a family history of atherosclerotic cardiovascular disease.
  • HDL high density lipoprotein
  • People who are identified as having one or more of the above-noted risk factors are intended to be included in the group of people considered at risk for developing atherosclerotic disease. People identified as having one or more of the above-noted risk factors, as well as people who already have atherosclerosis, are intended to be included within the group of people considered to be at risk for having an atherosclerotic disease event.
  • the oral dosage amount of the dihydroxy open acid statin is from about 1 to 200 mg/day, and more preferably from about 5 to 160 mg/day.
  • dosage amounts will vary depending on factors as noted above, including the potency of the particular compound.
  • the active drug of the present invention may be administered in divided doses, for example from one to four times daily, a single daily dose of the active drug is preferred.
  • the daily dosage amount may be selected from, but not limited to, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 40 mg, 50 mg, 75 mg, 80 mg, 100 mg, 150 mg and 160 mg.
  • the active drug employed in the instant therapy can be administered in such oral forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Oral formulations are preferred.
  • administration of the active drug can be via any pharmaceutically acceptable route and in any pharmaceutically acceptable dosage form.
  • An oral delayed-release dosage formulation of the instant drug is preferred, and particularly an enteric overcoat surrounding a rapid-release dosage unit, or the GEM controlled-release drug delivery device with an enteric overcoat surrounding the dosage unit, and most particularly an enteric overcoat surrounding a rapid-release dosage unit.
  • Additional suitable pharmaceutical compositions for use with the present invention are known to those of ordinary skill in the pharmaceutical arts; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
  • the active drug is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture.
  • Stabilizing agents such as antioxidants, for example butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT), propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite, hydroquinone, and 7- hydroxycoumarin, particularly BHA, propyl gallate and combinations thereof, can also be added to stabilize the dosage forms; the use of at least one stabilizing agent is preferred with the instant composition.
  • BHA butylated hydroxyanisole
  • BHT 2,6-di-tert-butyl-4-methylphenol
  • propyl gallate sodium ascorbate
  • citric acid calcium metabisulphite
  • hydroquinone hydroquinone
  • 7- hydroxycoumarin particularly BHA, propyl gallate and combinations thereof
  • an antioxidant is employed with dihydroxy open acid simvastatin or a salt thereof
  • Suitable components include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth or alginates, carboxyme hylcellulose, polyethylene glycol, waxes and the like.
  • the active drug can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Active drug may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drug may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl- methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining a dihydroxy open acid statin with a pharmaceutically acceptable carrier. Also encompassed is the pharmaceutical composition which is made by combining a dihydroxy open acid statin with a pharmaceutically acceptable carrier.
  • any suitable additional active agent or agents may be used in combination with the dihydroxy open acid statin in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration of the active agents.
  • One or more additional active agents may be administered with a dihydroxy open acid statin.
  • the additional active agent or agents can be lipid lowering compounds or agents having other pharmaceutical activities, or agents that have both lipid-lowering effects and other pharmaceutical activities.
  • additional active agents include but are not limited to HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT- 1 or ACAT-2 as well as dual inhibitors of ACAT- 1 and -2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; cholesterol absorption inhibitors such as SCH-58235, which is described in U.S.
  • HMG-CoA synthase inhibitors squalene epoxidase inhibitors
  • squalene synthetase inhibitors also known as squalene synthase inhibitors
  • acyl-coenzyme A cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of
  • dihydroxy open acid statins of this invention may be used in combination with anti -retro viral therapy in ALDS infected patients to treat lipid abnormalities associated with such treatment, for example but not limited to their use in combination with HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir.
  • a therapeutically or prophylactically effective amount, as appropriate, of a crystalline hydrated form of the calcium salt of dihydroxy open acid simvastatin, for example compound I can be used for the preparation of a medicament useful for inhibiting HMG-CoA reductase, as well as for treating and/or reducing the risk for diseases and conditions affected by inhibition of HMG-CoA reductase, such as treating lipid disorders, preventing or reducing the risk of developing atherosclerotic disease, halting or slowing the progression of atherosclerotic disease once it has become clinically manifest, and preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event.
