CN1993121A

CN1993121A - Novel statin pharmaceutical compositions and related methods of treatment

Info

Publication number: CN1993121A
Application number: CN 200580026639
Authority: CN
Inventors: H·古兹曼; O·阿尔马森; J·雷梅纳
Original assignee: Transform Pharmaceuticals Inc
Current assignee: Transform Pharmaceuticals Inc
Priority date: 2004-08-06
Filing date: 2005-08-05
Publication date: 2007-07-04
Also published as: ZA200701916B

Abstract

The invention provides novel omega-3 oil solutions of one or more statins. These solutions are readily bioavailable. Notably, because the solutions of the invention contain an omega-3 oil as the major ingredient, they not only provide an antihypercholesterolemic effect due to the statin active ingredient, they also provide recommended daily dosages of omega-3 oils (i.e., approximately 1 gram of omega-3 oil per day), or a portion thereof. The invention also provides novel salts of one or more statins.

Description

New statin pharmaceutical compositions and related methods of treatment

The application requires in the U.S. Provisional Application serial number 60/599 of submission on August 6th, 2004,543, the U.S. Provisional Application serial number of submitting on October 29th, 2,004 60/623,518 and the U.S. Provisional Application serial number 60/655 submitted on February 24th, 2005,982 benefit of priority is incorporated herein by reference its full content at this.

Invention field

The invention provides the new ω-3 ester group oil-suspending agent of Statins.This class suspending agent is basically without any food effect, and small size is promptly effective, and easy biological utilisation.

Background of invention

Know very much that it is the main hazard factor of coronary heart disease (CHD) that blood cholesterol levels raises recent decades always, studies show that much the danger that the CHD incident occurs can obtain reducing by treatment.Before 1987, blood fat reducing class material mainly is confined to low saturated fat and cholesterol diet, bile acid multivalent chelator (colestyramine and colestipol), nicotinic acid (niacin), the special class of shellfish and probucol.Unfortunately, all these treatments all have limited effect or toleration or both.Introducing (MEVACOR  along with lovastatin; Referring to United States Patent (USP) 4,231,938), the medication of can writing out a prescription in 1987 of first inhibitor of HMG-CoA reductase makes the doctor can realize for the first time that relatively large amplitude ground reduces plasma cholesterol, has few side effect simultaneously.

Except natural fermented product, mevastatin and lovastatin, also there are various semi-synthetic and complete synthesis HMG-CoA reductase inhibitors at present, comprise simvastatin (ZOCOR ; Referring to United States Patent (USP) 4,444,784), sodium salt of pravastatin (PRAVACHOL ; Referring to United States Patent (USP) 4,346,227), fluvastatin sodium salt (LESCOL ; Referring to United States Patent (USP) 5,354,772), atorvastatin calcium salt (LIPITOR ; Referring to United States Patent (USP) 5,273,995) and the cerivastatin sodium salt (also be known as rivastatin; Referring to United States Patent (USP) 5,177,080).Aforementioned HMG-CoA reductase inhibitor belongs to the chemical compound with following structure type, and it contains can be with 3-hydroxy-lactone loop type or the part that exists with corresponding open loop dihydroxy open loop acid form, and is commonly referred to as " Statins ".

Can prepare the salt of dihydroxy open loop acid, in fact as mentioned above, several commercially available Statins are all with dihydroxy open loop hydrochlorate form administration.Lovastatin and simvastatin go on the market with its form that lactonizes on the world market.

Confirmed the hypertriglyceridaemia effect of ω-3 oil from fish oil.Above and below every day 1 gram all demonstrate from the amount of ω-3 oil of fish oil and serum triglycerides concentration can be reduced about 25% to about 40%, reduce the VLDL blood plasma level, and rising LDL and HDL blood plasma level are (referring to for example Harris, William S, Clin.Cardiol.22, (Suppl.II), II-40-II-43 (1999)).Between picked-up of ω-3 oil and triglyceride reduction, there is dose response relation.Triglyceride is especially responsive to chronic ω-3 oil consumption after the meal.People such as Kris-Etherton, Circulation.2002; 106:2747.

Although existing a variety of known Statins dosage forms still need be at the statin pharmaceutical compositions of viable commercial, it has the bioavailability that has improved, and prepares easily and administration, and contains the composition that improves his spit of fland hypercholesterolemia effect.

Summary of the invention

The invention provides the new ω-3 oil base pharmaceutical composition of one or more Statins with unforeseeable character.These pharmaceutical compositions are easy to biological utilisation.It should be noted that because pharmaceutical composition of the present invention contains ω-3 oil as main component, therefore they not only have the hypercholesterolemia effect because of containing his spit of fland active component, but also recommended (promptly about 1 restrains oily every day of ω-3, according to the AHA handbook) or its a part of ω-3 oil are provided.

The present invention includes suspending agent or the heterogeneous body preparation of one or more Statins in ω-3 oil.In specific embodiments, the invention provides the suspending agent of unformed and/or crystalline particle in ω-3 oil of one or more Statins.

In one embodiment, pharmaceutical composition of the present invention contains ω-3 hydrocarbyl carbonate, preferred ω-3 ethyl ester.In another embodiment, pharmaceutical composition of the present invention contain ω-3 glycerol list-, two-or three-ester oil.

In another embodiment, the invention provides pharmaceutical composition, its contain have an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg more than or equal to the ω-3 of about 90% purity oil and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or 160mg one or more he spit of fland salt.In another embodiment, the invention provides pharmaceutical composition, it contains has an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or ω-3 oil formed more than or equal to about 90%EPA and DHA of 1500mg and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or 160mg one or more he spit of fland salt.

In another embodiment, described salt is the calcium salt of pravastatin.In another embodiment, described salt is the calcium salt of fluvastatin.In another embodiment, described salt is the magnesium salt of pravastatin.In another embodiment, described salt is the zinc salt of pravastatin.In another embodiment, described salt is crystallization.

In another embodiment, the invention provides pharmaceutical composition, its contain have an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg more than or equal to the ω-3 of about 90% purity oil and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or one or more Statins of 160mg.In another embodiment, the invention provides pharmaceutical composition, it contains has an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or ω-3 oil formed more than or equal to about 90%EPA and DHA of 1500mg and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or one or more Statins of 160mg.

In another embodiment, described ω-3 oil is ω-3 ester.In another embodiment, described ω-3 oil is ω-3 ethyl ester.In another embodiment, described his spit of fland is a lactone form.In another embodiment, described his spit of fland is a free acid.

In another embodiment, the purity of described ω-3 ester or ω-3 hydrocarbyl carbonates be at least about 50wt%, at least about 60wt%, at least about 70wt%, at least about 75wt%, at least about 80wt% or at least about 85wt%.In another embodiment, the purity of described ω-3 ester or ω-3 hydrocarbyl carbonates is about 25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,99wt% or higher.In another embodiment, the purity of described ω-3 ester or ω-3 hydrocarbyl carbonates is about 25 to about 100wt%, about 40 to about 100wt%, about 50 to about 100wt%, about 60 to about 100wt%, about 70 to about 100wt%, about 75 to about 100wt%, about 75 to about 95wt%, about 75 to about 90wt% or about 80 to about 85wt%.In another embodiment, the purity of described ω-3 ester or ω-3 hydrocarbyl carbonates be about 100wt%, about 99wt%, at least about 96wt%, at least about 92wt%, at least about 90wt%, at least about 85wt%, at least about 80wt%, at least about 75wt%, at least about 70wt%, at least about 65wt%, at least about 60wt%, at least about 55wt% or at least about 50wt%.

In another embodiment, the fluid composition of described EPA of containing and DHA be at least about 50wt%, at least about 60wt%, at least about 70wt%, at least about 75wt%, at least about 80wt% or at least about EPA and the DHA of 84wt%.In another embodiment, the fluid composition of described EPA of containing and DHA is about 25,30,35,40,45,50,55,60,65,70,75,80,85,90 or EPA and the DHA of 95wt%.In another embodiment, the fluid composition of described EPA of containing and DHA is about 25 to about 95wt%, about 40 to about 95wt%, about 50 to about 95wt%, about 60 to about 95wt%, about 70 to about 95wt%, about 75 to about 95wt%, about 75 to about 90wt%, about 75 to about 85wt% or about 80 to about 85wt% EPA and DHA.In another embodiment, described EPA and the DHA that contains the fluid composition of EPA and DHA for about 99wt%, about 96wt%, about 92wt%, about 90wt%, about 84wt%, about 80wt%, about 75wt%, about 70wt%, about 65wt%, about 60wt%, about 55wt% or about 50wt%.

In another embodiment, described ω-3 ester or ω-3 hydrocarbyl carbonates have the EPA of the EPA of the EPA of the EPA of the EPA of the EPA of the EPA of the EPA of the EPA of the EPA of the EPA for about 23: 19 ratios: DHA, about 75: 11 ratios: DHA, about 95: 1 ratios: DHA, about 9: 2 ratios: DHA, about 10: 1 ratios: DHA, about 5: 1 ratios: DHA, about 3: 1 ratios: DHA, about 2: 1 ratios: DHA, about 1: 1 ratio: DHA, about 1: 2 ratio: DHA, about 1: 3 ratio: the EPA of DHA or about 1: 5 ratio: DHA.In another embodiment, described ω-3 ester or ω-3 hydrocarbyl carbonates have the EPA for about 95: 1 ratios: DHA, the EPA of about 75: 1 ratios: DHA, the EPA of about 50: 1 ratios: DHA, the EPA of about 25: 1 ratios: DHA, the EPA of about 20: 1 ratios: DHA, the EPA of about 15: 1 ratios: DHA, the EPA of about 10: 1 ratios: DHA, the EPA of about 7.5: 1 ratios: DHA, the EPA of about 5: 1 ratios: DHA, the EPA of about 4: 1 ratios: DHA, the EPA of about 3: 1 ratios: DHA, the EPA of about 2: 1 ratios: DHA, the EPA of about 1.5: 1 ratios: DHA, the EPA of about 1: 1 ratio: DHA, the EPA of about 1: 1.5 ratio: DHA, the EPA of about 1: 2 ratio: DHA, the EPA of the EPA of about 1: 3 ratio: DHA or about 1: 5 ratio: DHA.In another embodiment, described ω-3 ester or ω-3 hydrocarbyl carbonates have about 95: 1 ratios EPA to about 1: 5 ratio: DHA, about 50: the 1 ratios EPA to about 1: 1 ratio: DHA, about 25: the 1 ratios EPA to about 1: 1 ratio: DHA, about 10: the 1 ratios EPA to about 1: 1 ratio: DHA, about 5: the 1 ratios EPA to about 1: 1 ratio: DHA, about 3: the 1 ratios EPA to about 1: 1 ratio: DHA, about 2: the 1 ratios EPA to about 1: 1 ratio: DHA or about 1.5: the 1 ratios EPA to about 1: 1 ratio: DHA.In another embodiment, described ω-3 ester or ω-3 hydrocarbyl carbonates have the EPA at least about 1: 5 ratio: DHA, at least about the EPA of 1: 1 ratio: DHA, at least about the EPA of 1.5: 1 ratios: DHA, at least about the EPA of 2: 1 ratios: DHA, at least about the EPA of 3: 1 ratios: DHA, at least about the EPA of 5: 1 ratios: DHA or at least about the EPA of 10: 1 ratios: DHA.

The invention provides the ω-3 ester group medicine of novel unforeseeable one or more Statins.This class medicine is easy to biological utilisation.It should be noted that because medicine of the present invention contains ω-3 ester group oil as main component, therefore they not only have the hypercholesterolemia effect because of containing his spit of fland active component, but also recommended (promptly about 1 restrains oily every day of ω-3, according to the AHA handbook) or its a part of ω-3 oil are provided.

In another embodiment, the invention provides the salt in his spit of fland.In another embodiment, the invention provides the salt of pravastatin or fluvastatin.In specific embodiments, provide the calcium salt of pravastatin.The magnesium salt of pravastatin is provided in another embodiment.The zinc salt of pravastatin is provided in another embodiment.The calcium salt of fluvastatin is provided in another embodiment.The divalent salts in his spit of fland is provided in another embodiment.In specific embodiments, provide the divalent salts of pravastatin or fluvastatin.In another embodiment, the salt in described his spit of fland is unformed.In another embodiment, the salt in described his spit of fland is crystallization.

In another embodiment, the invention provides solvate, hydrate, cocrystallization or the polymorph of the salt in his spit of fland.In another embodiment, the invention provides solvate, hydrate, cocrystallization or the polymorph of the salt of pravastatin or fluvastatin.In specific embodiments, provide solvate, hydrate, cocrystallization or the polymorph of pravastatin calcium salt.Solvate, hydrate, cocrystallization or the polymorph of pravastatin magnesium salt are provided in another embodiment.Solvate, hydrate, cocrystallization or the polymorph of pravastatin zinc salt are provided in another embodiment.Solvate, hydrate, cocrystallization or the polymorph of fluvastatin calcium salt are provided in another embodiment.Solvate, hydrate, cocrystallization or the polymorph of the divalent salts in his spit of fland are provided in another embodiment.In specific embodiments, provide solvate, hydrate, cocrystallization or the polymorph of pravastatin or fluvastatin divalent salts.In another embodiment, the solvate or the hydrate of the salt in described his spit of fland are unformed.In another embodiment, the solvate or the hydrate of the salt in described his spit of fland are crystallizations.

