CN110339365A - A kind of medical composition and application thereof that oral statins bioavailability can be improved - Google Patents
A kind of medical composition and application thereof that oral statins bioavailability can be improved Download PDFInfo
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- CN110339365A CN110339365A CN201810283391.0A CN201810283391A CN110339365A CN 110339365 A CN110339365 A CN 110339365A CN 201810283391 A CN201810283391 A CN 201810283391A CN 110339365 A CN110339365 A CN 110339365A
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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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
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- 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
Abstract
A kind of medical composition that oral statins bioavailability can be improved, the medical composition includes statins, pH-value regulator, coating or the coating of the safe inhibitor of metabolic ferments and modified release, the intestines and stomach pH value to absorb the drug can be adjusted and make the medical composition since bioavailability improves by the pH-value regulator, so because caused by individual difference blood level variation in vivo it is small, the increase of drug absorption can range of variation become smaller, the serious or even lethal side effect of the serious side effects of drug such as rhabdomyolysis etc. reduces, drug safety increases；The design of this special form not only reduces serious side effects that may be lethal, can also extend action time, reduces administration number of times, can be greatly reduced because patient forgets caused treatment failure of taking medicine.
Description
Technical field
The present invention relates to field of medicaments, especially with regard to a kind of doctor that oral statins bioavailability can be improved
Drug composition and application thereof.
Background technique
Hyperlipidemia is the puzzlement of sluggish metabolism, hyperalimentation or familial cardiovascular patient, American-European countries
Because diet heat is high, the diseases Probability such as obesity, coronary artery atherosclerosis, heart disease is higher than other countries, mistake
It goes during the decade, cardiovascular disease is also one of big cause of the death in the U.S. ten, and Taiwan is in recent years because apoplexy or heart disease lead to death
Data are also in soaring, therefore reducing blood lipid is critically important to health.
Statins (statins, HMG-CoA reductase inhibitor) are common blood lipid-lowering medicines, and it is solid to can inhibit gallbladder
The synthesis of alcohol predecessor mevalonic acid (mevalonate), this is the rate-determing step (rate- of cholesterol GCMS computer
Limiting step), therefore it is commonly used to treatment hypercholesterolemia (hypercholesterolemia), prevent cardiovascular disease
Sick (cardiovascular disease), Atorvastatin (Atorvastatin, trade name in statins), be synthesized by Pfizer (Pfizer) within 1985, be in statistics in 2003 sold in history it is best
Prescription medicine.Other than reducing blood lipid, statins can also inhibit vascular inflammatory, become wide effectiveness way medicine, or even replace in the past
General-purpose medicine aspirin (aspirin).
The metabolic pathway of Atorvastatin (pKa=4.46) includes stage I (Phase Ι) and stage II (Phase Π), former
Type medicine Atorvastatin will do it CYP3A4 and be metabolized to form active metabolite 2- hydroxyl Atorvastatin acid (2-OH
Atorvastatin acid) it is sour (4-OH atorvastatin acid) with 4- hydroxyl Atorvastatin, or by CYP3A4,
UGT1A1 and UGT1A3 is metabolized to Atorvastatin lactone (atorvastatin lactone), the 2- hydroxyl for not having pharmacological activity
Base Atorvastatin lactone (2-OH atorvastatin lactone) and 4- hydroxyl Atorvastatin lactone (4-OH
Atorvastatin lactone) (referring to Fig. 1).There are about 70% gross activity metabolins can disinthibite HMG-CoA also in vivo
Protoenzyme generates curative effect, and active metabolite 2- hydroxyl Atorvastatin acid and 4- hydroxyl Atorvastatin acid whereby, in vitro
It is proved in experiment, the prototype medicine of Atorvastatin is also equivalent to for the inhibitory effect of HMG-CoA reductase.Also there is document report
The metabolin for leading Atorvastatin also belongs to pH dependent form (pH-dependent) compound, because in gastro-intestinal tract,
It can carry out non-ferment (non-between acid (acid form) and lactone formula (lactone form)
Enzymatically it) converts.The UGT enzyme inhibitor silibinin (Silybin) being currently known belongs to flavonoids
(flavonoids), it is clinically commonly used to as antioxidant (antioxidants), anticarcinogen (anticancer
Agents), or even as hepatic (hepatoprotectants), also there is reported in literature Silybin for stage I
(Phase Ι) and stage II (Phase Π) drug metabolism ferment can all generate drug interaction, and in vitro, silibinin can
Inhibit a series of UGT enzyme such as UGT 1A6, UGT 1A9, and has very high inhibitory effect for UGT 1A1.
How Atorvastatin is reduced by addition UGT inhibitor be converted to not active Atorvastatin lactone
(atorvastatin lactone), 2- hydroxyl Atorvastatin lactone (2-OH atorvastatin lactone) and 4- hydroxyl
Base Atorvastatin lactone (4-OH atorvastatin lactone), and improve internal effective concentration and bioavailability
(bioavailability), be the invention solves project.
The common side effect of statins is related with musclar toxicity (myotoxic), such as striated muscle that can be lethal is molten
It solves disease (rhabdomyolysis), once statins occurred for Japan because side effect causes more than 20 people dead, caused side effect
The reason of be that blood drug concentration is excessively high, the high reason of blood drug concentration has two, 1) clinically statins and drop gallbladder are solid
Alcohol drug Gemfibrozil Capsules (gemfibrozil), which merge, to be taken orally, because of the reciprocation (drug-drug of drug
Interaction), it may will increase the risk of musclar toxicity, 2) due to the difference between individual, the intracorporal drug metabolism of biology
Ferment genotype is divided into eubolism drug ferment type (extensive metabolizer extensive metabolizer), medium metabolic person
(intermediate metabolizer) and extreme metabolic ferments type superelevation metabolizer (ultrarapid
Metaolizer), extremely low metabolizer (poor metabolizer), absorption of drugs amount also varies with each individual.
The bioavailability (bioavailability) of statins is not high, wherein the absolute raw body of Atorvastatin
Availability is 14%, and since bioavailability is low, needing to take a large amount of drug can be only achieved internal effective concentration, because making a living
A possibility that drug absorption difference causes the serious or even lethal side effect of such as rhabdomyolysis between object individual increase, needs
Avoid blood middle concentration is high from just can be reduced side effect；If the bioavailability of statins can be improved, will such as give birth to
Body availability has 14% to rise to 98%, then drug absorption difference is reduced by 7.14 times (14%~100%) between bion
For 1.02 times (98%~100%), since bioavailability is very high, because drug absorption difference causes blood between bion
Chinese medicine degree concentration is high and causes the serious or even lethal side effect possibility of such as rhabdomyolysis that will also be greatly reduced.
Although previously having there is the metabolin of reported in literature Atorvastatin to also belong to pH dependent form (pH-dependent) chemical combination
PH is adjusted the stability for being used to improve Atorvastatin, but is adjusted currently without success research case with pH and successfully improved by object
The bioavailability of Atorvastatin.
American invention (US20040138290) discloses a kind of pharmaceutical preparation, is active constituent it includes Atorvastatin calcium
With pH Auto-regulator, it is characterised in that their Atorvastatin calciums include amorphous atorvastatin calcium and the dissolution of micronization
In 900ml pH be 3 liquid aqueous medium when pharmaceutical preparation increase the medium pH value pH be equal to or more than Ah
The pKa+1 of atorvastatin calcium increases its dissolution in aqueous solution through the pharmaceutical preparation containing basifier or buffer substance
The bioavailability for improving Atorvastatin is spent with rate of dissolution.It is pKa+1 i.e. pH value that case, which discloses drug pH value, before this
There is high-dissolvability when being 5.5, although being mentioned in preceding case specification because bioavailability can be increased by improving solubility,
There is no the embodiments for increasing bioavailability in specification.
American invention (US20080138429) discloses a kind of particulate composition, wherein the particle includes active constituent,
It is a HMG-CoA reductase inhibitor and coating, wherein the coating includes: (a) in the group that polyvinyl alcohol forms
The protection film-forming material of selection, sodium carboxymethyl cellulose fibre element, hydroxyethyl cellulose and their combination and (b) are extremely
The drug excipient selected in a kind of few group selected from buffer, basifier and surfactant, wherein addition basifier and painting
Layer is to increase medicine stability.
American invention (US20110165239) discloses a kind of pharmaceutical composition, including Atorvastatin and is selected from L- essence ammonia
Group composed by acid and sodium bicarbonate, wherein the Atorvastatin is Atorvastatin free acid or pharmaceutically acceptable
Salt in the basifier that selects, and wherein the ratio of the alkalization additive and Atorvastatin is 1:1~6:1, alkalization addition
Agent can improve the stability of Atorvastatin.