  • the medicament may be comprised of about 1 mg to 200 mg of a crystalline hydrated form of the calcium salt of dihydroxy open acid simvastatin, or more particularly about 5 mg to 160 mg.
  • a therapeutically or prophylactically effective amount, as appropriate, of a dihydroxy open acid statin can be used for the preparation of an oral medicament adapted for delayed-release, wherein substantial release of the statin after oral administration does not occur until after passage of the medicament through the stomach, or alternately wherein at least 90% of the statin is delivered in its dihydroxy open acid form to the intestinal mucosa of a patient after oral administration.
  • Said oral medicaments are also useful for inhibiting HMG-CoA reductase, as well as for treating and/or reducing the risk for diseases and conditions affected by inhibition of HMG-CoA reductase, as described above.
  • the medicament comprised of a dihydroxy open acid statin, for example compound I may also be prepared with one or more additional active agents, such as those described supra.
  • Simvastatin is a semi-synthetic product which can be made from the natural product lovastatin.
  • Processes for preparing lovastatin and simvastatin are well documented in the published literature.
  • U.S. Patent No. 4,231,938, herein incorporated by reference describes a fermentation and isolation process for obtaining lovastatin using the microorganism Aspergillus terreus.
  • U.S. Patent No.'s 4,444,784, 4,820,850, 4,916,239 and 4,582,915, herein all incorporated by reference, describe methods for making dihydroxy open-acid and lactonized forms of simvastatin.
  • Compound I of the instant invention can generally be prepared as follows. Simvastatin and its dihydroxy open acid counterpart, including compound I, tend to fo ⁇ ri oxidative by-products; therefore, to minimize the formation of such byproducts, it is preferred that the procedures used to make compound I are performed under an inert atmosphere such as nitrogen. Although compound I can be obtained without using an inert atmosphere, the purity of the desired product will not be optimized.
  • Hydrolysis of the lactone ring of simvastatin can be accomplished by treating simvastatin with at least one equivalent, and preferably a slight excess of one equivalent, of an aqueous base. If more than a slight excess of base is used, the excess base is preferably neutralized before proceeding to the salt formation step in order to prevent formation of insoluble calcium hydroxide or calcium carbonate byproduct.
  • the base employed for the hydrolysis can be an aqueous solution of a metal hydroxide or metal carbonate, for example but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate. Sodium hydroxide is preferred.
  • the hydrolysis can be performed in water, an aqueous-protic organic solvent mixture, or an aqueous-aprotic organic solvent mixture.
  • Suitable protic organic solvents include but are not limited to methanol (MeOH), ethanol (EtOH), isopropyl alcohol, n-propyl alcohol (propanol).
  • suitable aprotic organic solvents include but are not limited to acetonitrile, dimethyl sulfoxide (DMF), N,N-dimethylformamide (DMSO), tetrahydrofuran (THF), tert-butyl methyl ether (MTBE) and toluene.
  • an aqueous ethanol or n- propyl alcohol solvent mixture may be used, and more particularly an aqueous n- propyl alcohol solvent mixture.
  • the pH of the reaction mixture is adjusted to about 6 to 11, particularly 6 to 9, and more particularly 7 to 8.5, by addition of an acid.
  • the dihydroxy open acid simvastatin will exist as a metal salt, for example as the sodium salt if the base used in the hydrolysis step is sodium hydroxide or sodium carbonate.
  • Any acid that is capable of forming a soluble calcium salt such as calcium chloride or calcium citrate, is suitable.
  • a soluble calcium salt is intended to be a salt that is soluble in the solvent sytem employed in the instant process.
  • an acid such as acetic acid (HOAc) or a mineral acid is employed, particularly HC1.
  • a small portion, e.g., about one-quarter, of the calcium acetate hydrate solution can be added to the pH-adjusted reaction mixture over a short period of time, for example over about 30 minutes, and then the resulting mixture can be allowed to age for an additional short period of time at room temperature, optionally followed by a further period of aging at a temperature up to about 50°C, for example from about 10°C up to about 50°C, particularly from room temperature up to about 50°C, more particularly from about 30 to 40°C, and most particularly from about 30 to 35°C, after which the remaining calcium acetate hydrate solution can be added in portions over several hours at a temperature up to about 50°C, for example from about 10°C up to about 50°C, particularly from room temperature up to about 50°C, and more particularly from about 30 to 40°C, and most particularly from about 30 to 35°C.
