JP2000256191A - HMG-CoA reductase inhibitor dihydroxy open acids and salts thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method and a pharmaceutical composition for inhibiting HMG-CoA reductase, and for treating and / or reducing the risk of diseases and conditions affected by inhibition of HMG-CoA reductase. Offer things. SOLUTION: The compound is formulated as a delayed release dosage form containing a therapeutically effective amount of a compound selected from statins dihydroxy open acid and pharmaceutically acceptable salts or esters thereof together with a pharmaceutically acceptable carrier. An oral pharmaceutical composition, wherein sufficient release of the compound from the dosage form is delayed until after the dosage form has passed through the stomach.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 3-hydroxy-3-
The use of statins, dihydroxy open acid inhibitors and their salts and esters, which are inhibitors of methylglutaryl coenzyme A (HMG-CoA) reductase, in a manner that minimizes their in vivo lactonization, It relates to a specific crystalline hydrated form of the calcium salt of simvastatin dihydroxy open acid, referred to herein as compound I.

[0002]

BACKGROUND OF THE INVENTION In recent decades, coronary heart disease (CH)
It has been revealed that the major risk factor for D) is elevated blood cholesterol, and many studies have shown that CHD
It has been shown that the risk of developing can be reduced by lipid-lowering therapy. Prior to 1987, medical supplies for lowering lipids were essentially restricted to a low-saturated fat / cholesterol diet, bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), fibrates and probucol. I was Unfortunately, all of these treatments have limited efficacy or tolerability or both. Lovastatin (MEVACOR®), the first inhibitor of HMG-CoA reductase made available as a prescription drug in 1987; U.S. Pat.
For the first time, physicians were able to achieve a significant reduction in plasma cholesterol with negligible side effects.

The natural fermented product mevastatin (mevas)
In addition to tatin) and lovastatin, various semi-synthetic or fully synthetic HMG-CoA reductase inhibitors are presently present, for example, simvastatin (ZOCOR (registered trademark); see U.S. Patent No. 4,444,784), pravastatin (pravastatin). )
Sodium salt (PRAVACHOL®; U.S. Pat.
227), fluvastatin sodium salt (LESCOL®; see U.S. Pat.No. 5,354,772), atorvastatin calcium salt (LIPITOR
(Registered trademark); U.S. Pat. No. 5,273,995) and cerivastatin sodium salt (also known as rivastatin; see U.S. Pat. No. 5,177,080). The structural formulas for these and additional HMG-CoA reductase inhibitors are described in M. Yalpani, "Cholesterol Lowering Gr.
ugs ", Chemistry & Industry, pp. 85-89 (February 5, 1996
Page 87). The above HMG-CoA reductase inhibitors belong to the structural class of compounds containing a moiety that can be present as either a 3-hydroxylactone ring or the corresponding open cyclic dihydroxyopenic acid,
Often called "statins". The structure of the lactone portion of the statin and its corresponding open acid form is shown below.

[0004]

Embedded image Lactone dihydroxy open acid

[0005] Salts of dihydroxy open acids can be prepared, and indeed, as mentioned above, some statins on the market are administered in the form of salts of dihydroxy open acid. Lovastatin and simvastatin are marketed worldwide in their lactonized form. The structure of lovastatin is represented by Formula II below, and the structure of simvastatin is represented by Formula III below.

[0006]

Embedded image

While the lactonized form of statins is not an active inhibitor of HMG-CoA reductase, the dihydroxy open acid form is active. It is known that under acidic conditions below about pH 4, the dihydroxy open acid form of the statin is condensed to the corresponding lactonized form. Thus, because of the low gastric pH, statins, usually administered orally in the form of lactones, remain predominantly in their lactone form in the stomach. After oral administration of lactone, most of the drug will still remain in the lactone form when absorbed from the gut. After absorption, the lactone enters the liver and is metabolized in the hepatocytes to the active open acid form, a reaction that involves two hepatic esterases or "lactonases", one in the cytosolic fraction and the other in the cytosolic fraction. (In the microsomal fraction). Once in the blood, there is another plasma esterase, which also hydrolyzes lactones to open acids. Very little chemical or non-enzymatic hydrolysis can occur in the blood or liver. However, at blood and liver pH, lactonization, the reverse conversion of open acids to lactones, will not occur.

[0008] Statins, usually administered orally in the form of dihydroxy open acids or pharmaceutically acceptable salts or esters thereof, are susceptible to conversion into the lactone form in the acidic environment of the stomach, and are therefore compatible with the open acid form. A mixture with the ring-closing form will coexist. For example, M.
J. Kaufman, International Journal of Pharmaceutic
s, 1990, 66 (Dec 1), pp. 97-106. There is a hydrous that can be used to simulate the extent of drug degradation that occurs in acidic gastric juice after oral administration of several structurally related hypocholesterolemic drugs, including simvastatin and lovastatin. Decomposition data is shown. AS Kearney et al., Pharmaceutical Research, 1993, discussing the interconversion kinetics and equilibrium of CI-981 (atorvastatin in the free acid form).
See 10 (10), pp. 1461-1465. Therefore,
Even after the usual oral administration of a statin in dihydroxy open acid form or a salt or ester thereof,
By the time it is absorbed from the intestine, there will be a mixture of the drug's open acid and the corresponding lactone.

The preparation of the natural compound lovastatin and the semisynthetic analog simvastatin result in a mixture of the lactone form and an open cyclic dihydroxy acid. Several methods have been described for the production of simvastatin from lovastatin, most of which start with the step of opening the lactone ring at some point in the process, sometimes forming the resulting salt of the carboxylic acid, and finally simvastatin. A ring closure step has been performed to produce the final product. For example, U.S. Pat. No. 4,820,850 describes a method for preparing simvastatin, which opens the lactone ring of lovastatin, forms the resulting alkylamide of the carboxylic acid, and then protects the two hydroxy groups. And methylating the 8 ′ acyl side chain. After the methylation step, a step of removing the hydroxy protecting group, hydrolyzing the amide to a free acid, forming an ammonium salt of the free acid, and then relactonizing is performed. In U.S. Patent No. 4,444,784,
In the first step, the 8'-acyl side chain of lovastatin is removed to open the lactone ring, and then the ring is relactonized to protect its hydroxy group. The 8 ′ position is then acylated to introduce the simvastatin side chain and a deprotection step yields the final simvastatin product. In another method, described in U.S. Patent No. .

[0010] Since its availability, simvastatin has been administered to the general public and has set an excellent safety record for the drug. But Physician's Desk
Rarely, as noted in the Reference (PDR),
The use of all statins, including simvastatin, can be associated with myopathy. The mechanism of statin-related myopathy is currently poorly understood. Also, many drugs, including certain statins such as simvastatin, are cytochrome P450 3A4 (CYP3A
4) It is known to be metabolized by the enzyme system. In addition, as noted in the PDR, potent CYP3A4 inhibitors such as itraconazole and CYP3A4
It has been found that the combined use of statins that are metabolized by the drug causes serious problems of adverse drug interactions, and some cases of myopathy occur in patients with such drugs. Simvastatin has been administered to over 20 million patients worldwide over the past 11 years and has proven to be extremely safe. However, when simvastatin is administered with a potent CYP3A4 inhibitor, there is a very low risk but a substantial increase in myopathy. Simvastatin has a good overall safety record, but CYP3
It would be desirable to further optimize its safety profile by reducing the likelihood of drug interaction with inhibitors of A4. It would also be desirable to further reduce the incidence of myopathy associated with the use of any statin, albeit at an already low incidence. Statins are among the most widely used drugs in the world,
Therefore, further optimization of its safety profile is of great significance.

[0011]

One object of the present invention is to minimize or eliminate in vivo lactonization of the statin dihydroxy open acid. For oral administration, statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof minimizes the formation of lactonized statins, thereby minimizing the amount of lactonized statins absorbed from the intestine. At the same time, it should be administered to maximize the amount of statin dihydroxy open acid absorbed from the intestine.

Accordingly, the present invention relates to a method of inhibiting HMG-CoA reductase by an inhibitory effective amount of an orally administered statin, said method comprising at least 90% of a statin administered in the form of a dihydroxy open acid such a treatment. In the intestinal mucosa of a patient in need thereof.

The present invention further provides methods for inhibiting HMG-CoA reductase, and for treating and / or reducing the risk of diseases and conditions affected by inhibition of HMG-CoA reductase. The method comprises orally administering a therapeutically effective amount of a compound selected from a statin dihydroxy open acid and a pharmaceutically acceptable salt or ester thereof in a delayed release pharmaceutical dosage form to a patient in need of such treatment. Comprising
In that case, a sufficient release of the compound from the dosage form is delayed until after the dosage form has passed through the stomach.

[0014] One embodiment of the first problem is that the delayed release pharmaceutical dosage form is a gel extrusion mod- ule.
ule: GEM).

[0015] Another embodiment of the first object is to provide the above method wherein the delayed release pharmaceutical dosage form comprises an enteric coated pharmaceutical dosage form. Another aspect of this embodiment is that the delayed release pharmaceutical dosage form is an enteric coated rapid-release pharmaceutical dosage form and an enteric coated time controlled-release pharmaceutical dosage form. It is to provide said method characterized in that it is selected from dosage forms. Yet another aspect of this embodiment is that
It is an object of the present invention to provide the method wherein the delayed release pharmaceutical dosage form comprises an enteric coated gel extrusion module (GEM) drug delivery device.

The compounds used for the above objects and embodiments are, in particular, simvastatin dihydroxy open acid and its pharmaceutically acceptable salts, and more particularly, their pharmaceutically acceptable salts.

A second object of the present invention is to provide a crystalline hydrated form of the calcium salt of simvastatin dihydroxy open acid, in particular a novel HMG-CoA reductase inhibitor which is a compound referred to herein as compound I. It is to be.

Another object is to provide simvastatin dihydroxy open acid for inhibiting HMG-CoA reductase and for treating and / or reducing the risk of diseases and conditions affected by inhibition of HMG-CoA reductase. To provide for the use of crystalline hydrated forms of calcium salts of, particularly Compound I, as well as fast release, delayed release and time, such as GEM drug delivery devices and enteric coated dosage forms usable with said compounds. It is to provide a pharmaceutical formulation including a controlled release formulation.
A further object is to provide a process for preparing compound I. Other challenges will become apparent from the detailed description below.

[0019]

SUMMARY OF THE INVENTION The present inventors have now found that statins of dihydroxy open acid are not as dependent on CYP3A4 metabolism as their closed cyclic lactonized counterparts. The present invention relates to a method and a medicament for oral administration of an HMG-CoA reductase inhibitor, a ring-opened dihydroxy open acid statin or a salt or ester thereof, in such a manner as to minimize the conversion to its lactonized counterpart. Compositions. This makes it possible to deliver the dihydroxy open acid statin directly to the absorbing mucosa of the small intestine without conversion to its lactone counterpart, and therefore the absorption of the open acid statin into the portal circulation, hepatocytes Permeation by the active open acid statin into the cell is achieved, resulting in increased potency and systemic exposure to the open acid component. More specifically, it is formed in the body by delayed release of orally administered statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof (eg, simvastatin dihydroxy open acid or a salt thereof) until after passage in the stomach. To reduce the amount of lactone absorbed. Maintaining statins in their open acid form in the body results in statins, whose metabolism is mediated by CYP3A4, and CYP3
The potential for drug interaction with other active agents that inhibit the A4 enzymatic pathway is reduced, and increased potency is also obtained. Furthermore, maintaining statins in their open acid form in the body
For any statin, even a statin that is not significantly metabolized by the CYP3A4 enzymatic pathway will have additional clinical effects.

