WO2015139512A1 - 氟伐他汀钠药物组合物 - Google Patents

氟伐他汀钠药物组合物 Download PDF

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Publication number
WO2015139512A1
WO2015139512A1 PCT/CN2015/000168 CN2015000168W WO2015139512A1 WO 2015139512 A1 WO2015139512 A1 WO 2015139512A1 CN 2015000168 W CN2015000168 W CN 2015000168W WO 2015139512 A1 WO2015139512 A1 WO 2015139512A1
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Prior art keywords
pharmaceutical composition
solid pharmaceutical
composition according
sodium
weight
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PCT/CN2015/000168
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English (en)
French (fr)
Inventor
魏世峰
汪鹤龄
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北京罗诺强施医药技术研发中心有限公司
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Publication of WO2015139512A1 publication Critical patent/WO2015139512A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the technical field of medicine and relates to a new stable solid pharmaceutical formula, which is particularly suitable for treating hypercholesterolemia and hyperlipidemia. More particularly, the present invention relates to a novel stable solid pharmaceutical formulation containing the active substance HMG-CoA reductase inhibitor fluvastatin or a pharmaceutically active salt thereof. In particular, it relates to a solid pharmaceutical composition of fluvastatin sodium, and more particularly to a solid pharmaceutical composition of fluvastatin sodium having excellent stability characteristics. The invention still further relates to a process for the preparation of the fluvastatin sodium solid pharmaceutical composition.
  • Fluvastatin is known as an HMG-CoA reductase inhibitor and has been clinically used as a preparation against hypercholesterolemia as a statin. Unlike simvastatin, HMG-CoA reductase inhibitors produced by fermentation using microorganisms belonging to different species of Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor, or Penicillium, fluvastatin It is the first fully synthetic HMG-CoA reductase inhibitor and is distinguished in part from the fungal derivatives of such therapeutic agents.
  • Fluvastatin is usually used in the clinic as its sodium salt. It has good mouthfeel, high hygroscopicity, low solubility in acidic medium, low stability to heat, humidity and light, and instability in acidic aqueous medium.
  • the fluvastatin sodium is generally formulated into a suitable formulation with an alkaline medium such that the pH of the aqueous fluvastatin or dispersion is at least 8.
  • statins are highly susceptible to degradation at pH less than 8, so prior art pharmaceutical compositions also include alkalizing stabilizers or alkalizing agents to maintain a high pH and avoid HMG. - Degradation of CoA reductase inhibitors.
  • alkalizing stabilizers such as calcium carbonate, calcium hydroxide, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, magnesium aluminum hydroxide, lithium hydroxide, potassium hydroxide, Sodium hydrogencarbonate, sodium borate, sodium carbonate, sodium hydroxide, and the like.
  • statins are unstable under moist and light conditions, low water content formulations are usually produced.
  • the purity of the active substance is an important factor in the production of a safe and effective pharmaceutical formula. If long-term use of the drug is necessary to treat or prevent an increase in blood cholesterol levels, the highest purity of the drug is particularly important, and the accumulation of impurities in the low-purity drug can be Causes various side effects during treatment. In addition to the impurities that cannot be completely eliminated during the preparation of the active material to the left, it is also a problem that the final drug formulation is exposed to various environmental factors such as temperature, humidity, low pH, and degradation products produced by light. HMG-CoA reductase inhibitors such as fluvastatin, which is present in the form of a salt in the final pharmaceutical formulation, are particularly susceptible to acidic environments in which the hydroxy acid is degraded to lactones and other impurities.
  • the inhibition factor of the stability of the active substance in an acidic environment is one of the main problems in the case of a salt form.
  • One possible solution to the above problem is the solution set forth in EP 0336298, which separates a stable pharmaceutical formulation of pravastatin.
  • the essence of this formulation is to maintain an alkaline environment such that the aqueous dispersion of the pharmaceutical formulation has a pH of above 9 and preferably about 10.
  • the composition of the invention includes an alkalizing agent such as magnesium oxide having a pH of 9 above the aqueous dispersion of the above formulation. This formulation is effective in view of the stability of the active substance.
  • the local alkaline environment occurring at the dissolution site of the drug formulation has certain side effects on the gastric mucosa which should normally have an acidic environment.
  • This side effect is a gastric mucosal lesion in which the gastric mucosa does not produce an effective acidic environment in the stomach for normal digestive function.
  • the injured patients are particularly obvious. This is very important in long-term therapies for prevention or treatment with HMG-CoA reductase inhibitors.
  • Controlled release tablet formulations of fluvastatin sodium are reported in U.S. Patent Application Serial No. 10/100,656 and U.S. Patent No. 6,624,2003. The disclosed tablets are reported to be administered once a day, yielding an effective plasma drug concentration of more than 12 hours.
  • US Patent Application Publication No. US 2002/0169145 A1 reports a dosage form of a commercial formulation comprising an HMG-CoA reductase inhibitor compound comprising hypromellose and a nonionic hydrophilic polymer to prevent premature release of large amounts of activity ingredient.
  • the nonionic hydrophilic polymer is reported to be selected from the group consisting of hydroxyethyl cellulose (molecular weight of about 90,000 to 1,300,000), hydroxypropyl cellulose (molecular weight of about 370,000 to 1,500,000), and polyalkylene oxide (molecular weight of about 100,000 to 500,000). ).
  • U.S. Patent No. 6,624,2003 discloses the use of hypromellose and fluvastatin having a defined particle size to provide a color stable extended release formulation.
  • a variety of methods for stabilizing acid-sensitive statins are disclosed in U.S. Patent No. 5, 356, 896, U.S. Patent No. 6, 531, 507 and U.S. Pat.
  • 5,356,896 discloses a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising an alkalized stabilizing medium capable of administering an aqueous solution or dispersion of said compound to a pH of at least 8.
  • U.S. Patent No. 6,531,507 discloses an alternative method for stabilizing statins by co-crystallizing or co-precipitating an acid-sensitive active ingredient with a buffer or alkalizing substance to maintain the stability of the statin active ingredient.
  • WO2004/071402 discloses an active ingredient comprising more than one pH-sensitive active ingredient and more than one pharmaceutically acceptable excipient, wherein the water content is less than about 3.5% and is free of stabilizers or buffers or combinations thereof.
  • the object of the present invention is to provide a solid preparation of fluvastatin sodium having excellent properties, for example, having at least one of the following aspects: little or no alkalizing agent to avoid the damaging effect of the alkalizing agent on the acidic environment of gastric juice, and having good
  • the chemical stability for example, increases the rate of impurities more slowly during storage, and has good safety, such as reducing the biological safety hazard caused by the formation of impurities.
  • the present inventors have found that a fluvastatin sodium solid pharmaceutical composition having a particular formulation surprisingly exhibits at least one of the above-described superior characteristics. The present invention has been completed based on this finding.
  • a first aspect of the invention provides a solid pharmaceutical composition comprising fluvastatin sodium, an inorganic salt, and optionally a pharmaceutically acceptable adjuvant.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention wherein the inorganic salt is selected from the group consisting of: dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium silicate, magnesium aluminate, sodium hydrogencarbonate, sodium carbonate , potassium hydrogencarbonate, potassium carbonate, sodium borate, sodium chloride, potassium chloride or a combination thereof.
  • the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, or a combination thereof.
  • the amount of the other pharmaceutical excipients other than the inorganic salt and fluvastatin sodium is not particularly limited, and is usually added in an amount to give a suitable dosage form of the composition, for example, a preparation sheet.
  • These pharmaceutical excipients may be appropriately added in small amounts because of the small total weight of the dosage form, and for example, when the granules are prepared, the medicinal excipients may be appropriately added because the total weight of the dosage form can be large.
  • the combination of sodium fluvastatin and the inorganic salt imparts specific properties to the composition and imparts excellent chemical stability to fluvastatin sodium, i.e., a particular contribution of the present invention to the prior art is found.
  • This particular combination, and thus the pharmaceutical excipients may or may not be included in the combinations and excipients of the present invention.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention, wherein the filler includes, but is not limited to, starch or a derivative thereof such as corn starch, pregelatinized starch, improved Starch, etc.; cellulose or its derivatives such as microcrystalline cellulose, ethyl cellulose, methyl cellulose, etc.; sugars such as glucose, sucrose, lactose, mannitol, sorbitol; neutral minerals such as calcium carbonate , calcium hydrogen phosphate, and the like, and combinations thereof.
  • starch or a derivative thereof such as corn starch, pregelatinized starch, improved Starch, etc.
  • cellulose or its derivatives such as microcrystalline cellulose, ethyl cellulose, methyl cellulose, etc.
  • sugars such as glucose, sucrose, lactose, mannitol, sorbitol
  • neutral minerals such as calcium carbonate , calcium hydrogen phosphate, and the like, and combinations thereof.
  • the term "diluent” or “filler” is defined as an inert material used to increase the weight and/or size of a pharmaceutical composition, and the diluent or filler may be in the form of a substance or a mixture of compounds in the composition. presence.
  • a diluent or filler is added when the amount of active ingredient and other excipients is too small to obtain a tablet of a suitable size.
  • the weight percentage of the diluent or filler necessary for the pharmaceutical composition according to the present invention can be determined according to conventional methods well known to those skilled in the art, especially after the amounts of other adjuvants such as disintegrants, binders, lubricants, etc. are determined. Use a proper amount of diluent or filler depending on the size of the preparation.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention wherein the disintegrating agent includes, but is not limited to, crosslinked polyvinylpolypyrrolidone, sodium starch glycolate, croscarmellose sodium, low substitution Hydroxypropyl cellulose and the like and combinations thereof.
  • the pharmaceutical composition comprises 0 to 10% of a disintegrant, for example 0 to 8% of a disintegrant, for example 0 to 5% of a disintegrant, relative to the total weight of the pharmaceutical composition, which may also be according to the present invention. It is also common to use the experience of those skilled in the art; pharmaceutical preparations which do not use or use less disintegrants, such as turbid skeleton sustained release tablets which are prepared for sustained release purposes.
  • the solid pharmaceutical compositions of the present invention in the form of preparations may not have disintegrating properties in some cases, for example, when they are in a capsule, in which case no disintegrant may be added to the solid pharmaceutical composition of the present invention.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention wherein the binder includes, but is not limited to, polyethylene glycol, starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like, and combinations thereof.
  • the binder includes, but is not limited to, polyethylene glycol, starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like, and combinations thereof.
  • water as a wetting agent as a potential binder
  • the solid pharmaceutical composition of the present invention is used to remove these water as a wetting agent in the final product.
  • the materials of many solid pharmaceutical preparations are inherently adhesive and can be directly tableted or directly encapsulated.
  • the binder may or may not be added to the solid pharmaceutical composition of the present invention. Even with wet granulation techniques, the adhesive can still be dispensed. If added, the amount of binder used is from 0.1 to 10%, from 0.2 to 5%, or from 0.5 to 2.5%, based on the total weight of the pharmaceutical composition, which can also be used according to the experience of those skilled in the art.
  • the lubricant includes, but are not limited to, magnesium stearate, calcium stearate, talc, starch, stearic acid, colloidal silica, polyethylene glycol, and the like. If added, the amount of lubricant used is from 0.2 to 10%, from 0.25 to 5%, based on the total weight of the pharmaceutical composition, which can also be used according to the experience of those skilled in the art.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention which may further comprise a release modifier.
  • the release modifier can modulate or control the rate and extent of drug release of the solid pharmaceutical composition in the digestive juice.
  • pharmaceutical preparations such as sustained release tablets which are expected to delay release.
  • Typical drug release modifiers such as, but not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium alginate, xanthan gum, polyvinyl alcohol, glyceryl behenate, and the like Its combination.
  • the amount of drug release modifying agent added to the tablet for sustained release is readily determinable by those skilled in the art, for example, when they are present, typically from 5 to 50%, such as from 10 to 40%, by weight based on the total weight of the composition.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention which is a pharmaceutical dosage form selected from the group consisting of a tablet, a capsule, a granule, and the like.
  • a solid pharmaceutical composition according to any one of the first aspects of the invention which is a tablet that is uncoated or coated with a coating material.
  • a solid pharmaceutical composition according to any of the first aspects of the invention which is a coated tablet.
  • the coated tablet comprises from 1% to 6%, from 2% to 5%, of the coating material relative to the total weight of the tablet.
  • the coating material is selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose, and methacrylic acid-alkyl acrylate copolymers.
  • the coating material is an aqueous dispersion of hydroxypropyl methylcellulose.
  • the coating material is Is an aqueous dispersion of hydroxypropyl methylcellulose; further, the coating material is selected from 85F20694, 85F32004, 85F23452 and 85F18422.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention comprising:
  • the medicinal adjuvant is 0 to 500 parts by weight.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention comprising:
  • the medicinal adjuvant is 10 to 400 parts by weight.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention comprising:
  • the pharmaceutical excipient is 25 to 250 parts by weight.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention which does not include the coated pharmaceutical composition (for example, a granular material before tableting, an uncoated plain tablet, or a coated coating)
  • the core has a contact angle of less than 110°, for example having a contact angle of less than 100°, for example having a contact angle of less than 90°, for example having a contact angle of less than 85°; however, from an industrial applicability, the contact angle should not Less than 30°.
  • the pharmaceutical compositions of the invention such as tablets, have a contact angle with water of from 30 to 100, such as from 30 to 90, such as from 30 to 85.
  • a solid pharmaceutical composition according to any one of the first aspects of the present invention wherein said contact angle means a contact angle with water.
  • the contact angle means an angle at which water droplets dropped on the surface of a solid preparation composition such as a tablet come into contact with the surface of the composition.
  • an exemplary method of measurement is as follows: in a needle (for example, model SNSO52/026; manufactured by HAMILTON, stainless steel, inner diameter 0.26 mm, external) 1 ⁇ l of pure water (MILLI-Q; MILLIPORE) droplets are formed by a needle tip of 0.52 mm; or a needle of similar size can be used, and then passed through a contact angle measuring device (for example, OCA-15 type, Data physics; or similar) Other brands or models of contact angle measuring devices of the function) measure the contact angle after water droplets are applied to the surface of the tablet for 60 ms.
  • a contact angle measuring device for example, OCA-15 type, Data physics; or similar
  • Other brands or models of contact angle measuring devices of the function measure the contact angle after water droplets are applied to the surface of the tablet for 60 ms.
  • the contact angle is measured after being corrected to a straight line in the analysis; it is usually measured at room temperature.
  • the contact angle of the present invention is measured by the following method: at room temperature, at a needle (SNSO52/026; manufactured by HAMILTON, stainless steel, inner diameter 0.26 mm, outer diameter 0.52 mm)
  • the tip of the needle was formed into 1 ⁇ l of pure water (MILLI-Q; MILLIPORE) droplets, and the contact angle after water droplets were applied to the surface of the tablet for 60 msec was measured by a contact angle measuring device (Model OCA-15, Data physics).
  • a solid preparation other than a tablet such as a capsule, a granule, a powder, or the like
  • it can be measured by pressing a powder, a granule, a semi-solid substance or the like contained in the preparation into a tablet shape, for example, for a capsule.
  • the contents of the capsules were taken out, and about 200 mg of them were pressed into a flat and smooth surface having a diameter of 8 mm and a thickness of 3.5 mm to measure the contact angle.
  • the coating on the surface of the tablet can be scraped off, then the tablet can be ground and then referenced.
  • the powder obtained by grinding the tablet is re-compressed into tablets and then measured.
  • the uncompressed tablet when the uncompressed tablet is prepared, it can be determined by pressing an appropriate amount of the powder into a tablet; when it is prepared into an uncoated tablet, it can be directly determined; it is prepared by coating.
  • the coating layer on the surface of the tablet can be scraped off, and then the tablet is ground, and the resulting powder is re-compressed into tablets and then measured.