  • the reaction mixture can be seeded with crystalline Compound I.
  • the resulting slurry must be aged until turnover of the resulting amorphous calcium salt of dihydroxy open acid simvastatin to the crystalline product is complete, usually for at least several hours.
  • Complete turnover to the crystalline product can be assessed by standard techniques in the art, for example, by examining a sample of the product under a microscope.
  • This aging step can be performed at a temperature up to about 50°C, for example from about 10°C up to about 50°C, particularly from room temperature up to about 50°C, and more particularly from about 30 to 40°C, and most particularly from about 30 to 35°C.
  • the use of lower temperatures will lead to crystallized product; however, it has been found that as the temperature drops, the rate of crystal turnover becomes slower, making the procedure less time-efficient.
  • the slurry is then allowed to cool to room temperature and is collected by suction filtration.
  • the recovered solid is suction dried under a moist atmosphere (about 30 to 70% relative humidity, particularly 40 to 70%), preferably a moist inert atmosphere such as nitrogen, and particularly at a temperature from about 10 to 40°C, and more particularly 25 to 35°C.
  • the final step of suction filtration in the recovery of compound I should be done under a moist atmosphere, and preferably a moist inert atmosphere in order to minimize oxidative by-products. If an additional step of adding an antioxidant to compound I is performed, as described below, then the final suction filtration is the one performed after combining the antioxidant with compound I.
  • compound I has a tendency to oxidize upon contact with air, and one way to minimize oxidation is to perform the reaction sequence under an inert atmosphere.
  • one or more anti-oxidants such as BHA, BHT, propyl gallate, ascorbic acid, calcium metabisulphite, hydroquinone, nordihydroguaiaracetic acid (NDGA) or 7-hydroxycoumarin can be combined with compound I. This is done by agitating a slurry of compound I with one or more of the antioxidants and recovering the resulting solid by suction filtration.
  • ammonium salt of dihydroxy open acid simvastatin can be used as the starting material to be combined with the calcium acetate hydrate, thus avoiding the hydrolysis and pH adjustment steps needed when starting with lactonized simvastatin.
  • the other reaction conditions desc ⁇ bed above, such as solvents, temperatures, etc., can otherwise be employed.
  • the calcium salt was delumped with a single pass through a cleaned QUADROTM COMIL® (Model 197S).
  • the wet cake was washed with 4 L 30% EtOH-H 2 O, 4 L 20% EtOH-H 2 O, followed by 6 L x 3 of D.I. water.
  • the solid was suction dried under atmosphere of moist N 2 (40 to 70% RH) at room temperature to give 1 I Kg of wet cake.
  • a 72 L three-necked round bottom flask was equipped with a temperature probe, a N 2 inlet, an additional funnel, and an overhead stirrer. 28.5 L of D.I. H O was added and purged with N 2 for 10 min. 1.5 Kg simvastatin was added, followed by 788mL of 5N NaOH in one portion at room temperature. The hydrolysis reaction is usually complete in 2 h. as analyzed by HPLC (> 99.9% conversion). 1.5L of nPrOH was added and the pH of the reaction solution was adjusted to 9.5 to 11.0 by adding 2 N HO Ac (about 170 mL).
  • Example 3 Then, 100 ml nPrOH was added and the solution pH was adjusted to 9 to 11 with 1 N HO Ac. The resulting solution and a solution of Ca(OAc) 2 .H 2 O (23.2 g) in 1.0 L of 20% nPrOH were added separately but simultaneously to a suspension of 10-50 wt% Ca salt in 10% nPrOH (30 volume 10% PrOH relative to the amount of the seed) at 30 to 40 °C over 3 h. After 5 h age at 30 to 40 °C, the slurry was cooled to room temperature, filtered, and loaded with anti-oxidant and dried as described in conventional addition mode process. 95% yield.