In addition, this time, the novel crystalline hydrated form of the calcium salt of simvastatin dihydroxy open acid is now a pharmaceutically suitable drug with desirable physical properties for formulation into an anti-hypercholesterolemic drug composition. It was found to be in salt form.

As used herein, the term "statin (s)" refers to HMG-CoA which belongs to the structural class of compounds containing a moiety which may be present as a 3-hydroxylactone ring or as its corresponding open cyclic dihydroxyopenic acid. It is defined as a reductase inhibitor, and the lactone moiety of the statin and its corresponding dihydroxy open acid form are represented by the formula:

[0022]

Embedded image Lactone dihydroxy open acid

Hydrates, solvates and polymorphic crystalline forms of the above HMG-CoA reductase inhibitors containing a lactone / dihydroxy open acid moiety are all included within the term "statin (s)". Also, pharmaceutically acceptable salts and esters of the statin dihydroxy open acid are included within the scope of the term "statin (s)".

Statins inhibit HMG-CoA reductase in their dihydroxy open acid form. Compounds having inhibitory activity on HMG-CoA reductase can be easily identified using assays well known in the art. For example, US Pat. No. 4,231,938 (column 6) and
See the assays described or cited in WO 84/02131 (pages 30-33).

The term "dihydroxy open acid statin (s)" is defined as a statin containing a dihydroxy open acid moiety, and also includes pharmaceutically acceptable salts and esters thereof. The phrases "statin dihydroxy open acid (s)" and "statin dihydroxy open acid (s) and pharmaceutically acceptable salts and esters thereof" are used interchangeably herein.
Unless otherwise indicated, both are intended to include the statin open acid and its salts and esters. Hydrates, solvates and polymorphic crystalline forms are all included within the term "statin (s) dihydroxy open acid".

In the broadest embodiment, any statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof can be used in the present invention. Examples of dihydroxy open acid statins that can be used in the present invention include, but are not limited to, lovastatin (see US Pat. No. 4,342,767); simvastatin (see US Pat. No. 4,444,784); pravastatin, especially its sodium salt; Fluvastatin, especially its sodium salt; Atorvastatin, especially its calcium salt; Cerivastatin, especially its sodium salt; NK
-104 (see PCT International Publication No. WO 97/23200) and ZD-4522 (US Pat. No. 5,260,440).
And Drugs of the Future, 1999, 24 (5), pp. 511-
513).

In a narrower embodiment, any statin of dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof, as listed above, is used in the present invention, provided that the statin is not pravastatin or fluvastatin. Can be used. In a class of this embodiment, the open acid statins include the dihydroxy open acids lovastatin, simvastatin, atorvastatin, cerivastatin, nisvastatin, and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of the simvastatin dihydroxy open acid, especially the ammonium and calcium salt forms, are suitable for use in the methods and compositions of the present invention.
More specifically, the calcium salt of simvastatin dihydroxy open acid includes the crystalline hydrated form of the calcium salt of simvastatin dihydroxy open acid, particularly the hydrated calcium salt of simvastatin dihydroxy open acid, referred to herein as Compound I. .

As used herein, the term "pharmaceutically acceptable salt" generally refers to the non-toxic nature of the compounds used in this invention, prepared by reacting the free acid with a suitable organic or inorganic base. Salts, especially sodium, potassium,
Aluminum, calcium, lithium, magnesium,
Zinc, salts formed from cations such as tetramethylammonium, as well as ammonia, ethylenediamine,
N-methylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-yl -Methylbenzimidazole, diethylamine, piperazine, morpholine, 2,4,4-trimethyl-2
-Means salts formed from amines such as pentamine, tris (hydroxymethyl) aminomethane. Pharmaceutically acceptable esters at the carboxylic acid group can be prepared by treating a dihydroxy open acid statin with an alcohol. Examples of pharmaceutically acceptable esters of statin dihydroxy open acid include, but are not limited to, -C1-4 alkyl and -C1-4 alkyl substituted with phenyl-, dimethylamino- or acetylamino. included. Here, `` C 1-4 alkyl '' is a linear or branched aliphatic chain containing 1-4 carbon atoms, for example, methyl, ethyl, n-propyl, n-butyl, iso-propyl, Including sec-butyl and tert-butyl.

The present invention relates to a method for orally administering the HMG-CoA reductase inhibitor ring-opened dihydroxy open acid statin or a salt or ester thereof in such a manner as to minimize its conversion to its lactonized counterpart. Methods as well as pharmaceutical compositions. This makes it possible to deliver the dihydroxy open acid statin directly to the absorbing mucosa of the small intestine without conversion to its lactone counterpart, and therefore the absorption of the open acid statin into the portal circulation, hepatocytes Permeation by the active open acid statin into the cell is achieved, resulting in increased potency and systemic exposure to the open acid component. More specifically, it is formed in the body by delayed release of orally administered statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof (eg, simvastatin dihydroxy open acid or a salt thereof) until after passage in the stomach. To reduce the amount of lactone absorbed. Maintaining statins in their open acid form in the body results in statins, whose metabolism is mediated by CYP3A4, and CYP3
The potential for drug interaction with other active agents that inhibit the A4 enzymatic pathway is reduced, and increased potency is also obtained. When the statin in open acid form is administered in such a way as to minimize its conversion to its lactonized counterpart, for example by using an oral delayed release dosage form, the statin of the open acid form or its lactonized counterpart is usually (Eg, the use of an oral immediate release dosage form) will reduce the likelihood of drug interaction.

It is an object of the present invention to provide a method for reducing the amount of lactonized statins formed and absorbed in the body after oral administration of a statin dihydroxy open acid to enhance clinical efficacy. A way to achieve this is to administer the statin dihydroxy open acid in a slow release pharmaceutical dosage form. A delayed release pharmaceutical dosage form as defined herein is an oral administration that does not release a sufficient amount of the active compound, i.e., a statin dihydroxy open acid, until the dosage form has passed through the stomach. A possible pharmaceutical dosage form or device. Thus, a sufficient release of the active compound will only take place after entering the duodenum. "Sufficient release" refers to release of at least 90% by weight of the active compound in the delayed release dosage form after entering the duodenum, and 10% of the active compound in the delayed release dosage form.
Less than% by weight is released in the stomach, ie active vs.
Plasma AUC of total HMG-CoA reductase inhibitory activity (blood concentration-
It is intended that the geometric mean ratio of the area under the time curve) is equal to or greater than 90%. In particular, the amount of active compound released in the stomach before entering the duodenum is less than 5% by weight, ie the geometric mean ratio of plasma AUC of active vs. total HMG-CoA reductase inhibitory activity is equal to or less than 95%. Is greater. More particularly, the amount of active compound released in the stomach before entering the duodenum is less than 1% by weight,
That is, the geometric mean ratio of plasma AUC of active versus total HMG-CoA reductase inhibitory activity is equal to or greater than 99%.

It should be recognized that metabolism of the statin dihydroxy open acid occurs mainly in the liver after oral administration as a slow release dosage form. However, since the lactonization of the dihydroxy open acid statin has been substantially avoided by the use of delayed release dosage forms, the active and inactive metabolites formed will also be in the form of the dihydroxy open acid. Essentially, when administering the statin dihydroxy open acid in a delayed release dosage form,
Internal exposure to the lactonized parent compound and also to active and inactive lactonized metabolites will be minimized.

One example of a suitable delayed release dosage form is a pH dependent enteric coated dosage form. Enteric coatings do not dissolve in the acidic environment in the stomach, but do in the higher pH environment in the duodenum. Thus, enteric-coated dosage forms do not release significant amounts of the active compound from the dosage form in the stomach, but do so once the enteric coating has dissolved in the duodenum. Compositions suitable for enteric coatings that can be used in the present invention are known to those skilled in the pharmaceutical art, and are described, for example, in L. Lachman, The Theor.
y and Practice of Industrial Pharmacy, 3rd edition, H. L
See the contribution by iebermann & J. Kanig (Lea & Febiger, 1986). Examples of suitable enteric coatings include, but are not limited to, SU sold by Colorcon
There is RETERIC WHITE, which contains polyvinyl acetate phthalate, titanium dioxide, talc, colloidal silicon dioxide, triethyl acetate, polyethylene glycol, sodium bicarbonate, purified stearic acid and sodium alginate. Many other preferred enteric coating materials are commercially available and are known in the art. Additional coatings utilized in the preparation of such dosage forms (eg, those used to obtain simple and aesthetically pleasing end products or for other purposes) can be applied before, after, before or after enteric coating. Is also good.

[0033] Enteric coated pharmaceutical dosage forms suitable for use in the present invention include the usual enteric coated rapid release (also referred to as intermediate release) pharmaceutical dosage forms (when the enteric coating is disrupted). , The drug is released relatively quickly) and enteric-coated time-controlled release dosage forms such as, but not limited to, the enteric GEM delivery devices described below. Time-controlled release dosage forms are also well known in the pharmaceutical arts, and may be used for a period of time (eg, about 6-24 hours).
It is designed to slowly release the active compound in the body over time). The use of an enteric-coated time-controlled release dosage form is preferred when a stronger dosage of statin dihydroxy open acid is used to reduce systemic exposure of the active statin. The enteric coating, whether in an enteric-coated fast-release or time-controlled release form, prevents a substantial amount of the active compound from being released from the dosage form in the stomach. right.

[0034] Enteric coated pharmaceutical dosage forms also include dosage forms or dosage units containing dihydroxy open acid statin in enteric coated overcoated tablets, capsules or similar, and enteric coated statin dihydroxy open acid. There are, but are not limited to, dosage forms or dosage units consisting of tablets, capsules or similar containing the coated granules. If a dosage form is provided with an enteric overcoat, the enteric coating may be the outermost outer coating of the dosage form, and one or more additional finish coatings may be applied over the enteric coating. In a more limited embodiment, when the delayed release dosage unit comprises enteric coated granules of the drug, the drug is selected from lovastatin and the dihydroxy open acid form of simvastatin and pharmaceutically acceptable salts and esters thereof, More preferably, it is a salt of simvastatin dihydroxy open acid, most preferably its calcium or ammonium salt. In another embodiment, provided that no statin is administered as a single pharmaceutical dosage form or dosage unit comprising enteric coated granules of statin and enteric coated or non-enteric coated granules of aspirin, any dihydroxy open Acid statins or pharmaceutically acceptable salts or esters thereof (eg, those described herein) may also be used in the present invention.