Although having in above-mentioned preceding case using pH-value blender (alkaline agent), its purposes is drug stabilization agent or increase
Drug solubility is not disclosed using pH-value blender as the bioavailability for improving Atorvastatin, in addition, preceding case discloses
The range of pH-value reconciliation agent content is very big or is not particularly limited, but arrives again since oral drugs can first pass through acid stomach
The enteron aisle of alkalinity, drug need a certain amount of pH-value blender to be likely to be adjusted to the pH of stomach and enteron aisle that atropic can be improved
The pH environment of the bioavailability of statin is cut down, excessive or very few pH-value blender can not all be reached.
Modified release (modified release) drug can change and release the time in organism, takes off currently without people
Biological availability can be improved in dew certain ph, and total dose of modified release dosage form is higher, statins such as Atorvastatin
Bioavailability is low, and interpersonal difference is big, cause the absorptivity of groups of people higher or to drug reactivity compared with
By force, it is therefore desirable to increase bioavailability, lower individual difference after patient's medication, makes the degree decline that blood level is inconsistent,
The safety and curative effect for making average medication increase, and increase the biddability of sufferer medication, and Atorvastatin is made by reduction releases control
Drug can generate the chance of the serious or even lethal side effect of such as rhabdomyolysis.
Therefore the statins novel form with high bioavailability how is developed, due to increasing bioavailability,
Blood level caused by individual difference is inconsistent after attenuating patient's medication, and reduces the serious of such as rhabdomyolysis or even cause
Dead side effect, and the destruction of pharmaceutical compositions safety gastric acid can be enable using modified release dosage form and smoothly reach intestines
Position just discharge and increase drug stability and absorptivity, more can control the time released in organism and reduce because of patient
Forget treatment failure caused by medication, becomes the important topic of the invention to be solved herein.
Summary of the invention
The purpose of the present invention is to provide a kind of medicinal combination that oral statins bioavailability can be improved
Object, the medical composition include statins and improve raw body utilization rate substance, wherein the raising raw body utilization rate substance packet
Contain: 1) pH-value regulator and modified release dosage form or/and 2) metabolic ferments inhibitor, the pH-value regulator can be by enteron aisles
PH value is adjusted, which can enable the destruction of effective ingredient safety gastric acid and smoothly reach the positions of intestines.
For up to aforementioned invention purpose, wherein gut pH can be adjusted to 4.9~8.5 by the pH-value regulator.
For up to aforementioned invention purpose, wherein gut pH can be adjusted to 5.8~7.8 by the pH-value regulator.
For up to aforementioned invention purpose, wherein the pH-value regulator includes sodium carbonate (sodium carbonate), carbonic acid
Hydrogen sodium (sodium bicarbonate), sodium hydroxide (Sodium hydroxide), boric acid (boric acid), potassium chloride
(potassium chloride), sodium dihydrogen phosphate (SodiumDihydrogenPhosphate), disodium hydrogen phosphate
(disodium hydrogen phosphate), potassium dihydrogen phosphate (Potassium dihydrogen phosphate), phosphoric acid
Hydrogen dipotassium (Dipotassium phosphate), glycine (glycine), ammonia (ammonia), ammonium lactate (ammonium
Lactate), ammonium hydrogen carbonate (ammonium bicarbonate), ammonium hydroxide (ammonium hydroxide), phosphoric acid hydrogen
Diammonium (ammonium phosphate dibasic), monoethanolamine (monoethanolamine), diethanol amine
(diethanolamine), triethanolamine (triethanolamine), trihydroxy methyl first ammonia
(trihydroxymethylaminomethane), ethylenediamine (ethylenediamine), N- methyl glucose osamine (N-
Methyl glucamide), 6N- methyl glucose osamine (6N-methyl glucamine), meglucamine diatrizoate
(meglucamine), L-lysine and 2- amino -2- (methylol) -1,3- propylene glycol (L-lysine and 2-amino-2-
At least one of (hydroxymethyl) -1,3-propanediol) or any combination thereof.
For up to aforementioned invention purpose, wherein the weight of the pH-value regulator is 200~11800mg.
For up to aforementioned invention purpose, wherein the quality of the pH-value regulator is 20~90% (w/ of the medical composition
w)。
For up to aforementioned invention purpose, wherein the statins be selected from by Atorvastatin (atorvastatin),
Pravastatin (pravastatin), Simvastatin (simvastatin), Lovastatin (lovastatin), mevastatin
(mevastatin), cut down statin (compactin), Fluvastatin (fluvastatin), simvastatin (cerivastatin),
Group composed by Rosuvastatin (rosuvastatin), Pitavastatin (pitavastatin).
For up to aforementioned invention purpose, wherein the UGT1A3 inhibitor includes NaLS (Sodium lauryl
Sulfate, SLS), the fresh general potassium that relaxes (Acesulfame potassium) of second, colloidal silicon dioxide (Aerosil 200), ocean member
Sui flavine (Apigenin), shellfish add flavones (Baicalin), benzoic acid (Benzyl alcohol), Ben Jia Suan Benzyl ester (Benzyl
Benzoate), fourth hydrocarbon fennel ether (BHA), polyethylene glycol cetyl ether (Brij 58), the hard ester group ether (Brij of polyoxyethylene 10
76), cherry flavor (Cherry), citric acid (Citric acid), cross-linked carboxymethyl cellulose sodium (Croscarmellose
Sodium), dextrates (Dextrates), disodium ethylene diamine tetraacetate (EDTA 2Na), glycerol (Glycerin), sweet
Careless element (Glycyrrhizin), hydroxypropyl cellulose (Hydroxy propyl cellulose), hypromellose phthalate
(Hydroxypropyl methylcellulose), polyvinylpyrrolidone (kollidon VA64), lactose (Lactose), list
It is Lactose hydrate (Lactose monohydrate), Lactose S.G, lemon oil (Lemon oil), locust tree (Locust), low
Replace the third cellulose of hydrocarbon (Low-substituted hydroxypropylcellulose), maltodextrin
(Maltodextrin), mannitol (Mannitol), methyl hydroxybenzoate (Methyl paraben), menthol (Menthol), hard
40 ester of resin acid polyoxyethylene (Myri 52), methylcellulose (Methyl cellulose), NF hydrate (NF
Hydrate), β-how flavones (β-Naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG
2000), Macrogol 4000 (PEG4000), PLURONICS F87 (Pluronic F68), poloxamer188 (Pluronic
F127), polyoxyl 40 hydrogenated castor oil (polyoxyl 40hydrogenated castor oil, RH 40), Nipasol
(Propyl paraben), polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin (saccharin), hexamethylene alkylamino sulphur
Sour sodium (Sodium cyclamate), sour first determine powder and receive (Sodium starch glycolate), sodium benzoate (Sodium
Benzolate), sorbic acid (Sorbic acid), D-sorbite (Sorbitol solution), sorbitan list are stearic
Acid esters (Span 60), sorbital monooleate rouge 80 (Span 80), hydroxyl sugar chlorine (Sucralose), acetic starch (Starch
Acetate), trans-aconitic acid (Trans-Aconitic acid), triethyl citrate (triethyl citrate), lemon
Sour trisodium (trisodium citrate), polysorbate 20 (Tween20, TW20), polysorbate 40 (Tween 40, TW40),
Polyoxyethylene sorbitan monoleate (Tween 80, TW80), ursolic acid (Ursolic Acid), sodium dihydrogen phosphate (sodium dihydrogen
Phosphate), dicalcium phosphate dihydrate (Dicalcium phosphate dihydrate), Dextrates, NF hydration
At least one of object (Dextrates, NF hydrate) and cholic acid (Cholic acid) or any combination thereof.