In another embodiment, provide pharmaceutical composition or medicament, it contains the salt in his spit of fland.In another embodiment, provide pharmaceutical composition or medicament, it contains solvate, hydrate, cocrystallization or the polymorph of the salt in his spit of fland.In another embodiment, provide pharmaceutical composition or medicament, it contains solvate, hydrate, cocrystallization or polymorph and ω-3 oil of the salt in his spit of fland.

In another embodiment, the invention provides the method for the salt for preparing his spit of fland.

In another embodiment, the method for preparing the salt in his spit of fland comprises:

(a) Ta Ting and salt are mixed in solution;

(b) make the salt in described his spit of fland begin precipitation; And

(c) the described salt in described his spit of fland of collection.

In another embodiment, his spit of fland in the step (a) can be a salt.For example, his spit of fland in the step (a) can be the alkali metal salt in his spit of fland, such as but not limited to sodium salt of pravastatin or fluvastatin sodium salt.In another embodiment, the salt in the step (a) can be alkali salt.For example, the salt in the step (a) can be calcium or magnesium salt, such as but not limited to calcium acetate or calcium chloride.

In another embodiment, by prevention being provided, having alleviated and/or having treated the method that cholesterol levels rising (for example hypercholesterolemia), atherosclerosis, hyperlipemia, cardiovascular event and disease comprise crown incident and cerebrovascular events and coronary artery disease and/or cerebrovascular disease to this prevention there being, alleviating and/or treating the mammal administration pharmaceutical composition of the present invention that needs.

To be described in more detail above-mentioned and other embodiment in the following detailed description.

The accompanying drawing summary

Fig. 1 shows the PXRD diffraction pattern of pravastatin calcium salt.

Fig. 2 shows the TGA pyrolysis curve of pravastatin calcium salt.

Fig. 3 shows the IR spectrum of pravastatin calcium salt.

Fig. 4 shows the DVS moisture sorption isotherm chart of pravastatin calcium salt.

Fig. 5 shows the DVS moisture sorption isotherm chart of sodium salt of pravastatin.

Fig. 6 shows several pravastatin salts at 25 ℃ of impurity percentage ratio charts after 26 weeks of placement in bottle and soft capsule.

Fig. 7 shows the impurity percentage ratio chart of several pravastatin salts after 40 and 60 ℃ of placements reached for 26 weeks.

Fig. 8 shows the PXRD diffraction pattern of fluvastatin calcium salt.

Fig. 9 shows the DSC pyrolysis curve of fluvastatin calcium salt.

Figure 10 shows the TGA pyrolysis curve of fluvastatin calcium salt.

Figure 11 shows the Raman spectrum of fluvastatin calcium salt.

Figure 12 shows the IR spectrum of fluvastatin calcium salt.

Figure 13 shows the PXRD diffraction pattern of pravastatin magnesium salt (A type).

Figure 14 shows the DSC pyrolysis curve of pravastatin magnesium salt (A type).

Figure 15 shows the TGA pyrolysis curve of pravastatin magnesium salt (A type).

Figure 16 shows the IR spectrum of pravastatin magnesium salt (A type).

Figure 17 shows the DVS moisture sorption isotherm chart of pravastatin magnesium salt (A type).

Figure 18 shows the PXRD diffraction pattern of pravastatin magnesium salt (Type B).

Figure 19 shows the DSC pyrolysis curve of pravastatin magnesium salt (Type B).

Figure 20 shows the TGA pyrolysis curve of pravastatin magnesium salt (Type B).

Figure 21 shows the IR spectrum of pravastatin magnesium salt (Type B).

Figure 22 shows the PXRD diffraction pattern of pravastatin magnesium salt.

Figure 23 shows the DSC pyrolysis curve of pravastatin magnesium salt.

Figure 24 shows the TGA pyrolysis curve of pravastatin magnesium salt.

Figure 25 shows the PXRD diffraction pattern of pravastatin zinc salt.

Figure 26 shows the DSC pyrolysis curve of pravastatin zinc salt.

Figure 27 shows the TGA pyrolysis curve of pravastatin zinc salt.

Figure 28 shows the IR spectrum of pravastatin zinc salt.

Figure 29 shows the Raman spectrum of pravastatin zinc salt.

Figure 30 shows the DVS moisture sorption isotherm chart of pravastatin zinc salt.

Figure 31 shows several pravastatin salts at 4 ℃ stability data (lactone percentage ratio).

Figure 32 shows several pravastatin salts at 40 ℃ stability data (lactone percentage ratio).

Figure 33 shows several pravastatin salts at 40 ℃ stability data (percentage ratio of other degradation product).

Detailed Description Of The Invention

Following term used herein has respectively following implication.

Term used herein " cardiovascular event " and " angiocardiopathy " refer to crown and/or cerebrovascular events and disease, comprise primary miocardial infarction, inferior myocardial inyaretion, myocardial ischemia, angina pectoris (comprising UA), congestive heart failure, sudden cardiac death, cerebral infarction, cerebral thrombosis, cerebral ischemia, TIA etc.

Term used herein " coronary artery disease " (CAD) refers to comprise coronary artery atherosclerotic, congenital miocardial infarction, ischemic, angina pectoris and/or disease in heart failure.

Term used herein " cranial vascular disease " refers to comprise the disease of encephalic and/or the outer artery atherosclerotic of cranium, cerebral infarction, cerebral thrombosis, cerebral ischemia, apoplexy and/or TIA.

" alkyl " refers to have saturated or unsaturated alkyl, ring-type or the non-cyclic hydrocarbon of the straight or branched of 1-10 carbon atom. Representative saturated straight chain alkyl comprises methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, n-hexyl etc.; And saturated branched hydrocarbyl comprises isopropyl, sec-butyl, isobutyl group, the tert-butyl group, isopentyl etc. Unsaturated alkyl contains at least one two keys or three key (also being respectively referred to as " alkenyl " or " alkynyl group ") between adjacent carbon atom. Representative straight chain and branched alkenyl comprise vinyl, acrylic, 1-cyclobutenyl, 2-cyclobutenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butene base, 2-methyl-2-cyclobutenyl, 2,3-dimethyl-2-cyclobutenyl etc.; And representative straight chain and side chain alkynyl group comprise acetenyl, propinyl, 1-butynyl, 2-butynyl, 1-pentynyl, valerylene base, 3-methyl-butynyl etc. Representative saturated cyclic alkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.; And the unsaturated cyclic alkyl comprises cyclopentenyl and cyclohexenyl group etc. Cyclic hydrocarbon radical also is known as " carbocyclic ring " ring system in this article, comprise having two of 8-14 carbon atom-and three-ring ring system, for example the cyclic hydrocarbon radical (for example pentamethylene or cyclohexane) carbocyclic fused with one or more aromatics (for example phenyl) or non-aromatic (for example cyclohexane). " alkenyl " can be used for referring to undersaturated in ω-3 preparation context.

Term used herein " auxiliary administration " refers to except the racemate of using his spit of fland or officinal salt, solvate, cocrystallization or the polymorph of stereoisomer, preferably outside the salt in his spit of fland, also one or more compounds of administration or active component, they can be simultaneously or before officinal salt, solvate, cocrystallization or the polymorph of the racemate in his spit of fland of administration or stereoisomer, between or afterwards certain intervals administration, thereby obtain desirable treatment or preventive effect.

" aliphatic acid " is important nutrition composition. Aliphatic acid (also being known as " free acid " or " free fatty ") is carboxylic acid, and classifies according to length and the saturated characteristic of carbochain. SCFA has 2 to about 5 carbon, and normally saturated. Medium chain fatty acid has about 6 to about 14 carbon, and also is saturated usually. LCFA has about 15-24 or more carbon, can be saturated or undersaturated. In LCFA more, can there be one or more unsaturated points, produce respectively term " cholesterol " and " how unsaturated ". Use among the present invention and have 20 or the long-chain polyunsaturated fatty acid (LCPs or LC-PUFAs) of more carbon.

With " long-chain " glycerine list-, two-, three-ester, ester, aliphatic acid etc. are defined as has about 15,16,17,18,19,20,21,22,23,24 or more carbon, and can be saturated or undersaturated. With " medium chain " glycerine list-, two-, three-ester, ester, aliphatic acid etc. are defined as has about 6,7,8,9,10,11,12,13 or 14 carbon, and also can be saturated or undersaturated. With " short chain " glycerine list-, two-, three-ester, ester, aliphatic acid etc. are defined as has about 2,3,4 or 5 carbon, and also can be saturated or undersaturated.

" glycerine list-diester " and " glycerine list-diester class " refers to contain simultaneously one or more mixtures of monoglyceride and diglyceride. The limiting examples of glycerine list-diester is Capmul  MCM, and it contains the monoglyceride of sad and capric acid aliphatic acid and the mixture of triglyceride form. Some mixture of monoglyceride and diglyceride can be called glycerine list-diester of the present invention especially. Glycerine list-diester can contain other material, for example triglycerides and glycerine.

According to generally acknowledged nomenclature well known to those of ordinary skill in the art, based on number and the position of two keys in the aliphatic acid LC-PTJFA is classified. The LC-PUFA that has two kinds of series or family, this depends on the position of double bond near the fatty acid methyl end: n-3 series contains two keys at the 3rd carbon, and n-6 series is until the 6th carbon just contains two keys. Therefore, arachidonic acid (AA or ARA) has the chain length of 20 carbon and has 4 two keys since the 6th carbon. Therefore, it is known as " 20:4 n-6 ". Similarly, DHA (DHA) has the chain length of 22 carbon and begins to have 6 two keys from the 3rd carbon of methyl end, therefore is known as " 22:6 n-3 ". Other important LC-PUFA is eicosapentaenoic acid (EPA), is known as (20:5 n-3). Term " n-3 " and " ω-3 " can Alternates.

AA (n-6 series) is different with the biosynthesis pathway that DHA (n-3 series) is set out by its corresponding C18 precursor, but they share prolongation and desaturation step, and this also is well-known. Therefore, other important LCPs be in above-mentioned biosynthesis pathway as the C18 aliphatic acid of precursor, alpha-linolenic acid (18:3 n-3) and the parinaric acid (18:4 n-3) in the linoleic acid in the n-6 approach (18:2 n-6) and gamma-Linolenic acid (18:3 n-6), the n-3 approach for example.

In fact aliphatic acid changes into the form appearance of alcohol usually with acyl ester. Glyceride is exactly the ester of a kind of so one or more aliphatic acid and glycerine (Glycerin). If a position is only arranged by fatty acid esterification on the glycerol backbone molecule, then generate " monoglyceride "; If two positions are esterified, then generate " diglyceride "; And if all three positions of glycerine then generate " triglycerides " or " triacylglycerol " all by fatty acid esterification. If identical aliphatic acid is contained in all esterification positions, then such glyceride is known as " single "; If perhaps comprise different aliphatic acid, then be known as " mixing ". Phosphatide is the diglyceride of specific type, and wherein be combined by phosphate with nitrogen-containing compound such as choline, serine, monoethanolamine, inositol etc. in the 3rd position of glycerol backbone. According to connected aliphatic acid, triglycerides and phosphatide are divided into long-chain (about 15-24 or more carbon) or medium chain (about 6 to about 14 carbon) usually.

Usually the monoglyceride that is commercially available also contains glycerine two and three esters of different content except containing monoglyceride. For example monoglyceride (such as Karlshamns AB, the Akoline of Sweden) can contain the 50-65% monoglyceride of having an appointment, 25-35% diglyceride and up to 5% triglycerides.

" essential fatty acid " (EFA) has two types: derived from alpha-linolenic n-3 (or ω-3) series and derived from linoleic n-6 (or ω-6) series.

" omega-fatty acid " is n-3 polyunsaturated long-chain fatty acids (n-3 PUFA), it be defined as comprise any carboxylic acid with at least 15 carbon atoms and at least 3 non-conjugated cis unsaturated bonds, away from a unsaturated bond of fatty acid chain methyl end between third and fourth carbon atom. Therefore, omega-fatty acid comprises the C that contains 5-7 two keys₁₆-C ₂₄Alkanoic acid, wherein last double bond position is between third and fourth carbon atom of fatty acid chain methyl end.

The example of omega-fatty acid comprises parinaric acid (SDA, C 18:4), eicosatetraenoic acid (ETA, C20:4), eicosapentaenoic acid (EPA, C20:5), clupanodonic acid (DPA, C22:5) and DHA (DHA, C22:6). For the object of the invention, think that alpha-linolenic acid (ALA, C18:3) is omega-fatty acid. Whether the term such as " EPA " and " DHA " refers to the kind of ω-3 oil, be not to describe this class oil to exist with for example triglycerides, diglyceride, monoglyceride, free acid, ester or salt form.