Examples of delayed release dosage forms that also function as time controlled release dosage forms are described in US Pat. No. 5,366,738, which is incorporated herein by reference. The controlled release drug delivery device described in US Pat. No. 5,366,738 is known as a gel extrusion module (GEM) delivery device. The GEM device comprises a compressed core prepared from a mixture comprising: (A) (i) a therapeutically effective amount of a beneficial agent; and (ii) a polymer that upon hydration forms gelatinous microscopic particles; and (B) A water-insoluble, water-impermeable polymer coating, including a polymer and a plasticizer, surrounding and adhering to the core, wherein the core coating is formed to expose about 1-75% of the core surface. Controlled dispersion of dispersions containing beneficial agents, such as pharmaceuticals, comprising a plurality of openings.
A drug delivery device for itu preparation and release, wherein the rate of release of the beneficial agent from the device is a function of the number and size of the openings.

In a GEM device, the polymer in the compressed core is preferably sodium polyacrylate, carboxypolymethylene, where carboxypolymethylene is prepared from acrylic acid cross-linked with sucrose or allyl ether of pentaerythritol. And carboxypolymethylene selected from acrylic acid cross-linked with sucrose or allyl ether of pentaerythritol, more preferably carboxypolymethylene selected from pharmaceutically acceptable salts thereof, such as sodium salt, and pharmaceutically acceptable salts thereof. Selected from salt. Most preferably, CARBOPOL
® 974P and its pharmaceutically acceptable salts, especially the sodium salt, are used as the polymer in the compressed core. In addition, the compressed core may include one or more polymer hydration modifiers,
Antioxidants, lubricants, fillers and excipients may also be included. Prior to applying the water-insoluble coating, the compressed core may be optionally sub-coated to aid in the manufacturing process. The subcoating can comprise, for example, hydroxypropylcellulose and hydroxypropylmethylcellulose. Additional coatings may be applied for aesthetic or functional purposes.

The water-insoluble, water-impermeable polymer coating preferably comprises: (1) a polymer selected from polyvinyl chloride, cellulose acetate, cellulose acetate butyrate, ethylcellulose and combinations of these polymers; and (2) phthalic acid It comprises a plasticizer selected from diethyl, dibutyl sebacate and triethyl citrate. More preferably, the polymer coating comprises cellulose acetate butyrate and triethyl citrate. GE
Since the M device does not function as an osmotic drug delivery device, the release function of the device relies on the transfer of fluid from the external environment of the body through the molded openings to the internal environment of the compressed core. The term `` water-insoluble, water-impermeable '' as used to describe polymer coatings defines a coating that is essentially water-insoluble and water-impermeable, where the drug is released from the GEM device into the body During the operation, there is no or minimal water transfer from the external environment of the body to the internal environment of the compressed core by passing through the polymer coating, except for the fluid transfer caused by passing through the perforated opening. It means that The very small amount of water passing through the water-insoluble, water-impermeable polymer coating is not substantial and does not significantly contribute to the function of the GEM device, ie the release rate of the drug by passing through the opening. Rather, the release rate of the drug from the GEM device is primarily
It is a function of the number and size of the openings in the device.

[0038] Finally, an external finish coating containing colorants, waxes and the like may be applied to the GEM delivery device to provide a simple and aesthetically pleasing end product. Also, before or after applying an additional finish coating, GEM
The device can also be enteric coated. Even without an enteric coating, extrusion of the polymer, which carries the drug in and out of the compressed core of the GEM device, can reduce gastric acidity.
It does not occur to a sufficient degree at pH. Thus, sufficient release of the drug should not occur in the stomach. Further details and examples of GEM delivery devices are described in U.S. Pat.
No. 6,738. The compound used in the GEM device can be, in particular, a pharmaceutically acceptable salt of simvastatin dihydroxy open acid, and more particularly an ammonium salt of simvastatin dihydroxy open acid.

The term "patient" includes mammals, especially humans, who use the active agents of the invention for preventing or treating a medical condition. Administration of a drug to a patient includes both self-administration and administration to the patient by others. Whether the patient may need treatment for an existing disease or medical condition,
One may want prophylactic treatment to prevent or reduce the risk of diseases and medical conditions affected by inhibition of HMG-CoA reductase.

The term "therapeutically effective amount" refers to a drug or agent that induces a biological or medical response in a tissue, organ system, animal or human that is being sought by a researcher, veterinarian, physician or other clinician. Means the amount of The term "prophylactically effective amount" refers to the risk of occurrence of a biological or medical event sought to be prevented in a tissue, organ system, animal or human by a researcher, veterinarian, physician or other clinician Prevent or reduce the amount of a drug. In particular, the dosage for the patient can be selected to provide the desired reduction in the amount of LDL (low density lipoprotein) cholesterol, and the dosage for the patient can be adjusted to achieve the target LDL level. May be evaluated over time. Dosing regimens utilizing the statin dihydroxy open acid include the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the efficacy of the compound to be administered; the route of administration; It is selected according to various factors such as function and liver function. A discussion of these factors to determine the therapeutically or prophylactically effective amount required to prevent, eliminate, or prevent the progression of symptoms is made by a clinician of ordinary skill in the art. Within the skill of

The novel compounds of the present invention are crystalline hydrated forms of the calcium salt of simvastatin dihydroxy open acid. Certain crystalline hydrated calcium salts of simvastatin dihydroxy open acid include 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.
It has an X-ray powder diffraction (XRPD) pattern obtained using CuKα radiation, characterized by reflections at interplanar spacings d of 93, 3.84, 3.67, 3.51 and 3.28 °. For convenience, the crystalline hydrated form of the calcium salt of simvastatin dihydroxy open acid having the XRPD pattern described above is also referred to herein as Compound I. Compound I can be shown two-dimensionally as a hydrated form of structural formula Ia below.

Embedded image

Compound I of the present invention is further characterized by the thermogravimetric (TG) curve shown in FIG. 1 in addition to the XPRD pattern described above. The TG curve of Compound I was measured under nitrogen flow.
Obtained at a heating rate of 10 ° C./min. This curve is characterized by a 6.3% weight loss from ambient room temperature to a stable weight loss plateau at about 175 ° C. Further weight loss due to the onset of compound degradation is observed above about 190 ° C.

Compound I was obtained by differential scanning calorimetry shown in FIG.
(DSC) curve. Compound I D
SC curves were obtained at a heating rate of 10 ° C./min in a cup without lid under a stream of nitrogen to 16.0 ° C. water. This curve was characterized by three cold endotherms with peak temperatures of 52, 77 and 100 ° C., with heats of 48, 90 and 21 J / g, respectively. In addition, the curves show peak temperatures of 222 and 2
It is characterized by two high-temperature endotherms due to decomposition with 41 ° C,
It was accompanied by heat of 163 and 92 J / g.

Compound I of the present invention was prepared in Example 1 of the present specification.
¹ H nuclear magnetic resonance (NMR) spectrum data as shown in
^It is further characterized by ¹³ C NMR and mass spectrum (MS) data.

Compound I is also characterized by the solid-state ¹³ C nuclear magnetic resonance spectrum shown in FIG. 4, which was analyzed on a Bruker DSX 400WB NMR system using Kel-
f Bruker MAS 400WB B with spinning module to accommodate 7mm zirconia rotor with end cap
Using L7 double resonance probe, 100.6MH about ¹³ C
z, ¹ H was completed by operating at 400.1 MHz. Solid-state ¹³ C nuclear magnetic resonance (NMR) spectra are high power using coherent polarization (CP), magic angle spinning (MAS), and variable amplitude coherent polarization and full sideband suppression
(〜59 kHz) Obtained using decoupling. The 90 ° + width of protons and carbon was 4.25 μs with a contact time of 2.0 ms. The sample was spun at 7.0 kHz and a total of 1024 scans were collected for the spectrum with a 3.0 second recycle delay. Before performing the FT, a line spread of 10 Hz was added to the spectrum. Chemical shifts were recorded on the TMS scale using the carbonyl carbon of glycine (176.03 ppm) as a secondary standard.

In the treatment and prevention methods, and pharmaceutical compositions and medicaments described herein, the statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof is used. The compound used is preferably a pharmaceutically acceptable salt of a dihydroxy open acid statin, more preferably a pharmaceutically acceptable salt of a dihydroxy open acid simvastatin such as an ammonium salt or a calcium salt, especially a compound such as compound I 2 is a crystalline hydrated form of the calcium salt of simvastatin dihydroxy open acid. All hydrates, solvates and polymorphic crystalline forms of the above compounds and their uses are included in the scope of the present invention.

The present invention is a method for inhibiting HMG-CoA reductase and a method for treating lipid disorders such as hypercholesterolemia, hypertriglyceridemia and complex hyperlipidemia, wherein such treatment is The method is provided, comprising administering to the person in need a therapeutically effective amount of a statin dihydroxy open acid. Further, a method of preventing or reducing the risk of developing atherosclerosis, and a method of stopping or delaying the progression of atherosclerosis when clinically evident, comprising a prophylactically or therapeutically effective amount, as appropriate. Such a method is provided which comprises administering a dihydroxy open acid statin to a mammal at risk of developing atherosclerosis or already having atherosclerosis.

[0048] Atherosclerosis is one that includes vascular diseases and conditions that are recognized and understood by physicians active in the medical field. Restenosis after revascularization,
Atherosclerotic cardiovascular disease such as coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease such as multiple cerebral infarction dementia, and peripheral vascular disease such as erectile dysfunction Are all clinical manifestations of atherosclerosis and are therefore included in “atherosclerosis”.

The administration of a statin dihydroxy open acid may prevent or reduce the risk of the occurrence, or potential relapse, of coronary heart disease events, cerebrovascular events, and / or intermittent claudication. . Coronary heart disease events include CHD death, myocardial infarction (ie, heart attack) and coronary revascularization. Cerebrovascular events are those that include ischemic or hemorrhagic stroke (also known as cerebrovascular stroke) and transient cerebral ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vascular disease. The term "atherosclerosis event" as used herein includes coronary heart disease events, cerebrovascular events and intermittent claudication. Those who have previously experienced one or more non-fatal atherosclerotic events are considered likely to have a recurrence of such events.

Thus, the present invention provides a method for preventing or reducing the risk of the onset of an atherosclerosis event, including the administration of a prophylactically effective amount of a statin dihydroxy open acid to a patient suspected of such an event. It also provides a way to do that. The patient may or may not have atherosclerosis at the time of administration, or may be at risk of developing it.

The present invention is also a method for preventing and / or treating only an inflammatory disease or disorder or the treatment of the above-mentioned symptoms, which comprises administering a statin dihydroxy open acid to a patient in need of such treatment. There is also provided the method comprising: Such treatments include, for example, non-steroidal anti-inflammatory drugs, rheumatoid arthritis, and degenerative joint diseases, osteoarthritis.
eoarthritis), dementia, Alzheimer's disease,
Treatment of multiple sclerosis, inflammatory bowel disease, asthma, psoriasis, systemic lupus erythematosus, enteritis, gout, adrenoleukodystrophy, diabetic retinopathy, nephropathy and type II diabetes mellitus.