For up to aforementioned invention purpose, wherein the UGT1A1 inhibitor includes NaLS (Sodium lauryl
Sulfate, SLS), the fresh general potassium that relaxes (Acesulfame potassium) of second, colloidal silicon dioxide (Aerosil 200), ocean member
Sui flavine (Apigenin), shellfish add flavones (Baicalin), benzoic acid (Benzyl alcohol), Ben Jia Suan Benzyl ester (Benzyl
Benzoate), fourth hydrocarbon fennel ether (BHA), polyethylene glycol cetyl ether (Brij 58), the hard ester group ether (Brij of polyoxyethylene 10
76), cherry flavor (Cherry), citric acid (Citric acid), cross-linked carboxymethyl cellulose sodium (Croscarmellose
Sodium), dextrates (Dextrates), disodium ethylene diamine tetraacetate (EDTA 2Na), glycerol (Glycerin), sweet
Careless element (Glycyrrhizin), hydroxypropyl cellulose (Hydroxy propyl cellulose), hypromellose phthalate
(Hydroxypropyl methylcellulose), polyvinylpyrrolidone (kollidon VA64), lactose (Lactose), list
It is Lactose hydrate (Lactose monohydrate), Lactose S.G, lemon oil (Lemon oil), locust tree (Locust), low
Replace the third cellulose of hydrocarbon (Low-substituted hydroxypropylcellulose), maltodextrin
(Maltodextrin), mannitol (Mannitol), methyl hydroxybenzoate (Methyl paraben), menthol (Menthol), hard
40 ester of resin acid polyoxyethylene (Myri 52), methylcellulose (Methyl cellulose), NF hydrate (NF
Hydrate), β-how flavones (β-Naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG
2000), Macrogol 4000 (PEG4000), PLURONICS F87 (Pluronic F68), poloxamer188 (Pluronic
F127), polyoxyl 40 hydrogenated castor oil (polyoxyl 40hydrogenated castor oil, RH 40), Nipasol
(Propyl paraben), polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin (saccharin), hexamethylene alkylamino sulphur
Sour sodium (Sodium cyclamate), sour first determine powder and receive (Sodium starch glycolate), sodium benzoate (Sodium
Benzolate), sorbic acid (Sorbic acid), D-sorbite (Sorbitol solution), sorbitan list are stearic
Acid esters (Span 60), sorbital monooleate rouge 80 (Span 80), hydroxyl sugar chlorine (Sucralose), acetic starch (Starch
Acetate), trans-aconitic acid (Trans-Aconitic acid), triethyl citrate (triethyl citrate), lemon
Sour trisodium (trisodium citrate), polysorbate 20 (Tween20, TW20), polysorbate 40 (Tween 40, TW40),
Polyoxyethylene sorbitan monoleate (Tween 80, TW80), ursolic acid (Ursolic Acid), sodium dihydrogen phosphate (sodium dihydrogen
Phosphate), dicalcium phosphate dihydrate (Dicalcium phosphate dihydrate), Dextrates, NF hydration
At least one of object (Dextrates, NF hydrate) and cholic acid (Cholic acid) or any combination thereof.
For up to aforementioned invention purpose, wherein the modified release dosage form can further include sustained release effect.
For up to aforementioned invention purpose, wherein the medical composition is that tablet, particle, capsule, powder or other medicine can connect
The dosage form received.
For up to aforementioned invention purpose, wherein excipient can be further added in the medical composition.
For up to aforementioned invention purpose, wherein the excipient can be diluent, filler, bonding agent, disintegrating agent, lubricant
Or other acceptable excipient of medicine.
Another object of the present invention is to provide the use that a kind of composition is used to improve statins biomass utilization rate
On the way, the composition includes: 1) pH-value regulator and modified release dosage form or/and 2) metabolic ferments inhibitor, which releases
Put the position that dosage form can enable the destruction of statins effective ingredient safety gastric acid and smoothly reach intestines, the soda acid
Value regulator can be adjusted gut pH to improve drug stability and absorptivity.
For up to aforementioned invention purpose, wherein the pH-value regulator includes sodium carbonate (sodium carbonate), carbonic acid
Hydrogen sodium (sodium bicarbonate), sodium hydroxide (Sodium hydroxide), boric acid (boric acid), potassium chloride
(potassium chloride), sodium dihydrogen phosphate (SodiumDihydrogenPhosphate), disodium hydrogen phosphate
(disodium hydrogen phosphate), potassium dihydrogen phosphate (Potassium dihydrogen phosphate), phosphoric acid
Hydrogen dipotassium (Dipotassium phosphate), glycine (glycine), ammonia (ammonia), ammonium lactate (ammonium
Lactate), ammonium hydrogen carbonate (ammonium bicarbonate), ammonium hydroxide (ammonium hydroxide), phosphoric acid hydrogen
Diammonium (ammonium phosphate dibasic), monoethanolamine (monoethanolamine), diethanol amine
(diethanolamine), triethanolamine (triethanolamine), trihydroxy methyl first ammonia
(trihydroxymethylaminomethane), ethylenediamine (ethylenediamine), N- methyl glucose osamine (N-
Methyl glucamide), 6N- methyl glucose osamine (6N-methyl glucamine), meglucamine diatrizoate
(meglucamine), L-lysine and 2- amino -2- (methylol) -1,3- propylene glycol (L-lysine and 2-amino-2-
At least one of (hydroxymethyl) -1,3-propanediol) or any combination thereof.
For up to aforementioned invention purpose, wherein the UGT1A3 inhibitor includes NaLS (Sodium lauryl
Sulfate, SLS), the fresh general potassium that relaxes (Acesulfame potassium) of second, colloidal silicon dioxide (Aerosil 200), ocean member
Sui flavine (Apigenin), shellfish add flavones (Baicalin), benzoic acid (Benzyl alcohol), Ben Jia Suan Benzyl ester (Benzyl
Benzoate), fourth hydrocarbon fennel ether (BHA), polyethylene glycol cetyl ether (Brij 58), the hard ester group ether (Brij of polyoxyethylene 10
76), cherry flavor (Cherry), citric acid (Citric acid), cross-linked carboxymethyl cellulose sodium (Croscarmellose
Sodium), dextrates (Dextrates), disodium ethylene diamine tetraacetate (EDTA 2Na), glycerol (Glycerin), sweet
Careless element (Glycyrrhizin), hydroxypropyl cellulose (Hydroxy propyl cellulose), hypromellose phthalate
(Hydroxypropyl methylcellulose), polyvinylpyrrolidone (kollidon VA64), lactose (Lactose), list
It is Lactose hydrate (Lactose monohydrate), Lactose S.G, lemon oil (Lemon oil), locust tree (Locust), low
Replace the third cellulose of hydrocarbon (Low-substituted hydroxypropylcellulose), maltodextrin
(Maltodextrin), mannitol (Mannitol), methyl hydroxybenzoate (Methyl paraben), menthol (Menthol), hard
40 ester of resin acid polyoxyethylene (Myri 52), methylcellulose (Methyl cellulose), NF hydrate (NF
Hydrate), β-how flavones (β-Naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG
2000), Macrogol 4000 (PEG4000), PLURONICS F87 (Pluronic F68), poloxamer188 (Pluronic
F127), polyoxyl 40 hydrogenated castor oil (polyoxyl 40hydrogenated castor oil, RH 40), Nipasol
(Propyl paraben), polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin (saccharin), hexamethylene alkylamino sulphur
Sour sodium (Sodium cyclamate), sour first determine powder and receive (Sodium starch glycolate), sodium benzoate (Sodium
Benzolate), sorbic acid (Sorbic acid), D-sorbite (Sorbitol solution), sorbitan list are stearic
Acid esters (Span 60), sorbital monooleate rouge 80 (Span 80), hydroxyl sugar chlorine (Sucralose), acetic starch (Starch
Acetate), trans-aconitic acid (Trans-Aconitic acid), triethyl citrate (triethyl citrate), lemon
Sour trisodium (trisodium citrate), polysorbate 20 (Tween20, TW20), polysorbate 40 (Tween 40, TW40),
Polyoxyethylene sorbitan monoleate (Tween 80, TW80), ursolic acid (Ursolic Acid), sodium dihydrogen phosphate (sodium dihydrogen
Phosphate), dicalcium phosphate dihydrate (Dicalcium phosphate dihydrate), Dextrates, NF hydration
At least one of object (Dextrates, NF hydrate) and cholic acid (Cholic acid) or any combination thereof.