  • a second aspect of the invention provides a method of preparing a solid pharmaceutical composition according to any of the first aspects of the invention, comprising the steps of:
  • a solid pharmaceutical composition in the form of a solid pharmaceutical preparation is prepared by mixing the mixed powder material treated in the step (1) with an optional pharmaceutical adjuvant according to a conventional solid pharmaceutical preparation.
  • the solid pharmaceutical preparation prepared in the step (2) is selected from the group consisting of: a tablet, a capsule, and a granule.
  • the granules can be prepared by a wet granulation method or a dry granulation method, and then pressed according to a conventional method. Tablets, capsules or granules.
  • the obtained powder mixture can be directly subjected to powder direct compression and powder capsule without performing granulation.
  • the powder is divided into granules (the powdered granules are also commonly referred to as powders)
  • the solid pharmaceutical composition comprises sodium fluvastatin, an inorganic salt, and optionally a pharmaceutically acceptable adjuvant.
  • the inorganic salt in the solid pharmaceutical composition is an acid-basic substantially neutral inorganic salt.
  • the inorganic salt in the solid pharmaceutical composition is selected from the group consisting of: dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium silicate, magnesium aluminate, sodium hydrogencarbonate , sodium carbonate, potassium hydrogencarbonate, potassium carbonate, sodium borate, sodium chloride, potassium chloride or a combination thereof.
  • the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, or a combination thereof.
  • the weight ratio of the inorganic salt to the fluvastatin sodium in the solid pharmaceutical composition is from 2 to 50:100, for example, the weight ratio of the two is from 3 to 30: 100, for example, the weight ratio of the two is 5 to 30:100.
  • the fluvastatin sodium in the solid pharmaceutical composition comprises from 1 to 99%, for example from 2 to 80%, such as 5, based on the total weight of the solid pharmaceutical composition. ⁇ 75%.
  • the amount of the other pharmaceutical excipients other than the inorganic salt and fluvastatin sodium is not particularly limited, and is usually added in an amount to give a suitable dosage form of the composition, for example, a preparation sheet.
  • These pharmaceutical excipients may be appropriately added in small amounts because of the small total weight of the dosage form, and for example, when the granules are prepared, the medicinal excipients may be appropriately added because the total weight of the dosage form can be large.
  • the pharmaceutical excipient is one or more selected from the group consisting of a filler, a disintegrant, a binder, and a lubricant.
  • Agent the combination of sodium fluvastatin and the inorganic salt imparts specific properties to the composition and imparts excellent chemical stability to fluvastatin sodium, i.e., a particular contribution of the present invention to the prior art is found. This particular combination, and thus the pharmaceutical excipients may or may not be included in the combinations and excipients of the present invention.
  • the filler (generally also referred to as a diluent) in the solid pharmaceutical composition includes, but is not limited to, starch or a derivative thereof such as corn starch, pre- Gelatinized starch, modified starch, etc.; cellulose or its derivatives such as microcrystalline cellulose, ethyl cellulose, methyl cellulose, etc.; sugars such as glucose, sucrose, lactose, mannitol, sorbitol; neutral Minerals such as calcium carbonate, calcium hydrogen phosphate, and the like, and combinations thereof.
  • starch or a derivative thereof such as corn starch, pre- Gelatinized starch, modified starch, etc.
  • cellulose or its derivatives such as microcrystalline cellulose, ethyl cellulose, methyl cellulose, etc.
  • sugars such as glucose, sucrose, lactose, mannitol, sorbitol
  • neutral Minerals such as calcium carbonate, calcium hydrogen phosphate, and the like, and combinations thereof.
  • the term "diluent” or “filler” is defined as an inert material used to increase the weight and/or size of a pharmaceutical composition, and the diluent or filler may be in the form of a substance or a mixture of compounds in the composition. presence.
  • a diluent or filler is added when the amount of active ingredient and other excipients is too small to obtain a tablet of a suitable size.
  • the weight percentage of the diluent or filler necessary for the pharmaceutical composition according to the present invention can be determined according to conventional methods well known to those skilled in the art, especially after the amounts of other adjuvants such as disintegrants, binders, lubricants, etc. are determined. Use a proper amount of diluent or filler depending on the size of the preparation.
  • the disintegrant in the solid pharmaceutical composition includes, but is not limited to, cross-linked polyvinylpolypyrrolidone, sodium starch glycolate, croscarmellose. Sodium, low substituted hydroxypropyl cellulose, and the like, and combinations thereof.
  • the pharmaceutical composition comprises 1 to 10% of a disintegrant, for example 2 to 8% of a disintegrant, for example 2 to 5% of a disintegrant, relative to the total weight of the pharmaceutical composition, which may also be according to the present invention. The experience of the field technicians is used.
  • the solid pharmaceutical compositions of the present invention in the form of preparations may not have disintegrating properties in some cases, for example, when they are in a capsule, in which case no disintegrant may be added to the solid pharmaceutical composition of the present invention.
  • the binder in the solid pharmaceutical composition includes, but is not limited to, polyethylene glycol, starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose And so on.
  • the materials of many solid pharmaceutical preparations have a certain degree of adhesion and water can be used as a wetting agent for wet granulation
  • water it is also possible in the present invention to use water as a wetting agent as a potential binder, although The solid pharmaceutical composition of the present invention is used to remove these water as a wetting agent in the final product.
  • the materials of many solid pharmaceutical preparations are inherently adhesive and can be directly tableted or directly encapsulated.
  • the binder may or may not be added to the solid pharmaceutical composition of the present invention. Even with wet granulation techniques, the adhesive can still be dispensed. If added, the amount of binder used is from 0.1 to 10%, from 0.2 to 5%, or from 0.5 to 2.5%, based on the total weight of the pharmaceutical composition, which can also be used according to the experience of those skilled in the art.
  • the lubricant (including a glidant) in the solid pharmaceutical composition functions to enable the powder material to be smoothly formed into a preparation, for example, preparation.
  • the powder material can be uniformly filled into the capsule shell.
  • the powder material can be uniformly filled into the mold of the tableting machine and the sticking can be avoided.
  • lubricants include, but are not limited to, magnesium stearate, calcium stearate, talc, starch, stearic acid, colloidal silica, polyethylene glycol, and the like. If added, the amount of lubricant used is from 0.2 to 10%, from 0.25 to 5%, based on the total weight of the pharmaceutical composition, which can also be used according to the experience of those skilled in the art.
  • a release regulator may also be included in the solid pharmaceutical composition.
  • the release modifier can modulate or control the rate and extent of drug release of the solid pharmaceutical composition in the digestive juice.
  • pharmaceutical preparations such as sustained release tablets which are expected to delay release.
  • Typical drug release modulators are, for example but not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, glyceryl behenate, and the like.
  • the amount of drug release modifying agent added to the tablet for sustained release is readily determinable by those skilled in the art, for example, when they are present, typically from 5 to 50%, such as from 10 to 40%, by weight based on the total weight of the composition.
  • the solid pharmaceutical composition is in a pharmaceutical dosage form selected from the group consisting of a tablet, a capsule, a granule, and the like.
  • the following processing step is further included: the obtained mixed powder material is supplemented by a thickness of not more than one centimeter
  • the stainless steel plate was placed in a sealed box sealed with an ethanol saturated atmosphere for 24 to 30 hours.
  • the solid pharmaceutical composition is a tablet that is uncoated or coated with a coating material.
  • the solid pharmaceutical composition is a coated tablet.
  • the coated tablet comprises from 1% to 6%, from 2% to 5%, of the coating material relative to the total weight of the tablet.
  • the coating material is selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose, and methacrylic acid-alkyl acrylate copolymers.
  • the coating material is an aqueous dispersion of hydroxypropyl methylcellulose.
  • the coating material is Is an aqueous dispersion of hydroxypropyl methylcellulose; further, the coating material is selected from 85F20694, 85F32004, 85F23452 and 85F18422.
  • the solid pharmaceutical composition comprises:
  • the medicinal adjuvant is 0 to 500 parts by weight.
  • the solid pharmaceutical composition comprises:
  • the medicinal adjuvant is 10 to 400 parts by weight.
  • the solid pharmaceutical composition comprises:
  • the pharmaceutical excipient is 25 to 250 parts by weight.
  • the coated solid pharmaceutical composition is not included (for example, a granular material before tableting, an uncoated tablet, or a coated coating)
  • the core has a contact angle of less than 110°, for example having a contact angle of less than 100°, for example having a contact angle of less than 90°, for example having a contact angle of less than 85°; however, from an industrial applicability, the contact angle should not be less than 30°.
  • the pharmaceutical compositions of the invention such as tablets, have a contact angle with water of from 30 to 100, such as from 30 to 90, such as from 30 to 85.
  • a third aspect of the invention relates to the use of the solid pharmaceutical composition according to any one of the first aspects of the invention for the preparation of a medicament for the treatment or prevention of hypercholesterolemia and hyperlipidemia.
  • a third aspect of the present invention relates to the solid pharmaceutical composition according to any one of the first aspects of the present invention, which is useful for the treatment or prevention of primary hypercholesterolemia and primary mixed blood lipids for incomplete control of diet. Use in drugs for abnormalities (Fredrickson Type IIa and IIb).
  • % is a weight/weight percentage unless otherwise stated.
  • fluvastatin sodium is: [R*, S*-(E)]-( ⁇ )-7-[3-(4-fluorophenyl)-1-(1-methyl Ethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt
  • the usual indications for the fluvastatin sodium of the present invention are: primary hypercholesterolemia and primary mixed dyslipidemia (Fredrickson Type IIa and IIb) for which the diet is not fully controlled.
  • the unit dose can be: 20 mg, 40 mg, or 80 mg.
  • the conventional recommended dose for conventional dosage forms is 20 or 40 mg once daily, and the conventional single dose of sustained release is 80 mg; swallowed at dinner or before bedtime.
  • doses are adjusted based on the individual's response to the drug and diet and the accepted treatment guidelines. High cholesterol or poor response to drugs. Increase the dose to 40 mg twice daily. After administration, the effect of maximal reduction of low-density lipoprotein cholesterol (LDL-C) was achieved within four weeks. Long-term use continues to be effective.
  • LDL-C low-density lipoprotein cholesterol
  • Fluvastatin sodium is a fully synthetic cholesterol-lowering drug that is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that competes with HMG-CoA reductase to inhibit the conversion of HMG-CoA to 3-methyl 3--3,5-dihydroxyvaleric acid, and 3-methyl-3,5-dihydroxyvaleric acid is a precursor of sterols including cholesterol.
  • HMG-CoA hydroxymethylglutaryl coenzyme A reductase inhibitor that competes with HMG-CoA reductase to inhibit the conversion of HMG-CoA to 3-methyl 3--3,5-dihydroxyvaleric acid, and 3-methyl-3,5-dihydroxyvaleric acid is a precursor of sterols including cholesterol.
  • the action site of this product is mainly in the liver and has a synthesis that inhibits endogenous cholesterol. Reduces the content of cholesterol in liver cells, stimulates the synthesis of low-density lipoprotein (LDL)
  • TC total cholesterol
  • LDL-C low density lipoprotein cholesterol
  • apo-B apolipoprotein B
  • TG triglycerides
  • fluvastatin sodium has an LD50 of more than 2 g/kg in mice and an LD50 of more than 0.7 g/kg in rats.
  • Needle Model SNSO52/026; manufactured by HAMILTON, stainless steel, inner diameter 0.26mm, outer diameter 0.52mm;
  • Pure water pure water made by MILLI-Q (manufactured by MILLIPORE);
  • Assay method 1 ⁇ l of pure water droplets were formed on the tip of the needle, and the contact angle after dropping to the surface of the sheet for 60 milliseconds was measured.
  • Sample treatment the material before tableting is first pressed into a flat tablet and then the contact angle is measured; the tablet that has been pressed and formed is directly measured, but if it is a non-planar tablet, the curvature of the surface of the tablet is corrected in the calculation; The piece of clothing, completely scraped off the coat layer, and then researched into The fine powder is then measured by pressing into a flat tablet; for the granule or capsule, the contents are ground into a fine powder, and then pressed into a flat tablet and then measured.
  • the granules before tableting (which can be directly encapsulated or dispensed into granules), the pressed plain tablets, and the coated tablets include the coating.
  • the pressed tablets were subjected to the same measurement of the contact angles of the three samples after the "sample treatment" described above (the difference between the three cases was not more than 5).
  • Test Method Example 2 Determination of the content of active ingredients by HPLC
  • the present invention can determine the content of the active ingredient in the bulk drug, the formulation intermediate, and the final formulation.
  • pH 7.2 buffer - 40 mL of 25% tetramethylammonium hydroxide aqueous solution was diluted with water to 1 L, and adjusted to pH 7.2 ⁇ 0.2 with about 4.5 mL of phosphoric acid;
  • Methanol-acetonitrile mixture mixing 3 volumes of methanol and 2 volumes of acetonitrile, ie;
  • Solution A Mixing pH 7.2 buffer with methanol-acetonitrile mixture at a volume ratio of 87.5:12.5, filtering and degassing;
  • Solution B mixing methanol-acetonitrile mixture with pH 7.2 buffer at a volume ratio of 87.5:12.5, filtering and degassing;
  • Content determination stock solution accurately weigh the sample corresponding to fluvastatin sodium 200mg (may be raw materials, tablets, capsules, etc.) in a 100mL volumetric flask, add about 80ml of methanol, ultrasonic treatment for 30min, cooling to Dilute to the mark with methanol at room temperature, shake well, and filter to obtain (concentration about 2mg/ml);
  • the content determination solution precision measurement content 10 ml of the stock solution is placed in a 50 ml volumetric flask, and diluted to the mark with a diluent, which is obtained (concentration is about 400 ⁇ g/ml);
  • Chromatography System - Chromatographic operation was performed by high performance liquid chromatography as described in the Chinese Veterinary Pharmacopoeia 2010 Edition, Appendix VD.
  • the chromatographic conditions are as follows:
  • Chromatography column - octadecylsilane bonded silica gel column (such columns are commercially available from many commercial sources, and are not particularly limited in the present invention as long as they can meet HPLC measurement requirements; but in the specific test of the present invention
  • the column of Hyper Scientific-ODS is used by Thermo Scientific, and its specification is 4.6mm ⁇ 5cm ⁇ 5 ⁇ m);
  • the retention time of the fluvastatin peak should be approximately 5.4 min (if there is a deviation, for example by adjusting the flow rate of the mobile phase)
  • the relative retention time of fluvastatin is RRT of 1.0.
  • the RRT of fluvastatin diastereomer is 1.2; the resolution between fluvastatin diastereomer and fluvastatin Should not be less than 1.4; the relative standard deviation of repeated injections should not exceed 1.5% [Note - if the retention time of the fluvastatin peak exceeds 5.7 min, the isocratic elution step can be adjusted accordingly to make the fluvastatin peak And fluvastatin diastereomeric peaks peak in the isocratic elution region];
  • Operation Inject 25 ⁇ L of the standard solution and the content determination solution into the chromatograph, record the chromatogram, read the peak area of the fluvastatin peak, and calculate the fluvastatin sodium content in the sample by the external standard method.
  • the present invention can determine the content of impurities in the bulk drug, the formulation intermediate, and the final formulation.
  • Chromatography system - refer to test method example 2 above;
  • System Suitability Test Inject the system suitability solution, record the peak response at 305 nm as described in the "Operation" section below; determine the chromatographic peak of fluvastatin and fluvastatin diastereomers, fluvastatin diastereomer
  • the resolution with fluvastatin should not be less than 1.4; the relative standard deviation of repeated injections should not exceed 1.5%;
  • F is the relative response factor of the impurity relative to fluvastatin (which can be readily determined by routine experimentation in the art after determining the structure of the impurity), and 411.48 and 433.45 are fluvastatin and fluvastatin sodium, respectively.