[0052] People treated with this therapy include those at risk for developing atherosclerosis or suspected of having an atherosclerosis event. Standard atherosclerosis risk factors are known to the average physician working in the medical field. Such known 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. Published guidelines for determining those at risk for developing atherosclerosis are set out in the National Cholesterol Education National Program.
esterol Education Program), Second report of the sub-committee on detection, evaluation and treatment of high blood cholesterol in adults (Second report
of the Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (Adu
lt Treatment Panel II)), National Institutes of Health (National I)
nstitute of Health), National Hea
rt Lung and Blood Institute), NIH Announcement No. 93-3095, 1
September 993; Miniature: Sub-Committee on the Detection, Assessment and Treatment of High Blood Cholesterol in Adults, National Cholesterol Education National Program for the Detection, Assessment and Treatment of High Blood Cholesterol in Adults (NCEP) Summary of the Commission's Second Report (Subcommittee for Adult Therapy II),
See JAMA, 1993, 269, pp. 3015-23. 1
Those identified as having the above risk factors are among the group of people considered at risk for developing atherosclerosis. Those identified as having one or more of the above risk factors, as well as those who are already atherosclerotic, are among the group of people who are suspected of having an atherosclerotic event.

The oral dosage of crystalline forms of dihydroxy open acid statins, especially salts of dihydroxy open acid statins such as simvastatin, and more particularly the ammonium or calcium salts of dihydroxy open acid simvastatin such as compound I, is about 1 ~ 200mg /
Days, more preferably 5 to 160 mg / day. However, the dosage will vary depending on the above factors, such as the potency of the particular compound. The active drug of the present invention comprises, for example, 1
Although it may be administered in divided doses, such as one to four times a day, it is preferred to administer the active drug once a day. For example, daily doses include, but are not limited to, 5 mg, 10 mg, 15 mg, 20 m
g, 25 mg, 40 mg, 50 mg, 75 mg, 80 mg, 100 mg, 150 mg and 160 mg.

The active drugs used in this therapy include tablets, capsules, pills, powders, granules, elixirs,
It can be administered in oral dosage forms such as tinctures, suspensions, syrups and emulsions. Oral formulations are preferred.

For the crystalline hydrated form of the calcium salt of simvastatin dihydroxy open acid, for example Compound I, the administration of the active drug may be by any pharmaceutically acceptable route and in any pharmaceutically acceptable dosage form. Can be. This includes the use of the usual oral fast-release, time-controlled and delayed-release (as described above) pharmaceutical dosage forms. An oral delayed release dosage form of the drug of the invention is preferred, especially an enteric overcoat surrounding a fast release dosage unit, or a GEM controlled release drug delivery device having an enteric overcoat surrounding a dosage unit, most particularly The result is an enteric overcoat surrounding the immediate release dosage unit. Further pharmaceutical compositions suitable for use in the present invention are known to those of skill in the pharmaceutical arts, and include, for example, Remington's Pharmaceutical Sciences, Mack Publ.
See ishing Co., Easton, PA.

In the method of the present invention, the active drug is typically selected appropriately for the intended dosage form, ie, oral tablets, capsules, elixirs, syrups, etc. A suitable pharmaceutical diluent, excipient or carrier (collectively "carrier" herein) consistent with
(Referred to as ingredients).

For example, for oral administration in the form of a tablet or capsule, the active drug component can be lactose, starch, sucrose, glucose, modified sugars, modified starch, methylcellulose and its derivatives, dicalcium phosphate. Mixed with non-toxic pharmaceutically acceptable inert carriers such as calcium sulfate, mannitol, sorbitol and other reducing and non-reducing sugars, magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate be able to. For oral administration in a liquid state, the drug component can be mixed with a non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. further,
If desired or necessary, suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be added to the mixture. Stabilizers such as antioxidants, for example, butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT), propyl gallate, sodium ascorbate, citric acid, metabisulfite Calcium, hydroquinone, and 7-hydroxycoumarin, especially BHA, propyl gallate and combinations thereof, may also be used to stabilize the formulation, at least for the compositions of the invention.
The use of one stabilizer is preferred. Preferably, the antioxidant is used in the case of simvastatin dihydroxy open acid or a salt thereof, especially compound I. Other suitable ingredients include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth or alginates,
Carboxymethyl cellulose, polyethylene glycol, wax and the like can be mentioned.

The active drug can also be administered in the form of a liposome delivery system such as small, large and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Active drugs can also be delivered by using monoclonal antibodies as individual carriers to attach the compound molecules. The active drug can also be conjugated to a soluble polymer as a targetable drug carrier. Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy
-Ethyl-aspartamide-phenol or polyethylene oxide substituted with palmitoyl residue
-Polylysine may be mentioned. In addition, the active drug is a class of biodegradable polymers effective to obtain controlled release of the drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyεcaprolactone, polyhydroxybutyric acid, poly Orthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels can be linked to crosslinked or amphiphilic block copolymers.

The present invention also includes a method of preparing a pharmaceutical composition comprising combining a statin dihydroxy open acid with a pharmaceutically acceptable carrier. Also included are pharmaceutical compositions made by combining the statin dihydroxyopenate with a pharmaceutically acceptable carrier.

In a broad embodiment, one or more of any suitable additional active agents may be used with the statin dihydroxy open acid in one formulation, or may be administered to the patient in a separate formulation. The active agents can be administered simultaneously or sequentially. One or more additional active agents may be administered with the statin dihydroxy open acid. The one or more additional active agents can be lipid-lowering compounds or other pharmaceutically active agents, or agents that have both lipid-lowering and other pharmacological activities. Additional active agents that can be used include, but are not limited to,
For example, HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors); acyl coenzymes A; selective inhibitors of ACAT-1 or ACAT-2 Cholesterol acyltransferase (ACAT) inhibitors such as dual inhibitors of ACAT-1 and 2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; SCH-58235 (US Pat. No. 5,767,1
Cholesterol absorption inhibitors such as those described in US Pat. No. 15,846,966); bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors such as glycoprotein IIb / IIIa fibrinogen receptor Antagonists and aspirin; usually, for example, troglitazone, pioglitazone (pioglit
human peroxisomal proliferator-activated receptor gamma (PPARγ) agonists, such as compounds called glitazones such as azone) and rosiglitazone, and those compounds included in a structural class known as thiazolidinedione And their PPARγs other than the thiazolidinedione structural class
Agonists; clofibrate, fenofibrate such as micronized fenofibrate and PPARα agonists such as gemfibrozil; PPAR dual α / γ agonists; vitamin B ₆ (also known as pyridoxine)
And its pharmaceutically acceptable salts, such as the HCl salt; vitamin B ₁₂ (also known as cyanocobalamin); folate or its pharmaceutically acceptable salts or esters, such as the sodium and methylglucamine salts; vitamin
Antioxidant vitamins such as C and E and β-carotene;
beta-blockers; angiotensin II antagonists such as losartan; angiotensin-converting enzyme inhibitors such as enalapuri and captopril; calcium channel blockers such as nifedipine and diltiazam; endothelian antagonists; agents that increase ABC1 gene expression; FXR and LXR ligands, including both agents and agonists; alendronate sodium
bisphosphonic acid compounds such as (alendronate sodium);
And cyclooxygenase-2 inhibitors such as rofecoxib and celecoxib. Further, the dihydroxy open acid statins of the present invention, e.g., Compound I, may be used with antiretroviral therapy in AIDS infected patients, including, but not limited to, indinavir, nelfinavir, ritonavir and When used with an HIV protease inhibitor such as saquinavir, the lipid abnormalities associated with such treatment can be treated.

Optionally, a therapeutically or prophylactically effective amount of the crystalline hydrated form of the calcium salt of simvastatin dihydroxy open acid, eg, Compound I, is affected by inhibition of HMG-CoA reductase, as well as inhibition of HMG-CoA reductase. Treatment and / or reduction of the risk of diseases and conditions, such as treatment of lipid disorders, prevention or reduction of the risk of developing atherosclerosis, progression of atherosclerosis when clinically manifest atherosclerosis It can be used in the preparation of a medicament that is effective in, for example, preventing or reducing the risk of cessation or delay and the onset or subsequent occurrence of an atherosclerotic event. For example, a medicament may comprise about 1 mg to 200 mg, more particularly about 5 mg to 160 mg, of a crystalline hydrated form of the calcium salt of simvastatin dihydroxy open acid.

Optionally, a therapeutically or prophylactically effective amount of a statin dihydroxy open acid can be used in the preparation of an oral medicament adapted for delayed release, wherein sufficient release of the statin after oral administration is achieved by administering Does not occur until after gastric transit, or at least 90% of the statin is delivered to the patient's intestinal mucosa after oral administration in the form of its dihydroxy open acid. The oral medicament is also effective in inhibiting HMG-CoA reductase and treating and / or reducing the risk of diseases and conditions affected by inhibition of HMG-CoA reductase, as described above.

Also, statin dihydroxy open acid,
For example, a medicament comprising Compound I also comprises
It can be prepared with one or more additional active agents.

Simvastatin is a semi-synthetic product that can be produced from the natural product lovastatin. Methods for preparing lovastatin and simvastatin are well described in the published literature. For example, U.S. Pat.
8 (which is incorporated herein by reference) describes a culture and isolation method for obtaining lovastatin using the microorganism Aspergillus terreus. U.S. Patent No.
4,444,784, 4,820,850, 4,916,239 and 4,582,9
No. 15, which are incorporated herein by reference,
Methods for producing dihydroxy open acids and lactonates of simvastatin have been described.

Compound I of the present invention can generally be prepared as follows. Simvastatin and its dihydroxy open acid counterpart, such as Compound I, are
Because of the tendency to produce oxidative by-products, the operations used to prepare Compound I are performed under an inert atmosphere such as nitrogen to minimize the formation of such by-products. Compound I can be obtained without using an inert atmosphere,
The purity of the desired product is not optimized.

Hydrolysis of the lactone ring of simvastatin can be carried out by treating simvastatin with at least one equivalent, preferably a slight excess of one equivalent aqueous base. If more than a slight excess of base is used, it is preferred to neutralize the excess base prior to the salt formation step to prevent the formation of insoluble calcium hydroxide or calcium carbonate by-products. The base used for the hydrolysis can be an aqueous solution of a metal hydroxide or metal carbonate, such as, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate. Sodium hydroxide is preferred. The hydrolysis can be carried out in water, a water-protic organic solvent mixture, or a water-aprotic organic solvent mixture. Suitable protic organic solvents include, but are not limited to, methanol (MeOH), ethanol
(EtOH), isopropyl alcohol, and n-propyl alcohol (propanol). Suitable aprotic organic solvents include, for example, acetonitrile, dimethylsulfoxide (DMF), N, N-dimethylformamide (DMS
O), tetrahydrofuran (THF), tert-butyl methyl ether (MTBE) and toluene. In particular, a water-ethanol or n-propyl alcohol solvent mixture can be used, and more particularly a water-n-propyl alcohol solvent mixture can be used.

