CN114569605A - Atorvastatin-flavonoid co-amorphous compound and preparation method thereof - Google Patents
Atorvastatin-flavonoid co-amorphous compound and preparation method thereof Download PDFInfo
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- CN114569605A CN114569605A CN202210238496.0A CN202210238496A CN114569605A CN 114569605 A CN114569605 A CN 114569605A CN 202210238496 A CN202210238496 A CN 202210238496A CN 114569605 A CN114569605 A CN 114569605A
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- atorvastatin
- flavonoid
- amorphous
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- naringenin
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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
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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Abstract
The invention discloses an atorvastatin-flavonoid compound co-amorphous compound and a preparation method thereof, belonging to the field of biological medicines. When the compound is prepared, the flavonoid compounds including apigenin, naringenin and hesperetin are combined with atorvastatin in a certain proportion, and the two compounds are prepared into a co-amorphous compound together with a surfactant solution according to a combined administration proportion, so that the solubility of the drug and the flavonoid compounds is improved. The test research shows that the pharmaceutical composition and the co-amorphous compound of the flavonoid compound containing the pharmaceutical composition provided by the invention can obviously improve the oral bioavailability of atorvastatin and increase the concentration of the drug in the liver of a target organ, thereby enhancing the curative effect of reducing blood fat. In the combined administration of the two medicines, the use dosage of atorvastatin can be obviously reduced under the same effect, the side effects of hepatotoxicity and gastrointestinal tract stimulation are reduced, and the price of the medicine is reduced.
Description
The technical field is as follows:
the invention belongs to the technical field of medicines, and particularly relates to an atorvastatin-flavonoid compound co-amorphous compound and a preparation method thereof.
Background art:
cardiovascular diseases account for the first part of the global total death rate, and the number of cardiovascular diseases in China reaches 2.9 hundred million. Long-term hyperlipidemia can induce cardiovascular diseases such as atherosclerosis, coronary heart disease, myocardial infarction, sudden cardiac death and the like, seriously threatens human health, and is one of the leading causes of cardiovascular events. At present, the first-line hyperlipemia treating medicine is statins.
Atorvastatin (atorvastatin) is a commonly used clinical statin hypolipidemic drug, has a chemical name of (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) pyrrole-1-yl ] -3, 5-dihydroxy heptanoic acid, and has a chemical structural formula shown in the specification. Atorvastatin competitively inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase in a target organ liver, thereby reducing the biosynthesis of cholesterol in the liver and preventing cardiovascular diseases such as atherosclerosis, coronary heart disease, myocardial infarction and the like caused by hyperlipidemia.
The results of the pharmacokinetic study of atorvastatin show that the intestinal absorption rate is only 30%, the liver uptake rate is as high as 70%, the first pass effect of liver and intestine is serious, the oral absolute bioavailability of human body is only 12%, the oral absolute bioavailability of SD rat is about 5%, and almost more than 80% of the medicine is metabolized, discharged and unabsorbed by organism. The metabolic enzyme involved in the first-pass metabolism of atorvastatin is a phase metabolic enzyme CYP3A 4; efflux transporters that affect intestinal absorption are P-glycoproteins (P-gp). The main adverse reactions of atorvastatin after long-term administration are abnormal liver function, rhabdomyolysis, muscle pain, gastrointestinal discomfort and the like. These adverse effects seriously affect the quality of life of patients, especially elderly patients. At present, the bioavailability of the compound is urgently needed to be improved, the daily dosage is reduced, and the adverse reaction of long-term medication is improved, so that the production cost is reduced, and the treatment cost of patients is reduced.
The natural flavonoid compound has multiple biological activities of resisting oxidation, protecting liver, regulating blood fat, protecting vascular endothelium and the like, and particularly has the protection effect on heart and cerebral vessels. The mechanism of the invention is based on metabolic enzyme and efflux transporter, and the inhibition of the atorvastatin metabolic enzyme CYP3A4 and efflux transporter P-gp by the flavonoid compound is utilized to improve the bioavailability and the intrahepatic drug concentration of target organs. Therefore, the flavonoid compound and the atorvastatin can exert the synergistic interaction of the two, improve the efficacy of the medicine in reducing blood fat, delay the occurrence of cardiovascular diseases, reduce the side effect caused by the independent long-term administration of the atorvastatin, and have immeasurable market development potential and application value. However, atorvastatin and flavonoids have poor water solubility and influence the absorption of drugs, while the amorphous state of substances has higher Gibbs free energy and has higher solubility than the crystalline state of substances, but the amorphous state is easily transformed to a lower energy state of the crystalline form and finally exists in a stable state of the crystalline form. The surfactant and the cyclodextrin stabilize the amorphous state of the medicament and inhibit the crystallization of the medicament by utilizing the interaction between the surfactant and the medicament components. Therefore, the co-amorphous compound which has simple process and is easy for industrialized production is adopted as a delivery system, and the solubility and the bioavailability of the co-amorphous compound and the delivery system can be improved.