  • CS is the concentration of fluvastatin sodium in standard solution (mg/mL)
  • CT is the concentration of fluvastatin based on the labeled amount in the test solution (mg/mL)
  • ri is the peak response of each impurity in the test solution. Value
  • rS is the peak response of fluvastatin in the standard solution.
  • the impurity X i.e., [E,E]-( ⁇ )-7-[3-(4-fluorophenyl)-1-(methylethyl)-1H-indol-2-yl]- 3-hydroxy-4,6-heptadienoic acid monosodium salt
  • the above test method example 3 is simplified, and the test solution chromatogram is used to calculate the content of the impurity X contained in the test sample relative to the active ingredient fluvastatin sodium contained in the sample (%).
  • Impurity X content (%) [impurity X peak area ⁇ fluvastatin sodium peak area] ⁇ 100%
  • test samples were placed in a sealed aluminum-plastic composite film bag to isolate internal and external air exchange. The test sample was then placed in a 40 ° C incubator for 6 months to perform a conventional high temperature accelerated stability test.
  • the content of the active substance fluvastatin sodium in the samples was measured at 0 (not treated at 40 ° C) and at 6 (treated at 40 ° C).
  • Test method Example 2 Method determination, the unit can be expressed in mg mass per gram of fluvastatin sodium contained in the test sample, ie mg/g); then the fluvastatin sodium in each test sample is calculated by high temperature treatment as follows Residual content (%) after:
  • Residual content of fluvastatin sodium (%) [6 month content ⁇ 0 month content] ⁇ 100%
  • the residual content of the sample after being treated at 40 ° C to 6 months should be not less than 90. %, below 90%, the product is generally considered to be unqualified.
  • Test Method Example 5 Biological test (determination of LD50)
  • the same method was used to determine the impurity X, single gavage administration.
  • the LD50 is 0.82 g/kg body weight and the 95% confidence limit for LD50 is 0.66 to 0.97 g/kg body weight. It can be seen that fluvastatin sodium is significantly safer than impurity X from the perspective of drug safety.
  • the dissolution test of the solid preparation sample was carried out according to the 2010 edition of the Chinese Pharmacopoeia specification using a slurry method at a rotation speed of 50 rpm.
  • the preparation method of the mixed sample is as follows: (1) pulverizing each material to a fine powder which can pass through a 60 mesh sieve, and thoroughly mixing the prescribed amount of fluvastatin sodium with the inorganic salt to obtain a mixed powder material, which is conventionally Half of these blends were directly encapsulated and the other half compressed into tablets.
  • Ex1-06 100 20 97.5% twenty one% Ex1-07 100 30 97.7% twenty two% Ex1-08 100 45 92.7% 28% Ex1-09 100 75 88.7% 35% Ex1-10 100 100 84.3% 31%
  • the sample X is treated under the high temperature conditions simulated for long-term storage, and the impurity X is a relatively poor safety-related substance. It is lower than the sample without adding potassium chloride or less added, that is, the impurity X growth rate is very small when a certain amount of potassium chloride is contained, which is much smaller than the sample containing no potassium chloride. However, when the amount of potassium chloride is too high, for example, when the relative amount of potassium chloride is 45 parts by weight or more, the active ingredient is lowered rapidly.
  • Control Test 11 Refer to the method of Example 1 above and the formulation of Table 1, except that potassium chloride was replaced with an equivalent amount of sodium chloride, and the resulting sample tablets were also treated at 40 ° C to 6 months. The results show that these samples are basically the same as the use of potassium chloride in both the residual content of fluvastatin sodium and the increase in impurity X, that is, incorporation into it relative to 100 parts by weight of fluvastatin sodium.
  • the amount of sodium chloride is 5 parts by weight or more, the increase of the impurity X is less than or equal to 45%, and the active ingredient is Good stability, the residual content of fluvastatin sodium is more than 96%, both in the range of 96.5 ⁇ 98.5%; but when the relative amount of sodium chloride is greater than or equal to 45 parts by weight, the active ingredient is reduced faster, using 75 weight
  • the residual content of fluvastatin sodium in parts and 100 parts by weight of sodium chloride was 89.6% and 83.2%, respectively, which could not meet the stability requirements of general medicines.
  • Control Test 12 Refer to the method of Example 1 above and the formulation of Table 1, except that the potassium chloride is replaced with an equivalent amount of potassium bicarbonate (it is believed that the use of a weakly basic salt helps to increase fluvastatin sodium) Stability), also treated at 40 ° C - June.
  • the results showed that the residual content of fluvastatin sodium in the four samples of 5 to 30 parts by weight of potassium bicarbonate was in the range of 91.6 to 94.7% after 6 months, indicating that although it is acceptable, it is still inferior to the effect of the present invention.
  • the remaining 6 samples of potassium bicarbonate relative to less than 5 or more than 30 parts by weight decreased the residual content of fluvastatin sodium to less than 90% after 6 months, all in the range of 77.6 to 86.3%.
  • the increase of the impurity X in the range of 136 to 213% after 6 months showed that potassium hydrogencarbonate could not effectively suppress the increase of the impurity X.
  • Control Test 13 Refer to the method and formulation of Control Test 12 above, except that potassium bicarbonate is replaced with an equivalent amount of sodium bicarbonate (it is believed to be similar to potassium bicarbonate, which helps to increase fluvastatin sodium) Stability), also treated at 40 ° C - June.
  • Control test 14 Commercially available fluvastatin sodium capsule (National Medicine Zhunzi H20010517, it is believed that sodium bicarbonate was added as a stabilizer) and commercially available fluvastatin sodium sustained-release tablets (National Medicine Zhunzi H20090179, it is believed that carbonic acid was added Potassium hydrogen as a stabilizer) was also treated at 40 ° C to 6 months. Results The residual contents of fluvastatin sodium in the two samples after 6 months were 92.9% and 94.2%, respectively, indicating that although acceptable, the effect was not as good as the present invention; however, the increase of impurity X was 153% and 134%, respectively. It is shown that the commercial product is inferior to the product of the present invention in terms of the increase rate of the impurity X.
  • the pharmaceutical composition of the invention was prepared according to the basic formulation of Table 2 below:
  • ingredient Weight (mg) Fluvastatin sodium 20mg Potassium chloride Specified amount Microcrystalline cellulose 40mg starch 30mg Sodium starch glycolate 5mg PVPK30 3mg Magnesium stearate 2mg
  • the materials are separately pulverized and passed through a 60 mesh sieve, so that the main drug and the inorganic salt are uniformly mixed, and then the diluent microcrystalline cellulose and starch are uniformly mixed; the mixed powder is prepared with 5% PVP K30 in 50% ethanol.
  • the solution is made into a soft material as a binder, wet granulated, dried at 50 ° C to a moisture content of less than 2.5%; the obtained dry granules are uniformly mixed with the disintegrant and the lubricant; half of the material is dispensed into the hard capsule shell, and the other half is Compressed into tablets.
  • the amount of potassium chloride was combined according to the amount (parts by weight) of fluvastatin sodium and potassium chloride described in the sample numbers Ex2-01 to Ex2-10 listed in Table 3 below, to obtain 10 Tablets and capsules of a mixture sample.
  • Ex2-08 100 45 91.1% 38%
  • Ex2-09 100 75 85.9% 41%
  • Ex2-10 100 100 82.6% 37%
  • Control Test 21 Refer to the method of Example 2 above and the formulations of Tables 2 and 3, except that potassium chloride was replaced with an equivalent amount of sodium chloride, and the resulting sample capsules were also treated at 40 ° C to 6 months.
  • the results showed that these samples were substantially the same as the use of potassium chloride in Example 2 in terms of the residual content of fluvastatin sodium and the increase in impurity X, that is, relative to 100 parts by weight of fluvastatin sodium, When the sodium chloride is added in an amount of 5 parts by weight or more, the increase of the impurity X is ⁇ 50%, which is in the range of 30 to 45%; but when the relative amount of sodium chloride is in the range of 5 to 30 parts by weight, fluorine The residual content of vastatin sodium is in the range of 96.5 to 98.5%; and when the relative amount of sodium chloride is 45 parts by weight or more, the active ingredient is reduced rapidly, and fluvastatin is used when 75 parts by weight and 100 parts by weight of sodium chloride are used.
  • Control Test 22 Refer to the method of Example 2 above and the formulation of Tables 2 and 3, except that potassium chloride is replaced with an equivalent amount of potassium bicarbonate (it is believed that the use of weakly alkaline salts helps to improve fluorosis)
  • the stability of statin sodium is also treated at 40 ° C to 6 months.
  • the results showed that the residual content of fluvastatin sodium in the four samples of 5 to 30 parts by weight of potassium bicarbonate was in the range of 91.2 to 93.6% after 6 months, indicating that although it is acceptable, it is still inferior to the effect of the present invention.
  • the residual content of fluvastatin sodium decreased by less than 90% after 6 months in the remaining 6 samples with a relative amount of potassium bicarbonate of less than 5 or more than 30 parts by weight, both in the range of 74.2 to 85.3%.
  • the increase of the impurity X in the range of 132 to 24% after 6 months showed that potassium hydrogencarbonate could not effectively suppress the increase of the impurity X.
  • Control Test 23 Refer to the method and formulation of Control Test 22 above, except that potassium bicarbonate is replaced with an equivalent amount of sodium bicarbonate (it is believed to be similar to potassium bicarbonate, which helps to increase fluvastatin sodium) Stability), also treated at 40 ° C - June.
  • Example 3 Preparation of the pharmaceutical composition of the present invention (sustained release tablet)
  • compositions of the invention were prepared according to the following basic formulation of Table 4:
  • Glyceryl behenate 48 Potassium chloride According to the amount specified in Table 5 Microcrystalline cellulose 90 Hydroxypropyl cellulose 9 HPMC-75HD 100 30 HPMC-75HD 15000 30 Magnesium stearate 4 total 300
  • the materials are separately pulverized and passed through a 60 mesh sieve, so that the main drug and the inorganic salt are uniformly mixed, and then mixed with glyceryl behenate and microcrystalline cellulose in a mixer, hydroxypropyl cellulose and two kinds are added.
  • HPMC mixed evenly, wet granules with 60% ethanol, dried, added magnesium stearate, mixed evenly, pressed into tablets, that is.
  • the amount of potassium chloride was combined according to the amount (parts by weight) of fluvastatin sodium and potassium chloride described in sample numbers Ex3-01 to Ex3-10 listed in Table 5 below, to obtain 10 Tablets and capsules of a mixture sample.
  • Control Test 31 Refer to the method of Example 3 above and the formulations of Tables 4 and 5, except that potassium chloride was replaced with an equivalent amount of sodium chloride, and the resulting sample tablets were also treated at 40 ° C to 6 months.
  • the results show that the residual content and impurities of these samples in fluvastatin sodium
  • the two aspects of the increase in X are substantially the same as those in the case of using potassium chloride in Example 3, that is, the impurity is added thereto when 5 parts by weight or more of sodium chloride is incorporated with respect to 100 parts by weight of fluvastatin sodium.
  • the increase of X is ⁇ 50%, both in the range of 30 ⁇ 45%, but the impurity X increases very fast when the amount of sodium chloride is small; the fluvastatin sodium when the relative amount of sodium chloride is in the range of 5-30 parts by weight The residual content is in the range of 96.5 to 98.5%; and when the relative amount of sodium chloride is less than 5 parts by weight or more than 45 parts by weight, the active ingredient is lowered faster.
  • Control Test 32 Refer to the method of Example 3 above and the formulations of Tables 4 and 5, except that potassium chloride is replaced with an equivalent amount of potassium bicarbonate (it is believed that the use of weakly basic salts helps to improve fluorosis)
  • the stability of statin sodium is also treated at 40 ° C to 6 months.
  • the results showed that the residual content of fluvastatin sodium in the four samples of 5 to 30 parts by weight of potassium bicarbonate was in the range of 90.6 to 93.3% after 6 months, indicating that although it is acceptable, it is still inferior to the effect of the present invention.
  • the residual content of fluvastatin sodium decreased by less than 90% after 6 months for the remaining 6 samples with a relative amount of potassium bicarbonate of less than 5 or more than 30 parts by weight, both in the range of 71.4 to 83.7%.
  • the increase of the impurity X in the range of 146 to 226% after 6 months showed that potassium hydrogencarbonate could not effectively suppress the increase of the impurity X.
  • step (iii) mixing the mixed powder material treated in step (ii) with the optional remaining pharmaceutical excipients according to conventional tablet or sustained release tablet preparation specifications, according to conventional tablets Or a method for preparing a sustained release tablet, which is prepared as a solid pharmaceutical composition in the form of a tablet.
  • the obtained 12 tablet samples were respectively recorded as Ex41-04, Ex41-05, Ex41-06, Ex41-07, Ex42-04, Ex42-05, Ex42-06, Ex42-07, Ex43-04, Ex43-05. , Ex43-06, Ex43-07.
  • Ex41-04, Ex41-05, Ex41-06, Ex41-07, Ex42-04, Ex42-05, Ex42-06, Ex42-07, Ex43-04, Ex43-05 prepared in Example 4 were also measured.
  • the difference in contact angles of the 12 samples prepared in Examples 1 to 3 which were slightly different from the corresponding formulations but the preparation process were calculated that is, for the same prescription, the contact angle
  • the difference (°) is equal to the difference in the contact angle of the tablet obtained by the method of Example 4 minus the contact angle of the tablet obtained by the methods of Examples 1 to 3.
  • the contact angle difference (°) is equal to the difference between the Ex41-05 tablet contact angle minus the Ex1-05 tablet contact angle.
  • Time lag (%) [(t1--t0) ⁇ t0] ⁇ 100%
  • the commercially available product fluvastatin sodium capsule and the commercial fluvastatin sodium sustained-release tablet provided by the control test 14 were used, and the contact angles of the two were determined to be 26° and 103°, respectively; After °C-6 months, the two samples were measured to release a 50% time lag (%) after being treated at 40 ° C to 6 months. As a result, the time lags of the capsule and the sustained release tablets were 19% and 27%, respectively.
  • the contact angles of the 12 tablets prepared in the above Examples 1 to 3 were smaller than those of the tablets obtained by the method of Example 4 in the same formulation, indicating that the tablets were less hydrophilic after being treated by the method of Example 4. .
  • the solid preparation prepared exhibited excellent properties in terms of contact angle and dissolution stability when the active ingredient and the inorganic salt were previously subjected to an ethanol atmosphere treatment.
  • Control Test 41 Preparation of a pharmaceutical composition
  • each tablet containing 20 mg of a tablet containing a relatively large amount of alkaline substance sodium citrate and polyacrylin potassium is labeled # 538 tablets.
  • each tablet contains 20 mg of the tablet, and the other half of the material is encapsulated, which contains a relatively large amount of the alkaline substance sodium hydrogencarbonate.
  • the sample was labeled as #634 tablets.
  • Example 1-2 of CN1328454A (Chinese Patent Application No. 99812081.2)
  • a sustained-release tablet containing a relatively large amount of an alkaline substance potassium hydrogencarbonate which is labeled as #454 tablets, was prepared.
  • ingredient Weight (mg) Fluvastatin sodium 20mg Potassium chloride (inorganic salt) 5mg Microcrystalline cellulose (diluent) 150mg Lactose (diluent) 150mg HPMC (adhesive, used in 5% solution with 50% ethanol) 5mg Cross-linked sodium carboxymethyl cellulose (disintegrant) 8mg PEG6000 (lubricant) 2mg
  • Method separately pulverizing each material and passing through a 60 mesh sieve; mixing the main drug and the inorganic salt uniformly, and then adding the diluent to mix uniformly; the mixed powder is granulated with a binder, and dried at 50 ° C until the water content is less than 2.5 %; the obtained dry granules are uniformly mixed with the disintegrant and the lubricant; half of the material is dispensed into a hard capsule shell to form a capsule; the other half is compressed into a tablet; and the obtained tablet is directly sealed and packaged for treatment. Tablet; the other half of the tablets obtained 85F20694 is coated and the coating material is 3% of the total weight of the final tablet.