When the hydrolysis reaction is complete, the pH of the reaction mixture is adjusted to about 6-11, in particular 6-9, and more particularly 7-8.5, by adding an acid. In this pH range, simvastatin dihydroxy open acid is a metal salt,
For example, when the base used in the hydrolysis step is sodium hydroxide or sodium carbonate, it is present as a sodium salt. Any acid capable of forming a soluble calcium salt, such as calcium chloride or calcium citrate, is suitable. Soluble calcium salts are salts that are soluble in the solvent system used in the present method. Preferably acetic acid (HOA
Acids such as c) or mineral acids are used, especially HCl.

The resulting pH-adjusted reaction mixture containing the metal salt of simvastatin dihydroxy open acid was added to about 0.50-0.5.
55 equivalents of calcium acetate hydrate [Ca (OAc) ₂ xH ₂ O]
Or a water-organic solvent mixture such as water-EtOH, MeOH, i-
Mix with a solution of PrOH, n-PrOH, acetonitrile, DMF, DMSO, THF, especially water-EtOH or water-n-propyl alcohol. The pH adjusted reaction mixture can be added to the calcium acetate hydrate solution, or the calcium acetate hydrate solution can be added to the pH adjusted reaction mixture.
The addition can be done all at once or, optionally, in portions during aging. For example,
Add a small amount of calcium acetate hydrate solution, for example, about a quarter
The pH-adjusted reaction mixture can be added over a short period of time, for example, about 30 minutes, then the resulting mixture can be aged for a shorter time at room temperature, and then optionally at a temperature up to about 50 ° C., for example at about 50 ° C. 10 to about 50 ° C, especially room temperature to about
50 ℃, more specifically about 30-40 ℃, most specifically about
Further aging at 30-35 ° C., then the remaining calcium acetate hydrate solution is divided and divided into temperatures up to about 50 ° C., for example about 10 ° C. to about 50 ° C., especially room temperature to about 50 ° C., more particularly It can then be added at about 30-40 ° C, most particularly about 30-35 ° C, over several hours. Optionally, crystalline compound I can be added to the reaction mixture as a seed crystal.

To mix the pH-adjusted reaction mixture and the calcium acetate hydrate solution all at once,
The resulting slurry must be aged, usually for at least several hours, until the conversion of the resulting amorphous calcium salt of simvastatin dihydroxy open acid to a crystalline product is complete. Complete conversion to a 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 carried out at a temperature up to about 50 ° C., for example from about 10 ° C. to about 50 ° C., especially from room temperature to about 50 ° C., more particularly about 30-40 ° C., most particularly about 30-35 ° C. it can. During one or more aging periods,
It has been found that operating at lower temperatures produces crystallization products, but as the temperature decreases, the rate of crystallization conversion slows and the time efficiency of the operation decreases.

If necessary, cool the slurry to room temperature and collect by suction filtration. The recovered solid is placed under a humid atmosphere (about 30-70% relative humidity, especially 40-70%), preferably under a humid inert atmosphere such as nitrogen, especially about 10-40
Suction drying at a temperature of ℃, more specifically at a temperature of 25-35 ℃. The final step of suction filtration in the recovery of Compound I should be performed under a humid atmosphere, preferably under a humid inert atmosphere, to minimize the formation of oxidative by-products. When performing the further step of adding an antioxidant to Compound I, as described below, the final suction filtration is performed after mixing the Compound I with the antioxidant.

As mentioned above, Compound I tends to oxidize on contact with air, and one way to minimize oxidation is to perform the reaction step under an inert atmosphere. In addition, one or more antioxidants such as BHA, BHT, propyl gallate, ascorbic acid, calcium metabisulfite, hydroquinone, nordihydroguaiaretic acid (NDGA) or 7-hydroxycoumarin are mixed with Compound I. be able to. This is done by stirring the compound I slurry with one or more antioxidants and collecting the solid obtained by suction filtration.

Also, the ammonium salt of simvastatin dihydroxy open acid can be used as a starting material to be mixed with calcium acetate hydrate, thus avoiding the hydrolysis and pH adjustment steps required when starting from lactonized simvastatin. can do. Otherwise, other reaction conditions described above, such as solvent, temperature, etc., can be used.

Abbreviations that may be found herein are: MeOH is methanol; EtOH is ethanol; PrOH is propanol; HOAc is acetic acid;
MeCN is acetonitrile; DMF is dimethyl sulfoxide; DMSO is N, N-dimethylformamide;
Ca (OAc) ₂ is calcium acetate; HPLC is high performance liquid chromatography; min. Is minutes; h is time; DI is deionization; NMR is nuclear magnetic resonance; HR-EI MS is a high resolution electron impact mass spectrum; RH is relative humidity. The “seed crystal” used in the examples is Compound I.

[0075]

EXAMPLE 1 Crystalline Hydration of Simvastatin Dihydroxyopenate
Calcium salt (Compound I) Preparation 22L four-necked round bottom flask temperature probe, fitted with a N ₂ inlet, addition funnel and overhead stirrer.
Added 15% EtOH-H ₂ O in 8.0 L, the solution was purged for 10 minutes with N _2. Simvastatin (396 g, 0.946 mol) was added, the slurry was purged for 5 minutes with N _2. Then 5N NaOH (198 ml) was added at room temperature. After about 1 hour, analysis by HPLC indicated that the hydrolysis reaction was complete (> 99.9% conversion). The pH of the reaction solution is increased by adding 1N HCl (about 65 ml).
Adjusted to ~ 8.5. Ca (OAc) ₂・ H ₂ O (116.6 g, 0.662 mol)
Was dissolved in 4.0 L of 60% EtOH-H ₂ O and purged with nitrogen for 5 minutes. 1.0 L of this solution was converted to sodium salt solution
Added over 30 minutes. The resulting slurry was aged at room temperature for 30 minutes, then at 30-35 ° C for 1-2 hours.

Ca (OAc)_TwoThe rest of the EtOH-aqueous solution at 30-35 ° C
Over about 30 minutes. N slurry_Two Under atmosphere 3
Aged at 0-35 ° C for 5 hours. Cool the slurry to room temperature
And collected by suction filtration. 4L 30 wet cakes
% EtOH-H_TwoO, 4L of 20% EtOH-H _TwoWash with O, then 6L x 3
Was washed with DI water. Wet solid N_Two(40-70% relative humidity
Degree) Suction drying was performed at room temperature for 4 days under an atmosphere. Dihydro
Crystalline hydrated calcium of simvastatin xyopenate
The salt was obtained as a white powder.

This calcium salt is converted into a clean QUADRO ^™ COMIL
The lumps were removed by one pass through (registered trademark) (Model 197S).

HPLC conditions Column: YMC Basic 4.6 mm × 25 cm Detector: ABS 757 1 AU / volt output Sample solvent: EtOH / CH ₃ CN / H ₂ O (1: 1: 1) Column temperature: 25 ° C. (Anal. Dept.) Run the sample at 5 ° C. to prevent the formation of simvastatin on the column) Flow rate: 1.5 mL / min Wavelength: 238 and 210 nm Concentration gradient: time (min) % CH ₃ CN % H ₂ O (10 mM H ₂ PO ₄ -KH ₂ PO ₄ , pH = 6.5) 0.00 30 70 20.00 45 55 34.00 70 30 39.00 70 30 39.50 30 70 43.00 30 70 Retention time of simvastatin open acid: 17.07 minutes Retention time of simvastatin: 32.90 minutes

Spectral data

EI MS : m / e: 437 (M + H), 419 (M + HH ₂ O), 303

HR-EI MS : calcd for C ₂₅ H ₃₈ O ₅ : 4
18.2719, found: 418.2271

Example 2 Synthesis of simvastatin dihydroxy open acid using BHA
Preparation of Crystalline Hydrated Calcium Salt (Compound I) A 22 L three-neck round bottom flask was equipped with a temperature probe, an N ₂ inlet,
An addition funnel and overhead stirrer were attached. Added 15% EtOH-H ₂ O in 8.0 L, it was purged for 10 minutes with N _2. Simvastatin (396 g, 0.946 mol) was added, the slurry was purged for 5 minutes with N _2. Then 198 ml of 5N NaOH (0.9
93 mol, 1.05 eq) at room temperature. The hydrolysis reaction is usually completed in 1 hour as analyzed by HPLC (> 9
9.9% conversion). The pH of the reaction solution was adjusted to 7-8.5 by adding 1N HCl (about 65 ml).

A solution of Ca (OAc) ₂ .H ₂ O (91.7 g, 0.520 mol, 0.55 eq) in 4.0 L of 60% EtOH-H ₂ O was purged with nitrogen for 5 minutes. 1.0 L of this solution was added to the reaction solution over 30 minutes. The slurry was aged at room temperature for 30 minutes, then at 30-35 ° C for 1-2 hours. Et of Ca (OAc) ₂
The rest of the OH-water solution was added in small portions at 30-35 ° C over 3 hours. The slurry was 5 hours aged at 30 to 35 ° C. under N ₂ atmosphere. The slurry was cooled to room temperature and collected by suction filtration. 4L 30% EtOH-H ₂ O, 4L 20% wet cake
After washing with EtOH-H ₂ O, it was washed with 6 L × 3 of DI water.
The solid was suction dried at room temperature in a moist N ₂ (40~70% RH) of the atmosphere to obtain a wet cake of 1.7 kg.

The above wet cake was placed in a clean 20 L three-necked flask under a nitrogen atmosphere. BHA (2.603g, 0.2wt
% Eq.) In degassed 15% EtOH H ₂ O (8.5 L) was added, followed by degassed water (2.55 L) and the slurry was allowed
Stir for 2 hours. The solid was collected by suction filtration without washing under a wet N ₂ atmosphere to give 1.49 kg of cake. The solid was 4 days suction dried at room temperature in a moist N ₂ (RH 40~70%) under atmosphere. Obtained the title calcium salt product as a white powder
(Yield 94%, A 99.4% at 238 nm, BHA 0.2 wt%, KF =
7.3% wt).

Example 3 Simvastatin dihydroxy open acid in water-nPrOH
Preparation of crystalline hydrated calcium salt (Compound I) of
Adding Form Step 1: A three neck round bottom flask hydrolysis 72L, temperature probe, N ₂ inlet,
An addition funnel and overhead stirrer were attached. 28.5 L of DIH ₂ O was added and purged with N ₂ for 10 minutes.
Add 1.5 kg of simvastatin, then 788 ml of 5N NaO
H was added all at once at room temperature. The hydrolysis reaction is usually completed in 2 hours (> 99.9% conversion) as analyzed by HPLC. 1.5 L of nPrOH was added and the pH of the reaction solution was adjusted to 2N HOAc (about
170 ml) was adjusted to 9.5 to 11.0.

Step 2 : 150 g of seed crystals (compound I) for salt formation were added to the above solution, and the resulting slurry was heated to 35-40 ° C. Ca (OAc) ₂・ H ₂ O (347
A solution of g) in 15 L of 20% nPrOH was purged with nitrogen for 5 minutes and added to the slurry over 3 hours. The resulting slurry was aged at 35-40 ° C. under a N ₂ atmosphere for 5 hours, and then cooled to room temperature. Solids are collected by filtration and 10%
Washed with nPrOH-H ₂ O (15 L × 3).