For up to aforementioned invention purpose, wherein the UGT1A1 inhibitor includes NaLS (Sodium lauryl
Sulfate, SLS), the fresh general potassium that relaxes (Acesulfame potassium) of second, colloidal silicon dioxide (Aerosil 200), ocean member
Sui flavine (Apigenin), shellfish add flavones (Baicalin), benzoic acid (Benzyl alcohol), Ben Jia Suan Benzyl ester (Benzyl
Benzoate), fourth hydrocarbon fennel ether (BHA), polyethylene glycol cetyl ether (Brij 58), the hard ester group ether (Brij of polyoxyethylene 10
76), cherry flavor (Cherry), citric acid (Citric acid), cross-linked carboxymethyl cellulose sodium (Croscarmellose
Sodium), dextrates (Dextrates), disodium ethylene diamine tetraacetate (EDTA 2Na), glycerol (Glycerin), sweet
Careless element (Glycyrrhizin), hydroxypropyl cellulose (Hydroxy propyl cellulose), hypromellose phthalate
(Hydroxypropyl methylcellulose), polyvinylpyrrolidone (kollidon VA64), lactose (Lactose), list
It is Lactose hydrate (Lactose monohydrate), Lactose S.G, lemon oil (Lemon oil), locust tree (Locust), low
Replace the third cellulose of hydrocarbon (Low-substituted hydroxypropylcellulose), maltodextrin
(Maltodextrin), mannitol (Mannitol), methyl hydroxybenzoate (Methyl paraben), menthol (Menthol), hard
40 ester of resin acid polyoxyethylene (Myri 52), methylcellulose (Methyl cellulose), NF hydrate (NF
Hydrate), β-how flavones (β-Naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG
2000), Macrogol 4000 (PEG4000), PLURONICS F87 (Pluronic F68), poloxamer188 (Pluronic
F127), polyoxyl 40 hydrogenated castor oil (polyoxyl 40hydrogenated castor oil, RH 40), Nipasol
(Propyl paraben), polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin (saccharin), hexamethylene alkylamino sulphur
Sour sodium (Sodium cyclamate), sour first determine powder and receive (Sodium starch glycolate), sodium benzoate (Sodium
Benzolate), sorbic acid (Sorbic acid), D-sorbite (Sorbitol solution), sorbitan list are stearic
Acid esters (Span 60), sorbital monooleate rouge 80 (Span 80), hydroxyl sugar chlorine (Sucralose), acetic starch (Starch
Acetate), trans-aconitic acid (Trans-Aconitic acid), triethyl citrate (triethyl citrate), lemon
Sour trisodium (trisodium citrate), polysorbate 20 (Tween20, TW20), polysorbate 40 (Tween 40, TW40),
Polyoxyethylene sorbitan monoleate (Tween 80, TW80), ursolic acid (Ursolic Acid), sodium dihydrogen phosphate (sodium dihydrogen
Phosphate), dicalcium phosphate dihydrate (Dicalcium phosphate dihydrate), Dextrates, NF hydration
At least one of object (Dextrates, NF hydrate) and cholic acid (Cholic acid) or any combination thereof.
For up to aforementioned invention purpose, wherein the statins be selected from by Atorvastatin (atorvastatin),
Pravastatin (pravastatin), western horse statin (simvastatin), Lovastatin (lovastatin), mevastatin
(mevastatin), statin (compactin), Fluvastatin (fluvastatin), western rivastatin are cut down
(cerivastatin), group composed by rosuvastatin (rosuvastatin) and Pitavastatin (pitavastatin).
For up to aforementioned invention purpose, wherein the modified release dosage form can further include sustained release effect.
In summary, statins novel form of the invention has the advantage that
(1) using special dosage pH-value regulator adjustment enteron aisle pH-value (pH value) increase statins for example Ah
The bioavailability of atorvastatin.
(2) sour using metabolic ferments inhibitor reduction Atorvastatin and its active metabolite 2- hydroxyl Atorvastatin,
4- hydroxyl Atorvastatin acid is metabolised to do not have the Atorvastatin lactone of pharmacological activity, 2- hydroxyl Atorvastatin lactone
With 4- hydroxyl Atorvastatin lactone, and bioavailability is improved.
(3) it to release drug just in the environment of most proper pH value, is not released in gastric juice, utilizes modified release
(modified release) dosage form coating medicine dissolve drug can to enteron aisle just by stomach, so that drug is carried
Enteron aisle is changed into the proper pH value that bioavailability can be improved by enough alkaline agents, further increases bioavailability.
(4) it since drug bioavailability increases, reduces because of such as rhabdomyolysis caused by individual absorption difference
Serious or even lethal side effect occur, increase drug safety, more the safety of the high modified release dosage form of guarantee dosage
Property.
Detailed description of the invention
Fig. 1 is Atorvastatin (Atorvastatin) metabolic pathway in organism.
Fig. 2A be Atorvastatin (Atorvastatin) in different pH in different time points in rat intestinal wall
Efficiency is penetrated in vitro.
Fig. 2 B be Atorvastatin (Atorvastatin) in different pH at the 5th hour in the body of rat intestinal wall
Efficiency is penetrated outside.
Fig. 3 A is taken orally for SD rat (SD Rat)Lipitor (water, n=8), Atorvastatin
(atorvastatin) 7.4, n=11 pH), experimental group Atorvastatin (atorvastatin) simultaneously takes HUEXC41 (pH
7.4, n=6), the time of the summation (AT+2AT+4AT) of female medicine and two kinds of active metabolites is to blood level ongoing change figure.
Fig. 3 B is SD Oral Administration in RatsLipitor (water, n=8), atorvastatin (pH 7.4, n=11),
Experimental group Atorvastatin simultaneously takes HUEXC41 (pH 7.4, n=6), time of active metabolite (2AT) to blood level through when
Variation diagram.
Fig. 4 A is SD Oral Administration in RatsLipitor (water, n=8), atorvastatin (pH 7.4, n=
11), experimental group Atorvastatin and HUEXC85 (pH 6.8, n=6), the summation (AT+ of female medicine and two kinds of active metabolites are taken
Time 2AT+4AT) is to blood level ongoing change figure.
Fig. 4 B is SD Oral Administration in RatsLipitor (water, n=8), Atorvastatin (pH 7.4, n=11) are real
It tests group Atorvastatin and takes HUEXC85 (pH 7.4, n=6), the time of active metabolite (2AT) is to blood level through time-varying
Change figure.
Fig. 5 A is SD Oral Administration in RatsLipitor (water, n=8), Atorvastatin (water, n=11), experimental group
Atorvastatin (pH 7.4, n=11), the time of the summation (AT+2AT+4AT) of female medicine and two kinds of active metabolites is in blood
Concentration ongoing change figure.
Fig. 5 B is SD Oral Administration in RatsLipitor (water, n=8), Atorvastatin (water, n=11), experimental group
Atorvastatin (pH 7.4, n=11), the time of active metabolite (2AT) is to blood level ongoing change figure.
Specific embodiment
The present invention is to be demonstrated to illustrating with the following examples, but the present invention is not limited by following embodiments.
The statins new compound of high bioavailability provided by the present invention, is with Atorvastatin
(Atorvastatin) it is used as embodiment, but statin class drug is without being limited thereto.
The experimental provision and method penetrated in vitro
Vertical type disperser (Vertical diffusion cell) is adopted, as external penetration test, is configured to
The cylindrical glass container that can be separated up and down, upper end are columned double glazing spreading grooves, mainly can be used as storage and penetrate drug
Function, referred to as application end (donor), lower end be bottom have contact surface column glass tube, percutaneous absorbtion can be collected whereby
Penetrator content can fix between upper and lower glass container referred to as by medicine end (receptor) and penetrate barrier used in experimental design
Wall, its barrier is mainly worked as with SD rat preduodenal goldbeater's skin in this part, and glass outer is followed mainly as what water-bath was filled
Ring water flow, and temperature is controlled at 37 DEG C.When upper end and lower end are combined closely, inner section product is 0.785cm2(for reality
Penetrate area).This test is in the space filling inside upper end, with the Atorvastatin of the phosphate buffer configuration of different pH
7.4 phosphate buffer of pH of 6ml is then filled in the total 1ml of solution 0.5mg/ml, lower end inner space, and is put into magnetic in lower end base
Property stirring stone, put in being stirred on multipoint mode blender with the speed of 600rpm.Respectively 30 minutes, 1 hour, 2 hours, it is 3 small
When, 4 hours and 5 hours different time points extract medical fluid 0.5ml, reinject 7.4 phosphate buffer of pH of 0.5ml in by
Medicine end (pH value in simulation blood), to maintain capacity to fix, then is accumulated by medicine end drug with the analysis of high-effect liquid chromatography and is penetrated
Amount, and whether have statistical difference for control group with Student ' s t check analysis difference group.
In-vitro screening reagent and method
Hepatomicrosome enzyme preparation
With the male rat of 250~300g, source is prepared as hepatomicrosome enzyme (microsome), by fasting 16 hours
Above mouse is sacrificed, and weighing (and recording weight) after being cleaned after liver with ice KCl (1.15%) 34 is removed.After liver shreds,
Weight ratio (liver: KCl=1:4) ice KCl is added, and with homogenizer that liver homogeneous is complete, the complete liver liquid merging of homogeneous
High speed centrifugation pipe (every pipe about 15ml).Supercentrifuge is under 4 DEG C of environment, with 9000rpm (acceleration of gravity 12500g) centrifugation
20 minutes.Take out supernatant after the completion of centrifugation, then be placed in Ultracentrifuge, under 4 DEG C of environment 40000rpm (100,000g) from
The heart 2 hours.After the completion of centrifugation, supernatant is thrown aside, the KH with weights such as livers is added in the fragment precipitated in scraping pipe2PO4(pH7.4)
Buffer is sub-packed in 2ml centrifuge tube after homogeneous, and it is stored in -80 DEG C of refrigerators.
Protein content determination
The hepatomicrosome enzyme completed is prepared, quantifies contained protein concentration using Roche protein quantitative methods, this is quantitative
Between medium, detecting limit is about 0.05~0.5mg/ml for method sensitivity, is method that is widely used at present and having public credibility.