  • the contact angles of the three samples were all in the range of 63 to 69°.
  • the capsule, the plain tablet and the coated tablet obtained in the present example were sealed and packaged, and the stability was examined according to the method of Test Method Example 4.
  • the results showed that the residual content of fluvastatin sodium in capsules, plain tablets and coated tablets was in the range of 97.3 to 98.7%, and the increase of impurity X was in the range of 28 to 31%, indicating that they have good Chemical stability.
  • PEG2000 adheresive, used in 5% solution with water
  • Crosslinked polyethylene polypyrrolidone disintegrant
  • Colloidal silica lubricant
  • Stearic acid lubricant
  • Method separately pulverizing each material and passing through a 60 mesh sieve; mixing the main drug and the inorganic salt uniformly, and then adding the diluent to mix uniformly; the mixed powder is granulated with a binder, and dried at 50 ° C until the water content is less than 2.5 %; the obtained dry granules are uniformly mixed with the disintegrant and the lubricant; half of the material is dispensed into a hard capsule shell to form a capsule; the other half is compressed into a tablet; and the obtained tablet is directly sealed and packaged for treatment. Tablet; the other half of the tablets obtained The coating was applied at 85F23452, and the coating material accounted for 3% of the total weight of the final tablet. The contact angles of the three samples were all in the range of 77 to 81°.
  • the capsule, the plain tablet and the coated tablet obtained in the present example were sealed and packaged, and the stability was examined according to the method of Test Method Example 4.
  • the results showed that the residual content of fluvastatin sodium in capsules, plain tablets and coated tablets was in the range of 96.9-98.1%, and the increase of impurity X was in the range of 32-35%, indicating that they have good Chemical stability.
  • Method separately pulverizing each material and passing through a 60 mesh sieve; mixing the main drug and the inorganic salt uniformly, and then adding the diluent to mix uniformly; the mixed powder is granulated with a binder, and dried at 50 ° C until the water content is less than 2.5 %; the obtained dry granules are uniformly mixed with the disintegrant and the lubricant; half of the material is dispensed into a hard capsule shell to form a capsule; the other half is compressed into a tablet; and the obtained tablet is directly sealed and packaged for treatment. Tablet; the other half of the tablets obtained Coating was carried out on 85F32004, and the coating material accounted for 4% of the total weight of the final tablet.
  • the contact angles of the three samples were all in the range of 36 to 40°.
  • the capsule, the plain tablet and the coated tablet obtained in the present example were sealed and packaged, and the stability was examined according to the method of Test Method Example 4.
  • the results showed that the residual content of fluvastatin sodium in capsules, plain tablets and coated tablets was in the range of 96.6 to 97.8%, and the increase of impurity X was in the range of 29 to 33%, indicating that they have good Chemical stability.
  • Example 8 Preparation of the pharmaceutical composition of the present invention (sustained release tablet)
  • compositions of the invention were prepared according to the following basic formulation of Table 4:
  • Potassium chloride 15 Microcrystalline cellulose 90 Hydroxypropyl cellulose 35 HPMC-75HD 100 30 HPMC-75HD 15000 40 PVP-K30 7 Magnesium stearate 3
  • the materials are separately pulverized and passed through a 60 mesh sieve, so that the main drug and the inorganic salt are uniformly mixed, and then mixed with the microcrystalline cellulose in a mixer, and hydroxypropyl cellulose and two kinds of HPMC are added and uniformly mixed.
  • the 5% PVP-K30 solution (made of 60% ethanol) was made into wet granules, dried, added with magnesium stearate, uniformly mixed, and compressed into tablets. Half of the amount is directly sealed in plain tablets and the other half is used. Coating was carried out on 85F32004, and the coating material accounted for 4% of the total weight of the final tablet.
  • the contact angles of the two samples were all in the range of 56 to 59°.
  • the obtained primed tablets and coated tablets of this example were sealed and packaged, and the stability of the test method was examined according to the method of Test Method 4.
  • the results showed that the residual content of fluvastatin sodium in the plain and coated tablets was in the range of 96.9-97.4%, and the increase of impurity X was in the range of 34-37%, indicating that they have good chemical stability. .
  • the contact angles of the four samples were determined to be in the range of 42 to 78°.
  • Each tablet was tested for stability according to the method of Test Method Example 4. The results showed that the residual content of fluvastatin sodium in the four tablets was in the range of 96.5-98.1%, and the increase of impurity X was in the range of 25-36%, indicating that they have good chemical stability.
  • the four samples were released from 40 ° C to 6 months and the 50% time lag (%) was in the range of -3% to 8%.
  • Example 9 Four samples of Ex3-04, Ex3-05, Ex3-06, and Ex3-07 obtained in Example 3, the obtained tablets and coated tablets of Example 8, the sustained release tablets obtained in Example 9, and the control test 14 were provided.
  • Commercially available fluvastatin sodium sustained-release tablets, and a sample of these sustained-release preparations were subjected to a dissolution test in a slurry method (50 rpm) for 30 hours in 900 ml of water, and the results showed that Example 3, Example 8 and the implementation of the present invention were carried out.
  • Each sample of Example 9 was consistent with the release profile of a commercially available sustained release tablet and was slowly released within 20 hours.
  • Test articles coated tablets having the characteristics of the present invention obtained from Ex2-04 to Ex2-07 tablets, Ex3-04 to Ex3-07 tablets, Example 4 tablets, and Examples 5 to 9.
  • Detection method The method is tested according to the method under the USP 35 USP35 version 3270 "Fravastatin capsule".

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Abstract

一种氟伐他汀钠固体药物组合物，包含氟伐他汀钠、无机盐、和任选的药用辅料。所述固体药物组合物具有良好的化学稳定性。

Description

氟伐他汀钠药物组合物 技术领域
本发明属于医药技术领域，涉及一种新的稳定的固体药物配方，其特别适用于治疗高胆固醇血症及高脂血症。本发明尤其涉及一种含有活性物质HMG-CoA还原酶抑制剂氟伐他汀或者其药物活性盐的新的稳定的固体药物配方。具体涉及一种氟伐他汀钠的固体药物组合物，特别是涉及一种具有优良稳定特性的氟伐他汀钠固体药物组合物。本发明还进一步地涉及该氟伐他汀钠固体药物组合物的制备方法。
背景技术
氟伐他汀已知是HMG-CoA还原酶抑制剂，作为一种他汀类药物已在临床上用作抗高胆固醇血症制剂。与辛伐他汀等使用属于曲霉属、红曲霉属、诺卡茵属、Amycolatopsis、毛霉属或青霉属的不同物种的微生物通过发酵而生产的HMG-CoA还原酶抑制剂不同，氟伐他汀是第一个全合成的HMG-CoA还原酶抑制剂，并且其在部分结构上区别于此类治疗药物的真菌衍生物。
氟伐他汀在临床上通常以其钠盐使用，具有口感好，吸湿性高，在酸性介质中溶解度低，对热、潮湿、光照稳定性低，在酸性含水介质中不稳定等特点。在制备氟伐他汀钠制剂时，需要避免氟伐他汀直接接触空气，例如通过使用薄膜包衣来避免，而且还需要采取稳定措施以提高制剂的稳定性。一般用碱性介质将氟伐他汀钠制成适宜的制剂，使氟伐他汀水溶液或分散体的pH值至少为8。在现有技术中公知的是，他汀类药物在pH小于8时极易降解，因此现有技术中的药物组合物还包含碱化稳定剂或碱化剂以保持偏高的pH值并避免HMG-CoA还原酶抑制剂的降解。常用的碱化稳定剂例如碳酸钙、氢氧化钙、磷酸二钙、磷酸三钙、碳酸镁、氢氧化镁、硅酸镁、铝酸镁、氢氧化铝镁、氢氧化锂、氢氧化钾、碳酸氢钠、硼酸钠、碳酸钠、氢氧化钠等。此外，由于他汀类药物在潮湿和光照条件下不稳定，因此通常制造低含水量的制剂。