Omega-fatty acid comprises synthetic or naturally occurring omega-fatty acid, the omega-fatty acid of for example finding in fish oil is such as seabed mammal (such as sea dog) fat, cod-liver oil, walnut and walnut oil, wheat-germ oil, rapeseed oil, soybean lecithin, soybean, bean curd, common beans, butternut, marine alga and linseed oil. Omega-fatty acid can also be originated from genetic engineering, for example genetically modified plants. Referring to such as people such as Frasier, Nat Biotechnol.2004 May 16.

" ω-3 oil " or " ω-3 " refer to any contain omega-fatty acid, ω-3 ester, ω-3 hydrocarbyl carbonate or ω-3 glycerine list-, two-or the oil in three-ester source, fish oil for example is such as seabed mammal (such as sea dog) fat, cod-liver oil, walnut and walnut oil, wheat-germ oil, rapeseed oil, soybean lecithin derived oils, soy-derived oil, bean curd derived oils, common beans derived oils, butternut derived oils, marine alga derived oils, flax-borage oil and linseed oil. ω-3 oil of preferred Epax  (Pronova Biocare AS) trade mark. Other ω-3 oil that can be used for preparing pharmaceutical composition of the present invention includes but not limited to trade name Ω brite  (Ω Natural Science) and Epanova^TMω-3 oil of (Tillotts Pharma AG) listing. Some mixture of ester, aliphatic acid and/or glycerine list, two or three esters can be called especially according to oils of the present invention. For example, the mixture that is comprised of ω-3 ester and aliphatic acid can be considered to the oil according to ω of the present invention-3. In addition, one or more components also can be got rid of outside ω-3 oil according to the present invention especially. For example ω-3 oil can be got rid of outside ester according to the present invention, aliphatic acid and/or glycerine list, two or three esters especially. Therefore, the composition that for example is comprised of ω-3 ester is exactly according to ω of the present invention-3 oil.

The ester exchange that " ω-3 hydrocarbyl carbonate " can pass through ω-3 oil and alcohol (particular methanol or ethanol) and acid or reducing agent forms. Because usually be preferably formed the lower alkyl ester, should alcohol be the lower alkyl alcohol that contains 1-6 carbon atom preferably therefore. Should alcohol be methyl alcohol (itself and glyceride reaction form the methyl esters of fatty acid residue) or ethanol (itself and glyceride reaction form the ethyl ester of fatty acid residue) more preferably. Should alcohol be ethanol most preferably.

The term " crystallization " that uses in the whole text in the specification and claims comprises the solid that is described as " weak crystallization ".

Term " alkali metal salt " includes but not limited to that wherein equilibrium ion is the salt of Li, Na, K, Rb or other IA family equilibrium ion.

Term " alkali salt " includes but not limited to that wherein equilibrium ion is the salt of Be, Mg, Ca, Sr or other IIA family equilibrium ion.

Term " bivalence " is used to describe the oxidation state of metal ion, includes but not limited to Mg ²⁺, Ca ²⁺, Zn ²⁺, Be ²⁺And Sr ²⁺

Pharmaceutical composition and medicament can be described as the mixture of two or more " by volume " components, by volume is defined as the volume of a kind of volume of component divided by all components in the compositions in this article.This ratio can be transformed or be expressed as the percentage ratio of total composition volume.This quantity can also be expressed as " v/v " or " %v/v ".Similarly, phrase " by weight " and " in mass " are used for describing a kind of weight of component or quality weight or the quality divided by all components in the compositions.This ratio can be transformed or be expressed as the percentage ratio of total composition weight or quality.This quantity can also be expressed as " w/w ", " mass percent " or " %w/w ".

Term " pharmaceutical composition " and " preparation " are used interchangeably in description and claims in the whole text.

Term " E463808 " is used for description and has ω-3 oil that comprises 46%EPA, 38%DHA and 8% other ω-3 oil (mass percent) composition, and wherein EPA, DHA and other ω-3 oil are ethyl esters.

Term " E681010 " is used for description and has ω-3 oil that comprises 67.8%EPA (mg/g), 9.9%DHA (mg/g) and about 9.6% other ω-3 oil (mg/g) composition, and wherein EPA, DHA and other ω-3 oil are ethyl esters.

Term " chemically stable " or " chemical stability " are meant the liquid preparation in 25 ℃ of placements API loss of effectiveness (reclaiming API content)＜3.0% after 2 years.

" surfactant " and " surfactant of the present invention " is meant the capillary surface active cpd that can change the liquid that is dissolved in wherein; and include but not limited to polyoxyethylene ether 20 stearates; polyoxyethylene ether 35 Oleum Ricini; poloxamer; polyoxyethylene Sorbitan list isostearate; Polyethylene Glycol 40 Sorbitan diisopstearates; polyoxyethylene ether 40 castor oil hydrogenated; polysorbate; polysorbate 20; polysorbate 40; polyoxyethylene ether 60 stearates; polysorbate 85; polysorbate 60; poloxamer 331; polyoxyethylene fatty acid ester; polyoxyethylene ether 40 Oleum Ricini; poloxamer 188; polyoxyethylene polyoxypropylene 1800; oleic acid; sodium deoxycholate; ten dialkyl sodium sulfate; the Sorbitan monolaurate; sorbitan monooleate; sorbitan palmitate; sorbitan trioleate; N-carbamyl methoxy poly (ethylene glycol) 2000-1,2-distearyl alcohol; myristic acid; stearic alcohol ether (steareth); polyoxyethylene ether 40 stearates; sucrose stearate; tocopherol; the polyoxyethylene ether Oleum Ricini; synthetic glycerine three esters; myristin; glyceryl tristearate; magnesium stearate; lecithin; lauryl sulfate; vitamin E; egg yolk lecithin; docusate sodium; polysorbate 80; two myristoyl phosphatidyl glycerols; two myristoyl lecithin; Capryol 90 (Capryol 90); CapryolPGMC (Capryol 90); deoxycholate; cholesterol; Cremophor RH; Cremophor EL; the propylene glycol alginic acid ester; Croval A-10 (PEG 60 Semen Armeniacae Amarum glyceride); Labrafil 1944 (oleoyl Polyethylene Glycol-6 glyceride); Labrafil 2125 (inferior oleoyl Polyethylene Glycol-6 glyceride); Labrasol (decoyl caproyl Polyethylene Glycol-8 glyceride); Lauroglycol 90 (PGML); Lauroglycol FCC (propylene glycol laurate); calcium stearate; lecithin Centromix E; lecithin Centrophase 152; lecithin Centrol 3F21B; POE 26 glycerol; Olepal isosteariques (PEG-6 isostearate); Plurol diisostearique (polyglycereol-3-diisopstearate); PlurolOleique CC; POE 20 sorbitan trioleates; Tagat TO (polyoxyethylene triolein) or Solutol (Polyethylene Glycol-15 hydroxy stearic acid ester).

Surfactant also includes but not limited to polyoxyethylene 20 sorbitan monooleates; the polyoxyethylene hydrocarbyl carbonate of Brig-or Volpo series; the polyoxyethylene sorbitan fatty acid ester of Tween-or Crillet series; the Myrj 45 of Cerosynt-or Myrj series; lecithin; poloxamer; d-alpha-tocopherol base cetomacrogol 1000 succinate (vitamin E TPGS; TPGS); saturated polyglycolysed (polyglycolized) glyceride (Labrasol; Labrafl and Gelucires); cholic acid and cholate; deoxycholic acid and deoxycholate; taurocholic acid; taurocholate; glycocholic acid; polyvinylpyrrolidone; coco amine (cocamine); tristerin; olein; hydrogenated lanolin; lanoline; laurate and oleate; sorbitan monolaurate; Span 40; Sorbester P18; quaternary surfactant; sodium sulfate; the glyceryl chemical compound; Palmic acid and derivant thereof and oleic acid and derivant thereof.

The surfactant that contains PEG comprises but is not limited to Tween 85 , Tween 80  and Cremophor  EL.

For example, surfactant can be comprised in pharmaceutical composition of the present invention for facilitating digestion or reduction food effect.

Unless description is arranged in addition, term " water solubility " is meant the dissolubility that records in about 25 ℃ deionized water.

Acid catalyzed ester exchange reaction can be for example by being incubated realization with triglyceride in the mixture that is containing pure and mild acid (for example HCl) under about 0 ℃ to about 150 ℃, preferably at nonoxidizing atmosphere with do not exist under the condition of water and carry out.In one embodiment, described triglyceride/acid/alcohol mixture was refluxed at least about 2 hours.In another embodiment, described triglyceride/acid/alcohol mixture is kept spending the night down at 0 ℃ to about 50 ℃.Can use methanol to form methyl ester, use ethanol to form ethyl ester.Because acid catalyzed ester exchange reaction is normally reversible, the therefore preferred excessive alcohol in a large number that exist make reaction carry out substantially fully.The concentration of preferably glycerine three esters in alcohol/acid blend is about 0.1 to about 15wt%, most preferably is about 3wt%.If this acid is HCl, then the concentration of HCl in alcohol/HCl mixture is preferably about 4 to about 15wt%, most preferably is about 10wt%.This mixture can for example feed dry gaseous hydrogen chloride bubbling in the dehydrated alcohol by prepared in various methods known in the art, perhaps the 1mL chloroacetic chloride is added in the 10mL alcohol and (forms the alcoholic solution of about 10wt%HCl).

Although most preferably HCl also can substitute the acid of using other.One of them is a sulphuric acid, and it is usually to be about 0.5 to about 5wt% concentration use in alcohol.Yet, it should be noted, because sulphuric acid is strong oxidizer, therefore under long return time (promptly above about 6 hours), high concentration (promptly greater than about 5wt%) or high temperature (promptly greater than 150 ℃), preferably do not use.Another example of suitable acid is a boron trifluoride, and it preferably uses with about concentration of 1 to about 20wt% in alcohol.Yet it is not preferred that boron trifluoride is compared HCl, and this is because boron trifluoride is more prone to generate unwanted by-product.

In the ester exchange reaction of base catalysis, ω-3 oil in the presence of base catalyst by pure ester exchange.In this case, described alkali can be for example Feldalat NM, Feldalat KM, elements of Na, sodium hydroxide or potassium hydroxide.Preferred ω-3 oil is at least about 1: 1 with the volume ratio of alkali/alcohol mixture, most preferably is about 1: 2.The concentration of alkali in alcohol is preferably about 0.1 to about 2M.The ester exchange reaction of base catalysis can be carried out about 6 to about 20 hours under room temperature (promptly about 20 ° to about 25 ℃ temperature).Perhaps the ester exchange reaction of this base catalysis is carried out being higher than under the temperature of room temperature.

Preferably glyceride/alcohol/catalyst solution is heated at least about 40 ℃, more preferably from about 70 to about 150 ℃, 100 ℃ temperature most preferably from about.Solution can use the reflux condenser heating, the feasible temperature that reactant mixture can be heated above the boiling point of one or more components in the mixture, and be unlikely with component consumption in gas phase (promptly when component is evaporated, they rise up in the reflux condenser with chiller temperature, thus make steam be condensed into liquid and in the liquid mixture that backflows).

In ester-exchange reaction, preferably reactant mixture is placed nonoxidizing atmosphere, for example basically by noble gas, N ₂Or combinations thereof atmosphere in.If this ester exchange reaction is to carry out, then especially preferably use above-mentioned atmosphere under the time surpasses about 10 minutes.In order to prevent autoxidation, can also in reactant mixture, add oil-soluble inhibitor (for example ascorbyl cetylate or propyl gallate), and preferred especially in the situation of not using nonoxidizing atmosphere.

ω-3 hydrocarbyl carbonate comprises the ethyl ester of EPA and DHA.E463808, OMEGA-3/90 (K D Pharma) and Incromega (Croda/Bioriginal) ω-3 ethyl ester are several exemplary ω-3 hydrocarbyl carbonates.

The present invention includes the suspending agent of one or more his spit of fland salt in ω-3 oil.In one embodiment, this suspending agent contains the solid crystal granule of one or more his the spit of fland salt in ω-3 oil.In another embodiment, this suspending agent contains the solid amorphous pellets of one or more his the spit of fland salt in ω-3 oil.In another embodiment, this suspending agent contains the solid crystal and the solid amorphous pellets of one or more his the spit of fland salt in ω-3 oil.The present invention also comprises the pharmaceutical composition that contains the suspending agent of one or more his spit of fland salt in ω-3 oil in addition, and wherein a part of described one or more his spit of fland salt are dissolved in ω-3 oil or another component of compositions.For example, in another embodiment, the invention provides the pharmaceutical composition that contains ω-3 oil and one or more his spit of fland salt, wherein about 1.00,2.00,3.00,4.00,5.00,6.00,7.00,8.00,9.00,10.00,11.00,12.00,13.00,14.00 or his spit of fland of 15.00wt% be solution, and all the other his spits of fland are present in the suspension.