In vitro metabolism experiment
Model drug is respectively midazolam (midazolam), estradiol (estradiol) and chenodesoxycholic acid
(Chenodeoxycholic acid), they respectively correspond ferment CYP3A4, UGT1A1 and UGT 1A3.Testing group includes
Positive control group (positive control), negative sense control group (negative control) and experimental group.Every group of each sample
Product are all n=3, and the matrix being added is KH2PO4(pH7.4)53mM、MgCl25mM,NADPH,UDPGA.Model drug miaow
Up to 1.65 μ g/ml of azoles logical sequence, estradiol 0.24mM and chenodesoxycholic acid 0.24mM.Inhibitor ketoconazole (ketoconazole)
0.03mM and silibinin (silybin) 0.075mM.Hepatomicrosome enzyme 0.5mg/ml is to start reaction [table 8~9].Each
After sample adds reagent, 37 DEG C of water bath water-baths 1 hour are placed into 10 seconds with oscillator concussion.
Matrix added by experimental group is identical as control group, but without inhibitor replaces it with drug excipient to be sieved, added tax
Shape agent concentration is 33.3,16.7,3.33mg/ml from high to low, 0.033,0.0167,0.003 μ g/ml of reaction density, often
A sample adds after reagent to be put into 37 DEG C of water bath water-baths 1 hour after oscillator concussion 10 seconds.
After inspection product water-bath 1 hour, 1 '-hydroxyl of 1ml containing the internal standard-midazolam-D4 ice acetonitrile is added
(Acetonitrile) stopped reaction.Total volume 1.5ml sample is transferred to 2ml tube, 15000rpm is centrifuged 10 minutes, from
Taking-up inspection is savored supernatant 0.2ml and is analyzed after the heart.Analysis result brings formula into and seeks generating rate, relative to the hundred of control group
Divide rate (%control) and inhibits percentage (%inhibition).In-vitro screening is divided into the progress of 13 batches, every a batch
Secondary control group (control) and positive control group (positive control) all have statistical significant difference (P <
0.05)。
In vitro metabolism tests calibration curve preparation
This experiment is divided into 3 kinds of metabolins of analysis, therefore prepares three calibration curve, is 1'- hydroxyl-midazolam (CYP respectively
3A4) 16.7,33,83,167,330,830,1670ng/ml, QC point are 50,750,1500ng/ml to concentration range from low to high.
Same B- estradiol 3- (B-D- glucosiduronate) * sodium and CDCA 24- acyl-beta-D-Glucose thuja acid (UGT 1A1&UGT
1A3) 16.7,33,83,167,330,830,1670ng/ml, QC point are 50,750,1500ng/ml to concentration range from low to high.
Calculation formula:
I. generating rate V (pmol/min/mg)=(production quantity (ng/mL)/molecular weight) * 0.0005L/60min/0.5mg
Protein * 1000000
II.%control=(measuring metabolite concentration/control group mean concentration) * 100
III.%inhibition=100-%control
IV. in-vitro screening concentration conversion:
Give oral dose (mg)/3000ml (liver sausage volume) * 100%=in-vitro screening dosage of 60kg health adult
(mg)
The preparation of rat hepatic microsome enzyme
Protein content determination
Product preparation is examined in zoopery
Pharmacokinetic experiment room is carried out in SD rat, the point respectively 0min, 10min that takes a blood sample after animal oral drugs,
20min,40min,1hr,2hr,4hr,6hr,8hr,12hr,24hr.This experiment inspection product carry out generation with Solid Phase Extraction casket (HLB)
Thank to object extraction, inspection product preparation whole process all operates on ice.
The present invention analyzes altogether 6 kinds of metabolins, respectively Atorvastatin sour (AT), 2- hydroxyl-Atorvastatin acid
(2AT), 4- hydroxyl-Atorvastatin acid (4AT), Atorvastatin lactone (AT-lactone), 2- hydroxyl-Atorvastatin
Lactone (2AT- lactone), 4- hydroxyl-Atorvastatin lactone (4AT- lactone).
Atorvastatin acid and 2- hydroxyl-Atorvastatin acid calibration curve concentration range be respectively 0.25 from low to high,
0.5,1,5,10,20,50,100ng/ml, QC concentration range are 0.75,45,90ng/ml.Atorvastatin lactone, 2- hydroxyl-
Atorvastatin lactone and 4- hydroxyl-Atorvastatin lactone calibration curve concentration range be respectively 0.25 from low to high, 0.5,1,
2,5,10,15,25ng/ml, QC concentration range are 0.75,9,20ng/ml.
Solid Phase Extraction casket (HLB) animal examines product preparation flow:
Embodiment 1pH value penetrates the influence of efficiency to Atorvastatin in vitro
In order to improve the formula of Atorvastatin, in varying environment pH, assessment drug penetrates efficiency for progress, because
This carries out external breakthrough experiment using human stem cell (Franz-cell).Atorvastatin is through Franz-cell and big white mouse
The external breakthrough experiment of duodenum film: by Fig. 2A as a result, the Atorvastatin concentration amount that each time point is penetrated is shown,
Penetration difference caused by pH value obviously increases after 2 hours, and experimental result is shown, Atorvastatin pH5.8**,
Under pH6.3*, pH6.8**, pH7.4***, pH7.8*, pH8.0*** and pH8.5** environment, refer to for the 12 of SD rat
Goldbeater's skin, which has, well penetrates efficiency, all has optimal penetration effect at each time point with pH7.4；By Fig. 2 B as a result, the 5th hour
The breakthrough concentration of atorvastatin reaches highest in pH7.4, andLipitor intestines and stomach pH value (pH4.5) result
Significant difference is compared；(*P<0.05；**P<0.01；***P<0.001).Atorvastatin (pKa=4.46) is BCS system
Class Π acidic drug, physicochemical characteristic are low solubility high-penetration rate, therefore by external rat goldbeater's skin breakthrough experiment result
It is found that penetrance can be incremented by when environmental pH is greater than the pKa value of drug itself, it is dense up to penetrating when environment pH=7.4
Spend highest point.It is also verified in animal experiments, lipophilic drugs Atorvastatin can improve dissociation journey when pH7.4
Degree, and make the metabolin of Atorvastatin, intestines and stomach cell membrane (mucosa) can be smoothly penetrated, is reached on blood drug concentration
The result risen
2 usual excipients of embodiment or the pure ingredient of Chinese medicine efficacy-enhancing ingredient, influence active for Atorvastatin metabolic ferments
The hepatomicrosome enzyme (microsome) being purified into using weight 250~300g SD rat liver, protein contains
Measurement be surely follow Roche protein quantitative methods, and with ultraviolet light sub-ray spectrometer measurement light absorption value (OD 550) it is last again with
Protein standards (BSA) compare, and standard items calibration curve concentration is 5,10,20,30,40mg/ml.Measured liver particle
Body enzyme concentration is averagely about 10mg/ml.The usual excipients as the result is shown of 1~table of table 14 for UGT1A3, UGT1A1 and
The active influence of CYP3A4, the main ferment that screens is respectively CYP3A4, UGT1A1 and UGT1A3, the screening concentration of excipient by
It is high to low be respectively 33.3,16.7,3.33mg/ml, inhibitor influence hepatomicrosome enzyme extent of metabolism, ranking mode with
Based on UGT1A3, because it is the main force for participating in the reaction of Atorvastatin active metabolite glucuronidation, secondly then it is
UGT1A1, using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3, with ketoconazole
(Ketoconazole) (0.016 μ g/ml) as CYP3A4 positive control group (* p < 0.05, * * p < 0.01, * * * p <
0.001).The present invention, which needs to find, can inhibit the safe compounds of UGT1A1, UGT1A3 without inhibition CYP3A4 to be used for
Improve the biological availability of statins.