活性物质的纯度是生产安全且有效的药物配方的一个重要因素，如果必须长期服用药物以治疗或预防血液中胆固醇水平增高，则药物的最高纯度是尤为重要的，低纯度药物中的杂质累积可在治疗期间引起各种副作用。除了左制备活性物质过程中不能完全消除的杂质之外，最终药物配方接触各种环境因素如温度、湿度、低pH值及光照所产生的降解产物也是一个问题。在最终药物配方中以盐形式存在的HMG-CoA还原酶抑制剂如氟伐他汀尤其对酸性环境敏感，在此环境中羟酸被降解为内酯及其它杂质。
除了上述活性物质可被环境因素不稳定化之外，其也可通过与其它药物成分如填充剂，粘合剂，润滑剂，助流剂和崩解剂相互作用而加速降解。因而，制备药物配方的药物成分和方法应非常细致以避免上述非所需的相互作用及反应。
活性物质在酸性环境中的稳定性抑制因素是盐形式情况下的主要问题之一。上述问题的一个可能解决方案是EP0336298中阐述的方案，该专利分开了一个普伐他汀的稳定药物配方。该配方的精髓是保持碱性环境，这样药物配方的水分散系的pH值达到9以上，优选大约为10。除活性物质普伐他汀之外，该发明的组合物包括碱化剂如使上述配方的水分散系的pH值在9之上的氧化镁。考虑到活性物质的稳定性，这种配方是有效的。然而，在药物配方溶解位点发生的局部碱性环境对正常应具有酸性环境的胃粘膜有一定副作用。此副作用对胃粘膜在胃内不能产生有效的酸性环境以进行正常消化功能的胃粘膜损 伤的患者尤为明显。这在用HMG-CoA还原酶抑制剂进行预防或治疗的长期疗法中是非常重要的。
在美国专利申请US10/100656号和美国专利US6242003中，报道了氟伐他汀钠的控释片剂制剂。据报道，所公开的片剂每天给药一次，产生超过12小时的有效的血浆药物浓度。美国专利申请公开US2002/0169145A1号报道了包含HMG-CoA还原酶抑制剂化合物的商品制剂的剂型，所述剂型含有羟丙甲纤维素和非离子型亲水性聚合物以防止过早释放大量活性成分。据报导所述非离子型亲水性聚合物选自羟乙基纤维素(分子量约90000至1300000)、羟丙基纤维素(分子量约370000至1500000)和聚环氧烷(分子量约100000至500000)。美国专利US6242003报道了应用具有确定的颗粒粒度的羟丙甲纤维素和氟伐他汀，得到颜色稳定的延释制剂。美国专利US5356896、US6531507和US6558659和美国专利申请公开US2003/0109584A1公开了多种用于使对酸敏感的他汀类化合物稳定的方法。美国专利US5356896公开了稳定的药物组合物，所述组合物包含能够给予所述化合物的水溶液或分散体至少为8的pH值的碱化稳定介质。美国专利US6531507公开了用于稳定他汀类药物的替代方法，即通过将对酸敏感的活性成分与缓冲荆或碱化物质共结晶或共沉淀，以保持他汀类活性成分的稳定。
WO2004/071402公开了一种包含一种以上对pH敏感的活性成分和一种以上药用赋形剂，其中含水量小于约3.5％，并且不含稳定剂或缓冲剂或其组合。
中国专利申请号CN200510080626.9、CN01807914.8、CN93100650.3、CN200480017403.1、CN200780014499.X公开了氟伐他汀钠的制剂。这些制剂在为提高氟伐他汀钠药剂质量方面作出了诸多努力。
然而本领域技术人员仍然期待有新的方法以便制备具有优良性能的氟伐他汀钠的固体制剂，例如下列的至少一个方面：少用或不用碱化剂以避免碱化剂对胃液酸性环境的破坏作用，具有良好的化学稳定性例如在贮藏过程中杂质增加速度更慢，具有良好的安全性例如减少因杂质生成造成的生物学安全性隐患。
发明内容
本发明目的是提供一种具有优良性能的氟伐他汀钠的固体制剂，其例如具有下列的至少一个方面：少用或不用碱化剂以避免碱化剂对胃液酸性环境的破坏作用，具有良好的化学稳定性例如在贮藏过程中杂质增加速度更慢，具有良好的安全性例如减少因杂质生成造成的生物学安全性隐患。本发明发现具有特定配方的氟伐他汀钠固体药物组合物出人意料地呈现至少一个上述优异特征。本发明基于此发现而得以完成。
由此，本发明第一方面提供了一种固体药物组合物，其中包含氟伐他汀钠、无机盐、和任选的药用辅料。
根据本发明第一方面任一实施方案的固体药物组合物，其中所述的无机盐是酸碱性基本上呈中性的无机盐。
根据本发明第一方面任一实施方案的固体药物组合物，其中所述的无机盐选自：磷酸二钙、磷酸三钙、碳酸镁、硅酸镁、铝酸镁、碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、硼酸钠、氯化钠、氯化钾或其组合。在一个实施方案中，所述的无机盐选自氯化钠、氯化钾或其组合。
根据本发明第一方面任一实施方案的固体药物组合物，其中无机盐与氟伐他汀钠的重量比为2～50∶ 100，例如二者的重量比为3～30∶100，例如二者的重量比为5～30∶100。
根据本发明第一方面任一实施方案的固体药物组合物，其中所述氟伐他汀钠占该固体药物组合物总重量的1～99％，例如2～80％，例如5～75％。鉴于本发明使用无机盐与氟伐他汀钠组合配制成固体药物组合物，可以赋予该组合物优异的性能。因此，在该组合物中，除了所述无机盐与氟伐他汀钠之外，其它的药用辅料的量是不受特别限制的，通常以赋予该组合物适宜剂型的量添加，例如制备片剂或胶囊剂时因其剂型总重量较小而可以适当少地添加这些药用辅料；而例如制备颗粒剂时因其剂型总重量可以较大而可以适当多地添加这些药用辅料。
根据本发明第一方面任一实施方案的固体药物组合物，其中所述药用辅料是选自下列的一种或者多种：填充剂、崩解剂、粘合剂、润滑剂。鉴于本发明出人意料地发现，使氟伐他汀钠与所述无机盐混合后可以赋予组合物特定性能并使得氟伐他汀钠具有优异的化学稳定性，即本发明对现有技术的特殊贡献在于发现这种特殊组合，因此本发明组合和中可以包括所述的药用辅料，也可以不包括所述的药用辅料。
根据本发明第一方面任一实施方案的固体药物组合物，其中所述填充剂(通常亦可称为稀释剂)包括但不限于：淀粉或其衍生物例如玉米淀粉、预胶化淀粉、改良淀粉等；纤维素或其衍生物例如微晶纤维素、乙基纤维素、甲基纤维素等；糖类例如葡萄糖、蔗糖、乳糖、甘露醇、山梨醇；呈中性的矿物质例如碳酸钙、磷酸氢钙等及其组合。如本文所用，术语“稀释剂”或者“填充剂”定义为用于增加药物组合物的重量和/或尺寸的惰性材料，稀释剂或填充剂在组合物中可以物质的形式或化合物混合物的形式存在。优选地，当活性成分和其它赋形剂的量太少不能获得适宜尺寸的片剂时加入稀释剂或填充剂。可根据本领域技术人员熟知的常规方法来确定根据本发明药物组合物所必需的稀释剂或填充剂的重量百分数，特别是在其它辅料例如崩解剂、粘合剂、润滑剂等用量确定后，根据制剂尺寸要求适量使用稀释剂或填充剂。
根据本发明第一方面任一实施方案的固体药物组合物，其中所述崩解剂包括但不限于：交联聚乙烯聚吡咯烷酮、淀粉羟基乙酸钠、交联羧甲基纤维素钠、低取代羟丙基纤维素等及其组合。进一步地，药物组合物包括相对于药物组合物的总重量的0至10％的崩解剂，例如0至8％的崩解剂，例如0至5％的崩解剂，其亦可以根据本领域技术人员的经验使用；不使用或者少使用崩解剂的药物制剂也是常见的，例如出于缓释目的而制成的溶浊型骨架缓释片。鉴于本发明呈制剂形式的固体药物组合物在某些情况下可以不具崩解性能，例如当它们呈胶囊剂时，因此在这些情况下本发明固体药物组合物中可以不添加崩解剂。
根据本发明第一方面任一实施方案的固体药物组合物，其中所述粘合剂包括但不限于：聚乙二醇、淀粉、聚乙烯吡咯烷酮、羟丙基甲基纤维素等及其组合。鉴于许多固体药物制剂的物料本身具有一定的粘合性并且可以使用水作为润湿剂来进行湿法制粒，因此在本发明中还可以使用水为润湿剂来作为潜在的粘合剂，尽管在本发明固体药物组合物在最终成品中将这些作为润湿剂的水除尽。另外，许多固体药物制剂的物料本身具有粘合性而可实现粉末直接压片或粉末直接装胶囊。可见，粘合剂在本发明固体药物组合物中是可以添加的，也可以不添加的。即使是使用湿法制粒技术，粘合剂仍然可以不添加。如果添加，粘合剂的用量相对于药物组合物的总重量的0.1至10％、0.2至5％、或0.5至2.5％，其亦可以根据本领域技术人员的经验使用。
根据本发明第一方面任一实施方案的固体药物组合物，其中所述润滑剂(包括助流剂)，其作用是使得粉体物料能够顺利地进行制剂成型，例如制备胶囊剂时可以使粉体物料均匀填充到胶囊壳中，例如制备片剂时可以使粉体物料均匀填充到压片机的模中并且避免粘冲。润滑剂的实例包括但不限于：硬脂酸镁、硬脂酸钙、滑石粉、淀粉、硬脂酸、胶体二氧化硅、聚乙二醇等。如果添加，润滑剂的用量相对于药物组合物的总重量的0.2至10％、0.25至5％，其亦可以根据本领域技术人员的经验使用。
根据本发明第一方面任一实施方案的固体药物组合物，其中还可以包括释放调节剂。释放调节剂可以调节或控制所述固体药物组合物在消化液中药物的释放速度和程度。特别是对于期待延缓释放的药物制剂例如缓释片剂。典型的药物释放调节剂例如但不限于：羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、海藻酸钠、黄原胶、聚乙烯醇、山嵛酸甘油酯等及其组合。以缓释为目的向片剂中添加药物释放调节剂的量是本领域技术人员可以容易确定的，例如当它们存在时，通常占组合物总重量的5～50％，例如10～40％。
根据本发明第一方面任一实施方案的固体药物组合物，其是呈选自下列的药物剂型：片剂、胶囊剂、颗粒剂等。
根据本发明第一方面任一实施方案的固体药物组合物，其是未包衣的或用包衣材料包衣的片剂。
根据本发明第一方面任一实施方案的固体药物组合物，其是包衣的片剂。进一步地，该包衣片剂包括相对于片剂总重量1％至6％、2％至5％的包衣材料。在一个实施方案中，所述的包衣材料选自乙基纤维素、羟丙基甲基纤维素和甲基丙烯酸-烷基丙烯酸酯共聚物。在一个实施方案中，所述的包衣材料是羟丙基甲基纤维素含水分散体。在一个实施方案中，所述的包衣材料是
Figure PCTCN2015000168-appb-000001
是羟丙基甲基纤维素含水分散体；进一步地，包衣材料选自
Figure PCTCN2015000168-appb-000002
85F20694、
Figure PCTCN2015000168-appb-000003
85F32004、
Figure PCTCN2015000168-appb-000004
85F23452和
Figure PCTCN2015000168-appb-000005
85F18422。
根据本发明第一方面任一实施方案的固体药物组合物，其包含：
氟伐他汀钠20重量分、
无机盐0.4～10重量份、
药用辅料0～500重量份。
根据本发明第一方面任一实施方案的固体药物组合物，其包含：
氟伐他汀钠20重量分、
无机盐0.6～6重量份、
药用辅料10～400重量份。
根据本发明第一方面任一实施方案的固体药物组合物，其包含：
氟伐他汀钠20重量分、
无机盐1～6重量份、
药用辅料25～250重量份。
根据本发明第一方面任一实施方案的固体药物组合物，其中不包括包衣的所述药物组合物(例如临压片前的颗粒状物料、未包衣的素片、或者经过包衣的片芯)具有小于110°的接触角，例如具有小于100°的接触角，例如具有小于90°的接触角，例如具有小于85°的接触角；然而从工业适用性讲，接触角不应 小于30°。因此，在本发明一个实施方案中，本发明药物组合物例如片剂与水的接触角为30°～100°，例如30°～90°，例如30°～85°。
根据本发明第一方面任一实施方案的固体药物组合物，其中所述的接触角是指与水的接触角。具体地，接触角是指滴加于片剂等固体制剂组合物表面的水滴与组合物表面接触的角度。本领域技术人员知晓有许多测定接触角的方法和装置，在本发明中，一个示例性的测定方法如下：在针头(例如型号为SNSO52/026；HAMILTON公司产，不锈钢制、内径0.26mm、外径0.52mm；或者也可用具有类似规格的针头)的针尖形成1μl纯水(MILLI-Q；MILLIPORE公司)液滴，再通过接触角测定装置(例如OCA-15型，Data physics公司；或者具有类似功能的其它品牌或型号的接触角测定装置)测定水滴加到片剂表面60毫秒后的接触角。片剂表面有曲率时，在解析时要校正为直线后再测定接触角；通常是室温下测定。在本发明中，如未另外说明，本发明所述接触角是由以下方法测定的：在室温下，在针头(SNSO52/026；HAMILTON公司产，不锈钢制、内径0.26mm、外径0.52mm)的针尖形成1μl纯水(MILLI-Q；MILLIPORE公司)液滴，再通过接触角测定装置(OCA-15型，Data physics公司)测定水滴加到片剂表面60毫秒后的接触角。由于以上述类似条件测定得到的接触角，在不同环境(例如不同实验室)、不同设备(例如使用其它公司生产的接触角测定装置)，这些结果不会有明显的区别，因此在定义本发明所述组合物的接触角时，无需对接触角的具体测定过程和测定条件作限定。对于不是片剂的固体制剂，例如胶囊剂、颗粒剂、散剂等，可以通过将制剂中含有的粉末、颗粒、半固体物质等压制成片剂形状，再进行测定，例如对于胶囊剂，可通过取出胶囊内容物，取其中约200mg压制成直径8mm、厚度3.5mm的表面平坦且光滑的片剂来测定接触角。即使对于不能有效反映其真实属性的片剂，例如包薄膜衣、肠溶衣或者糖衣的片剂，也可以通过将片剂表面上的衣层刮去，然后再将片剂研碎，再参照上述胶囊剂的方式，将片剂研碎所得粉末重新压制成片后再测定。对于本发明组合物，其在制备未压制成片时，可以取粉末适量压制成片后进行测定；其在制备成未包衣的素片时，可以直接进行测定；其在经包衣制成包衣片时，可以将片剂表面上的衣层刮去，然后再将片剂研碎，再将所得粉末重新压制成片后测定。
进一步地，本发明第二方面提供了制备本发明第一方面任一实施方案所述固体药物组合物的方法，其包括以下步骤：
(1)将各物料分别粉碎至可通过60目筛，将处方量的氟伐他汀钠与无机盐充分混合均匀，得混合粉末物料；
(2)按常规固体药物制剂的方法，使经步骤(1)处理的混合粉末物料与任选的药用辅料混合，制备成呈固体药物制剂形式的固体药物组合物，即得。
根据本发明第二方面任一实施方案所述的方法，其中步骤(2)所制得的固体药物制剂选自：片剂、胶囊剂、颗粒剂。
根据本发明第二方面任一实施方案所述的方法，其中步骤(2)中在制备所述固体药物制剂时，可以按湿法制粒法、或者干法制粒法制备颗粒，再按常规方法压片、装胶囊或者分装成颗粒剂。
根据本发明第二方面任一实施方案所述的方法，其中步骤(2)中在制备所述固体药物制剂时，可以不进行制粒而直接使所得粉末混合物进行粉末直接压片、粉末装胶囊、或者粉末分装成颗粒剂(粉末装的颗粒剂通常亦称为散剂)