  • Method A 100 g of simvastatin was hydrolyzed in 1.9 L water as described in Example 3. Then, 100 ml nPrOH was added and the solution pH was adjusted to 9 to 11 with 1 N HO Ac. 10wt% seed was added and the slurry was allowed to warm up to 35 to 40 °C. A solution of Ca(OAc) 2 *H 2 O (23.2 g) and BHA (540 mg) in 1.0 L of 20% nPrOH were added to the slurry at 35 to 40 °C over 3 h.
  • Method B The procedure of Method A was employed with the following change. Instead of adding BHA to a Ca(OAc) 2 solution, the same amount of BHA was added into the pH adjusted solution of hydrolyzed simvastatin at room temperature. The solution was warmed to 35 to 40 °C to dissolve BHA. Then, 10wt% seed was introduced. The rest of the steps were as described in Method A. The final dried Ca salt title product contained 0.2wt% BHA. 95% yield.
  • the calcium salt of dihydroxy open acid simvastatin was crystallized, isolated, and washed as described in Example 3.
  • the first wet cake was transferred to a clean 100L vessel under atmosphere of N 2 .
  • a solution of BHA (9.2g) and propyl gallate (11.2 g) in 50 L 10% nPrOH was added to above vessel.
  • the slurry was aged at room temperature for lh.
  • the slurry was filtered with no wash.
  • the wet cake was dried under moist N 2 . 95% yield.
  • the dried salt was loaded with 0.07wt% propyl gallate and 0.2 wt% BHA.
  • simvastatin 100 g was hydrolyzed in 1.9 L water as described in Example 3. Then, 100 ml nPrOH was added and the solution pH was adjusted to 9 to 1 1 with 1 N HO Ac. 10wt% seed was added and the slurry was allowed to warm up to 35 to 40 °C. A solution of Ca(OAc) 2 -H 2 O (23.2 g) in 1.0 L of 20% nPrOH was added to a slurry at 35 to 40 °C over 3 h. After 5 h age at 30 to 40 °C, the slurry was cooled to room temperature.
  • the calcium salt slurry was filtered and washed with 10% nPrOH (500 mL x 1), followed by water (1L x 3).
  • a 7.2 L three-necked round bottom flask was equipped with a temperature probe, a N 2 inlet, an additional funnel, and an overhead stirrer.
  • 2.1 L of D.I. H 2 O was added and purged with N 2 for 10 min.
  • 150 g simvastatin was added, followed by 78.8mL of 5N NaOH in one portion at room temperature.
  • the hydrolysis reaction is usually complete in 2 h. as analyzed by HPLC (> 99.9% conversion).
  • 900 mL of MeCN was added and the pH of the reaction solution was adjusted to 9.5 to 1 1.0 by adding 2 N HOAc (about 17 mL).
  • 30.0 g crystalline seed was added to above solution and the resulting slurry was allowed to warm up to 30 to 35 °C.
  • the dihydroxy open acid simvastatin calcium salt slurry was filtered and washed with 20% MeOH (200 ml) and water (500 ml x 3). The wet cake was dried under moist N 2 . The final dried Ca salt title product was isolated in 96% yield.
  • Example 3 Then, 150 ml i-PrOH was added and the solution pH was adjusted to 7 to 1 1 with 1 N HO Ac. 10wt% seed was added and the slurry was allowed to warm up to 30-35 °C. A solution of Ca(OAc) 2 rH 2 O (11.6 g) in 500 mL of 30% i-PrOH was added to the slurry at 30-35 °C over 3 h. After 5 h age at 30-35 °C, the slurry was cooled to room temperature. Ca salt slurry was filtered and washed with 20% ml i-PrOH (200 ml) and with water (500 ml x 3). The wet cake was dried under moist N 2 . The final dried Ca salt title product was isolated in 96% yield.
  • Example 3 Then, the solution pH was adjusted to 11 with 1 N HO Ac. 10wt% seed was added and the slurry was allowed to warm up to 35-40 °C. A solution of Ca(OAc) 2 *H 2 O (11.6 g) in 500 L of water was added to the slurry at 35-40 °C over 5 h. After 10 h age at 35-40 °C, the slurry was cooled to room temperature. Ca salt slurry was filtered and washed with water (500 ml x 3). The wet cake was dried under moist N 2 . The final dried Ca salt title product was isolated in 96% yield.