In another embodiment, the invention provides the pharmaceutical composition that contains ω-3 oil and one or more his spit of fland salt, wherein his spit of fland at least about 80wt% exists with the solid particulate form in suspension.In another embodiment, the invention provides the pharmaceutical composition that contains ω-3 oil and one or more his spit of fland salt, wherein his spit of fland at least about 85wt% exists with the solid particulate form in suspension.In another embodiment, the invention provides the pharmaceutical composition that contains ω-3 oil and one or more his spit of fland salt, wherein his spit of fland at least about 90wt% exists with the solid particulate form in suspension.In another embodiment, the invention provides the pharmaceutical composition that contains ω-3 oil and one or more his spit of fland salt, wherein his spit of fland at least about 95wt% exists with the solid particulate form in suspension.In another embodiment, the invention provides the pharmaceutical composition that contains ω-3 oil and one or more his spit of fland salt, wherein his spit of fland at least about 99wt% exists with the solid particulate form in suspension.

In another embodiment, can randomly especially the specific salts in his spit of fland be got rid of outside the present invention.For example can especially pravastatin sodium be got rid of outside the present invention.

Oil purity is importance of the present invention.Oily purity is defined as a kind of component with respect to the percentage ratio of whole fluid composition (for example by volume or weight meter).Several examples of oil ingredient include but not limited to monoglyceride, diglyceride, triglyceride, free acid, ester and derivant, precursor and salt thereof.For example purity is that the ester oil of 95wt% contains at least 95% ester.All the other percentage ratios can contain free acid, glycerol list, two and/or three esters, perhaps other component.As another example, purity is that ω-3 ester oil of 90wt% contains at least 90% ω-3 ester, and all the other percentage ratios can contain any or multiple other oil ingredient.When measuring purity, do not need to consider a kind of mixture (C for example of component species ₈And C ₁₀Ester).Yet, (the C for example of concrete species in the component ₈And C ₁₀Ester) difference between also can be included in the specific embodiments of the present invention.

According to the present invention, preferred purity is higher than about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher ω-3 oil.ω-3 oil that preferably has high-purity ω-3 ester.According to the present invention, have that highly purified ω-3 oil contains by weight or stereometer greater than about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more a kind of component.Preferred ω-3 ester includes but not limited to EPA and DHA.Most preferred ω-3 ester comprises ω-3 ethyl ester.

Fluid composition is another importance of the present invention.Fluid composition can be described as the kind and the component of oil.Kind comprises concrete ω-3 oil, such as but not limited to EPA, DHA, linoleic acid, linolenic acid etc.Component includes but not limited to monoglyceride, diglyceride, triglyceride, free acid, ester and derivant, precursor and salt thereof.For example, E463808 contains about 46%EPA and about 38%DHA (mass percent) of ethyl ester form.Remainder basically by the oil of the ω-3 except that EPA and DHA non-with other-ω-3 line of oils becomes.Other ω that is commercially available-3 oil contains total EPA of higher or lower content and DHA as component, for example monoglyceride, diglyceride, triglyceride, ester, free acid etc. or its mixture.Preferably have and contain EPA and DHA mass percent and be equal to or greater than about 55% ω-3 oil of forming.More preferably have and contain EPA and DHA mass percent and be equal to or greater than about 75% ω-3 oil of forming.Most preferably have and contain EPA and DHA mass percent and be equal to or greater than about 80% ω-3 oil of forming.

According to the present invention, also comprise the mixture of ω-3 oil (for example fatty acid, triglyceride) of ω-3 hydrocarbyl carbonate and other form.The present invention includes the oil that contains high-purity or pure hydrocarbyl carbonate.

In another embodiment, the purity of described ω-3 ester or ω-3 hydrocarbyl carbonates be at least about 50wt%, at least about 60wt%, at least about 70wt%, at least about 75wt%, at least about 80wt% or at least about 85wt%.In another embodiment, the purity of described ω-3 ester or ω-3 hydrocarbyl carbonates is about 25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,99wt% or higher.In another embodiment, the purity of described ω-3 ester or ω-3 hydrocarbyl carbonates is about 25 to about 100wt%, about 40 to about 100wt%, about 50 to about 100wt%, about 60 to about 100wt%, about 70 to about 100wt%, about 75 to about 100wt%, about 75 to about 95wt%, about 75 to about 90wt% or about 80 to about 85wt%.In another embodiment, the purity of described ω-3 ester or ω-3 hydrocarbyl carbonates is about 100wt%, about 99wt%, about 96wt%, about 92wt%, about 90wt%, about 85wt%, about 80wt%, about 75wt%, about 70wt%, about 65wt%, about 60wt%, about 55wt% or about 50wt%.

In another embodiment, the fluid composition of described EPA of containing and DHA be at least about 50wt%, at least about 60wt%, at least about 70wt%, at least about 75wt%, at least about 80wt% or at least about 84wt%.In another embodiment, the fluid composition of described EPA of containing and DHA is about 25,30,35,40,45,50,55,60,65,70,75,80,85,90 or 95wt%.In another embodiment, the fluid composition of described EPA of containing and DHA is about 25 to about 95wt%, about 40 to about 95wt%, about 50 to about 95wt%, about 60 to about 95wt%, about 70 to about 95wt%, about 75 to about 95wt%, about 75 to about 90wt%, about 75 to about 85wt% or about 80 to about 85wt%.In another embodiment, the described fluid composition that contains EPA and DHA is about 99wt%, about 96wt%, about 92wt%, about 90wt%, about 84wt%, about 80wt%, about 75wt%, about 70wt%, about 65wt%, about 60wt%, about 55wt% or about 50wt%.

In another embodiment, the EPA of the EPA of the EPA of the EPA of the EPA of the EPA of described ω-3 ester or ω-3 hydrocarbyl carbonates with about 23: 19 ratios: DHA, about 75: 11 ratios: DHA, about 95: 1 ratios: DHA, about 9: 2 ratios: DHA, about 10: 1 ratios: DHA, about 5: 1 ratios: the EPA of the EPA of the EPA of the EPA of the EPA of about 3: 1 ratios of DHA: DHA, about 2: 1 ratios: DHA, about 1: 1 ratio: DHA, about 1: 2 ratio: DHA, about 1: 3 ratio: the EPA of DHA or about 1: 5 ratio: DHA.In another embodiment, the EPA of described ω-3 ester or ω-3 hydrocarbyl carbonates with about 95: 1 ratios: DHA, the EPA of about 75: 1 ratios: DHA, the EPA of about 50: 1 ratios: DHA, the EPA of about 25: 1 ratios: DHA, the EPA of about 20: 1 ratios: DHA, the EPA of about 15: 1 ratios: DHA, the EPA of about 10: 1 ratios: DHA, the EPA of about 7.5: 1 ratios: DHA, the EPA of about 5: 1 ratios: DHA, the EPA of about 4: 1 ratios: DHA, the EPA of about 3: 1 ratios: DHA, the EPA of about 2: 1 ratios: DHA, the EPA of about 1.5: 1 ratios: DHA, the EPA of about 1: 1 ratio: DHA, the EPA of about 1: 1.5 ratio: DHA, the EPA of about 1: 2 ratio: DHA, the EPA of the EPA of about 1: 3 ratio: DHA or about 1: 5 ratio: DHA.In another embodiment, described ω-3 ester or ω-3 hydrocarbyl carbonates have about 95: 1 ratios EPA to about 1: 5 ratio: DHA, about 50: the 1 ratios EPA to about 1: 1 ratio: DHA, about 25: the 1 ratios EPA to about 1: 1 ratio: DHA, about 10: the 1 ratios EPA to about 1: 1 ratio: DHA, about 5: the 1 ratios EPA to about 1: 1 ratio: DHA, about 3: the 1 ratios EPA to about 1: 1 ratio: DHA, about 2: the 1 ratios EPA to about 1: 1 ratio: DHA or about 1.5: the 1 ratios EPA to about 1: 1 ratio: DHA.In another embodiment, described ω-3 ester or ω-3 hydrocarbyl carbonates have the EPA at least about 1: 5 ratio: DHA, at least about the EPA of 1: 1 ratio: DHA, at least about the EPA of 1.5: 1 ratios: DHA, at least about the EPA of 2: 1 ratios: DHA, at least about the EPA of 3: 1 ratios: DHA, at least about the EPA of 5: 1 ratios: DHA or at least about the EPA of 10: 1 ratios: DHA.

In another embodiment, any or multiple above-mentioned or other concrete ratio, composition or the purity of ω-3 oil can be got rid of outside the present invention especially.The EPA of for example 3.3: 2,2.1: 1,3.1: 2,1.9: 1,1.7: 1,1.4: 1,1.1: 1,1: 1 and 1: 1.8 ratio: DHA can be got rid of outside the present invention especially.About 1: 1 EPA to about 2: 1 ratios: DHA also can be got rid of especially.In addition, contain have for example about 80.2,83.4,83.7,86.6,87.7 or the mixture formed of the EPA of 90.2wt% and DHA can be got rid of outside the present invention especially.ω-3 oil (for example OMACOR ) that contains 90% (w/w) ω-3 ethyl ester with 46%EPA and 38%DHA can be got rid of outside the present invention especially.Contain EPA: the DHA ratio is equal to or greater than 2: 1 ω-3 oil and can be got rid of outside the present invention especially.For example, EPA: the DHA ratio is that about 2: 1,2.5: 1,3: 1,3.5: 1,4: 1,4.5: 1,5: 1 or higher ω-3 oil can be got rid of especially.Contain EPA and DHA content more than or equal to 75,80,85,90,91,92,93,94 or ω-3 oil of 95wt% can be got rid of especially.Contain EPA: the DHA ratio equals ω-3 oil of about 1: 5,4.5: 1,95: 1,7.5: 1 or 1.21: 1 and can be got rid of outside the present invention especially.Other ω that is commercially available-3 oil also can be got rid of outside the present invention especially, includes but not limited to ω-3 oil that is commercially available from Croda International (England) and PronovaBiocare (Norway).

" his spit of fland " used herein includes but not limited to pravastatin, fluvastatin, atorvastatin, lovastatin, simvastatin, rosuvastatin and cerivastatin.He can be salt, hydrate, solvate, polymorph or cocrystallization form in the spit of fland.Statins can also be hydrate, solvate, polymorph or the cocrystallization form of salt.According to the present invention, Statins can also form with free acid or lactone and exist.

Term " effective dose ", " treatment effective dose " or " effective dose on the therapeutics " are meant the consumption or the concentration of the present composition of ω-3 oil that effectively produces required result and the recommended dietary level is provided in its administration or use occasion, comprise and for example reduce the plasma triglyceride level.Therefore, the term " effective dose " that uses in the whole text in this description is used for describing concentration or the consumption that is used in the pharmaceutical composition of the present invention that generation can be accepted to change in the disease to be treated or the patient's condition, no matter this variation is that the plasma triglyceride level reduces, plasma LDL levels raises, or other acceptable physiology result.

Term " patient " comprises animal, preferred mammal, and optimum is chosen.

" casing " is meant and protects sour unstable medicament to avoid the mode that gastric juice is attacked.A lot of casing can be released in active medicine the near-end of gastrointestinal catheter rapidly.A lot of casing are well known by persons skilled in the art, and limiting examples comprises the coating of being made up of the anionic polymer of methacrylic acid that contains carboxyl and methacrylate.Eudragit  L100 (Rohm Pharma) is preferred casing.

AUC is meant the area under curve of drug plasma concentration (not being the logarithm of concentration) to the time after the administration.This area is measured by " trapezoidal rule " easily: data point is coupled together by straightway, make vertical line from abscissa to each data point, calculate the triangle and the trapezoid area sum that so constitute.As the concentration (C that records at last _n, be positioned at time t _n) be not 0 o'clock, by t _nExtremely the AUC of infinite time is by Cn/k _ElEstimation.

AUC is at the total body clearance (Cl that estimates bioavailability of medicament and evaluation medicine _T) in have specific use.According to single vein dosage, for the single compartment system that satisfies first order kinetics, AUC=D/Cl _T, wherein D is a dosage; Perhaps AUC=C ₀/ k _El, k wherein _ElIt is the drug elimination rate constant.For the non-vein route of administration, AUC=FD/Cl _T, wherein F is the absolute bioavailability of medicine.

The AUC of one or more Statins can be used as the indication of the relative bioavailability of pharmaceutical composition of the present invention for reference group compound (for example PRAVACHOL ).

In another embodiment, the invention provides the salt in his spit of fland.In specific embodiments, provide the calcium salt of pravastatin.The magnesium salt of pravastatin is provided in another embodiment.The zinc salt of pravastatin is provided in another embodiment.The calcium salt of fluvastatin is provided in another embodiment.The divalent salts in his spit of fland is provided in another embodiment.In another embodiment, the salt in described his spit of fland is unformed.In another embodiment, the salt in described his spit of fland is crystallization.