The influence active for UGT1A3, UGT1A1 and CYP3A4 of 1 usual excipients of table
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；B. with ketone
Positive control group of the health azoles (Ketoconazole) (0.016 μ g/ml) as CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
2 usual excipients of table or the pure ingredient of Chinese medicine efficacy-enhancing ingredient, influence active for UGT1A3, UGT1A1 and CYP3A4
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；
B. using ketoconazole (Ketoconazole) (0.016 μ g/ml) as the positive control group of CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
3 usual excipients of table or the pure ingredient of Chinese medicine efficacy-enhancing ingredient, influence active for UGT1A3, UGT1A1 and CYP3A4
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；
B. using ketoconazole (Ketoconazole) (0.016 μ g/ml) as the positive control group of CYP3A4；
5 statistical methods: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
4 usual excipients of table or the influence active for UGT1A3, UGT1A1 and CYP3A4 of the pure ingredient of Chinese medicine efficacy-enhancing ingredient
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；
B. using ketoconazole (Ketoconazole) (0.016 μ g/ml) as the positive control group of CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
The influence active for UGT1A3, UGT1A1 and CYP3A4 of 5 usual excipients of table
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；B. with ketone
Positive control group of the health azoles (Ketoconazole) (0.016 μ g/ml) as CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
The influence active for UGT1A3, UGT1A1 and CYP3A4 of 6 usual excipients of table
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；B. with ketone
Positive control group of the health azoles (Ketoconazole) (0.016 μ g/ml) as CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
The influence active for UGT1A3, UGT1A1 and CYP3A4 of 7 usual excipients of table
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；B. with ketone
Positive control group of the health azoles (Ketoconazole) (0.016 μ g/ml) as CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
The influence active for UGT1A3, UGT1A1 and CYP3A4 of 8 usual excipients of table
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；B. with ketone
Positive control group of the health azoles (Ketoconazole) (0.016 μ g/ml) as CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
The influence active for UGT1A3, UGT1A1 and CYP3A4 of 9 usual excipients of table
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；B. with ketone
Positive control group of the health azoles (Ketoconazole) (0.016 μ g/ml) as CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
The influence active for UGT1A3, UGT1A1 and CYP3A4 of 10 usual excipients of table
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；B. with ketone
Positive control group of the health azoles (Ketoconazole) (0.016 μ g/ml) as CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
The influence active for UGT1A3, UGT1A1 and CYP3A4 of 11 usual excipients of table
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；B. with ketone
Positive control group of the health azoles (Ketoconazole) (0.016 μ g/ml) as CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
The influence active for UGT1A3, UGT1A1 and CYP3A4 of 12 usual excipients of table
A. using silibinin (silybin) (0.036 μ g/ml) as the positive control group of UGT1A1/UGT1A3；B. with ketone
Positive control group of the health azoles (Ketoconazole) (0.016 μ g/ml) as CYP3A4；
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group..
Ranking of 13 usual excipients of table for UGT1A1 activity influence
A.0.033 μ g/ml, b.0.167 μ g/ml, c.0.003 μ g/ml
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group.
Ranking of 14 usual excipients of table for UGT1A3 activity influence
A.0.033 μ g/ml, b.0.167 μ g/ml, c.0.003 μ g/ml
Statistical method: p < 0.001 two-way test .*p < 0.05, * * p < 0.01, * * * is compared with the control group.
Table 13 indicate UGT1A1 inhibiting rate ranking, TOP V inhibitor be respectively HUEXC40 (NaLS,
Sodium lauryl sulfate, SLS), HUEXC07 (the hard ester group ether of polyoxyethylene 10, Brij 76), HUEXC14 (sorb
Sugar alcohol list olein 80, Span 80), HUEXC77 (polyoxyl 40 hydrogenated castor oil, polyoxyl 40hydrogenated
Castor oil, RH 40) and HUEXC85 (trans-aconitic acid, Trans-Aconitic acid).However, inhibitory effect is most strong
It is then HUEXC40 (NaLS, Sodium lauryl sulfate, SLS) in 0.01667 μ g/ml of concentration, inhibits
Rate 84.4%；Secondly it is HUEXC07 (the hard ester group ether of polyoxyethylene 10, Brij 76) in 0.03334 μ g/ml of concentration, inhibits
Rate is 52.1%.It is respectively HUEXC40 (lauryl sulfate that table 14, which indicates to sift out the UGT1A3 inhibitor the first four place that sorts in vitro,
Sodium, Sodium lauryl sulfate, SLS), HUEXC32 (Nipasol, Propyl paraben), (the poly- mountain HUEXC01
Pear ester 20, Tween20, TW20) and HUEXC33 (methyl hydroxybenzoate, Methyl paraben), 0.01667 μ g/ml of inhibitor concentration
When, all have 50% or so for UGT1A3 inhibiting rate.It screens in inhibitor result in vitro, the best type of inhibitory effect is big
Mostly interfacial agent, however reverse effect can be but obtained into zoopery, possible cause is that surfactants are easy to draw
Experimental animal diarrhea is sent out, the result that oral drug absorption is bad is caused.
The influence of embodiment 3pH value and usual excipients to Atorvastatin bioavailability
Fig. 3 A indicates SD Oral Administration in RatsLipitor (water, n=8), Atorvastatin (pH 7.4, n=11),
Experimental group Atorvastatin simultaneously takes HUEXC41 (pH 7.4, n=6), female medicine and two kinds of active metabolite summation (AT+2AT+
Time 4AT) is to blood level ongoing change figure.Fig. 3 B indicates that SD Rat is oralLipitor (water, n=8), Ah
Atorvastatin (pH 7.4, n=11), experimental group Atorvastatin simultaneously take HUEXC41 (pH 7.4, n=6), active metabolite
The time of (2AT) is to blood level ongoing change figure.Table 15 is the results show that experimental group Atorvastatin 1mg/kg and take inhibition
Agent HUEXC41 10mg/kg (in pH7.4), with control groupLipitor (in water) is made comparisons, AUC∞Increase by 3.79
Again (P < 0.001), AUCtIncrease by 3.56 times (P < 0.001), CmaxIncrease by 3.38 times (P=0.001).
15 animal of table takes orally Atorvastatin and takes the pharmacokinetic parameter and statistical analysis of excipient (HUEXC41).
Statistical method: unidirectional to examine variance analysis
*p<0.05,**p<0.01,***p<0.001
Fig. 4 A indicates that SD Rat is oralLipitor (water, n=8), Atorvastatin (pH 7.4, n=
11) it, experimental group Atorvastatin and takes HUEXC85 (pH 7.4, n=6), female medicine and two kinds of active metabolite summation (AT+2AT
+ 4AT) time to blood level ongoing change figure.Fig. 4 B indicates SD Oral Administration in RatsLipitor (water, n=8),
Atorvastatin (pH 7.4, n=11), experimental group Atorvastatin simultaneously take HUEXC85 (pH 7.4, n=6), active metabolite
The time of (2AT) is to blood level ongoing change figure.Table 16 is shown, and if taking inhibitor HUEXC85 6mg/kg (in
PH7.4), with control groupLipitor (in water) is made comparisons, AUC∞Increase by 3.8 times (P < 0.001), AUCtIncrease
(P < 0.001) 3.74 again, CmaxIncrease by 3.21 times (P=0.001).
The oral Atorvastatin for improving formula and merging inhibitor of animal, withLipitor (in water) is done
Compare, the T of summation Atorvastatin and two kinds of active metabolites (AT/2AT/4AT)max=1~1.94hr, Cmax=0.11~
0.12 μm of ol/L, AUC∞=0.66hr* μm of ol/L.And its individual active metabolite Atorvastatin acid (AT) Tmax=0.61~
0.69hr, Cmax=6.23~11.43ng/ml, AUC∞=23.97~28.92 hr*ng/ml；2OH- Atorvastatin acid
(2AT)Tmax=1~2hr, Cmax=67.17~70.55ng/ml, AUC∞=383.62~406.06ng/ml.Change through this discovery
Kind Atorvastatin pharmaceutical formulation and merging inhibitor, can increase active metabolite in blood level, and can extend drug effect
Time (duration).
16 animal of table takes orally Atorvastatin and takes the pharmacokinetic parameter and statistical analysis of excipient (HUEXC85).
Statistical method: unidirectional to examine variance analysis
*p<0.05,**p<0.01,***p<0.001
The present invention is via the formula for improving Atorvastatin, and with pH appropriate and ferment inhibitor, collaboration promotes drug to exist
Solubility and absorption in intestines and stomach, what is made is conducive to penetrate into blood circulation, and extends drug residence time in vivo.Phase
Compared with genuine drugThe results of animal of Lipitor shows that the formula that UGT1A1/UGT1A3 inhibitor is added makes
The AUC of Atorvastatin∞Increase by 3.79~3.8 times, Cmax3.21~3.38 times, and significant increase Atorvastatin can be further added by
Bioavailability.
Influence of the embodiment 4pH value to Atorvastatin bioavailability
Oral Administration in Rats Lipitor or oral Atorvastatin 1mg/kg are dissolved in pure water and are dissolved in 7.4 buffer of pH,
Testing group is respectivelyLipitor (in water), Atorvastatin (in water) and Atorvastatin are (in pH7.4
In buffer).Fig. 5 A indicates that SD Rat is oralLipitor (water, n=8), Atorvastatin (water, n=11) are real
It tests a group Atorvastatin (pH 7.4, n=11), the time of female medicine and two kinds of active metabolite summations (AT+2AT+4AT) is to blood
Middle concentration ongoing change figure.Fig. 5 B indicates SD Oral Administration in RatsLipitor (water, n=8), Atorvastatin (water, n=
11), experimental group Atorvastatin (pH 7.4, n=11), the time of active metabolite (2AT) is to blood level ongoing change figure.