Step 3 : BHA Formulation The wet cake (9.1 kg) was transferred to a clean 72 L three-necked flask under a nitrogen atmosphere. 10% nPrOH degassed from BHA (7.6 g)
Was added a solution of the (45L), the slurry was stirred for 1 hour at room temperature, filtered under N ₂ atmosphere and then moist N ₂ (30 to 70% RH)
Vacuum dried at room temperature for 7 days under an atmosphere. 1.78 kg of the title Ca salt product were obtained as a white powder (94% yield, 99.4% of A at 238 nm, 0.2 wt% of BHA, KF = 6.6% wt).

Example 4 Simvastatin dihydroxy open acid in water-PrOH
Preparation of Crystalline Hydrated Calcium Salts: Simultaneous Addition Mode The method described in this example is such that in a semi-continuous process, half of the batch is always kept in a vessel as seed crystals.

100 g of simvastatin was hydrolyzed in 1.9 L of water as described in Example 3. Then 100 ml of n
PrOH was added and the pH of the solution was adjusted to 9-11 with 1 N HOAc.
The obtained solution and Ca (OAc) ₂ .H ₂ O (23.2 g) were mixed with 1.0 L of 20% nP
A suspension of a solution dissolved in rOH in which Ca salt is added to 10% nPrOH at 10 to 50% by weight (30 volumes of 10% PrOH based on the amount of seed crystals)
Were added separately but simultaneously at 30-40 ° C. over 3 hours. After aging at 30-40 ° C. for 5 hours, the slurry was cooled to room temperature, filtered, added with antioxidant and dried as described in the normal addition mode process. yield
95%.

Example 5 Simvastatin dihydroxy open acid in water-PrOH
Preparation of Crystalline Hydrated Calcium Salt of Compound (Compound I): Simultaneous Formation
Formulation A of BHA by crystallization : 100 g of simvastatin were hydrolyzed in 1.9 L of water as described in Example 3. Then 100ml
Of nPrOH was added and the pH of the solution was adjusted to 9-11 with 1N HOAc. 10 wt% seed crystals were added and the slurry was warmed to 35-40 ° C. 1.0L Ca (OAc) ₂・ H ₂ O (23.2g) and BHA (540mg)
Of 20% nPrOH was added to the slurry at 35-40 ° C over 3 hours. After aging at 30-40 ° C for 5 hours,
Cool the slurry to room temperature, filter and add BHA to 10% nPrOH.
(0.1 g / L) and washed with a solution (1 L × 3). The wet cake was dried in a wet N ₂ under as described in conventional addition manner processes. The final title Ca salt product, dried, contained 0.2 wt% BHA. 95% yield.

Method B : The procedure of Method A was used with the following changes. Instead of adding BHA to the Ca (OAc) ₂ solution, the same amount of BHA was added to a pH adjusted solution of simvastatin hydrolyzed at room temperature. The solution was warmed to 35-40 ° C to dissolve the BHA. Next, a seed crystal of 10 wt% was introduced. The remaining steps are as described in Method A. Dry title final
The Ca salt product contained 0.2 wt% BHA. Yield 95
%.

Example 6 Simvastatin dihydroxy open acid in water-PrOH
Preparation of crystalline hydrated calcium salt of Compound (Compound I):
Starting with 2.0 kg of simvastatin blending of propyl gallate , crystallizing the calcium salt of simvastatin dihydroxy open acid,
Isolated and washed as described in Example 3. It was transferred under N ₂ to the first wet cake of a clean 100L vessel. BHA (9.2 g) and propyl gallate (11.2 g) in 50 L
A solution dissolved in 0% nPrOH was added to the container. The slurry was aged at room temperature for 1 hour. The slurry was filtered without washing. The wet cake was dried in a wet N ₂ under. Yield 95
%. 0.07wt% propyl gallate and 0.2w for dried salt
It contained t% of BHA.

Example 7 Simvastatin dihydroxy open acid in water-PrOH
Preparation of Crystalline Hydrated Calcium Salt of Compound (Compound I): Gallic
Starting from simvastatin formulation 2.0kg of propyl, the calcium salt of dihydroxy open acid simvastatin was crystallized,
Isolated and washed as described in Example 3. The wet cake is then washed with propyl gallate in 10% nPrOH.
10L of solution (propyl gallate concentration = 0.224g / L)
And washed. Thereafter, 20 L of a solution of propyl gallate dissolved in 10% nPrOH (propyl gallate concentration = 0.224 g / L) was added, and the wet cake was mixed in the filter pot before filtration. The wet cake was dried in a wet N ₂ under. 95% yield. The dried salt contained 0.07 wt% propyl gallate.

Example 8 BHA, BHA / Vitamin E, and Vitamin E in Heptane
Of simvastatin dihydroxy open acid containing
Preparation of crystalline calcium hydrate salt (Compound I) 100 g of simvastatin were hydrolyzed in 1.9 L of water as described in Example 3. Then 100 ml of nPrOH was added and the pH of the solution was adjusted to 9-11 using 1 N HOAc.
10 wt% seed crystals were added and the slurry was warmed to 35-40 ° C. A solution of Ca (OAc) ₂ .H ₂ O (23.2 g) dissolved in 1.0 L of 20% nPrOH was added to the slurry at 35-40 ° C. over 3 hours. Three
After aging at 0-40 ° C. for 5 hours, the slurry was cooled to room temperature. Filter the calcium salt slurry and add 10% nPrO
Washed with H (500 ml × 1) and then with water (1 L × 3). The wet cake (KF = 75-80 wt% water) was then washed with 1 L of heptane to replace most of the water. The wet cake was washed with a solution of BHA or Vitamin E or BHA / Vitamin E (concentration = 1.38g / L, 800mL), and dried at a wet N ₂ below.

Example 9 Simvastatin dihydroxy open acid in water-MeCN
Three-necked round bottom flask temperature probe preparation 7.2L of crystalline hydrated calcium salt (Compound I), N ₂ inlet,
An addition funnel and overhead stirrer were attached. 2.1 L of DIH ₂ O was added and purged with N ₂ for 10 minutes. 150
After addition of g of simvastatin, 78.8 mL of 5N NaOH was added in one portion at room temperature. The hydrolysis reaction is usually completed in 2 hours as analyzed by HPLC (> 99.9% conversion).
900 mL of MeCN was added, and the pH of the reaction solution was adjusted to 2N HOAc (about 17 m
L) was adjusted to 9.5 to 11.0.

30.0 g of seed crystals were added to the above solution and the resulting slurry was warmed to 30-35 ° C. Ca (OAc) ₂・ H ₂ O
(34.7 g) in 1.5 L of 30% MeCN was purged with nitrogen for 5 minutes and added to the reaction slurry over 3 hours. The slurry was kept at 35-40 ° C. under N ₂ atmosphere for 5 hours. The slurry was cooled to room temperature and the solid was collected by filtration. Wash the wet cake with 30% MeCN (1.5L) and 10% MeCN (1.0L) and rinse / wash with degassed solution of BHA (0.9g / L) in 10% MeCN (1.0L x 2) Was done. The solid moist N ₂ (RH 30~70%)
Vacuum dried for 5 days at room temperature under an atmosphere. 1.67 kg of the title compound were obtained as a white powder (yield 88%, A 99.4% at 238 nm, BHA 0.2 wt%, KF = 6.6% wt).

Example 10 Simvastatin dihydroxy open acid in water-MeOH
Preparation of crystalline hydrated calcium salt (Compound I) of 50 g of simvastatin was prepared as described in
Hydrolyzed in 50 mL of water. Then 150 ml of MeOH was added and the pH of the solution was adjusted to 7-11 with 1 N HOAc. 10 wt% seed crystals were added and the slurry was warmed to 30-35 ° C. Ca (OA
c) A solution of ₂ · H ₂ O (11.6 g) in 500 mL of 30% MeOH was added to the slurry at 30-35 ° C. over 3 hours. After aging at 30-35 ° C. for 5 hours, the slurry was cooled to room temperature. The dihydroxy open acid simvastatin calcium salt slurry was filtered and washed with 20% MeOH (200 ml) and water (500 ml × 3). The wet cake was dried in a wet N ₂ under. The dried final Ca salt product of the title was isolated in 96% yield.

Example 11 Dihydroxyopenic acid in water-i-PrOH, DMF, DMSO
Of crystalline hydrated calcium salt of vastatin (compound I)
Prepare 50 g of simvastatin as described in Example 3
Hydrolyzed in 50 mL of water. The pH of the solution was then adjusted to 7-11 with 1 N HOAc by adding 150 ml of i-PrOH. 10wt
% Seeds were added and the slurry was warmed to 30-35 ° C.
A solution of Ca (OAc) ₂ .H ₂ O (11.6 g) in 500 mL of 30% i-PrOH was added to the slurry at 30-35 ° C. over 3 hours. 30-3
After aging at 5 ° C. for 5 hours, the slurry was cooled to room temperature. The Ca salt slurry was filtered, washed with 20% i-PrOH (200 ml), and washed with water (500 ml × 3). N ₂ wet cake wet
Dried under. The dried final Ca salt product of the title was isolated in 96% yield.

The same procedure could be applied for the preparation of compound I in DMF, DMSO and similar solvents.

Example 12 Crystals of simvastatin dihydroxy open acid in water
Preparation of calcium hydrated calcium salt (Compound I) 50 g of simvastatin were prepared as described in Example 3.
Hydrolyzed in 1.0 L of water. The solution pH was then adjusted to 1N HOAc
And adjusted to 11. Add 10wt% seed crystals and slurry
Warmed to 35-40 ° C. A solution of Ca (OAc) ₂ .H ₂ O (11.6 g) dissolved in 500 mL of water was added to the slurry at 35-40 ° C. over 5 hours. After aging at 35-40 ° C for 10 hours, the slurry was cooled to room temperature. Filter the Ca salt slurry and add water (500m
1 × 3). The wet cake was dried in a wet N ₂ under. The dried final Ca salt product of the title was isolated in 96% yield.

Example 13 Dihydroxy open acid simvastatin ammonium salt
Of simvastatin, a dihydroxy open acid from rice
Preparation method A of hydrated calcium salt (Compound I) : 50 g of dihydroxy open acid simvastatin ammonium salt are dissolved in 800 ml of 25% nPrOH and then Ca
(OAc) ₂ · H ₂ O (10.7 g) was added dropwise over 2 hours at room temperature to a solution of 75 ml of water. 30 ~ 3 of obtained slurry
Aged at 5 ° C. for 5 hours. After cooling to room temperature, the slurry was isolated by filtration. Wet cake
Washed with 10% nPrOH (500 ml × 3). The antioxidant incorporated into wet cake to afford the title product by drying in a wet N ₂ under as described above.

Method B : 50 g of simvastatin ammonium dihydroxyopenate was added to Ca (OAc) ₂ .H ₂ O (10.7 g)
Was added in one portion at room temperature to a solution of 1.5 L in 10% nPrOH. The resulting slurry was aged at 30-35 ° C for 5 hours. After cooling to room temperature, the slurry was isolated by filtration. The wet cake was washed with 10% nPrOH (500 ml × 3). The antioxidant incorporated into wet cake to afford the title product by drying in a wet N ₂ under as described above.