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中包含氟伐他汀钠、无机盐、和任选的药用辅料。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中的无机盐是酸碱性基本上呈中性的无机盐。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中的无机盐选自：磷酸二钙、磷酸三钙、碳酸镁、硅酸镁、铝酸镁、碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、硼酸钠、氯化钠、氯化钾或其组合。在一个实施方案中，所述的无机盐选自氯化钠、氯化钾或其组合。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中无机盐与氟伐他汀钠的重量比为2～50∶100，例如二者的重量比为3～30∶100，例如二者的重量比为5～30∶100。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中所述氟伐他汀钠占该固体药物组合物总重量的1～99％，例如2～80％，例如5～75％。鉴于本发明使用无机盐与氟伐他汀钠组合配制成固体药物组合物，可以赋予该组合物优异的性能。因此，在该组合物中，除了所述无机盐与氟伐他汀钠之外，其它的药用辅料的量是不受特别限制的，通常以赋予该组合物适宜剂型的量添加，例如制备片剂或胶囊剂时因其剂型总重量较小而可以适当少地添加这些药用辅料；而例如制备颗粒剂时因其剂型总重量可以较大而可以适当多地添加这些药用辅料。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中所述药用辅料是选自下列的一种或者多种：填充剂、崩解剂、粘合剂、润滑剂。鉴于本发明出人意料地发现，使氟伐他汀钠与所述无机盐混合后可以赋予组合物特定性能并使得氟伐他汀钠具有优异的化学稳定性，即本发明对现有技术的特殊贡献在于发现这种特殊组合，因此本发明组合和中可以包括所述的药用辅料，也可以不包括所述的药用辅料。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中所述填充剂(通常亦可称为稀释剂)包括但不限于：淀粉或其衍生物例如玉米淀粉、预胶化淀粉、改良淀粉等；纤维素或其衍生物例如微晶纤维素、乙基纤维素、甲基纤维素等；糖类例如葡萄糖、蔗糖、乳糖、甘露醇、山梨醇；呈中性的矿物质例如碳酸钙、磷酸氢钙等及其组合。如本文所用，术语“稀释剂”或者“填充剂”定义为用于增加药物组合物的重量和/或尺寸的惰性材料，稀释剂或填充剂在组合物中可以物质的形式或化合物混合物的形式存在。优选地，当活性成分和其它赋形剂的量太少不能获得适宜尺寸的片剂时加入稀释剂或填充剂。可根据本领域技术人员熟知的常规方法来确定根据本发明药物组合物所必需的稀释剂或填充剂的重量百分数，特别是在其它辅料例如崩解剂、粘合剂、润滑剂等用量确定后，根据制剂尺寸要求适量使用稀释剂或填充剂。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中所述崩解剂包括但不限于：交联聚乙烯聚吡咯烷酮、淀粉羟基乙酸钠、交联羧甲纤维素钠、低取代羟丙基纤维素等及其组合。进一步地，药物组合物包括相对于药物组合物的总重量的1至10％的崩解剂，例如2至8％的崩解剂，例如2至5％的崩解剂，其亦可以根据本领域技术人员的经验使用。鉴于本发明呈制剂形式的固体药物组合物在某些情况下可以不具崩解性能，例如当它们呈胶囊剂时，因此在这些情况下本发明固体药物组合物中可以不添加崩解剂。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中所述粘合剂包括但不限于：聚乙二醇、淀粉、聚乙烯吡咯烷酮、羟丙基甲基纤维素等及其组合。鉴于许多固体药物制剂的物料本身具有一定的粘合性并且可以使用水作为润湿剂来进行湿法制粒，因此在本发明中还可以使用水为润湿剂来作为潜在的粘合剂，尽管在本发明固体药物组合物在最终成品中将这些作为润湿剂的水除尽。另外，许多固体药物制剂的物料本身具有粘合性而可实现粉末直接压片或粉末直接装胶囊。可见，粘合剂在本发明固体药物组合物中是可以添加的，也可以不添加的。即使是使用湿法制粒技术，粘合剂仍然可以不添加。如果添加，粘合剂的用量相对于药物组合物的总重量的0.1至10％、0.2至5％、或0.5至2.5％，其亦可以根据本领域技术人员的经验使用。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中中所述润滑剂(包括助流剂)，其作用是使得粉体物料能够顺利地进行制剂成型，例如制备胶囊剂时可以使粉体物料均匀填充到胶囊壳中，例如制备片剂时可以使粉体物料均匀填充到压片机的模中并且避免粘冲。润滑剂的实例包括但不限于：硬脂酸镁、硬脂酸钙、滑石粉、淀粉、硬脂酸、胶体二氧化硅、聚乙二醇等。如果添加，润滑剂的用量相对于药物组合物的总重量的0.2至10％、0.25至5％，其亦可以根据本领域技术人员的经验使用。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中中还可以包括释放调节剂。释放调节剂可以调节或控制所述固体药物组合物在消化液中药物的释放速度和程度。特别是对于期待延缓释放的药物制剂例如缓释片剂。典型的药物释放调节剂例如但不限于：羟丙基甲基纤维素、羟丙基纤维素、聚乙烯醇、山嵛酸甘油酯等。以缓释为目的向片剂中添加药物释放调节剂的量是本领域技术人员可以容易确定的，例如当它们存在时，通常占组合物总重量的5～50％，例如10～40％。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物是呈选自下列的药物剂型：片剂、胶囊剂、颗粒剂等。
根据本发明第二方面任一实施方案所述的方法，其中在步骤(1)中，在得到混合粉末之后，还包括以下处理步骤：使所得混合粉末物料以不超过一厘米的厚度平辅在不锈钢平板上，再置于用乙醇饱和空气氛的密封箱中密封处置24～30小时。
根据本发明第二方面任一实施方案所述的方法，其中所述固体药物组合物是片剂，并且其中所述方法还包括对所述片剂进行包衣的步骤。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物是未包衣的或用包衣材料包衣的片剂。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物是包衣的片剂。进一步地，该包衣片剂包括相对于片剂总重量1％至6％、2％至5％的包衣材料。在一个实施方案中，所述的包衣材料选自乙基纤维素、羟丙基甲基纤维素和甲基丙烯酸-烷基丙烯酸酯共聚物。在一个实施方案中，所述的包衣材料是羟丙基甲基纤维素含水分散体。在一个实施方案中，所述的包衣材料是
Figure PCTCN2015000168-appb-000006
是羟丙基甲基纤维素含水分散体；进一步地，包衣材料选自
Figure PCTCN2015000168-appb-000007
85F20694、
Figure PCTCN2015000168-appb-000008
85F32004、
Figure PCTCN2015000168-appb-000009
85F23452和
Figure PCTCN2015000168-appb-000010
85F18422。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中其包含：
氟伐他汀钠20重量分、
无机盐0.4～10重量份、
药用辅料0～500重量份。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中其包含：
氟伐他汀钠20重量分、
无机盐0.6～6重量份、
药用辅料10～400重量份。
根据本发明第二方面任一实施方案所述的方法，所述固体药物组合物中其包含：
氟伐他汀钠20重量分、
无机盐1～6重量份、
药用辅料25～250重量份。
根据本发明第二方面任一实施方案所述的方法，其中不包括包衣的所述固体药物组合物(例如临压片前的颗粒状物料、未包衣的素片、或者经过包衣的片芯)具有小于110°的接触角，例如具有小于100°的接触角，例如具有小于90°的接触角，例如具有小于85°的接触角；然而从工业适用性讲，接触角不应小于30°。因此，在本发明一个实施方案中，本发明药物组合物例如片剂与水的接触角为30°～100°，例如30°～90°，例如30°～85°。
进一步地，本发明第三方面涉及本发明第一方面任一实施方案所述固体药物组合物在制备用于治疗或预防高胆固醇血症及高脂血症的药物中的用途。
本发明第三方面涉及本发明第一方面任一实施方案所述固体药物组合物在制备用于治疗或预防用于饮食未能完全控制的原发性高胆固醇血症和原发性混合型血脂异常(Fredrickson IIa和IIb型)的药物中的用途。
本发明任一方面或该任一方面的任一实施方案所具有的任一技术特征同样适用其它任一实施方案或其它任一方面的任一实施方案，只要它们不会相互矛盾，当然在相互之间适用时，必要的话可对相应特征作适当修饰。下面对本发明的各个方面和特点作进一步的描述。
本发明所引述的所有文献，它们的全部内容通过引用并入本文，并且如果这些文献所表达的含义与本发明不一致时，以本发明的表述为准。此外，本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表述的含义为准。
下面对本发明的各个方面作进一步描述。
在本发明中，如无另外说明，％是重量/重量的百分数。
在本发明中，氟伐他汀钠的化学名为：[R*，S*-(E)]-(±)-7-[3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基]-3，5-二羟基-6-庚烯酸单钠盐，英文化学名为：[R*，S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-y1]-3，5-dihydroxy-6-heptenoic acid，monosodium salt，有时亦称为(3RS，55R，6E)-7-[3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基]-3，5-羟基庚-6-烯酸钠，分子式C24H25FNO4·Na，分子量433.5，其化学结构式为：
Figure PCTCN2015000168-appb-000011
及其对映体。
本发明氟伐他汀钠通常的适应症为：用于饮食未能完全控制的原发性高胆固醇血症和原发性混合型血脂异常(Fredrickson IIa和IIb型)。通常单位剂量可以是：20mg、40mg、或80mg。常规剂型的常规推荐剂量为20或40mg，每日一次，缓释剂的常规一次剂量为80mg；晚餐时或睡前吞服。通常而言，要根据个体对药物和饮食治疗的反应以及公认的治疗指南来调整剂量。胆固醇极高或对药物反应不佳者.可增加剂量至40毫克每日两次。给药后，四周内达到最大降低低密度脂蛋白胆固醇(LDL-C)作用。长期服用持续有效。
氟伐他汀钠是一个全合成的降胆固醇药物，是羟甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂，可与HMG-CoA还原酶竞争，抑制HMG-CoA转化为3-甲基-3，5-二羟戊酸，而3-甲基-3，5-二羟戊酸是甾醇包括胆固醇的前体物质。本品的作用部位主要在肝脏，具有抑制内源性胆固醇的合成。降低肝细胞内胆固醇的含量，刺激低密度脂蛋白(LDL)受体的合成，提高LDL微粒的摄取，降低血浆总胆固醇浓度的作用。在高胆固醇血症和混合性血脂紊乱的患者中，本品可以减少总胆固醇(TC)，低密度脂蛋白胆固醇(LDL-C)，载脂蛋白B(apo-B)和甘油三酯(TG)水平，增加高密度脂蛋白胆固醇(HDL-C)水平。在使用药物2周内出现良好的治疗效果，从治疗开始4周之内出现最大的效应，此效应在整个治疗过程中持续存在。已知氟伐他汀钠对小鼠的LD50大于2g/kg，对大鼠的LD50大于0.7g/kg。
具体实施方式
所提供的以下实施例仅用于解释目的而不是用于，也不应被解释为以任何方式限制本发明。本领域那些技术人员将会认识到在不超越本发明的精神或范围的情况下可对以下实施例做出常规变化和修改。以下制备组合物的例子中，如未另外说明，以投料1万单位制剂例如(片剂、胶囊剂)的量制备，每片或每粒胶囊含活性成分为20mg(缓释片剂含活性成分80mg/片)。以下制备组合物的例子中，如未另外说明，各种物料在使用前均进行粉碎并且可以通过80目筛子。
A、测试方法例部分
测试方法例1：测定接触角
针头：型号为SNSO52/026；HAMILTON公司产，不锈钢制、内径0.26mm、外径0.52mm；
纯水：MILLI-Q(MILLIPORE公司产)制纯水；
接触角测定装置：CA-15型，Data physics公司产；
测定方法：在针尖形成1μl纯水液滴，测定其滴到压制成片的表面60毫秒后的接触角。
试样处理：压片前的物料先将其压制成平面药片再测定接触角；已经压制成形的药片直接测定，但如果是非平面药片时在计算时对片剂表面的曲率作校正；对于已经包衣的片，将衣层完全刮除，再研成 细粉，然后再压制成平面药片后测定；对于颗粒剂或者胶囊剂，将其内容物研成细粉，然后再压制成平面药片后测定。
已经在试验中发现，对于每一批样品，其在压片前的颗粒(其可直接装胶囊或者分装成颗粒剂)、压制成的素片、经包衣的片剂括除包衣再压制成的片，在按上述“试样处理”后，三种试样测得的接触角基本相同(三种情形相差不超过5°)。
测试方法例2：HPLC法测定活性成分的含量
本发明可以测定原料药、制剂中间体、最终的制剂中的活性成分含量的含量。
pH 7.2缓冲液——将40mL的25％四甲基氢氧化铵水溶液用水稀释至1L，并用约4.5mL磷酸调节pH值7.2±0.2，即得；
甲醇-乙腈混合液——将3体积甲醇和2体积乙腈混合，即得；
溶液A——将pH 7.2缓冲液与甲醇-乙腈混合液以体积比87.5∶12.5混合，过滤、脱气，即得；
溶液B——将甲醇-乙腈混合液与pH 7.2缓冲液以体积比87.5∶12.5混合，过滤、脱气，即得；
流动相——使用下文色谱系统中所述的溶液A与溶液B的变化体积的混合物；
稀释液——将pH 7.2缓冲液与甲醇-乙腈混合液以体积比54∶46混合，即得；
系统适用性溶液——准确称取氟伐他汀钠适量，使其用稀释液溶解并稀释制成浓度约0.42mg/mL的溶液；
标准溶液——准确称取氟伐他汀钠对照品适量，使其用稀释液溶解并稀释制成浓度约0.42mg/mL的溶液；
含量测定贮备液——精密称取相当于含氟伐他汀钠200mg的样品(可以是原料药、片剂、胶囊剂等)置于100mL量瓶中，加入甲醇约80ml，超声波处理30min，冷却至室温，用甲醇稀释至刻度，摇匀，过滤，即得(浓度约2mg/ml)；
含量测定溶液——精密量取含量测定贮备液10ml置于50ml量瓶中，用稀释液稀释至刻度，即得(浓度约400μg/ml)；
色谱系统——色谱操作照中国药典2010年版二部附录VD所载高效液相色谱法进行，色谱条件如下：
色谱柱——十八烷基硅烷键合硅胶色谱柱(此类色谱柱可通过众多商业途径购得，在本发明中不作特别限制，只要它们能满足HPLC测定要求；但是在本发明的具体试验中，使用的是Thermo Scientific公司的品牌为Hypersil-ODS的色谱柱，其规格为4.6mm×5cm×5μm)；
检测器——紫外检测器，波长305nm；
流速——约2mL/min；
洗脱程序——
时间(min) 溶液A(％) 溶液B(％) 洗脱
0-6 54 46 等度
6-17 54－＞17 46－＞83 线性梯度
17-20 17 83 等度
20-20.1 17－＞54 83－＞46 线性梯度
20.1-26.1 54 46 平衡
系统适用性试验——注入系统适用性溶液，如下文“操作”中的方法记录峰响应：氟伐他汀峰的保留时间应约为5.4min(如果有偏离，可通过例如调整流动相流速的方式调节)；以氟伐他汀的相对保留时间RRT为1.0计，在本色谱条件下，氟伐他汀非对映体的RRT为1.2；氟伐他汀非对映体与氟伐他汀之间的分离度应不低于1.4；重复进样的相对标准偏差不超过1.5％[注意——如果氟伐他汀峰的保留时间超过5.7min，则可相应地调节等度洗脱步骤，以便使氟伐他汀峰和氟伐他汀非对映体峰在等度洗脱区域出峰]；
操作——分别将25μL的标准溶液和含量测定溶液注入色谱仪，记录色谱图，读取氟伐他汀峰的峰面积，按外标法以峰面积计算样品中的氟伐他汀钠的含量。
测试方法例3：HPLC法测定有关物质含量
本发明可以测定原料药、制剂中间体、最终的制剂中的杂质的含量。
pH7.2缓冲液、甲醇-乙腈混合液、溶液A、溶液B、流动相、稀释液、系统适用性溶液、标准溶液分别参见上文测试方法例2的相应溶液，测试溶液参见上文测试方法例2的含量测定溶液；
色谱系统——参照上文测试方法例2；
系统适用性试验——注入系统适用性溶液，如下文“操作”中的方法在305nm处记录峰响应；确定氟伐他汀与氟伐他汀非对映体的色谱峰，氟伐他汀非对映体与氟伐他汀之间的分离度应不低于1.4；重复进样的相对标准偏差不超过1.5％；
操作——分别将25μL的标准溶液和测试溶液注入色谱仪，记录色谱图，确定色谱图中的各杂质归属，并计算峰响应值；计算样品中各种杂质的百分含量，计算式如下：
100(1/F)(411.48/433.45)(CS/CT)(ri/rS)
其中F是杂质相对于氟伐他汀的相对响应因子(其在确定杂质结构后本领域技术人员可以容易的通过常规试验确定杂质的响应因子)，411.48和433.45分别是氟伐他汀和氟伐他汀钠的分子量，CS为标准溶液中氟伐他汀钠的浓度(mg/mL)，CT为测试溶液中基于标示量的氟伐他汀的浓度(mg/mL)，ri是测试溶液中各杂质的峰响应值，rS是标准溶液中氟伐他汀的峰响应值。
已经发现，杂质X(即，[E，E]-(±)-7-[3-(4-氟苯基)-1-(甲基乙基)-1H-吲哚-2-基]-3-羟基-4，6-庚二烯酸单钠盐)在305nm波长处与氟伐他汀的响应强度相当。因此，在本发明中，对以上测试方法例3简化，使用测试溶液色谱图，以计算测试样品中所含的杂质X相对于该样品中所含的活性成分氟伐他汀钠的含量(％)，该只要物料中杂质X与氟伐他汀二者的相对量不同，不论该物料中添加多少辅料，该含量不会因为物料中辅料用量不同而改变。杂质X含量的计算式如下：