  • Method A 50 g of dihydroxy open acid simvastatin ammonium salt was dissolved into 800 ml of 25% nPrOH which was then added dropwise to a solution of Ca(OAc) 2 *H 2 O (10.7 g) in 75 ml of water at room temperature over 2h. The resulting slurry was aged at 30 to 35 °C 5 h. After cooling to room temperature, the slurry was isolated by filtration. The wet cake was washed with 10% nPrOH (500 ml x 3). The wet cake was loaded with antioxidants and dried under moist N 2 as described above to give the title product.
  • Method B 50 g of dihydroxy open acid simvastatin ammonium salt was added into a solution of Ca(OAc) 2 *H 2 O (10.7 g) in 1.5 L of 10% nPrOH in one portion at room temperature. The resulting slurry was aged at 30 to 35 °C 5 h. After cooling to room temperature, the slurry was isolated by filtration. The wet cake was washed with 10% nPrOH (500 ml x 3). The wet cake was loaded with antioxidants and dried under moist N2 as described above to give the title product.
  • the title product could also prepared from ammonium salt in the following aqueous solvents: acetone, MeOH, EtOH, iPrOH, , MeCN, neat water, DMF, DMSO, and similar solvents.
  • Dried Compound I (21 g) was dissolved in 150ml of 40% nPrOH at 35°C and line filtered. This solution was added dropwise to a slurry of 10 wt% seed in 480 ml of 4% PrOH at 35 to 40°C over 3 to 5 h. After aging overnight at 35 to 40°C, the slurry was allowed to cool to room temperature. The solid was filtered and washed with 10% nPrOH (200ml x 2). The wet cake was dried under moist N 2 . 95% yield.
  • Treatment A subjects received itraconazole 200 mg (2 x 100-mg capsule) for 4 days followed by a single dose of 5-mg dihydroxy open acid simvastatin solution administered intraduodenally on day 4, 1 hour after the fourth daily dose of itraconazole.
  • Treatment B subjects were given a single dose of 5-mg dihydroxy open acid simvastatin solution administered intraduodenally on day 1.
  • Intraduodenal administration was accomplished via a nasoduodenal tube placed under fluoroscopic guidance by an experienced gastroenterologist just prior to dosing and removed following the 1-hr postdose measurements.
  • Treatments C and D were similar to those of Treatments A and B, except that orally dosed simvastatin 20-mg conventional film coated tablet was used.
  • the wash out between treatment periods was at least 7-days following a treatment containing itraconazole or at least 3 days following a treatment without itraconazole.
  • Plasma samples were collected at appropriate time intervals for up to 24 hours following simvastatin or dihydroxy open acid simvastatin administration, for analysis of total and active HMG-CoA reductase inhibitory activities as well as for simvastatin and dihydroxy open acid simvastatin concentrations.
  • Plasma concentrations of simvastatin and dihydroxy open acid simvastatin acid were determined simultaneously by an improved liquid chromatography/tandem mass spectrometry (LC/MS/MS) method using lovastatin and dihydroxy open acid lovastatin acid as internal standards.
  • An enzymatic assay method was used to determine plasma concentrations of active and total (active plus potentially active) HMG-CoA reductase inhibitory activity.
  • Pharmacokinetics The area under the plasma concentration-time profile from time zero to the last sampling time (AUCO-last) was calculated using linear trapezoidal rule.
  • Pretreatment with itraconazole caused minimal changes (1.3-1.5-fold) in the systemic exposure as measured by AUC and C m ax of HMG-CoA reductase inhibitory activity (total or active) following administration of dihydroxy open acid simvastatin 5-mg intraduodenally, as compared to that observed following oral administration of simvastatin 20-mg tablet (1.3-3.8- fold) (see Table 2)
  • the effect of itraconazole observed following dihydroxy open acid simvastatin administration was also minimal (1.5-fold) and was much less than the corresponding measure obtained following simvastatin administration (19-fold) (see Table 3).