By using both methods A and B above, the title product was prepared using the following solvents: acetone, Me
OH, EtOH, iPrOH, MeCN, pure water, DMF, DMSO, and aqueous solutions of similar solvents could also be prepared from ammonium salts.

Example 14 Recrystallization Method Using nPrOH-H ₂ O Dry Compound I (21 g) was dissolved in 150 ml of 40% nPrOH at 35 ° C. and line filtered. 480 m
35-40 to a slurry of 10% by weight of seed crystals in 4% PrOH
C. was added dropwise over 3-5 hours. After aging overnight at 35-40 ° C., the slurry was cooled to room temperature. The solid was filtered and washed with 10% nPrOH (200 ml × 2). The wet cake was dried in a wet N ₂ under. The yield was 95%.

Example 15 Recrystallization Method Using EtOH-H ₂ O Method A : 25 g of Compound I was dissolved in 425 ml of 95% EtOH at 40 ° C. and filtered by line. 10% w of the filtered solution in 825 ml of water
The mixture was added dropwise at 30 to 35 ° C over 3 to 5 hours in the presence of a seed crystal of t. The slurry was aged overnight and filtered before filtration.
Cool to ５5 ° C. The wet cake was washed with 30% EtOH in 250 ml, and dried at a wet N ₂ at room temperature under. Yield 92%.

Method B : 25 g of compound I was added to 625 ml of 95% EtOH
At 30-40 ° C. and filtered through a line. 525 ml of water 30
Added at 4040 ° C. After adding 10 wt% of seed crystals, 825 ml of water was added dropwise at 30-40 ° C over 3 hours. The slurry was aged overnight and cooled to 0-5 ° C before filtration. The wet cake was washed with 30% EtOH in 250 ml, and dried at room temperature in a wet N ₂ below. Yield 92%.

Example 16 Intraduodenal Administration of Dihydroxyl in Healthy Male Subjects
Simvastatin monobutyrate vs oral simvastatin
Comparison of the effects of itraconazole on single-dose pharmacokinetics
Open randomized 4-period cross-over study (open, ran
domized, four-period, crossover study) Objectives: (1) Active and total forms of a solution containing 5 mg of simvastatin dihydroxy open acid after a single administration in the duodenum.
HMG-CoA reductase inhibitory activity is potent against plasma AUC
Measuring the effect of the CYP3A inhibitor itraconazole; (2) vs simvastatin after a single intraduodenal administration of a solution containing 5 mg of simvastatin dihydroxy open acid
Dose-adjusted plasma A of active HMG-CoA reductase inhibitory activity after single oral administration of 20 mg film-coated tablet (FCT)
Measuring and comparing UC; (3) Measuring the effect of itraconazole on plasma AUC of simvastatin dihydroxy open acid and simvastatin lactone concentrations after a single intraduodenal administration of a solution containing 5 mg of simvastatin dihydroxy open acid.

Study Design: The study was designed in an open four-period, cross-randomized manner. Twelve healthy male subjects received four treatments (A, B, C and D). Treatment A
In subjects, itraconazole 200 mg (2 x 100 mg
Capsule) for 4 days, and 1 hour after the fourth dose of itraconazole on the fourth day, 5 mg of simvastatin dihydroxy open acid solution was administered once in the duodenum. In treatment B, subjects received a single intraduodenal administration of 5 mg of the simvastatin dihydroxy open acid solution on the first day. Intraduodenal administration was performed via a nasal-duodenal tube placed immediately prior to administration based on the guidance of a fluoroscopy examination by an experienced gastroenterologist and removed after 1 hour post administration. Treatments C and D were similar to treatments A and B except that simvastatin was administered orally using 20 mg of conventional film-coated tablets. Wash out between treatment periods was at least 7 days after treatment with itraconazole or at least 3 days after treatment without itraconazole.
Plasma samples were collected at appropriate time intervals over 24 hours after simvastatin or simvastatin dihydroxyopenate administration for analysis of total and active HMG-CoA reductase inhibitory activity and simvastatin and simvastatin dihydroxyopenate concentrations.

Analytical methodology: Simvastatin and dihydroxyopenic acid Simvastatinic acid plasma concentrations were determined by improved liquid chromatography / tandem mass spectrometry (LC / MS / MS) using lovastatin and dihydroxyopenic acid lovastatinic acid as internal standards. Measured simultaneously. Plasma concentrations of active and total (active + potentially active) HMG-CoA reductase inhibitory activity were measured using an enzyme assay.

Pharmacokinetics: The area under the plasma concentration-time profile from time 0 to the last sampling time (AUC 0 to last) is determined by the linear trapezoidal rule.
Was calculated. Apparent disappearance rate constant (k) of simvastatin and simvastatin dihydroxy open acid
Was estimated by least-squares regression analysis of the log-linear part of the simvastatin and simvastatin dihydroxy open acid concentration-time data, and the apparent elimination half-life (t _1/2 ) was t
Calculated as _1/2 = 0.693 / k. All calculations are based on the indicated sampling time, or if the actual sampling time differs from the indicated sampling time by more than 10 minutes,
It is based on the actual sampling time.

Discussion of the results: This was an open randomized 4-period crossover study in 12 healthy male subjects.
The result is that the dihydroxy open acid simvastatin 5m
Activated HMG-CoA obtained by intraduodenal administration of g solution
Dose-adjusted plasma AUC of reductase inhibitory activity was shown to be higher (approximately 4-fold) than oral administration of simvastatin 20 mg tablets (Table 1). Following administration of simvastatin dihydroxy open acid, unchanged simvastatin dihydroxy open acid was the major component (approximately 60%) contributing to plasma HMG-CoA reductase inhibitory activity, while simvastatin was the minor component (<10%). AUC values for total inhibitor and active inhibitor are comparable (Table 1)
Low levels of simvastatin in plasma (10% of simvastatin dihydroxy open acid simvastatin AUC)
(AUC less than) (see Table 3), the occurrence of lactonization of simvastatin dihydroxy open acid or any of its active metabolites was minimal after intraduodenal administration of simvastatin dihydroxy open acid. Pretreatment with itraconazole was performed with HMG-C after intraduodenal administration of 5 mg of simvastatin dihydroxy open acid.
Minimal change in systemic exposure (1.3 to 3.8 fold) compared to that observed after oral administration of simvastatin 20 mg tablet (1.3 to 3.8 fold) as measured by AUC and Cmax of oA reductase inhibitory activity (total or active). ~ 1.5 times) (Table 2
reference). When measured as unchanged drug, the effect of itraconazole observed after administration of simvastatin dihydroxyopenate was also minimal (1.5-fold) and significantly lower than the corresponding measurement obtained after administration of simvastatin (19-fold) ( See Table 3). Moderate effects on simvastatin AUC and Cmax after treatment with itraconazole before administration of simvastatin dihydroxy open acid
(3-4 fold increase) (see Table 3). However,
The apparent t1 / 2 values of the dihydroxy open acid simvastatin or simvastatin were essentially unchanged by itraconazole (see Table 3). Overall,
These results indicate that in humans, the pharmacokinetics of simvastatin dihydroxy open acid is less altered by itraconazole, a potent CYP3A inhibitor, than with simvastatin. From these results, it is clear that dihydroxy open acid is a substrate for CYP3A, but is metabolized in human liver microsomes with a much lower intrinsic clearance than that of simvastatin.

[0112]

TABLE 1 5 mg for 12 healthy male volunteers
Parameters of total and active HMG-CoA reductase inhibitors after intraduodenal administration of simvastatin dihydroxy open acid (SVA) or oral administration of 20 mg simvastatin (SV) tablets. Results are the average of data obtained from 12 subjects. The value in parentheses is SD.

[0113]

Table 2. Duodenum of 5 mg simvastatin dihydroxy open acid (SVA) with or without pretreatment with itraconazole (2 x 100 mg capsule, qd) for 12 healthy male volunteers for 4 days Pharmacokinetic parameters for total HMG-CoA reductase inhibitors after internal administration or after oral administration of 20 mg simvastatin (SV) tablets. Results are the average of data obtained from 12 subjects. The value in parentheses is SD.

[0114]

Table 3 Duodenum of 5 mg simvastatin dihydroxy open acid (SVA) with or without pretreatment with itraconazole (2 x 100 mg capsules, qd) for 4 healthy male volunteers for 4 days Pharmacokinetic parameters for simvastatin or simvastatin dihydroxy open acid after internal administration or after oral administration of 20 mg simvastatin (SV) tablets. Results are the average of data obtained from 12 subjects. The value in parentheses is SD.

While the invention has been described and described with respect to particular embodiments thereof, those skilled in the art will recognize that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention. Will be. For example, the diversity of responsiveness of mammals to be treated for any of the indications of the active agents used in the present invention as described above may result in effective doses other than the specified dosage as described herein due to the variable responsiveness. Dosage is applicable. Similarly, the particular pharmacokinetic response observed is dependent on the individual active compound selected,
Or the presence or absence of a pharmaceutical carrier, and may further vary depending on the type of formulation used, and such changes or differences in the expected results are considered in accordance with the objects and practices of the present invention. You. Accordingly, the invention is defined in the following claims, which are to be construed broadly and reasonably.

[Brief description of the drawings]

FIG. 1 is a diagram showing a weight loss curve by thermogravimetry (TG) of Compound I obtained under a nitrogen flow at a heating rate of 10 ° C./min.

FIG. 2: placed in a cup without lid at a heating rate of 10 ° C./min
FIG. 2 shows a differential scanning calorimetry (DSC) curve of Compound I obtained by passing a nitrogen stream through 16.0 ° C. water.

FIG. 3 shows an X-ray powder diffraction (XRPD) pattern of Compound I. The ordinate or y-axis is the X-ray intensity (cpm),
The abscissa, or x-axis, is the angle of 2 theta (2θ) in degrees.