In another embodiment, provide pharmaceutical composition or medicament, wherein contained the salt in his spit of fland.

(a) Ta Ting and salt are mixed in solution;

(b) make the salt in described his spit of fland begin precipitation; Then

(c) the described salt in described his spit of fland of collection.

In another embodiment, beginning in the step (b) precipitated and can finish by cooling solution, evaporating liquid or a part wherein or one or more technology well known by persons skilled in the art.

In another embodiment, the collection salt in the step (c) can be by filtering, come down in torrents or one or more technology well known by persons skilled in the art being finished.

In another embodiment, pharmaceutical composition of the present invention or medicament contain and have an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg ω-3 ester and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75 or the salt of 80mg pravastatin.

In another embodiment, pharmaceutical composition of the present invention or medicament contain and have an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg ω-3 ester and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or the salt of 160mg fluvastatin.

In another embodiment, pharmaceutical composition of the present invention or medicament contain and have an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg ω-3 ethyl ester and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or the salt in his spit of fland of 160mg.

According to the present invention, the quality of the salt in his spit of fland is measured with respect to the quality of free form.For example the salt in his spit of fland of 80mg consumption is meant his spit of fland of free form of 80mg, does not comprise cationic quality.

In another embodiment, thickening agent can be added in the pharmaceutical composition of the present invention such as but not limited to calcium carbonate or silicon dioxide.

In another embodiment, pharmaceutical composition of the present invention or medicament can reach for 8 weeks and not observe his spit of fland degraded in about 25 ℃ of storages.In another embodiment, pharmaceutical composition of the present invention can reach for 12 weeks and not observe his spit of fland degraded in about 25 ℃ of storages.In another embodiment, pharmaceutical composition of the present invention can reach for 16 weeks and not observe his spit of fland degraded in about 25 ℃ of storages.In another embodiment, pharmaceutical composition of the present invention can reach for 26 weeks and not observe his spit of fland degraded in about 25 ℃ of storages.

In another embodiment, the pravastatin calcium salt has unforeseeable high stability in ω-3 oil suspension for other pravastatin salt, shown in an embodiment.Beat allly be that the suspension of pravastatin calcium salt demonstrates in ω-3 oil than other pravastatin salt for example sodium and the higher stability of potassium salt.Pravastatin magnesium and zinc salt and fluvastatin calcium salt are preferred his spit of fland of the present invention equally.

In another embodiment, the pravastatin zinc salt has unforeseeable high stability in the suspension of ω-3 oil and alcohol for other pravastatin salt, shown in an embodiment.Beat allly be that the suspension of pravastatin zinc salt demonstrates in ω-3 oil than other pravastatin salt higher stability of sodium, calcium and potassium salt for example.

In another embodiment, comprise the method for crown incident and cerebrovascular events and coronary artery disease and/or cerebrovascular disease by prevention is provided, alleviates and/or treats raise (for example hypercholesterolemia), atherosclerosis, hyperlipemia, cardiovascular event and disease of cholesterol levels to the mammal administration pharmaceutical composition of the present invention that needs to prevent, alleviate and/or treat.In another embodiment, described mammal is the people.

In another embodiment, the present invention includes water solubility less than about 200.00mg/mL, for example less than about 200.00,190.00,180.00,170.00,160.00,150.00,140.00,130.00,120.00,110.00,100.00,90.00,80.00,75.00,70.00,65.00,60.00,55.00,50.00,45.00,40.00,35.00 or less than the salt in his spit of fland of about 30.00mg/mL.In another embodiment, the present invention includes water solubility and be the salt of about 0.10mg/mL to his spit of fland of about 25mg/mL less than about 25.00mg/mL or water solubility.In another embodiment, the present invention includes water solubility less than about 200.00mg/mL, for example less than about 200.00,190.00,180.00,170.00,160.00,150.00,140.00,130.00,120.00,110.00,100.00,90.00,80.00,75.00,70.00,65.00,60.00,55.00,50.00,45.00,40.00,35.00 or less than the salt of the pravastatin of about 30.00mg/mL.In another embodiment, pravastatin salt of the present invention has less than the water solubility of about 25.00mg/mL or is about 0.10mg/mL water solubility of about 25mg/mL extremely.In another embodiment, the present invention includes water solubility less than (or less than about) 25.00,24.00,23.00,22.00,21.00,20.00,19.00,18.00,17.00,16.00,15.00,14.00,13.00,12.00,11.00,10.00,9.00,8.00,7.00,6.00,5.00,4.00,3.00,2.00,1.00,0.90,0.80,0.70,0.60,0.50,0.40,0.30,0.20 or his spit of fland salt of 0.10mg/mL or pravastatin salt (above-mentioned solubility values should be understood to include and for any mark dissolubility that is spaced apart 0.01mg/mL provides written support, and why these dissolubility are not introduced into is for simplicity herein and avoids the description long).Do not comprise insoluble salt (dissolubility is the salt of 0.00mg/mL) in the scope of the invention.Between about 0.10mg/mL to the water solubility of the above-mentioned scope of about 25.00mg/mL be believed to comprise and between about 0.10mg/mL extremely any mark dissolubility that is spaced apart 0.01mg/mL between about 25.00mg/mL written description and support are provided.The water solubility of pravastatin salt of the present invention can also be described to have the water solubility less than (or less than about) X.YZ mg/mL, wherein X is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25, Y is 0,1,2,3,4,5,6,7,8 or 9, and Z is 0,1,2,3,4,5,6,7,8 or 9 (condition is when X is 0, and Y and Z can not be that X, Y and Z can not independently be 0 separately for 0[simultaneously]).

In another embodiment, the present invention includes water solubility less than about 200.00mg/mL, for example less than about 200.00,190.00,180.00,170.00,160.00,150.00,140.00,130.00,120.00,110.00,100.00,90.00,80.00,75.00,70.00,65.00,60.00,55.00,50.00,45.00,40.00,35.00 or less than the salt of the fluvastatin of about 30.00mg/mL.In another embodiment, the present invention includes water solubility and be the salt of about 0.10mg/mL to the fluvastatin of about 25mg/mL less than about 25.00mg/mL or water solubility.In another embodiment, the present invention includes water solubility less than about 25.00,24.00,23.00,22.00,21.00,20.00,19.00,18.00,17.00,16.00,15.00,14.00,13.00,12.00,11.00,10.00,9.00,8.00,7.00,6.00,5.00,4.00,3.00,2.00,1.00,0.90,0.80,0.70,0.60,0.50,0.40,0.30,0.20 or the salt of the fluvastatin of 0.10mg/mL (above-mentioned solubility values should be understood to include and for any mark dissolubility that is spaced apart 0.01mg/mL provides written support, and why these dissolubility are not introduced into is for simplicity herein and avoids the description long).Do not comprise insoluble salt (dissolubility is the salt of 0.00mg/mL) in the scope of the invention.Between about 0.10mg/mL to the water solubility of the above-mentioned scope of about 25.00mg/mL be believed to comprise and between about 0.10mg/mL extremely any mark dissolubility that is spaced apart 0.01mg/mL between about 25.00mg/mL written description and support are provided.The water solubility of fluvastatin salt of the present invention can also be described to have the water solubility less than (or less than about) X.YZ mg/mL, wherein X is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25, Y is 0,1,2,3,4,5,6,7,8 or 9, and Z is 0,1,2,3,4,5,6,7,8 or 9 (condition is when X is 0, and Y and Z can not be that X, Y and Z can not independently be 0 separately for 0[simultaneously]).

In another embodiment, the invention provides the pharmaceutical composition of the salt in above-mentioned his spit of fland, the salt in wherein said his spit of fland has the water solubility less than about 25mg/mL.

In another embodiment, pharmaceutical composition of the present invention or medicament contain has an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg ω-3 oil and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or the salt in his spit of fland of 160mg, and wherein said salt has the water solubility less than about 200mg/mL.In another embodiment, pharmaceutical composition of the present invention or medicament contain has an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg ω-3 oil and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or the salt in his spit of fland of 160mg, and wherein said salt has the water solubility less than about 50mg/mL.In another embodiment, pharmaceutical composition of the present invention or medicament contain has an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg ω-3 oil and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or the salt in his spit of fland of 160mg, and wherein said salt has the water solubility less than about 25mg/mL.In specific embodiments, pharmaceutical composition of the present invention or medicament contain has an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg ω-3 oil and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or the salt in his spit of fland of 160mg, and wherein said salt has the water solubility for about 15-17mg/mL.In another embodiment, pharmaceutical composition of the present invention or medicament contain has an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg ω-3 oil and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or the salt in his spit of fland of 160mg, and wherein said salt has the water solubility for about 0.5mg/mL.In another embodiment, pharmaceutical composition of the present invention or medicament contain has an appointment 500,600,700,800,900,1000,1100,1200,1300,1400 or 1500mg ω-3 oil and about 1,2,3,4,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or the salt in his spit of fland of 160mg, and wherein said salt has the water solubility for about 0.3mg/mL.

The treatment of ω-3 oil can be accepted daily dose and be recommended by a plurality of countries or international organization and approve, includes but not limited to American Heart Association (AHA) and InternationalSociety for the Study of Fattly Acids and Lipids (ISSFAL).Table 1 has comprised by the daily dose of the ω of several tissue approval/recommendations-3.

The daily dose of table 1-ω-3

ω-3 dosage (gram)/sky	Remarks
ω-3 dosage (gram)/sky	Remarks	0.65	ISSFAL approves (1999)
1.0	AHA recommends (2000,2004)	0.65	ISSFAL approves (1999)
1.0	AHA recommends (2000,2004)	1.8	Omacor  dosage
3.0	FDA is to the restriction of general crowd's daily consumption	1.8	Omacor  dosage
3.0		3.6	Omacor  dosage

Pharmaceutical composition and dosage form

Pharmaceutical dosage form of the present invention can by in oral, the non-intestinal, suction, spraying, part, rectum, intranasal, cheek, vagina or by the implanted reservoir administration.Oral and non-intestinal pharmaceutical composition and dosage form are preferred dosage forms.The preferred oral dosage form is homogenizing or heterogeneous body preparation, rectum dosage form or capsule (non-limiting hard gelatin capsule, starch capsule, HPMC capsule and the soft elastic gelatin capsule of comprising).Other preferred dosage form comprises intradermal dosage form, intramuscular dosage form, subcutaneous dosage form and intravenous dosage forms.

That pharmaceutical unit dosage forms of the present invention is fit to is oral, mucosa delivery (for example in intranasal, Sublingual, vagina, the cheek or rectum), non-intestinal (for example intramuscular, subcutaneous, intravenous, intra-arterial or pill injection (bolus injection)), part or percutaneous dosing be to the patient.The example of dosage form includes but not limited to: capsule, dispersion; Suppository; Ointment; Paste (poultice); Unguentum; Powder; Dressing; Emulsion; Plaster; Solution; Patch; Aerosol (for example nasal spray or inhalant); Gel; Be fit to the oral or mucosa delivery liquid dosage form to the patient, (for example on-aqueous liquid suspending agent, solution and elixir and suitable parenterai administration are to patient's liquid dosage form to comprise suspending agent.

The composition of dosage form of the present invention, shape and type are different and different according to its purposes.For example, the dosage form that is used for acute treatment disease or obstacle can contain than the dosage form that is used for chronic treatment same disease or obstacle and more manys the active component of consumption.Similarly, non-parenteral dosage forms can contain than the peroral dosage form that is used for the treatment of same disease or the obstacle active component of consumption still less.Be included in that above-mentioned and alternate manner in the particular dosage form within the scope of the invention can change each other and be conspicuous to those skilled in the art.Referring to for example Remington ' sPharmaceutical Sciences, 18 editions, Mack Publishing, Easton PA (1990) or Remington:The Science and Practice of Pharmacy, 19 editions, MackPublishing, Easton PA (1995).

Exemplary dosage form of the present invention contains the 1mg that has an appointment and is about 5mg his spit of fland of about 160mg extremely to about 160mg, preferable amount.For example, preferably contain 5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,90,100,110,120,130,140,150 or the dosage form of his spit of fland of 160mg or his spit of fland salt.

Peroral dosage form

The pharmaceutical composition of the present invention that is fit to oral administration can present with discrete dosage form, such as but not limited to above-mentioned capsule and liquid, such as but not limited to syrup, elixir, solution or suspending agent.This class dosage form can be by method of pharmacy preparation well known to those skilled in the art.General referring to Remington ' s Pharmaceutical Sciences, 18 editions, Mack Publishing, EastonPA (1990) or Remington:The Science and Practice of Pharmacy, 19 editions, Mack Publishing, Easton PA (1995).