杂质X含量(％)＝[杂质X峰面积÷氟伐他汀钠峰面积]×100％
测试方法例4：稳定性考察
将各种测试样品置于密封的铝塑复合膜袋中以隔绝内外空气交换。然后将测试样品置于40℃恒温箱中放置6个月以执行常规的高温加速稳定性考察试验。
测定各试样在0月(未经40℃处置)和6月(经40℃处置)时样品中的活性物质氟伐他汀钠的含量(用 测试方法例2方法测定，单位可以以每1g测试样品中所含的氟伐他汀钠的mg质量表示，即mg/g)；接着按下式计算各测试样品中氟伐他汀钠在经高温处理后的残余含量(％)：
氟伐他汀钠的残余含量(％)＝[6月含量÷0月含量]×100％
上述残余含量(％)越接近于100％越稳定，当活性成分长期贮藏而因各种原因含量降低时，一般而言，样品在经40℃-6月处置后该残余含量应不低于90％，低于90％时通常认为产品不合格。
另外，以下式计算各测试样品中杂质X在经高温处理前后的增量(％)：
杂质X的增量(％)＝[(6月杂质X含量-0月杂质X含量)÷0月杂质X含量]×100％
上述增量(％)越接近于0越稳定，而当该增量越大时则表明样品中杂质X增加越多。
测试方法例5：生物学试验(LD50的测定)
参照文献(冬凌草二萜类成分半数致死量的测定，中国医院药学杂志，2011，31(2)：163)所述方法，使用Bliss法设计试验，对小鼠单次灌胃，观察14d内小鼠的毒性反应和死亡情况，以小鼠急性死亡率为指标，测定氟伐他汀钠或杂质X(购自西格玛奥德里奇公司)对小鼠的LD50和LD50的95％可信限。结果：氟伐他汀钠单次灌胃给药的LD50为13.3g/kg体重，LD50的95％可信限为11.3～14.8g/kg体重；同法测定杂质X，单次灌胃给药的LD50为0.82g/kg体重，LD50的95％可信限为0.66～0.97g/kg体重。可见，从药物的安全性角度讲，氟伐他汀钠明显比杂质X的安全性更好。
测试方法例6：溶出度测定
使用900ml水为溶出介质，使用浆法，转速50rpm，照2010年版中国药典规范进行固体制剂样品的溶出度测定。
B、实施例部分
实施例1：制备本发明药物组合物
按以下表1中所列样品编号Ex1-01至Ex1-10所述氟伐他汀钠与氯化钾的量(重量份)进行组配得到10个混合物试样。混合试样的配制方法如下：(1)将各物料分别粉碎至可通过60目筛的细粉，将处方量的氟伐他汀钠与无机盐充分混合均匀，得混合粉末物料，按常规方法将这些混合物料一半直接装胶囊，另一半压制成片剂。
使这10个试样的片剂照测试方法例4的方法进行稳定性考察，计算这些样品在经6个月后的氟伐他汀钠的残余含量(％)和杂质X的增量(％)结果如下：
表1：
样品No. 氟伐他汀钠 氯化钾 氟伐他汀钠的残余含量 杂质X的增量
Ex1-01 100 0 85.7％ 215％
Ex1-02 100 1 93.8％ 153％
Ex1-03 100 2.5 95.2％ 97％
Ex1-04 100 5 98.6％ 35％
Ex1-05 100 12.5 98.1％ 27％
Ex1-06 100 20 97.5％ 21％
Ex1-07 100 30 97.7％ 22％
Ex1-08 100 45 92.7％ 28％
Ex1-09 100 75 88.7％ 35％
Ex1-10 100 100 84.3％ 31％
出人意料地显示，当氟伐他汀钠与大于等于5份的氯化钾混合时，样品在经模拟长期贮藏的高温条件下处理之后，杂质X这种安全性较差的有关物质的增量显著地比未添加氯化钾或者少添加的试样更低，即在含有一定量的氯化钾时杂质X增长速度非常小，远小于不含氯化钾的试样。但是当氯化钾的量过高时，例如氯化钾相对量大于等于45重量份时，活性成分降低较快。可见，当相对于100重量份氟伐他汀钠而言，向其中掺入5～30重量份的氯化钾时，在长期贮藏过程中不但可以使活性成分维持在高的稳定水平，而且有关杂质增长缓慢。
另外经测定，以上Ex1-01至Ex1-10这10个混合试样的片剂和胶囊剂，对于每一配方，它们的片剂和胶囊剂在氟伐他汀钠的残余含量和杂质X的增量两个参数方面均一致(相差均不超过1.4％)。下面对照试验11至对照试验13中均显示同样的结果，即具体剂型不影响氟伐他汀钠的残余含量和杂质X的增量这两个参数的变化特征。
对照试验11：参考以上实施例1的方法以及表1的配方，不同的是将其中的氯化钾替换为等量的氯化钠，所得样品片剂同样进行40℃-6月处置。结果显示，这些试样在氟伐他汀钠的残余含量和杂质X的增量两方面与使用氯化钾的情况基本相同，即：相对于100重量份氟伐他汀钠而言，向其中掺入大于等于5重量份的氯化钠时其杂质X的增量＜45％，均在20～42％范围内；当氯化钠相对量小于等于30重量份但大于等于5重量份时活性成分有较好的稳定性，氟伐他汀钠的残余含量均大于96％，均在96.5～98.5％范围内；但是当氯化钠相对量大于等于45重量份时，活性成分降低较快，使用75重量份和100重量份氯化钠时氟伐他汀钠的残余含量分别为89.6％和83.2％，已经不能满足一般药品的稳定性的要求。
对照试验12：参考以上实施例1的方法以及表1的配方，不同的是将其中的氯化钾替换为等量的碳酸氢钾(据信使用弱碱性盐有助于提高氟伐他汀钠的稳定性)，同样进行40℃-6月处置。结果显示，碳酸氢钾相对用量为5～30重量份的四个试样在6个月后氟伐他汀钠残余含量均在91.6～94.7％范围内，显示尽管可以接受但仍不如本发明的效果；碳酸氢钾相对量低于5或大于30重量份的其余6个试样在6个月后氟伐他汀钠残余含量均降低于90％以下，均在77.6～86.3％范围内。但是对于全部碳酸氢钾相对用量范围的试样，在6个月后它们的杂质X的增量均在136～213％范围内，显示碳酸氢钾不能有效抑制杂质X的增加。
对照试验13：参考以上对照试验12的方法以及的配方，不同的是将其中的碳酸氢钾替换为等量的碳酸氢钠(据信与碳酸氢钾类似，其有助于提高氟伐他汀钠的稳定性)，同样进行40℃-6月处置。结果显示与使用碳酸氢钾结果类似，即碳酸氢钠相对用量为5～30重量份的四个试样在6个月后氟伐他汀钠残余含量均在91.9～94.3％范围内，显示尽管可以接受但仍不如本发明的效果；碳酸氢钠相对量低于5或大于30重量份的其余6个试样在6个月后氟伐他汀钠残余含量均降低于90％以下，均在75.6～87.5％范围 内。但是对于全部碳酸氢钠相对用量范围的试样，在6个月后它们的杂质X的增量均在122～198％范围内，显示碳酸氢钠不能有效抑制杂质X的增加。
对照试验14：取市售氟伐他汀钠胶囊(国药准字H20010517，据信添加了碳酸氢钠作为稳定剂)和市售氟伐他汀钠缓释片(国药准字H20090179，据信添加了碳酸氢钾作为稳定剂)，同样进行40℃-6月处置。结果二个试样在6个月后氟伐他汀钠残余含量分别为92.9％、94.2％，显示尽管可以接受但仍不如本发明的效果；但是杂质X的增量分别为153％和134％，显示市售品在杂质X增加速度方面不及本发明产品。
实施例2：制备本发明药物组合物
按以下表2基本配方制备本发明药物组合物：
表2：
成分 重量(mg)
氟伐他汀钠 20mg
氯化钾 规定量
微晶纤维素 40mg
淀粉 30mg
淀粉羟基乙酸钠 5mg
PVPK30 3mg
硬脂酸镁 2mg
制法：将各物料分别粉碎并过60目筛，使主药与无机盐混合均匀，再加入稀释剂微晶纤维素、淀粉混合均匀；将该混合粉末用50％乙醇配制的5％PVP K30溶液作为粘合剂制软材，湿法制粒，50℃干燥至水分低于2.5％；将所得干颗粒与崩解剂和润滑剂混合均匀；一半物料分装到硬胶囊壳中，另一半物料压制成片剂。
根据表2的配方，其中氯化钾的量按以下表3中所列样品编号Ex2-01至Ex2-10所述氟伐他汀钠与氯化钾的量(重量份)进行组配，得到10个混合物试样的片剂和胶囊剂。
使这10个试样的胶囊剂照测试方法例4的方法进行稳定性考察，计算这些样品在经6个月后的氟伐他汀钠的残余含量(％)和杂质X的增量(％)结果见表3：
表3：
样品No. 氟伐他汀钠 氯化钾 氟伐他汀钠的残余含量 杂质X的增量
Ex2-01 100 0 77.3％ 275％
Ex2-02 100 1 84.2％ 183％
Ex2-03 100 2.5 93.5％ 137％
Ex2-04 100 5 97.4％ 43％
Ex2-05 100 12.5 96.7％ 47％
Ex2-06 100 20 97.3％ 41％
Ex2-07 100 30 96.7％ 32％
Ex2-08 100 45 91.1％ 38％
Ex2-09 100 75 85.9％ 41％
Ex2-10 100 100 82.6％ 37％
结果显示，即使添加有其它药剂领域的常规辅料，这些片剂仍然在氟伐他汀钠的残余含量(％)和杂质X的增量(％)两个方面呈现典型的氯化钾用量相关性，即不用或少用氯化钾(＜5重量份)时两个参数均不能令人接受，而当氯化钾用量过多(＞30重量份)时活性成分含量不能令人接受。当相对于100重量份氟伐他汀钠而言，向其中掺入5～30重量份的氯化钾时，在长期贮藏过程中不但可以使活性成分维持在高的稳定水平，而且有关杂质增长缓慢。
对照试验21：参考以上实施例2的方法以及表2、3的配方，不同的是将其中的氯化钾替换为等量的氯化钠，所得样品胶囊剂同样进行40℃-6月处置。结果显示，这些试样在氟伐他汀钠的残余含量和杂质X的增量两方面与实施例2中使用氯化钾的情况基本相同，即：相对于100重量份氟伐他汀钠而言，向其中掺入大于等于5重量份的氯化钠时其杂质X的增量＜50％，均在30～45％范围内；但是当氯化钠相对量在5～30重量份范围内时氟伐他汀钠的残余含量均在96.5～98.5％范围内；而当氯化钠相对量大于等于45重量份时，活性成分降低较快，使用75重量份和100重量份氯化钠时氟伐他汀钠的残余含量分别为89.6％和83.2％，已经不能满足一般药品的稳定性的要求。
对照试验22：参考以上实施例2的方法以及表2、3的配方，不同的是将其中的氯化钾替换为等量的碳酸氢钾(据信使用弱碱性盐有助于提高氟伐他汀钠的稳定性)，同样进行40℃-6月处置。结果显示，碳酸氢钾相对用量为5～30重量份的四个试样在6个月后氟伐他汀钠残余含量均在91.2～93.6％范围内，显示尽管可以接受但仍不如本发明的效果；碳酸氢钾相对量低于5或大于30重量份的其余6个试样在6个月后氟伐他汀钠残余含量均降低于90％以下，均在74.2～85.3％范围内。但是对于全部碳酸氢钾相对用量范围的试样，在6个月后它们的杂质X的增量均在132～242％范围内，显示碳酸氢钾不能有效抑制杂质X的增加。
对照试验23：参考以上对照试验22的方法以及的配方，不同的是将其中的碳酸氢钾替换为等量的碳酸氢钠(据信与碳酸氢钾类似，其有助于提高氟伐他汀钠的稳定性)，同样进行40℃-6月处置。结果显示与使用碳酸氢钾结果类似，即碳酸氢钠相对用量为5～30重量份的四个试样在6个月后氟伐他汀钠残余含量均在90.7～94.1％范围内，显示尽管可以接受但仍不如本发明的效果；碳酸氢钠相对量低于5或大于30重量份的其余6个试样在6个月后氟伐他汀钠残余含量均降低于90％以下，均在75.1～89.6％范围内。但是对于全部碳酸氢钠相对用量范围的试样，在6个月后它们的杂质X的增量均在145～192％范围内，显示碳酸氢钠不能有效抑制杂质X的增加。
实施例3：制备本发明药物组合物(缓释片剂)
按以下表4基本配方制备本发明药物组合物：
表4：
成分 重量(mg)
氟伐他汀钠 80
山嵛酸甘油酯 48
氯化钾 按表5规定量
微晶纤维素 90
羟丙纤维素 9
HPMC-75HD 100 30
HPMC-75HD 15000 30
硬脂酸镁 4
总计 300
制法：将各物料分别粉碎并过60目筛，使主药与无机盐混合均匀，再与山嵛酸甘油酯、微晶纤维素在混合机中混合均匀，加入羟丙纤维素和两种HPMC，混合均匀，用60％乙醇制湿颗粒，干燥，加入硬脂酸镁，混合均匀，压制成片剂，即得。
根据表4的配方，其中氯化钾的量按以下表5中所列样品编号Ex3-01至Ex3-10所述氟伐他汀钠与氯化钾的量(重量份)进行组配，得到10个混合物试样的片剂和胶囊剂。
使这10个试样的片剂照测试方法例4的方法进行稳定性考察，计算这些样品在经6个月后的氟伐他汀钠的残余含量(％)和杂质X的增量(％)结果见表5：
表5：
样品No. 氟伐他汀钠 氯化钾 氟伐他汀钠的残余含量 杂质X的增量
Ex3-01 100 0 83.3％ 257％
Ex3-02 100 1 87.2％ 196％
Ex3-03 100 2.5 93.6％ 157％
Ex3-04 100 5 96.7％ 46％
Ex3-05 100 11.25 97.5％ 43％
Ex3-06 100 20 96.9％ 45％
Ex3-07 100 30 97.7％ 35％
Ex3-08 100 45 92.4％ 33％
Ex3-09 100 75 88.7％ 40％
Ex3-10 100 100 84.6％ 34％
结果显示，即使添加有其它缓释药剂领域的常规辅料，这些片剂仍然在氟伐他汀钠的残余含量(％)和杂质X的增量(％)两个方面呈现典型的氯化钾用量相关性，即不用或少用氯化钾(＜5重量份)时两个参数均不能令人接受，而当氯化钾用量过多(＞30重量份)时活性成分含量不能令人接受。当相对于100重量份氟伐他汀钠而言，向其中掺入5～30重量份的氯化钾时，在长期贮藏过程中不但可以使活性成分维持在高的稳定水平，而且有关杂质增长缓慢。
对照试验31：参考以上实施例3的方法以及表4、5的配方，不同的是将其中的氯化钾替换为等量的氯化钠，所得样品片剂同样进行40℃-6月处置。结果显示，这些试样在氟伐他汀钠的残余含量和杂质 X的增量两方面与实施例3中使用氯化钾的情况基本相同，即：相对于100重量份氟伐他汀钠而言，向其中掺入大于等于5重量份的氯化钠时其杂质X的增量＜50％，均在30～45％范围内，但是氯化钠用量较少时杂质X增加非常快；当氯化钠相对量在5～30重量份范围内时氟伐他汀钠的残余含量均在96.5～98.5％范围内；而当氯化钠相对量小于5重量份或者大于等于45重量份时，活性成分降低较快。
对照试验32：参考以上实施例3的方法以及表4、5的配方，不同的是将其中的氯化钾替换为等量的碳酸氢钾(据信使用弱碱性盐有助于提高氟伐他汀钠的稳定性)，同样进行40℃-6月处置。结果显示，碳酸氢钾相对用量为5～30重量份的四个试样在6个月后氟伐他汀钠残余含量均在90.6～93.3％范围内，显示尽管可以接受但仍不如本发明的效果；碳酸氢钾相对量低于5或大于30重量份的其余6个试样在6个月后氟伐他汀钠残余含量均降低于90％以下，均在71.4～83.7％范围内。但是对于全部碳酸氢钾相对用量范围的试样，在6个月后它们的杂质X的增量均在146～226％范围内，显示碳酸氢钾不能有效抑制杂质X的增加。
实施例4：制备本发明药物组合物
(1)分别参照上文实施例1～实施例3制备的Ex1-04、Ex1-05、Ex1-06、Ex1-07、Ex2-04、Ex2-05、Ex2-06、Ex2-07、Ex3-04、Ex3-05、Ex3-06、Ex3-07这些使用氯化钾的试样的配方，但是使用以下方法制备成片剂：(i)将各物料分别粉碎至可通过60目筛，将处方量的氟伐他汀钠与无机盐充分混合均匀，得混合粉末物料；(ii)使步骤(i)所得混合粉末物料以不超过一厘米的厚度平辅在不锈钢平板上，再置于用乙醇饱和空气氛的密封箱中密封处置30小时；(iii)使经步骤(ii)处理的混合粉末物料与任选的其余药用辅料按常规片剂或缓释片剂制备规范混合，按常规片剂或者缓释片剂制备规范方法，制备成呈片剂形式的固体药物组合物，即得。得到的12个片剂试样分别记为Ex41-04、Ex41-05、Ex41-06、Ex41-07、Ex42-04、Ex42-05、Ex42-06、Ex42-07、Ex43-04、Ex43-05、Ex43-06、Ex43-07。
(2)使本实施例4制备得到的这12个片剂试样照测试方法例4的方法进行稳定性考察，计算这些样品在经6个月后的氟伐他汀钠的残余含量(％)和杂质X的增量(％)。结果显示，这12个以区别于实施例1-3相应配方样品制备方法制备得到的片剂，它们在氟伐他汀钠的残余含量(％)和杂质X的增量(％)两个参数方面均与其在实施例1-3制备得到的相应配方样品的结果一致(相差均不超过3个百分点)，例如这12个片剂6月时的氟伐他汀钠的残余含量均在96.5％～98.8％范围内，杂质X的增量均在20％～50％范围内。
(3)接触角测定：
测定实施例1～实施例3制备的Ex1-04、Ex1-05、Ex1-06、Ex1-07，Ex2-04、Ex2-05、Ex2-06、Ex2-07，Ex3-04、Ex3-05、Ex3-06、Ex3-07这12个片剂的接触角。