FIG. 4 shows a solid state ¹³ C nuclear magnetic resonance spectrum of Compound I.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/47 A61K 31/47 31/505 31/505 47/10 47/10 47/14 47/14 47/30 47 / 30 A61P 3/06 A61P 3/06 9/10 9/10 101 101 43/00 111 43/00 111 (72) Inventor Paul Jay. Raiders United States 07065-0907 East Rin Khan Avenue, Rahway, NJ 126 (72) Inventor Edward Jay. Jay. Grabowski, USA 07065-0907 East Rin Khan Avenue 126, Rahway, NJ 126 (72) Inventor Fenshu United States 07065-0907 Rahway, NJ East Rin Khan Ave 126 (72) Inventor Jose M. Vega United States 07065-0907 East Rin Khan Avenue, Rahway, New Jersey 126

Claims (61)

[Claims] 1. A delayed release dosage form comprising a therapeutically effective amount of a compound selected from statins dihydroxy open acid and pharmaceutically acceptable salts or esters thereof together with a pharmaceutically acceptable carrier. Or oral pharmaceutical composition, wherein sufficient release of the compound from the dosage form after oral administration to a patient is delayed until after the dosage form has passed through the stomach. 2. The pharmaceutical composition according to claim 1, wherein at most 10% by weight of the statin is released in the stomach of the patient after administration. 3. The pharmaceutical composition according to claim 2, wherein at most 5% by weight of the statin is released in the stomach of the patient after administration. 4. The pharmaceutical composition according to claim 3, wherein at most 1% by weight of statin is released in the stomach of the patient after administration. 5. The pharmaceutical composition according to claim 1, wherein said composition is enteric coated. 6. The pharmaceutical composition according to claim 5, wherein the periphery of the dosage form is enteric coated. 7. The pharmaceutical composition according to claim 5, wherein said dosage form comprises enteric coated granules of a statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof. 8. The pharmaceutical composition according to claim 5, wherein said dosage form comprises enteric coated granules of simvastatin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof. 9. The method of claim 5, wherein the dosage form comprises enteric coated granules of a statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof, provided that the dosage form does not comprise aspirin granules. Pharmaceutical composition. 10. The pharmaceutical composition according to claim 5, wherein said composition is formulated in an enteric-coated fast-release pharmaceutical dosage form. 11. The composition of claim 5, wherein the composition is formulated in an enteric coated time-controlled release pharmaceutical dosage form.
The pharmaceutical composition according to any one of the preceding claims. 12. A compressed core prepared from a mixture wherein the composition comprises: (A) (i) a therapeutically effective amount of the compound, (ii) a polymer that forms gelatinous microscopic particles upon hydration. And (B) a water-insoluble, water-impermeable polymer coating comprising a polymer and a plasticizer surrounding and adhering to the core, wherein the coating exposes about 1-75% of the core surface 2. A drug delivery device comprising a plurality of openings formed as described above, wherein the release rate of the compound from the device is a function of the number and size of the openings. The pharmaceutical composition according to any one of the preceding claims. 13. The pharmaceutical composition of claim 12, wherein the drug delivery device further comprises an enteric overcoat on the outer surface of the water-insoluble, water-impermeable polymer coating. 14. The pharmaceutical composition of claim 1, wherein said statin is selected from lovastatin, simvastatin, atorvastatin, cerivastatin, nisvastatin and the dihydroxy open acid form of ZD-4522 and pharmaceutically acceptable salts and esters thereof. object. 15. The pharmaceutical composition according to claim 1, wherein said statin is selected from the dihydroxy open acid forms of lovastatin and simvastatin, and pharmaceutically acceptable salts and esters thereof. 16. The pharmaceutical composition according to claim 1, wherein said statin is selected from the dihydroxy open acid form of simvastatin and pharmaceutically acceptable salts and esters thereof. 17. The pharmaceutical composition according to claim 1, wherein said statin is a pharmaceutically acceptable salt of simvastatin dihydroxy open acid. 18. The pharmaceutical composition according to claim 1, wherein said statin is a calcium salt of simvastatin dihydroxy open acid. 19. The pharmaceutical composition according to claim 1, wherein said statin is an ammonium salt of simvastatin dihydroxy open acid. 20. The statin is a crystalline hydrated calcium salt of simvastatin dihydroxy open acid, wherein the crystalline hydrated calcium salt is 30.7, 24.6, 15.9, 11.2, 8.
58, 7.31, 6.74, 6.06, 5.35, 5.09, 4.93, 4.60, 3.9
The pharmaceutical composition according to claim 1, having an X-ray powder diffraction pattern obtained using CuKα radiation, characterized by reflections at interplanar spacings d of 3, 3.84, 3.67, 3.51 and 3.28 °. 21. The pharmaceutical composition according to claim 5, wherein said statin is selected from lovastatin, simvastatin, atorvastatin, cerivastatin, nisvastatin and the dihydroxy open acid form of ZD-4522 and pharmaceutically acceptable salts and esters thereof. object. 22. The pharmaceutical composition according to claim 5, wherein said statin is selected from the dihydroxy open acid forms of lovastatin and simvastatin and pharmaceutically acceptable salts and esters thereof. 23. The pharmaceutical composition according to claim 5, wherein said statin is selected from the dihydroxy open acid form of simvastatin and pharmaceutically acceptable salts and esters thereof. 24. The pharmaceutical composition according to claim 5, wherein said statin is a pharmaceutically acceptable salt of simvastatin dihydroxy open acid. 25. The pharmaceutical composition according to claim 5, wherein said statin is a calcium salt of simvastatin dihydroxy open acid. 26. The pharmaceutical composition according to claim 5, wherein said statin is an ammonium salt of simvastatin dihydroxy open acid. 27. The statin is a crystalline hydrated calcium salt of simvastatin dihydroxy open acid, wherein the crystalline hydrated calcium salt is 30.7, 24.6, 15.9, 11.2, 8.
58, 7.31, 6.74, 6.06, 5.35, 5.09, 4.93, 4.60, 3.9
The pharmaceutical composition according to claim 5, having an X-ray powder diffraction pattern obtained using CuKα radiation, characterized by reflections at interplanar spacings d of 3, 3.84, 3.67, 3.51 and 3.28 °. 28. The pharmaceutical composition according to claim 27, further comprising BHA. 29. The pharmaceutical composition according to claim 27, further comprising propyl gallate. 30. The pharmaceutical composition according to claim 27, further comprising BHA and propyl gallate. 31. A pharmaceutical preparation prepared by combining a therapeutically effective amount of a compound selected from statins dihydroxy open acid and pharmaceutically acceptable salts or esters thereof with a pharmaceutically acceptable carrier into a delayed release dosage form. Oral pharmaceutical compositions. 32. An oral pharmaceutical composition comprising a compound selected from statin dihydroxyopenate and a pharmaceutically acceptable salt or ester thereof combined with a pharmaceutically acceptable carrier to form a delayed release dosage form. Preparation method. 33. Use of a statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof for preparing an oral medicament adapted for delayed release, wherein sufficient release of the statin after oral administration is provided. The use according to the above, which does not occur until after the medicament has passed through the stomach. 34. The use according to claim 33, wherein at most 10% by weight of the statin is released in the stomach of the patient after administration. 35. The use according to claim 33, wherein at most 5% by weight of statin is released in the stomach of the patient after administration. 36. The use according to claim 33, wherein at most 1% by weight of the statin is released in the patient's stomach after administration. 37. Use of simvastatin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof for preparing the medicament according to claim 33. 38. A statin dihydroxy open acid for preparing an oral medicament adapted for delayed release effective to deliver at least 90% by weight of a statin in dihydroxy open acid form to the intestinal mucosa of a patient after oral administration. Or use of a pharmaceutically acceptable salt or ester thereof. 39. The use according to claim 38, wherein at least 95% by weight of the statin is delivered to the patient's intestinal mucosa after oral administration in its dihydroxy open acid form. 40. The use of claim 38, wherein at least 99% by weight of the statin is delivered to the intestinal mucosa of the patient after oral administration in its dihydroxy open acid form. 41. Use of simvastatin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof for preparing the medicament according to claim 38. 42. The use of a statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof for the preparation of an oral medicament adapted for delayed release effective to inhibit HMG-CoA reductase in a patient. So,
Use according to the preceding claims, characterized in that the sufficient release of the statin after oral administration is delayed until after the drug has passed through the stomach. 43. Use of a statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof for preparing an oral medicament adapted for delayed release effective to treat hypercholesterolemia in a patient. So,
Use according to the preceding claims, characterized in that the sufficient release of the statin after oral administration is delayed until after the drug has passed through the stomach. 44. A statin dihydroxy open acid or a statin thereof for preparing an oral medicament adapted for delayed release effective to prevent or reduce the risk of developing atherosclerosis in a patient suspected of having atherosclerosis. Use of a pharmaceutically acceptable salt or ester, wherein sufficient release of the statin after oral administration is delayed until after the medicament has passed through the stomach. 45. The use of claim 44, wherein said medicament is effective in preventing or reducing the risk of developing atherosclerosis selected from cardiovascular, cerebrovascular and peripheral vascular diseases. 46. The method according to claim 44, wherein the medicament is effective in preventing or reducing the risk of developing coronary heart disease.
Use of the description. 47. Use of a statin dihydroxy open acid or a pharmaceutically acceptable salt or ester thereof for the preparation of an oral medicament adapted for delayed release effective for treating atherosclerosis in a patient. Wherein the sufficient release of the statin after oral administration is delayed until after the drug has passed through the stomach. 48. The use according to claim 47, wherein said medicament is effective for treating atherosclerosis selected from cardiovascular, cerebrovascular and peripheral vascular diseases. 49. The use according to claim 47, wherein said medicament is effective in treating coronary heart disease. 50. A dihydroxy open for preparing an oral medicament adapted for delayed release effective to prevent or reduce the risk of the onset or recurrence of an atherosclerosis event in a human suspected of having atherosclerosis. Use of an acid statin or a pharmaceutically acceptable salt or ester thereof, wherein the sufficient release of the statin after oral administration is delayed until after the medicament has passed through the stomach. 51. The method of claim 50, wherein the medicament is effective in preventing or reducing the risk of occurrence or recurrence of an atherosclerotic event in atherosclerotic humans.
Use of the description. 52. The use of claim 50, wherein said medicament is effective in preventing or reducing the risk of developing or recurring atherosclerotic events in a human suspected of having atherosclerosis. 53. The method wherein the medicament is a coronary heart disease event;
51. The use according to claim 50, which is effective to prevent or reduce the risk of occurrence or recurrence of an atherosclerotic event selected from cerebrovascular events and intermittent claudication. 54. The medicament is effective for preventing or reducing the risk of occurrence or recurrence of a coronary heart disease event selected from death from coronary heart disease, myocardial infarction and coronary revascularization. Use according to 50. 55. The use according to claim 50, which is effective to prevent or reduce the risk of occurrence or recurrence of a cerebrovascular event selected from cerebrovascular and transient ischemic attacks. 56. The use according to any one of claims 42 to 55, wherein said statin is selected from the dihydroxy open acid forms of lovastatin and simvastatin and pharmaceutically acceptable salts and esters thereof. 57. The use according to any one of claims 42 to 55, wherein said statin is selected from simvastatin dihydroxy open acid and pharmaceutically acceptable salts and esters thereof. 58. The use according to any one of claims 42 to 55, wherein said statin is a pharmaceutically acceptable salt of simvastatin dihydroxy open acid. 59. The statin is a calcium salt of simvastatin dihydroxy open acid.
55. Use according to any one of the items 55. 60. The statin is an ammonium salt of simvastatin dihydroxy open acid.
56. Use according to any one of the preceding items. 61. The statin is a crystalline hydrated calcium salt of simvastatin dihydroxy open acid, wherein the crystalline hydrated calcium salt is 30.7, 24.6, 15.9, 11.2, 8.
58, 7.31, 6.74, 6.06, 5.35, 5.09, 4.93, 4.60, 3.9
56. Use according to any one of claims 42 to 55, having an X-ray powder diffraction pattern obtained using Cu Ka radiation, characterized by reflections at interplanar spacings d of 3, 3.84, 3.67, 3.51 and 3.28 °. .