Experimental result shows (table 17)The pharmacokinetics results of Lipitor (in water) and Atorvastatin (in water)
It is similar, and experimental group Atorvastatin (in the buffer of pH7.4) withLipitor (in water) is made comparisons,
AUC∞Increase by 3.39 times (P < 0.001), AUCtIncrease by 3.02 times (P < 0.001), CmaxIncrease by 1.77 times (P=0.002).It is dissolved in
In pure waterLipitor give animal it is oral after, summation Atorvastatin and two kinds of active metabolite (AT/2AT/
T 4AT)max=0.58hr, Cmax=0.03 μm of ol/L, AUC∞=0.17hr* μm of ol/L.And its individual active metabolite
atorvastatin acid(AT)Tmax=0.54hr, Cmax=11.99ng/ml, AUC∞=30.91hr*ng/ml；2OH- Ah
Atorvastatin acid (2AT) Tmax=1hr, Cmax=16.07ng/ml, AUC∞=91.04hr*ng/ml.
After table 17 adjusts intestines and stomach pH value, animal takes orally the pharmacokinetic parameter and statistical analysis of Atorvastatin.
Statistical method: unidirectional to examine variance analysis
*p<0.05,**p<0.01,***p<0.001
Possibility research of the 5 pH-value regulator of embodiment to adjustment gut pH
The permeability of Atorvastatin and bioavailability are best when confirming pH7.4 by above-described embodiment, therefore this implementation
Example is further inquired into adds pH-value regulator to the feasibility of adjustment gut pH in medical composition.
80mg Atorvastatin powder is added manually to intend intestinal juice 150ml (pH 4.5 is formulated according to United States Pharmacopeia USP 39)
Last (daily dosage of Atorvastatin about 10-80mg), first surveys its pH value, then measures the buffer solution for needing how many volume, can make
Intestines and stomach pH value is maintained at pH7.4.Table 18 is attempted with various ealkaline buffers to adjust manually quasi- intestinal juice pH-value, by people
Work intends intestinal juice and is adjusted to pH 7.4 by pH 4.5, and calculates wherein required buffer agent and the wherein dosage of various salts.Wherein delay
Electuary Na2CO3/ NaHCO3(pH8.6~pH10.1), NaHCO3/ NaOH, alkali borate (boric acid/KCL/NaOH) (pH10)
Only need to be buffered salt using 236~826mg successfully can be intended artificial intestinal juice and be adjusted to pH 7.4 by pH 4.5, and by
PH-value regulator is added to adjustment intestinal pH less than 1 gram, therefore in medical composition in the dosage of the buffering salt used
Value is feasible.In addition it can be found that intending intestinal juice by artificial required for the pH higher buffer of original and being adjusted to pH by pH 4.5
Dosage required for 7.4 is fewer.
Table 18 intends intestinal juice (pH4.5) with 150ml and speculates the alkalization agent content for maintaining enteron aisle required when the pH 7.4
The above results confirm that the medical composition of statins of the invention utilizes:
1) special dosage pH-value regulator and utilization enteric film coating medicine, and oral drugs can be made to enteron aisle
Dissolution adjusts enteron aisle pH-value (pH value)；Or
2) merge and use metabolic ferments inhibitor, reduce Atorvastatin and its active metabolite 2-OH Atorvastatin
Acid, 4-OH Atorvastatin acid be metabolised to not have the Atorvastatin lactone of pharmacological activity, 2-OH Atorvastatin lactone with
4-OH Atorvastatin lactone；
To increase the bioavailability of the statins such as Atorvastatin, since drug bioavailability increases, reduce
Because the serious or even lethal side effect of such as rhabdomyolysis caused by individual absorption difference occurs, increases drug and pacify
Quan Xing, therefore modified release dosage form can be made in the medical composition of the statins.
The present invention has hereinbefore specifically sufficiently disclosed the relevant technologies content by preferred embodiment, is so familiar with this item
Operator should be understood that the embodiment is only used for describing the present invention, when cannot limit the scope of the patents of the invention with this；It is ripe
The personage in technique field is known when can change and modify to it and reach after understanding spirit of the invention with principle
Purpose is imitated, and these are changed and modification, should be all covered by the scope that claim as described later is defined.
In conclusion the medical composition of the oral statins of the high bioavailability of the invention, is not only matching
Really belong to innovation in side, and there is the serious or even lethal side effect etc. for increasing bioavailability and reducing such as rhabdomyolysis
Multinomial effect really has a practicability, the utilization of technological means also for it is novel undoubtedly, and effect is really accorded with purpose of design
It closes, has claimed rationally progressive to bright.
Claims (17)
1. a kind of medical composition that oral statins bioavailability can be improved, which includes statins
Object includes with raising raw body utilization rate substance, wherein the raising raw body utilization rate substance:
1) pH-value regulator and modified release dosage form；Or/and
2) metabolic ferments inhibitor；
The pH-value regulator can be adjusted the intestines and stomach pH value to absorb the drug, which can enable effective ingredient
Safety stomach smoothly reaches the position of intestines.
2. medical composition according to claim 1, which is characterized in that the pH-value regulator can be by gut pH tune
Section is 4.9~8.5.
3. medical composition according to claim 1, which is characterized in that the pH-value regulator can be by gut pH tune
Section is 5.8~7.8.
4. medical composition according to claim 1, which is characterized in that the pH-value regulator includes sodium carbonate
(sodium carbonate), sodium bicarbonate (sodium bicarbonate), sodium hydroxide (Sodium hydroxide), boron
Acid (boric acid), potassium chloride (potassium chloride), sodium dihydrogen phosphate
(SodiumDihydrogenPhosphate), disodium hydrogen phosphate (disodium hydrogen phosphate), biphosphate
Potassium (Potassium dihydrogen phosphate), dipotassium hydrogen phosphate (Dipotassium phosphate), glycine
(glycine), ammonia (ammonia), ammonium lactate (ammonium lactate), ammonium hydrogen carbonate (ammonium
Bicarbonate), ammonium hydroxide (ammonium hydroxide), diammonium hydrogen phosphate (ammonium phosphate
Dibasic), monoethanolamine (monoethanolamine), diethanol amine (diethanolamine), triethanolamine
(triethanolamine), trihydroxy methyl first ammonia (trihydroxymethylaminomethane), ethylenediamine
(ethylenediamine), N- methyl glucose osamine (N-methyl glucamide), 6N- methyl glucose osamine (6N-
Methyl glucamine), meglucamine diatrizoate (meglucamine), L-lysine and 2- amino -2- (methylol) -1,3- third
At least one of glycol (L-lysine and 2-amino-2- (hydroxymethyl) -1,3-propanediol) or its
Any combination.
5. medical composition according to claim 1, which is characterized in that the weight of the pH-value regulator is 200~
1180mg。
6. medical composition according to claim 1, which is characterized in that the quality of the pH-value regulator is the medicine
20~90% (w/w) of composition.
7. medical composition according to claim 1, which is characterized in that the statins are to be selected to be cut down by atropic
Statin (atorvastatin), Pravastatin (pravastatin), Simvastatin (simvastatin), Lovastatin
(lovastatin), mevastatin (mevastatin), cut down statin (compactin), Fluvastatin (fluvastatin), west
It cuts down composed by statin (cerivastatin), Rosuvastatin (rosuvastatin), Pitavastatin (pitavastatin)
Group.