Controlled release form

He can pass through controlled release or the administration of slow release mode in the spit of fland.The controlled release medicine has the general objects that improves curative effect of medication for non-controlled release reference substance.It is desirable to, in therapeutic treatment, use the controlled release preparation of design optimization to be characterised in that to use minimum medicine in the shortest time, to cure or control the patient's condition.The advantage of controlled release preparation comprises: 1) prolong drug activity; 2) reduce administration frequency; 3) improve patient's compliance; 4) use medicine total amount still less; 5) reduce part or system's side effect; 6) the medicine savings is minimized; 7) reduce the haemoconcentration fluctuation; 8) improve therapeutic effect; 9) potentiation or the loss of reduction pharmaceutically active; And 10) improve the control disease or the patient's condition speed (Kim, Cherng-ju, Controlled Release dosage Design, 2Technomic Publishing, Lancaster, Pa.:2000).In the present invention, the control advantage of disengaging may be that concentrated area more acts on the position that liver and lipid microdroplet generate.

Regular dosage form disengages medicine usually fast or immediately from preparation.According to the pharmacology and the pharmacokinetics of medicine, use regular dosage form may cause the concentration of medicine in blood samples of patients or other tissue to occur fluctuating widely.This fluctuation may influence various parameters, for example the phase of keeping of administration frequency, onset of effect, efficient persistent period, treatment blood levels, toxic reaction, side effect etc.Advantageously, controlled release preparation can be used to control the persistent period of pharmaceutically-active outbreak, effect, blood plasma level and the blood peak concentration in the treatment window.Especially; controlled release or slow release formulation or preparation can be used to guarantee that the maximum effectiveness that obtains medicine minimizes possible side effect and safety problem simultaneously, and this may appear at drug dose following (promptly being lower than minimum treatment level) simultaneously and surpass on the drug toxicity level.

Most of controlled release preparations are designed to disengage at first a certain amount of medicine (active component), and this medicine produces rapidly required therapeutic effect, then gradually and continue to disengage the medicine of its surplus with this treatment of maintenance or preventive effect concentration in long-time.In order to keep the above-mentioned constant level of medicine in vivo, medicine must disengage to substitute by the speed of the drug dose of metabolism and discharge health from dosage form.The controlled release of active component can stimulate by different condition, includes but not limited to pH, ion concentration, osmotic pressure, temperature, enzyme, water and other physiological condition or chemical compound.

Various known controlled releases or slow release formulation, preparation and device are suitable for compositions of the present invention.The example includes but not limited to be described in United States Patent (USP): 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; With 6,365, those among 185 B1 are introduced into as a reference at this.These dosage forms can be used to provide slow release or one or more active component of controlled release, for example adopt hydroxypropyl emthylcellulose, other polymeric matrix, gel, permeable membrane, osmotic system (OROS  (Alza Corporation for example, MountainView, Calif.USA)), multiple coatings, microgranule, liposome or microsphere or its combination, thereby the required curve that disengages of different proportion is provided.

One embodiment of the invention comprise the unit dosage forms that contains Ta Ting and one or more pharmaceutically acceptable excipient or diluent, and wherein pharmaceutical composition or dosage form are used for controlled release drug administration by preparation.Concrete dosage form has been used the penetrating pharmaceutical delivery system.

Also as a case description of the slow release formulation of time controlled release form at United States Patent (USP) 5,366, in 738, its full content is incorporated herein by reference at this.Be described in United States Patent (USP) 5,366, the controlled release drug delivery apparatus in 738 is called as gel extrusion mode (GEM) delivery apparatus.This GEM device is that in-situ control contains useful the medicament for example generation of the dispersant of medicine and the drug delivery device that disengages, and wherein contains:

(A) compressed core that makes by the mixture that contains following compositions:

(i) the useful medicament of treatment effective dose; With

(ii) form the polymer of gluey fine particle after the hydration; With

(B) water-insoluble, water that contains polymer and plasticizer oozing property polymer coating not, it holds and attached on the core, coating has a plurality of established holes that account for core surfaces about 1 to about 75% that are exposed to; And the speed that wherein said useful medicament disengages from device is the function of hole number and size.

In the GEM device, polymer in the compressed core is preferably selected from for example sodium salt of sodium polyacrylate, carboxyl polymethylene and officinal salt thereof, wherein the carboxyl polymethylene is by making with the crosslinked acrylic acid of the allyl ether of sucrose or tetramethylolmethane, and more preferably it is selected from by the carboxyl polymethylene and the officinal salt thereof that make with the crosslinked acrylic acid of the allyl ether of sucrose or tetramethylolmethane.Most preferably CARBOPQL  974P and officinal salt thereof, particularly sodium salt are used as the polymer in the compressed core.In addition, this compressed core can also contain one or more polymer hydration regulators, antioxidant, lubricant, filler and excipient.The end clothing of choosing wantonly can be executed before using water-insoluble coating assistance preparation should be to compressed core.End clothing can be made up of for example hydroxypropyl cellulose and hydroxypropyl emthylcellulose.Can also use other coating to realize aesthstic or functional purpose.

This water-insoluble, water not oozing property polymer coating preferably are selected from the combination of polrvinyl chloride, cellulose acetate, cellulose acetate-butyrate, ethyl cellulose and these polymer by (1); (2) plasticizer that is selected from diethyl phthalate, dibutyl sebacate and triethyl citrate is formed.More preferably, this polymer coating is made up of cellulose acetate-butyrate and triethyl citrate.This GEM device can not be as the penetrating pharmaceutical delivery apparatus, so the function of disengaging of this device depends on that liquid arrives the passage of compressed core internal medium by established hole from the health external environment condition.The polymer coating of water insoluble basically and impermeable water intended being used for describing in term " water-insoluble, water is oozing property not ", this means at medicine and be released into the intravital process from the GEM device, this polymer coating allows minimum to there not being aquaporin to arrive the compressed core internal medium by coating from the health external environment condition, except the fluid passage that occurs by the boring hole.Any trace really by water-insoluble, water or not of oozing property polymer coating be seldom, and the release rate that the function of GEM device is a medicine by the hole is not had much influences.His the spit of fland speed of disengaging from GEM mainly is the function of hole number and size on the device on the contrary.

For exquisiteness, joyful final products on the aesthetics, can use outside polishing coating to the GEM delivery apparatus that contains coloring agent, wax etc. at last.This GEM device can also have enteric coating before or after using other polishing coating.Even without casing, carry polymer the extruding under the acid pH that yet can not appear at stomach basically from the compressed core of GEM device in his spit of fland, so his the remarkable release in spit of fland can not take place under one's belt.About other details of GEM and case description at United States Patent (USP) 5,366, in 738.

Usually preferably, the method for pharmaceutical compositions comprises that the use noble gas purges.This class noble gas is for example nitrogen, argon etc.It is ideal using insulator to keep hypoxia condition, but optional for the storage of pharmaceutical composition of the present invention.

In the following embodiments will be to the present invention above-mentioned and other embodiment further illustrate, these embodiment only are exemplary and be construed as limiting never in any form.

Embodiment

Material and method

The differential scanning calorimetric (DSC) of sample is analyzed and is adopted Q1000 differential scanning calorimetry (DSC) (TAInstruments, New Castle, DE, U.S.A.) carry out, the latter uses Advantage for QW-Series, 1.0.0.78 version, Thermal Advantage Release 2.0 (2001 TAInstruments-Water LLC).In addition, used analysis software is Universal Analysis2000 for Windows 95/98/2000/NT, the 3.1E version; Build 3.1.0.40 (2001 TAInstruments-Water LLC).

For dsc analysis, used purge gas is a drying nitrogen, and control material is the empty aluminum dish with fold, and sample purged 50mL/ minute.

The dsc analysis of sample has the aluminum dish that the fold disk seal closes and carries out by the modafinil sample is placed.Initial temperature is generally 20 ℃, and the rate of heat addition is 10 ℃/minute, and final temperature is 200 ℃.Unless otherwise indicated, the DSC indicator of all reports is shown in the locational neither endothermic nor exothermic transition temperature of its respective peaks, and error is+/-2 ℃.

Q500 Thermogravimetric Analyzer (TA Instruments is adopted in the thermogravimetry of sample (TGA), New Castle, DE, U.S.A.) carry out, the latter uses Advantage forQW-Series, 1.0.0.78 version, Thermal Advantage Release 2.0 (2001 TAInstruments-Water LLC).In addition, used analysis software is Universal Analysis2000 for Windows 95/98/2000/NT, the 3.1E version; Build 3.1.0.40 (2001 TAInstruments-Water LLC).

For the TGA experiment, used purge gas is a drying nitrogen, and balance purges and is 40mL/ minute N ₂, sample purges and is 60mL/ minute N ₂

By the modafinil sample being placed the platinum dish on sample, carry out TGA.Initial temperature is generally 20 ℃, and the rate of heat addition is 10 ℃/minute, and final temperature is 300 ℃.

The powder X-ray diffraction of sample (PXRD) pattern uses D/Max Rapid, Contact (Rigaku/MSC, The Woodlands, TX, U.S.A.) obtain, the latter uses contrast software RINT Rapid Control Software, Rigaku Rapid/XRD, 1.0.0 version (1999Rigaku Co.).In addition, used analysis software is RINT Rapid display software, 1.18 versions (Rigaku/MSC) and JADE XRD Pattern Processing, 5.0 and 6.0 versions ((1995-2002, Materials Data, Inc.).

Analyze for PXRD, acquisition parameter is as follows: emission source is the Cu with the K line that is positioned at 1.5406 ; The x-y object stage is manual; Collimator is of a size of 0.3mm; (MA U.S.A.) is 0.3mm ID to capillary tube for Charles Supper Company, Natick; Use reflective-mode; Power to X-ray tube is 46kV; Electric current to the X-ray is 40mA; ω-axle vibrates in 0-5 ° scope with 1 °/minute speed; -axle is with the speed in the 2 °/second scope internal rotation at 360 °; 0.3mm collimator; Acquisition time is 60 minutes; Temperature is a room temperature; Do not use heater.Sample is presented under the X-ray source in rich boron glass capillary tube.

In addition, analytical parameters is as follows: integration 2-θ scope is 2-60 °; Integration χ scope is 0-360 °; The number of χ section is 1; Used step-length is 0.02; Integration is used cylint; Use normalization; Calculating mentally number is 8; The ω displacement is 180; χ and  displacement are 0.

The PXRD diffraction pattern can also obtain by Bruker AXS D8 Discover X-rayDiffractometer.This device is equipped with GADDS ^TM(General AreaDiffraction Detection System), Bruker AXS HI-STAR Area Detector is 15.05cm according to the system calibration distance, the copper source (Cu/K[α] 1.54056 dusts), the x-y-z of automatization object stage, 0.5mm collimator.With the tight pellet shape of sample, be installed on the x-y-z object stage.Diffraction pattern obtains in environmental condition and power setting are the reflective-mode of 40kV and 40mA, and sample is maintained fixed simultaneously.Open-assembly time is variable, and is specific to every kind of sample.Resulting diffraction pattern carries out the space step that remaps, with the geometry barrel distortion of reference area detector, then along χ by-118.8 to-61.8 ° of integrations, 2.1-37 ° of 2-θ is set at the hopper normalizing with 0.02 ° of normalization of step-length.

The relative intensity at peak is not essential restriction for the PXRD pattern in the diffraction pattern, and this is because peak intensity may change with sample variation, for example because crystalline impurities.In addition, the angle at each peak can change approximately+and/-0.1 °, preferred+/-0.05.Whole pattern or most of pattern peak also may because of between calibration difference, setting and the Other Instruments and change between the operator displacement approximately+/-0.1 °.Whole PXRD peak error of other local report of accompanying drawing, embodiment and this paper is pact+-0.1 ° of 2-θ.

Comprise PXRD data in the harmony in the exterior accompanying drawing for this paper, every kind of compositions of the present invention can be with any one, any two, any three, any four, any five, any six, any seven or any eight or more a plurality of 2 θ horns characterize.Any one, two, three, four, five or six DSC change and also can be used for characterizing the present composition.The various combination that PXRD peak and DSC change also can be used for characterizing the present composition.

By ultraviolet (UV) absorptiometry dissolubility

Absolute ethanol solution by the API of several concentration known of preparation in volumetric flask is drawn out calibration curve.In each concentration, the above-mentioned solution of 200 microlitres is transferred in the clear bottom UV plate of 96-hole.In the UV spectrophotometer, locate the measuring samples absorption value in 280nm (unless otherwise noted).Find that absorption value vs. concentration relationship is linearly up at least 100 micrograms/mL.

For the API concentration in the measuring samples, add little aliquot sample and dilute (normally 2000 times) in volumetric flask with absolute ethanol, make last roughly concentration less than 100 micrograms/mL.Measurement is positioned at absorption value that 280nm (unless otherwise noted) locates and calculates dissolubility according to calibration curve.Use above-mentioned technology under 20-25 ℃ temperature, to measure the dissolubility of several his spit of fland salt.