另外，还测定了实施例4制备的Ex41-04、Ex41-05、Ex41-06、Ex41-07，Ex42-04、Ex42-05、Ex42-06、Ex42-07，Ex43-04、Ex43-05、Ex43-06、Ex43-07这12个片剂的接触角；结果显示这12个片剂的接触角均在30～85°范围内。
但是对于上述实施例4的12个试样，计算它们与其相应配方但制备工艺稍有差异的实施例1～实施例3制备的12个试样的接触角差值，即对于同一处方，接触角差值(°)等于该处方用实施例4方法所得片剂的接触角减去该处方用实施例1～3方法所得片剂的接触角所得的差值。例如关于Ex1-05样品处方的 接触角差值(°)，等于Ex41-05片剂接触角减去Ex1-05片剂接触角所得的差值。已经出人意料地发现，上述12个处方的片剂，接触角差值(°)均在16°～29°范围内；例如Ex42-05片剂接触角为43°，Ex2-05片剂接触角为24°，接触角差值＝19°。即，对于同一处方，使用实施例1～3方法制备的片剂的接触角偏低，而使用实施例4方法有增加并且均在30～85°范围内。接触角在30°～85°范围内是有益的，一方面可以避免因接触角太小(例如接触角小于25°)物料引湿性过强而引发的制剂加工贮藏等方面的诸多技术问题，另一方面还可避免因接触角太大(例如接触角大于90°)物料疏水性过强而引发的药物溶出性能变差等方面的诸多技术问题。
(4)溶出度测定：对于本实施例4提及的24个片剂试样，测定它们在未经40℃-6月处置时释放50％所需要的时间(t0)，接着测定它们在经40℃-6月处置后释放50％所需要的时间(t1)。对于同一个试样，用下式计算其在经40℃-6月处置后释放50％的时滞(％)
时滞(％)＝[(t1--t0)÷t0]×100％
结果显示：
对于Ex1-04、Ex1-05、Ex1-06、Ex1-07、Ex2-04、Ex2-05、Ex2-06、Ex2-07这些常规释放片剂它们的时滞均在17％至29％范围内，各片剂呈现释放延迟的不利变化；但是对于Ex41-04、Ex41-05、Ex41-06、Ex41-07、Ex42-04、Ex42-05、Ex42-06、Ex42-07，这些相同处方但制备工艺稍有不同的常规释放片剂它们的时滞均在-3％至7％范围内，各片剂释放延迟现象不明显；对于Ex3-04、Ex3-05、Ex3-06、Ex3-07这些缓释片剂它们的时滞均在21％至34％范围内，各片剂呈现释放延迟的不利变化；但是对于Ex43-04、Ex43-05、Ex43-06、Ex43-07，这些相同处方但制备工艺稍有不同的缓释片剂它们的时滞均在-2％至8％范围内，各片剂释放延迟现象不明显。
另外，使用对照试验14所提供的市售品氟伐他汀钠胶囊和市售品氟伐他汀钠缓释片，测定二者的接触角分别为26°和103°；另外对两个样品进行40℃-6月处置，测定两个试样在经40℃-6月处置后释放50％的时滞(％)，结果胶囊剂和缓释片的时滞分别为19％和27％。
上述实施例1～实施例3制备的12个片剂接触角比之于相同处方使用实施例4方法所得片剂的接触角更小，这表明经实施例4方法处理后片剂亲水性降低。但是完全出人意料的是，亲水性更强的片剂在释放度方面却表现为在长期贮藏之后释放性能出现延迟的现象，尽管这种现象对于常规释放片剂而言对制剂体内行为的影响或许不大，但是对于缓释片剂而言这可能是不利的，这种出人意料的结果是完全难以用现有理论加以解释的。根据本实施例4的结果可见，当使活性成分与无机盐预先进行乙醇气氛处理后，所制备的固体制剂在接触角和溶出稳定性方面呈现优异的性能。
另外，参考以上Ex41-04、Ex41-05、Ex41-06、Ex41-07、Ex42-04、Ex42-05、Ex42-06、Ex42-07、Ex43-04、Ex43-05、Ex43-06、Ex43-07这12个配方和方法，不同的仅是将其中的氯化钾改为等量的氯化钠，得到的12个片剂同样进行氟伐他汀钠的残余含量(％)和杂质X的增量(％)的测定，以及接触角测定和溶出时滞测定以考察片剂在接触角和溶出稳定性等方面的性能。结果显示这些样品均呈现出与使用氯化钾相同的变化趋势并且结果基本相同。
对照试验41：制备药物组合物
照CN102188421A(中国专利申请号201010123483.6)说明书[0025]至[0030]段所述配方和方法制备片 剂，该试样标记为#421片。
照CN1330538A(中国专利申请号99814403.7)说明书实施例1的配方和方法制备每片含20mg规格的片剂，其中含有较大量的偏碱性物质枸橼酸钠和polyacrylin钾，该试样标记为#538片。
照CN1091634A(中国专利申请号93100650.3)说明书实施例4的配方和方法，一半物料制备每片含20mg规格的片剂，另一半物料装胶囊，其中含有较大量的偏碱性物质碳酸氢钠，该试样标记为#634片。
照CN1328454A(中国专利申请号99812081.2)说明书实施例1-2的配方和方法，制备缓释片剂，其中含有较大量的偏碱性物质碳酸氢钾，该试样标记为#454片。
以上五个试样照测试方法例4方法进行稳定性考察。结果显示，五种制剂的氟伐他汀钠的残余含量均在89.2～92.6％范围内，杂质X的增量均在均在178～251％范围内，显示化学稳定性不足，特别是杂质X增加非常大。这四个片剂经40℃-6月处置后释放50％的时滞(％)均在17％至31％范围内，显示药物释放稳定性不足。
实施例5：制备本发明药物组合物
成分 重量(mg)
氟伐他汀钠 20mg
氯化钾(无机盐) 5mg
微晶纤维素(稀释剂) 150mg
乳糖(稀释剂) 150mg
HPMC(粘合剂，用50％乙醇配制成5％溶液使用) 5mg
交联羧甲基纤维素钠(崩解剂) 8mg
PEG6000(润滑剂) 2mg
制法：将各物料分别粉碎并过60目筛；使主药与无机盐混合均匀，再加入稀释剂混合均匀；将该混合粉末用粘合剂进行制粒，50℃干燥至水分低于2.5％；将所得干颗粒与崩解剂和润滑剂混合均匀；一半物料分装到硬胶囊壳中制成胶囊剂；另一半物料压制成片剂；将所得片剂一半直接密封包装处理，为素片；所得片剂另一半用
Figure PCTCN2015000168-appb-000012
85F20694进行包衣，包衣材料占最终片剂总重量的3％。三种试样的接触角均在63～69°范围内。
将本实施例所得胶囊剂、素片、包衣片密封包装，照测试方法例4方法进行稳定性考察。结果显示，胶囊剂、素片、包衣片的氟伐他汀钠的残余含量均在97.3～98.7％范围内，杂质X的增量均在均在28～31％范围内，显示它们具有良好的化学稳定性。
实施例6：制备本发明药物组合物
成分 重量(mg)
氟伐他汀钠 20mg
氯化钾(无机盐) 4mg
微晶纤维素(稀释剂) 40mg
玉米淀粉(稀释剂) 20mg
PEG2000(粘合剂，用水配制成5％溶液使用) 5mg
交联聚乙烯聚吡咯烷酮(崩解剂) 8mg
胶体二氧化硅(润滑剂) 2mg
硬脂酸(润滑剂) 1mg
制法：将各物料分别粉碎并过60目筛；使主药与无机盐混合均匀，再加入稀释剂混合均匀；将该混合粉末用粘合剂进行制粒，50℃干燥至水分低于2.5％；将所得干颗粒与崩解剂和润滑剂混合均匀；一半物料分装到硬胶囊壳中制成胶囊剂；另一半物料压制成片剂；将所得片剂一半直接密封包装处理，为素片；所得片剂另一半用
Figure PCTCN2015000168-appb-000013
85F23452进行包衣，包衣材料占最终片剂总重量的3％。三种试样的接触角均在77～81°范围内。
将本实施例所得胶囊剂、素片、包衣片密封包装，照测试方法例4方法进行稳定性考察。结果显示，胶囊剂、素片、包衣片的氟伐他汀钠的残余含量均在96.9～98.1％范围内，杂质X的增量均在均在32～35％范围内，显示它们具有良好的化学稳定性。
实施例7：制备本发明药物组合物
成分 重量(mg)
氟伐他汀钠 20mg
氯化钾(无机盐) 3mg
乳糖(稀释剂) 40mg
玉米淀粉(稀释剂) 60mg
水(润湿剂) 适量
低取代羟丙基纤维素(崩解剂) 5mg
硬脂酸镁(润滑剂) 2mg
制法：将各物料分别粉碎并过60目筛；使主药与无机盐混合均匀，再加入稀释剂混合均匀；将该混合粉末用粘合剂进行制粒，50℃干燥至水分低于2.5％；将所得干颗粒与崩解剂和润滑剂混合均匀；一半物料分装到硬胶囊壳中制成胶囊剂；另一半物料压制成片剂；将所得片剂一半直接密封包装处理，为素片；所得片剂另一半用
Figure PCTCN2015000168-appb-000014
85F32004进行包衣，包衣材料占最终片剂总重量的4％。三种试样的接触角均在36～40°范围内。
将本实施例所得胶囊剂、素片、包衣片密封包装，照测试方法例4方法进行稳定性考察。结果显示，胶囊剂、素片、包衣片的氟伐他汀钠的残余含量均在96.6～97.8％范围内，杂质X的增量均在均在29～33％范围内，显示它们具有良好的化学稳定性。
实施例8：制备本发明药物组合物(缓释片剂)
按以下表4基本配方制备本发明药物组合物：
表4：
成分 重量(mg)
氟伐他汀钠 80
氯化钾 15
微晶纤维素 90
羟丙基纤维素 35
HPMC-75HD 100 30
HPMC-75HD 15000 40
PVP-K30 7
硬脂酸镁 3
制法：将各物料分别粉碎并过60目筛，使主药与无机盐混合均匀，再与微晶纤维素在混合机中混合均匀，加入羟丙纤维素和两种HPMC，混合均匀，用5％的PVP-K30溶液(60％乙醇制)制湿颗粒，干燥，加入硬脂酸镁，混合均匀，压制成片剂，即得。一半量以素片直接密封包装，另一半量用
Figure PCTCN2015000168-appb-000015
85F32004进行包衣，包衣材料占最终片剂总重量的4％。二种试样的接触角均在56～59°范围内。
将本实施例所得素片、包衣片密封包装，照测试方法例4方法进行稳定性考察。结果显示，素片、包衣片的氟伐他汀钠的残余含量均在96.9～97.4％范围内，杂质X的增量均在均在34～37％范围内，显示它们具有良好的化学稳定性。
实施例9：制备本发明药物组合物(片剂)
分别参考实施例5～实施例8的配方以及它们的制备方法，不同的是在各自制法中，在主药与无机盐混合均匀后执行下一操作之前，使所得主药-无机盐混合粉末物料以不超过一厘米的厚度平辅在不锈钢平板上，再置于用乙醇饱和空气氛的密封箱中密封处置24小时，接着分别将它们制备成片剂。
经测定，四种试样的接触角均在42～78°范围内。各片剂照测试方法例4方法进行稳定性考察。结果显示，四种片剂的氟伐他汀钠的残余含量均在96.5～98.1％范围内，杂质X的增量均在均在25～36％范围内，显示它们具有良好的化学稳定性。这四个试样经40℃-6月处置后释放50％的时滞(％)均在-3％至8％范围内。
实施例3所得Ex3-04、Ex3-05、Ex3-06、Ex3-07四个试样，实施例8所得素片和包衣片，实施例9所得缓释片，以及对照试验14所提供的市售品氟伐他汀钠缓释片，使这些缓释制剂试样在水900ml中以浆法(50rpm)进行30小时的溶出度试验，结果显示，本发明实施例3、实施例8和实施例9的各样品与市售缓释片的释放曲线一致，在20小时内缓缓释放。
实施例10：质量检测
检品：Ex2-04至Ex2-07片剂、Ex3-04至Ex3-07片剂、实施例4片剂、实施例5至实施例9所得具有本发明特征的包衣片剂。
检测方法：参照美国药典USP35版3270页“氟伐他汀胶囊”项下的方法进行检测。
结果：对上述检品进行检测，各项指标均符合该标准规定(例如氟伐他汀羟二烯杂质的量均低于0.8％，在标准规定＜1.0％的限度范围内)。

Claims (32)

  1. 一种固体药物组合物，其中包含氟伐他汀钠、无机盐、和任选的药用辅料。
  2. 根据权利要求1的固体药物组合物，其中所述的无机盐是酸碱性基本上呈中性的无机盐。
  3. 根据权利要求1的固体药物组合物，其中所述的无机盐选自：磷酸二钙、磷酸三钙、碳酸镁、硅酸镁、铝酸镁、碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、硼酸钠、氯化钠、氯化钾或其组合。
  4. 根据权利要求1的固体药物组合物，其中所述的无机盐选自氯化钠、氯化钾或其组合。
  5. 根据权利要求1的固体药物组合物，其中无机盐与氟伐他汀钠的重量比为2～50∶100。
  6. 根据权利要求1的固体药物组合物，其中无机盐与氟伐他汀钠的重量比为为3～30∶100。
  7. 根据权利要求1的固体药物组合物，其中无机盐与氟伐他汀钠的重量比为为5～30∶100。
  8. 根据权利要求1的固体药物组合物，其中所述氟伐他汀钠占该固体药物组合物总重量的1～99％。
  9. 根据权利要求1的固体药物组合物，其中所述氟伐他汀钠占该固体药物组合物总重量的2～80％。
  10. 根据权利要求1的固体药物组合物，其中所述氟伐他汀钠占该固体药物组合物总重量的5～75％。
  11. 根据权利要求1的固体药物组合物，其中所述药用辅料是选自下列的一种或者多种：填充剂、崩解剂、粘合剂、润滑剂。
  12. 根据权利要求11的固体药物组合物，其中所述填充剂选自：淀粉或其衍生物例如玉米淀粉、预胶化淀粉、改良淀粉等；纤维素或其衍生物例如微晶纤维素、乙基纤维素、甲基纤维素等；糖类例如葡萄糖、蔗糖、乳糖、甘露醇、山梨醇；呈中性的矿物质例如碳酸钙、磷酸氢钙等及其组合。
  13. 根据权利要求11的固体药物组合物，其中所述崩解剂选自：交联聚乙烯聚吡咯烷酮、淀粉羟基乙酸钠、交联羧甲基纤维素钠、低取代羟丙基纤维素等及其组合。
  14. 根据权利要求11的固体药物组合物，其中所述粘合剂选自：聚乙二醇、淀粉、聚乙烯吡咯烷酮、羟丙基甲基纤维素等及其组合。
  15. 根据权利要求11的固体药物组合物，其中所述润滑剂选自：硬脂酸镁、硬脂酸钙、滑石粉、淀粉、硬脂酸、胶体二氧化硅、聚乙二醇等。
  16. 根据权利要求1-15的固体药物组合物，其中还可以包括释放调节剂。
  17. 根据权利要求16的固体药物组合物，所述释放调节剂选自：羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、海藻酸钠、黄原胶、聚乙烯醇、山嵛酸甘油酯等及其组合。
  18. 根据权利要求1-17的固体药物组合物，其是呈选自下列的药物剂型：片剂、胶囊剂、颗粒剂等。
  19. 根据权利要求1-18的固体药物组合物，其是未包衣的或用包衣材料包衣的片剂。
  20. 根据权利要求1-19的固体药物组合物，其包含：氟伐他汀钠20重量分、无机盐0.4～10重量份、药用辅料0～500重量份；或者，其包含：氟伐他汀钠20重量分、无机盐0.6～6重量份、药用辅料10～400重量份；或者，其包含：氟伐他汀钠20重量分、无机盐1～6重量份、药用辅料25～250重量份。
  21. 根据权利要求1-20的固体药物组合物，其中不包括包衣的所述药物组合物(例如临压片前的颗粒状物料、未包衣的素片、或者经过包衣的片芯)具有小于110°的接触角。
  22. 根据权利要求1-20的固体药物组合物，其中不包括包衣的所述药物组合物具有小于100°的接触 角。
  23. 根据权利要求1-20的固体药物组合物，其中不包括包衣的所述药物组合物具有小于90°的接触角。
  24. 根据权利要求1-20的固体药物组合物，其中不包括包衣的所述药物组合物具有小于85°的接触角。
  25. 根据权利要求1-24的固体药物组合物，其与水的接触角为30°～100°。
  26. 根据权利要求1-24的固体药物组合物，其与水的接触角为30°～90°。
  27. 根据权利要求1-24的固体药物组合物，其与水的接触角为30°～85°。
  28. 制备权利要求1-27任一项的固体药物组合物的方法，其包括以下步骤：
    (1)将各物料分别粉碎至可通过60目筛，将处方量的氟伐他汀钠与无机盐充分混合均匀，得混合粉末物料；
    (2)按常规固体药物制剂的方法，使经步骤(1)处理的混合粉末物料与任选的药用辅料混合，制备成呈固体药物制剂形式的固体药物组合物，即得。
  29. 根据权利要求28的方法，其中步骤(2)所制得的固体药物制剂选自：片剂、胶囊剂、颗粒剂。
  30. 根据权利要求28的方法，其中所述固体药物组合物是片剂，并且其中所述方法还包括对所述片剂进行包衣的步骤。
  31. 权利要求1-27任一项的固体药物组合物在制备用于治疗或预防高胆固醇血症及高脂血症的药物中的用途。
  32. 权利要求1-27任一项的固体药物组合物在制备用于治疗或预防用于饮食未能完全控制的原发性高胆固醇血症和原发性混合型血脂异常(Fredrickson IIa和IIb型)的药物中的用途。
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