8. medical composition according to claim 1, which is characterized in that the metabolic ferments inhibitor includes lauryl sulphur
Sour sodium (Sodium lauryl sulfate, SLS), the fresh general potassium that relaxes (Acesulfame potassium) of second, colloidal silicon dioxide
(Aerosil 200), foreign member Sui flavine (Apigenin), shellfish add flavones (Baicalin), benzoic acid (Benzyl alcohol),
Ben Jia Suan Benzyl ester (Benzyl Benzoate), fourth hydrocarbon fennel ether (BHA), polyethylene glycol cetyl ether (Brij 58), polyoxy second
The hard ester group ether (Brij 76) of alkene 10, cherry flavor (Cherry), citric acid (Citric acid), cross-linked carboxymethyl cellulose sodium
It is (Croscarmellose sodium), dextrates (Dextrates), disodium ethylene diamine tetraacetate (EDTA 2Na), sweet
Oil (Glycerin), glycyrrhizin (Glycyrrhizin), hydroxypropyl cellulose (Hydroxy propyl cellulose), hydroxypropyl
Methylcellulose phthalate ester (Hydroxypropyl methylcellulose), polyvinylpyrrolidone (kollidon VA64), cream
Sugared (Lactose), monohydrate lactose (Lactose monohydrate), Lactose S.G, lemon oil (Lemon oil), thorn
Chinese scholartree (Locust), the third cellulose of low substitution hydrocarbon (Low-substituted hydroxypropylcellulose), malt magma
It is smart (Maltodextrin), mannitol (Mannitol), methyl hydroxybenzoate (Methyl paraben), menthol (Menthol), hard
40 ester of resin acid polyoxyethylene (Myri 52), methylcellulose (Methyl cellulose), NF hydrate (NF
Hydrate), β-how flavones (β-Naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG
2000), Macrogol 4000 (PEG4000), PLURONICS F87 (Pluronic F68), poloxamer188 (Pluronic
F127), polyoxyl 40 hydrogenated castor oil (polyoxyl 40 hydrogenated castor oil, RH 40), oxybenzene third
Ester (Propyl paraben), polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin (saccharin), hexamethylene alkylamino
Sodium sulfonate (Sodium cyclamate), sour first determine powder and receive (Sodium starch glycolate), sodium benzoate (Sodium
Benzolate), sorbic acid (Sorbic acid), D-sorbite (Sorbitol solution), sorbitan monostearate
Ester (Span 60), sorbital monooleate rouge 80 (Span 80), hydroxyl sugar chlorine (Sucralose), acetic starch (Starch
Acetate), trans-aconitic acid (Trans-Aconitic acid), triethyl citrate (triethyl citrate), lemon
Sour trisodium (trisodium citrate), polysorbate 20 (Tween20, TW20), polysorbate 40 (Tween 40, TW40),
Polyoxyethylene sorbitan monoleate (Tween 80, TW80), ursolic acid (Ursolic Acid), sodium dihydrogen phosphate (sodium dihydrogen
Phosphate), dicalcium phosphate dihydrate (Dicalcium phosphate dihydrate), Dextrates, NF hydrate
At least one of (Dextrates, NF hydrate) and cholic acid (Cholic acid) or any combination thereof.
9. medical composition according to claim 1, which is characterized in that the modified release dosage form, which can further include, prolongs
Slow releasing effect.
10. according to medical composition described in claim the 1, which is characterized in that the medical composition be tablet, particle,
Capsule, powder or other acceptable dosage forms of medicine.
11. medical composition according to claim 1, which is characterized in that tax can be further added in the medical composition
Shape agent.
12. medical composition according to claim 11, which is characterized in that the excipient can for diluent, filler,
Bonding agent, disintegrating agent, lubricant or other acceptable excipient of medicine.
13. a kind of composition is used to improve the purposes of statins biomass utilization rate, the composition includes:
1) pH-value regulator and modified release dosage form, or/and
2) metabolic ferments inhibitor, the modified release dosage form can enable the broken of statins effective ingredient safety gastric acid
Position that is bad and smoothly reaching intestines, the pH-value regulator can be adjusted gut pH to improve drug stability and absorptivity.
14. purposes according to claim 13, which is characterized in that the pH-value regulator includes sodium carbonate (sodium
Carbonate), sodium bicarbonate (sodium bicarbonate), sodium hydroxide (Sodium hydroxide), boric acid (boric
Acid), potassium chloride (potassium chloride), sodium dihydrogen phosphate (SodiumDihydrogenPhosphate), phosphoric acid hydrogen
Disodium (disodium hydrogen phosphate), potassium dihydrogen phosphate (Potassium dihydrogen phosphate),
Dipotassium hydrogen phosphate (Dipotassium phosphate), glycine (glycine), ammonia (ammonia), ammonium lactate (ammonium
Lactate), ammonium hydrogen carbonate (ammonium bicarbonate), ammonium hydroxide (ammonium hydroxide), phosphoric acid hydrogen two
Ammonium (ammonium phosphate dibasic), monoethanolamine (monoethanolamine), diethanol amine
(diethanolamine), triethanolamine (triethanolamine), trihydroxy methyl first ammonia
(trihydroxymethylaminomethane), ethylenediamine (ethylenediamine), N- methyl glucose osamine (N-
Methyl glucamide), 6N- methyl glucose osamine (6N-methyl glucamine), meglucamine diatrizoate
(meglucamine), L-lysine and 2- amino -2- (methylol) -1,3- propylene glycol (L-lysine and 2-amino-2-
(hydroxymethyl) -1,3-propanediol) at least one or any combination thereof.
15. purposes according to claim 13, which is characterized in that the metabolic ferments inhibitor includes NaLS
The fresh general potassium that relaxes (Acesulfame potassium) of (Sodium lauryl sulfate, SLS), second, colloidal silicon dioxide
(Aerosil 200), foreign member Sui flavine (Apigenin), shellfish add flavones (Baicalin), benzoic acid (Benzyl alcohol),
Ben Jia Suan Benzyl ester (Benzyl Benzoate), fourth hydrocarbon fennel ether (BHA), polyethylene glycol cetyl ether (Brij 58), polyoxy second
The hard ester group ether (Brij 76) of alkene 10, cherry flavor (Cherry), citric acid (Citric acid), cross-linked carboxymethyl cellulose sodium
It is (Croscarmellose sodium), dextrates (Dextrates), disodium ethylene diamine tetraacetate (EDTA 2Na), sweet
Oil (Glycerin), glycyrrhizin (Glycyrrhizin), hydroxypropyl cellulose (Hydroxy propyl cellulose), hydroxypropyl
Methylcellulose phthalate ester (Hydroxypropyl methylcellulose), polyvinylpyrrolidone (kollidon VA64), cream
Sugared (Lactose), monohydrate lactose (Lactose monohydrate), Lactose S.G, lemon oil (Lemon oil), thorn
Chinese scholartree (Locust), the third cellulose of low substitution hydrocarbon (Low-substituted hydroxypropylcellulose), malt magma
It is smart (Maltodextrin), mannitol (Mannitol), methyl hydroxybenzoate (Methyl paraben), menthol (Menthol), hard
40 ester of resin acid polyoxyethylene (Myri 52), methylcellulose (Methyl cellulose), NF hydrate (NF
Hydrate), β-how flavones (β-Naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG
2000), Macrogol 4000 (PEG4000), PLURONICS F87 (Pluronic F68), poloxamer188 (Pluronic
F127), polyoxyl 40 hydrogenated castor oil (polyoxyl 40 hydrogenated castor oil, RH 40), oxybenzene third
Ester (Propyl paraben), polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin (saccharin), hexamethylene alkylamino
Sodium sulfonate (Sodium cyclamate), sour first determine powder and receive (Sodium starch glycolate), sodium benzoate (Sodium
Benzolate), sorbic acid (Sorbic acid), D-sorbite (Sorbitol solution), sorbitan monostearate
Ester (Span 60), sorbital monooleate rouge 80 (Span 80), hydroxyl sugar chlorine (Sucralose), acetic starch (Starch
Acetate), trans-aconitic acid (Trans-Aconitic acid), triethyl citrate (triethyl citrate), lemon
Sour trisodium (trisodium citrate), polysorbate 20 (Tween20, TW20), polysorbate 40 (Tween 40, TW40),
Polyoxyethylene sorbitan monoleate (Tween 80, TW80), ursolic acid (Ursolic Acid), sodium dihydrogen phosphate (sodium dihydrogen
Phosphate), dicalcium phosphate dihydrate (Dicalcium phosphate dihydrate), Dextrates, NF hydrate
At least one of (Dextrates, NF hydrate) and cholic acid (Cholic acid) or any combination thereof.
16. purposes according to claim 13, which is characterized in that the statins are selected from by Atorvastatin
(atorvastatin), Pravastatin (pravastatin), western horse statin (simvastatin), Lovastatin
(lovastatin), mevastatin (mevastatin), cut down statin (compactin), Fluvastatin (fluvastatin), west
Composed by rivastatin (cerivastatin), rosuvastatin (rosuvastatin) and Pitavastatin (pitavastatin)
Group.
17. purposes according to claim 13, which is characterized in that the modified release dosage form can further include delay and release
Put effect.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
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| CN201810283391.0A CN110339365A (en) | 2018-04-02 | 2018-04-02 | A kind of medical composition and application thereof that oral statins bioavailability can be improved |
| PCT/CN2018/098524 WO2019192112A1 (en) | 2018-04-02 | 2018-08-03 | Pharmaceutical composition for promotion of bioavailability of oral statins and applications thereof |
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|---|---|---|---|
| CN201810283391.0A CN110339365A (en) | 2018-04-02 | 2018-04-02 | A kind of medical composition and application thereof that oral statins bioavailability can be improved |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114569605A (en) * | 2022-03-10 | 2022-06-03 | 沈阳药科大学 | Atorvastatin-flavonoid co-amorphous compound and preparation method thereof |
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