Embodiment 1

The pravastatin calcium salt

To pravastatin Na salt (1.470g; 3.292mmol) water (15.0mL) solution in add calcium acetate (268mg; 1.70mmol) water (5.0mL) solution.Resulting solution concentration (evaporate anhydrate by nitrogen current) is cooled to 0 ℃ to about 15mL.By filtering the white solid of collecting precipitation.Filtrate is cooled to 0 ℃ once more, further separates out precipitation.After the filtration, combining solid is also dry in dessicator.Recording resulting solid is the pravastatin calcium salt.Resulting salt is pravastatin-calcium salt of 2: 1.

Fig. 1 shows the PXRD diffraction pattern (Bruker collects data) of pravastatin calcium salt.The pravastatin calcium salt can be by any one in Fig. 1, any two, any three or any four or more a plurality of PXRD peak sign.As if according to this PXRD diffraction pattern, the pravastatin calcium salt is weak crystallization.

The TGA of pravastatin calcium salt shows about 3.5% loss in weight (referring to Fig. 2) between about 25 ℃ to 100 ℃.

Can also use IR spectrum to characterize the pravastatin calcium salt.The pravastatin calcium salt can characterize by any one in Fig. 3, any two, any three, any four, any five or any six or more a plurality of IR peak, and these peaks include but not limited to 2360,1728,1561,1444,1186,855 and 668cm ^-1

Can also gather its kinetics vapor absorption (DVS) data to pravastatin calcium salt and sodium salt of pravastatin.Fig. 4 shows the moisture absorption-desorption cycle of pravastatin calcium salt.This calcium salt shows the continuous water absorption as relative humidity (RH) function, up to obtaining about 11 quality %.This is consistent with amorphous compound.In desorption cycle, observe hysteresis.Fig. 5 shows the moisture absorption-desorption cycle of sodium salt of pravastatin.This sodium salt is a crystal salt, demonstrates along with humidity increases to about 54%RH, and its quality increases gradually.Surpass 54%RH, the water of absorption significantly increases.In desorption cycle, observe tangible hysteresis.Sodium salt of pravastatin demonstrates the hygroscopicity higher than calcium salt.

Also used other method to prepare the pravastatin calcium salt.To pravastatin Na salt (496mg; 1.11mmol) water (5.0mL) solution in add calcium chloride (69mg; 0.62mmol) water (2.0mL) solution.Resulting solution evaporation obtains white solid.Pravastatin Ca salt is used dehydrated alcohol (10.0mL) extraction after-filtration by above-mentioned solid.Evaporating liquid obtains grease, and it is ground with ether (10.0mL).Powdery white solid (100mg) is also air-dry with cold water (5.0mL) washing.Recording resulting solid is the pravastatin calcium salt.

The water solubility that records the pravastatin calcium salt is about 17-20mg/mL (detecting 20-25 ℃ by UV).The water solubility that records sodium salt of pravastatin is greater than 300mg/mL.

Embodiment 2

The 26 all dissolubility datas of pravastatin salt in E463808

With several salt suspensions of pravastatin in E463808 ω-3 oil and place band medicated cap vial or airtight gelatine capsule.Soft capsule 25 ℃ use and

vial

25,40 and 60 ℃ of uses.The suspension of salt in oil carried out periodic measurement, continued for 26 weeks.Use HPLC to measure the degraded of pravastatin salt.

Fig. 6 shows bottle and gelatine capsule (soft capsule) at 25 ℃ stability data.The calcium salt that changes pravastatin along with the time demonstrates than the sodium salt in the soft capsule or the potassium salt in the bottle remarkable impurity of lower percentage ratio all.Calcium salt in all salt after 25 ℃ were placed for 26 weeks in soft capsule or bottle in the bottle demonstrates minimum degraded.

Fig. 7 shows pravastatin salt in the band medicated

cap bottle

40 and 60 ℃ stability.Calcium salt demonstrates under assigned temperature its degraded once more and significantly is lower than sodium or potassium salt.Surprisingly, the calcium sample demonstrates than potassium salt 40 ℃ of remarkable lower degradeds at 60 ℃, and similar in the degraded in 40 ℃ of 8 week to sodium salt.

Embodiment 3

The fluvastatin calcium salt

505.9mg (1.167mmol) fluvastatin Na salt is dissolved in the 15mL water.94.2mg (0.595mmol) calcium acetate is dissolved in the 2mL water.In fluvastatin Na solution, add after the calcium acetate solution, form precipitation immediately.By solid collected by filtration, at first in 65 ℃ vacuum oven dry 0.5 hour, place the nitrogen current under the room temperature to spend the night then.Drying solid placed mortar to grind with newborn mallet before characterizing.Resulting solid uses PXRD, DSC, TGA, Raman and IR spectral characterization, is measured as the calcium salt of fluvastatin.Resulting salt is fluvastatin-calcium salt of 2: 1.

The dissolubility of fluvastatin sodium salt and calcium salt is measured and is carried out in 23 ℃ water.Dissolubility carries out gravimetric analysis and measures in deionized water.5.5mg fluvastatin sodium salt is dissolved in about 130-150 microliters of water, and the water solubility that obtains sodium salt is about 37-42mg/mL.5.5mg calcium salt is not dissolved in the water fully, even dissolving fully not yet after adding 20mL water.The water solubility that records calcium salt is less than or equal to about 0.275mg/mL.

The fluvastatin calcium salt can be by any one in Fig. 8, any two, any three, any four, any five or any six or more a plurality of PXRD peak sign, these peaks include but not limited to 3.7,7.5,11.3,12.9,18.1,21.9 and 25.4 ° of 2-θ (Rigaku collects data).As if based on the PXRD diffraction pattern, the fluvastatin calcium salt is weak crystallization.

DSC carries out with 10 ℃/minute to 230 ℃ at 25 ℃.DSC demonstrates at about 79 ℃ and locates to exist endothermic transition (referring to Fig. 9).Notice that heat release about 100 ℃ and slight heat absorption are the errors of instrument, and irrelevant with sample.

TGA (13.083mg) carries out with 10 ℃/minute to 300 ℃ at 25 ℃.TGA demonstrates and have 6.3% the loss in weight between 25 ℃ and 130 ℃, and this is equivalent to about 1.5 normal water (referring to Figure 10).

Also used Raman spectrum to characterize the fluvastatin calcium salt.The fluvastatin calcium salt can by in Figure 11 any one, any two, any three, any four, any five or any six or more a plurality of Raman shift characterize, and include but not limited to 1657,1604,1542,1500,1457,1216,814 and 352cm ^-1

Also used IR spectrum to characterize the fluvastatin calcium salt.The fluvastatin calcium salt can characterize by any one in Figure 12, any two, any three, any four, any five or any six or more a plurality of IR peak, includes but not limited to 2361,1560,1500,1457,1345,1216,1155,839,741 and 560cm ^-1

Embodiment 4

The pharmacokinetic study of pravastatin calcium salt in Canis familiaris L.

Use six fasting beagles to carry out bidirectional crossed experiment, with the pharmacokinetic parameter of contrast pravastatin calcium salt and sodium salt of pravastatin.Sodium salt of pravastatin is obtained by PRAVACHOL  tablet.The pravastatin calcium salt obtains by the method for describing among the embodiment 1.Administration is given the pravastatin calcium salt dosage form of Canis familiaris L. and is made up of 11.0mg pravastatin calcium salt in the Perle shell (being equivalent to the acid of 10mg pravastatin) and 744mg Ropufa 75 omega-fatty acid ethyl esters.That finishes this capsule externally disengages test, finds in its deionized water that is dissolved in 37 ℃ fully.Mean dose with the pravastatin free acid of PRAVACHOL  form administration is 0.85mg/kg, and is 0.95mg/kg with the mean dose of the pravastatin free acid of pravastatin calcium salt administration.After the administration, gathering plasma sample before the administration and after the administration in 0.25,0.5,1,1.5,2,3,4,6,8,12 and 24 hour.Use the pravastatin concentration of LC/MS methods analyst plasma sample.Table 2 shows the important drugs kinetic parameter of the pravastatin in two kinds of oral formulations that are administered to six fasting beagles.

Table 2-is administered to the pharmacokinetic parameter of pravastatin in bidirectional crossed research in two kinds of oral formulations of six fasting beagles

The pravastatin calcium salt
The pravastatin calcium salt							Animal	AUC _0-t (ng/mL×hr)	AUC _inf (ng/mL× hr)	C _max (ng/mL)	T _max (hr)	t _1/2 (hr)	Relative bioavailability ^a
1001	512.94	518.11	99.0	1	3.44	134	Animal	AUC _0-t (ng/mL×hr)	AUC _inf (ng/mL× hr)	C _max (ng/mL)	T _max (hr)	t _1/2 (hr)	Relative bioavailability ^a
1001	512.94	518.11	99.0	1	3.44	134	1002	264.11	268.01	87.2	0.5	1.85	62.1
1003	488.36	494.27	182	1	1.67	74.9	1002	264.11	268.01	87.2	0.5	1.85	62.1
1003	488.36	494.27	182	1	1.67	74.9	2001	438.55	453.69	131	0.5	2.5	99.7
2002	505.30	515.14	166	0.25	1.89	148	2001	438.55	453.69	131	0.5	2.5	99.7
2002	505.30	515.14	166	0.25	1.89	148	2003	380.68	396.20	182	1	2.76	200
Mean	431.66	440.90	141.20	0.71	2.35	121	2003	380.68	396.20	182	1	2.76	200
Mean	431.66	440.90	141.20	0.71	2.35	121	SD	95.879	96.306	41.822	0.332	0.679	54.0
％CV	22.2	21.8	29.6	46.9	28.9	44.6	SD	95.879	96.306	41.822	0.332	0.679	54.0
％CV	22.2	21.8	29.6	46.9	28.9	44.6	PRAVACHOL
1001	333.39	345.11	94.0	0.5	2.44	N/A	PRAVACHOL
1001	333.39	345.11	94.0	0.5	2.44	N/A	1002	375.46	378.47	117	1	1.69	N/A
1003	575.07	581.85	192	1	1.79	N/A	1002	375.46	378.47	117	1	1.69	N/A
1003	575.07	581.85	192	1	1.79	N/A	2001	350.84	414.58	40.2	1	10.18	N/A
2002	297.63	312.21	129	1	2.59	N/A	2001	350.84	414.58	40.2	1	10.18	N/A
2002	297.63	312.21	129	1	2.59	N/A	2003	165.66	171.78	33.6	0.5	2.06	N/A
Mean	349.68	367.33	100.97	0.83	3.46	-	2003	165.66	171.78	33.6	0.5	2.06	N/A
Mean	349.68	367.33	100.97	0.83	3.46	-	SD	132.89	134.27	59.345	0.26	3.31	-
％CV	38.0	36.6	58.8	31.0	95.8	-	SD	132.89	134.27	59.345	0.26	3.31	-

^aThe bioavailability AUC that calculates with respect to PRAVACHOL  _Inf, the dosage normalization that each value is accepted according to each animal.

In general, for the numerical value of PRAVACHOL  tablet, the AUC of pravastatin calcium salt and C _MaxBe worth high slightly.The T of each preparation _MaxValue quite.Therefore, as if the relative bioavailability (according to dosage normalization) of pravastatin is slightly higher than PRAVACHOL 's after administration pravastatin calcium salt.The above results shows that the suspension of pravastatin calcium salt in medicine ω-3 ethyl ester do not influence the pharmacokinetics behavior of pravastatin significantly.

Embodiment 5

The pravastatin magnesium salt

The magnesium chloride solution that in the pravastatin sodium solution of 3mL 30.5 quality %, adds 0.7mL 49.5 quality %.The solvent of two kinds of solution all is a deionized water.Observing two kinds of liquid in 30 minutes occurs being separated.Crystallization appears in intensive spending the night in mutually.Collect two kinds of solid phases (crystal type): the packed solid that " fluffy " suspended phase that (A) is positioned at the reaction vessel top and (B) are positioned at the reaction solution bottom mutually.Resulting salt is pravastatin-magnesium salt of 2: 1.

Pravastatin magnesium salt (A type) can be by any one in Figure 13, any two, any three, any four, any five or any six or more a plurality of PXRD peak sign, include but not limited to 4.57,6.97,9.15,10.87,11.81,13.21,13.73,16.31,17.51,18.55,19.17,20.73,22.71,23.73 and 24.99 ° of 2-θ (Rigaku collects data).At observed peak, 31.709 ° of 2-θ places corresponding to sodium chloride as impurity.

DSC carries out with 10 ℃/minute to 300 ℃ on (pravastatin magnesium salt A type) 25 ℃.DSC demonstrates at about 99 ℃ and locates to occur endothermic transition (referring to Figure 14).Locate to occur heat release at about 131 ℃ and may represent the recrystallization incident.

TQA carries out with 10 ℃/minute to 300 ℃ on (pravastatin magnesium salt A type) 25 ℃.TGA shows, occurs about 12% loss in weight between 25 ℃ to about 120 ℃, occurs about 25% loss in weight (referring to Figure 15) between 25 ℃ to about 160 ℃.