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Abstract

L'invention concerne des procédés et des compositions pharmaceutiques pour l'inhibition de la HMG-CoA réductase, ainsi que pour le traitement et/ou la réduction du risque de maladies et d'états modifiés par l'inhibition de la HMG-CoA réductase. Lesdits procédés consistent à administrer par voie orale une dose efficace au plan thérapeutique d'un composé choisi parmi une statine d'acide ouvert en dihydroxy, un sel acceptable au plan pharmaceutique ou un ester, dans une forme galénique à effet retard, à un patient ayant besoin dudit traitement, la libération du composé par la forme galénique étant retardée jusqu'à ce que la forme galénique soit passée dans l'estomac.
EP00907111A 1999-03-08 2000-02-02 Acide ouvert en dihydroxy et sels d'inhibiteurs de la hmg-co-a reductase Withdrawn EP1161236A1 (fr)

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EP1225880A2 (fr) * 1999-11-04 2002-07-31 Andrx Corporation Methode de traitement de troubles lies au precurseur beta-amyloide
JP2004508347A (ja) * 2000-09-06 2004-03-18 メルク　エンド　カムパニー　インコーポレーテッド シンバスタチンのジヒドロキシ開環酸塩
ZA200302507B (en) * 2000-10-12 2004-03-31 Nisaan Chemical Ind Ltd Preventives and remedies for complications of diabetes.
US6777552B2 (en) 2001-08-16 2004-08-17 Teva Pharmaceutical Industries, Ltd. Processes for preparing calcium salt forms of statins
EP1425287A4 (fr) * 2001-08-16 2005-09-07 Teva Pharma Procedes permettant de preparer des formes salines calciques de statines
CN1612747A (zh) * 2002-01-09 2005-05-04 克鲁塞尔荷兰公司 促红细胞生成素在预防或治疗心力衰竭中的用途
TW200404544A (en) * 2002-06-17 2004-04-01 Kowa Co Controlled release pharmaceutical composition
AR040588A1 (es) 2002-07-26 2005-04-13 Schering Corp Formulacion farmaceutica que comprende un inhibidor de la absorcion del colesterol y un inhibidor de una hmg- co a reductasa
US8987322B2 (en) * 2003-11-04 2015-03-24 Circ Pharma Research And Development Limited Pharmaceutical formulations for carrier-mediated transport statins and uses thereof
ATE428411T1 (de) * 2003-11-07 2009-05-15 Jj Pharma Inc Hdl-verstärkende kombinationstherapie-komplexe
EP3058089B1 (fr) 2013-10-18 2018-12-05 Institut National de la Santé et de la Recherche Médicale (INSERM) Petits arn dérivés de rny en tant que biomarqueurs pour des troubles associés à l'athérosclérose
JP7300720B2 (ja) * 2017-05-15 2023-06-30 ユニバーシティ・オブ・シンシナティ シンバスタチンの１つまたは複数の代謝産物を直接投与することによって無血管性軟骨組織における欠損を処置するための組成物および方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5225202A (en) * 1991-09-30 1993-07-06 E. R. Squibb & Sons, Inc. Enteric coated pharmaceutical compositions
HU217629B (hu) * 1991-12-12 2000-03-28 Novartis Ag. Eljárás fluvasztatint tartalmazó stabilizált gyógyszerkészítmények előállítására
CZ288545B6 (cs) * 1995-12-22 2001-07-11 Kowa Company, Ltd. Stabilizovaná farmaceutická kompozice na bázi kyseliny (E)-3,5-dihydroxy-7-[4´-4´´-fluorfenyl-2´-cyklopropylchinolin-3´-yl]-6-heptenové
US5916595A (en) * 1997-12-12 1999-06-29 Andrx Pharmaceutials, Inc. HMG co-reductase inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0053173A1 *

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AU2866400A (en) 2000-09-28
AR022856A1 (es) 2002-09-04
CO5150193A1 (es) 2002-04-29
JP2000256191A (ja) 2000-09-19
CA2364253A1 (fr) 2000-09-14
SV2002000036A (es) 2002-02-05
PE20001559A1 (es) 2001-01-16
JP2002538202A (ja) 2002-11-12
WO2000053173A1 (fr) 2000-09-14

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