Also used IR spectrum to characterize pravastatin magnesium salt (A type).This salt can characterize by any one in Figure 16, any two, any three, any four, any five or any six or more a plurality of IR peak, includes but not limited to 1726,1557,1425,1177,1078,1019 and 641cm ^-1IR spectrum obtains with conduction mode, and sample is pressed into the KBr sheet.Spectrum carries out baseline correction.

Figure 17 shows kinetics vapor absorption (DVS) isothermal line of pravastatin magnesium salt (A type).It is finished at 25 ℃, and its data show that the stability region is in about 10 between about 60% relative humidity (RH).

Record the dissolubility (by UV detect) of pravastatin magnesium salt (A type) in water and be 14.22mg/mL.

Pravastatin magnesium salt (Type B) can be by any one in Figure 18, any two, any three, any four, any five or any six or more a plurality of PXRD peak sign, include but not limited to 4.57,6.99,9.13,10.41,10.87,12.05,13.19,13.77,16.37,17.43,18.53,19.13,20.71,22.73 and 25.01 ° of 2-θ (Rigaku collects data).

DSC carries out with 10 ℃/minute to 200 ℃ (pravastatin magnesium salt Type B) 25 ℃.DSC demonstrates at about 107 ℃ and locates to exist endothermic transition (referring to Figure 19).

TGA carries out with 10 ℃/minute to 300 ℃ (pravastatin magnesium salt Type B) 25 ℃.TGA demonstrates and 12% loss in weight (referring to Figure 20) occurs between 25 ℃ to about 120 ℃.

Also used IR spectrum to characterize pravastatin magnesium salt (Type B).This salt can characterize by any one in Figure 21, any two, any three, any four, any five or any six or more a plurality of IR peak, includes but not limited to 1726,1553,1459,1426,1177,1079,1039 and 827cm ^-1IR spectrum obtains with conduction mode, and sample is pressed into the KBr sheet.Spectrum carries out baseline correction.

Recording the dissolubility (by UV detect 20-25 ℃) of pravastatin magnesium salt (Type B) in water is 16.12mg/mL.

Embodiment 6

The pravastatin magnesium salt

Prepare pravastatin once more.To sodium salt of pravastatin (1.0057g; 2.25mmol) add the propylene glycol (0.171g) of 2 molar equivalents in the 49 quality % solution in deionized water.Add magnesium chloride (230.0g; 1.14mmol) behind the 53.1 quality % solution in deionized water, find the pravastatin magnesium salts crystalise.After spending the night, it is complete to observe crystallization.Resulting salt is pravastatin-magnesium salt of 2: 1.

The pravastatin magnesium salt can be by any one in Figure 22, any two, any three, any four, any five or any six or more a plurality of PXRD peak sign, include but not limited to 4.55,6.97,9.13,10.87,11.81,13.21,13.73,16.31,17.49,18.55,19.15,20.73,22.69,23.71 and 24.97 ° of 2-θ (Rigaku collects data).At observed peak, 31.710 ° of 2-θ places corresponding to sodium chloride as impurity.

DSC carries out with 10 ℃/minute to 200 ℃ (pravastatin magnesium salt) 40 ℃.DSC is presented at about 99 ℃ and locates to exist endothermic transition (referring to Figure 23).

TGA carries out with 10 ℃/minute to 280 ℃ (pravastatin magnesium salt) 25 ℃.TGA is presented between 25 ℃ to about 150 ℃ and has about 11% loss in weight (referring to Figure 24).

Recording the dissolubility (by UV detect 20-25 ℃) of pravastatin magnesium salt in water is 17.24mg/mL.

Embodiment 7

The pravastatin zinc salt

2 equivalent pravastatin sodiums are dissolved in the deionized water, with the solution reaction of 1 equivalent zinc chloride in deionized water.At room temperature find crystallization pravastatin zinc precipitation immediately.Resulting salt is pravastatin-zinc salt of 2: 1.

The pravastatin zinc salt can be by any one in Figure 25, any two, any three, any four, any five or any six or more a plurality of PXRD peak sign, include but not limited to 3.78,7.56,9.58,11.34,17.05,18.76,19.80,21.91,24.57 and 26.55 ° of 2-θ (Rigaku collects data).

DSC carries out with 10 ℃/minute to 300 ℃ (pravastatin zinc salt) 25 ℃.DSC is presented at about 136 ℃ and locates to exist endothermic transition (referring to Figure 26).

TGA carries out with 10 ℃/minute to 300 ℃ (pravastatin zinc salt) 25 ℃.TGA is presented at about 100 ℃ to about 190 ℃ and about 12% loss in weight occurs, wherein at can ignore up to about 100 ℃ loss in weight (referring to Figure 27).

Also used IR spectrum to characterize the pravastatin zinc salt.This salt can characterize by any one in Figure 28, any two, any three, any four, any five or any six or more a plurality of IR peak, includes but not limited to 1731,1574,1179,1044,849 and 754cm ^-1IR spectrum obtains with conduction mode, and sample is pressed into the KBr sheet.Spectrum carries out baseline correction.

Also used Raman spectrum to characterize the pravastatin zinc salt.The pravastatin zinc salt can characterize by any one in Figure 29, any two, any three, any four, any five or any six or more a plurality of Raman shift, includes but not limited to 1654,1449,1208,1121,1050,846 and 427cm ^-1

Figure 30 shows kinetics steam heat absorption (DVS) isothermal line of pravastatin zinc salt.It is finished at 25 ℃, and these data show that its humidity absorbs rising gradually.

Recording the dissolubility (by UV detect 20-25 ℃) of pravastatin zinc salt in water is 0.53mg/mL.

Embodiment 8

Pravastatin salt is at E68101Q: 12 peripheral stability data in the alcohol mixture

With several salt suspensions of pravastatin in 87: 13 E681010: in the alcohol mixture and place band medicated cap vial.With every part of pravastatin calcium, pravastatin magnesium, pravastatin sodium or pravastatin zinc at 87: 13 E681010: the suspension in the ethanol carries out periodic measurement, continues for 12 weeks.Use HPLC to measure the degraded of pravastatin salt.

Figure 31 shows the stability data (lactone percentage ratio) at 4 ℃.

Figure 32 shows the stability data (lactone percentage ratio) at 40 ℃.It is minimum that zinc salt is degraded into lactone, 12 week back degradeds about 3%.

Figure 33 shows the stability data (percentage ratio of other degradation product) at 40 ℃.Find that once more as if zinc salt is the most stable.

Claims

1. pharmaceutical composition, it contains Ta Ting and ω-3 oil.

2. the pharmaceutical composition of claim 1, wherein said his spit of fland is a salt.

3. pharmaceutical composition, it contains pravastatin and ω-3 oil.

4. the pharmaceutical composition of claim 3, wherein said pravastatin is a salt.

5. the pharmaceutical composition of claim 4, wherein said salt is calcium, magnesium or zinc salt.

6. the pharmaceutical composition of claim 4, wherein said salt is divalent salts.

7. the pharmaceutical composition of claim 4, wherein said pravastatin is chemically stable.

8. the pharmaceutical composition of claim 3, wherein said ω-3 oil is ω-3 ethyl ester.

9. the pharmaceutical composition of claim 3, wherein said ω-3 oil is ω-3 triglyceride.

10. the pharmaceutical composition of claim 3, it is about 70 to about 90wt% EPA and DHA that wherein said ω-3 oil contains content.

11. the pharmaceutical composition of claim 3, wherein said ω-3 oil have about 3: 1 to about 1: 1 EPA: the DHA ratio.

12. the pharmaceutical composition of claim 3, wherein said ω-3 oil have about 10: 1 to about 5: 1 EPA: the DHA ratio.

13. a pharmaceutical composition, it contains pravastatin and ω-3 oil, and wherein said ω-3 oil exists with about content of 500 to about 1500mg, and described pravastatin exists with about content of 5 to about 160mg.

14. the pharmaceutical composition of claim 13, wherein said pravastatin is a salt.

15. the pharmaceutical composition of claim 14, wherein said salt are calcium, magnesium or zinc salt.

16. the pharmaceutical composition of claim 14, wherein said salt is divalent salts.

17. the pharmaceutical composition of claim 14, wherein said salt has the water solubility less than about 200mg/mL.

18. the pharmaceutical composition of claim 14, wherein said salt has the water solubility less than about 50mg/mL.

19. the pharmaceutical composition of claim 14, wherein said salt is crystallization.

20. a pharmaceutical composition, it contains fluvastatin and ω-3 oil.

21. the pharmaceutical composition of claim 20, wherein said fluvastatin is a salt.

22. the pharmaceutical composition of claim 21, wherein said salt is divalent salts.

23. the pharmaceutical composition of claim 21, wherein said salt is chemically stable.

24. the pharmaceutical composition of claim 21, wherein said salt is calcium salt.

25. the pharmaceutical composition of claim 21, wherein said salt has the water solubility less than about 200mg/mL.

26. the pharmaceutical composition of claim 21, wherein said salt has the water solubility less than about 50mg/mL.

27. the pharmaceutical composition of claim 20, it further contains 500 to about 1500mg ω-3 oil and about 5 of having an appointment to about 160mg fluvastatin.

28. a prevention, alleviate or treat the method that cholesterol levels rising, atherosclerosis, hyperlipemia, cardiovascular event and disease comprise crown incident and cerebrovascular events and coronary artery disease and/or cerebrovascular disease, described method by to this prevention of needs, alleviate or the pharmaceutical composition of the mammal administration claim 3 for the treatment of provides.

29. the calcium salt of pravastatin.

30. the calcium salt of claim 29, wherein it shows basically powder x-ray diffraction pattern as shown in Figure 1.

31. the calcium salt of claim 29, wherein it shows basically IR spectrum as shown in Figure 3.

32. the calcium salt of claim 29, wherein the IR spectrum of its demonstration comprises and is positioned at 2360,1728,1561,1444,1186 and 855cm ^-1The peak at place.

33. a pharmaceutical composition, it contains the calcium salt of claim 29.

34. the calcium salt of claim 29, wherein said salt is crystallization.

35. the magnesium salt of pravastatin.

36. the magnesium salt of claim 35, wherein it shows basically powder x-ray diffraction pattern as shown in figure 13.

37. the magnesium salt of claim 35, wherein the powder x-ray diffraction pattern of its demonstration comprises the peak that is positioned at 4.57,6.97,9.15,10.87,11.81,13.21,13.73,16.31,17.51,18.55,19.17,20.73,22.71,23.73 and 24.99 ° of 2-θ places.

38. the magnesium salt of claim 35, wherein it shows basically powder x-ray diffraction pattern as shown in figure 18.

39. the magnesium salt of claim 35, wherein the powder x-ray diffraction pattern of its demonstration comprises the peak that is positioned at 4.57,6.99,9.13,10.41,10.87,12.05,13.19,13.77,16.37,17.43,18.53,19.13,20.71,22.73 and 25.01 ° of 2-θ places.

40. the magnesium salt of claim 35, wherein the powder x-ray diffraction pattern of its demonstration comprises the peak that is positioned at 4.57,6.99,9.13,13.77 and 20.71 ° of 2-θ places.

41. a pharmaceutical composition, it contains the magnesium salt of claim 35.

42. the magnesium salt of claim 35, wherein said salt is crystallization.

43. the zinc salt of pravastatin.

44. the zinc salt of claim 43, wherein it shows basically powder x-ray diffraction pattern as shown in figure 25.

45. the zinc salt of claim 43, wherein the powder x-ray diffraction pattern of its demonstration comprises the peak that is positioned at 3.78,7.56,9.58,11.34,17.05,18.76,19.80,21.91,24.57 and 26.55 ° of 2-θ places.

46. the zinc salt of claim 43, wherein the powder x-ray diffraction pattern of its demonstration comprises the peak that is positioned at 3.78,7.56,9.58 and 17.05 ° of 2-θ places.

47. a pharmaceutical composition, it contains the zinc salt of claim 43.

48. the zinc salt of claim 43, wherein said salt is crystallization.

49. the divalent salts of pravastatin.

50. the divalent salts of claim 49, wherein said salt has the water solubility less than about 25mg/mL.

51. a prevention, alleviate or treat the method that cholesterol levels rising, atherosclerosis, hyperlipemia, cardiovascular event and disease comprise crown incident and cerebrovascular events and coronary artery disease and/or cerebrovascular disease, described method by to this prevention of needs, alleviate or the calcium salt of the mammal administration claim 29 for the treatment of provides.

52. a prevention, alleviate or treat the method that cholesterol levels rising, atherosclerosis, hyperlipemia, cardiovascular event and disease comprise crown incident and cerebrovascular events and coronary artery disease and/or cerebrovascular disease, described method by to this prevention of needs, alleviate or the magnesium salt of the mammal administration claim 35 for the treatment of provides.

53. a prevention, alleviate or treat the method that cholesterol levels rising, atherosclerosis, hyperlipemia, cardiovascular event and disease comprise crown incident and cerebrovascular events and coronary artery disease and/or cerebrovascular disease, described method by to this prevention of needs, alleviate or the zinc salt of the mammal administration claim 43 for the treatment of provides.