Through a large number of experimental researches, the combination oral administration of the flavonoid compound and the atorvastatin can obviously improve the bioavailability of the atorvastatin and the concentration of the drug in target organs. At present, reports related to the combined use of atorvastatin and flavonoids to improve the bioavailability and intrahepatic concentration of atorvastatin and the preparation of a co-amorphous compound of atorvastatin and flavonoids are not found.
The invention content is as follows:
the invention aims to overcome the defects in the prior art and provides an atorvastatin-flavonoid co-amorphous compound and a preparation method thereof. The invention aims to inhibit the metabolism and efflux transporters of atorvastatin through flavonoid compounds, and adopts an amorphous compound delivery system to increase the water solubility of the atorvastatin and the efflux transporters, thereby improving the bioavailability of the atorvastatin, reducing the side effect and the production cost of the medicine, improving the blood fat reducing effect of the medicine, improving the life quality of patients and reducing the treatment cost.
In order to achieve the purpose, the invention adopts the following technical scheme:
the atorvastatin-flavonoid compound co-amorphous compound comprises the following components in parts by mass: and (3) flavonoid compounds: surfactant 1: (6-30): (1-10), wherein the flavonoid compound is one or a mixture of several of apigenin, naringenin or hesperetin, and the mixing ratio is any ratio.
Preferably, atorvastatin: flavonoid compound ═ 1: (15-30).
More preferably, atorvastatin: flavonoid compound ═ 1: 30.
the surfactant is sodium dodecyl sulfate or cyclodextrin.
Preferably, the surfactant is sodium lauryl sulfate.
The preparation method of the atorvastatin-flavonoid co-amorphous compound comprises the following steps:
(1) according to the mass ratio, atorvastatin: and (3) flavonoid compounds: surfactant 1: (6-30): (1-10), respectively weighing atorvastatin, a flavonoid compound and a surfactant, adding the atorvastatin and the flavonoid compound into an organic solvent, and performing ultrasonic dissolution to obtain a solution A;
(2) dissolving a surfactant in distilled water to obtain a solution B;
(3) adding the solution A into the solution B, and fully and uniformly mixing;
(4) and (3) after ultrasonic treatment in ice bath, carrying out reduced pressure rotary evaporation to remove the organic solvent, and freeze-drying to prepare the atorvastatin-flavonoid compound co-amorphous compound.
In the step (1), the organic solvent is any one of methanol, ethanol or dimethyl sulfoxide.
In the step (2), the molar concentration of the surfactant in the solution B is 0.1-10 mM/L.
In the step (4), the ultrasonic time is 10-50min, and the ultrasonic power is 20-30 KHZ.
In a pharmacokinetic experiment and an atorvastatin distribution experiment in a target organ liver, a pharmacokinetic result shows that the bioavailability of the atorvastatin subjected to combined administration is remarkably improved after the atorvastatin is independently administered and the atorvastatin-flavonoid compound co-amorphous compound is administered. The results of the change of the concentration of the atorvastatin in the liver show that the concentration of the atorvastatin in the liver is obviously increased after the combined administration of the flavone and the atorvastatin compared with the single administration of the atorvastatin.
The invention has the beneficial effects that:
according to the invention, the flavonoid compound and the atorvastatin are prepared into a co-amorphous compound for administration, the delivery system and the flavonoid compound improve the bioavailability of the atorvastatin, the concentration of the drug in the liver of a target organ is obviously increased, the synergistic effect of the atorvastatin and the atorvastatin can be exerted, and meanwhile, the flavonoid compound has the effects of oxidation resistance, cardiovascular protection and liver protection, so that the side effect caused by the fact that the atorvastatin is taken alone for a long time is reduced.
Description of the drawings:
fig. 1 is a differential scanning calorimetry plot characterizing the starting material and the co-amorphous composite prepared as in example 1, wherein a: sodium lauryl sulfate, b: atorvastatin drug substance, c: apigenin bulk drug, d: physical mixture of atorvastatin and apigenin (molar ratio 1: 1), e: atorvastatin-apigenin co-amorphous complex;
fig. 2 is a differential scanning calorimetry plot characterizing the starting material employed in example 2 and the co-amorphous composite prepared, wherein a: sodium lauryl sulfate, b: atorvastatin drug substance, c: naringenin raw material medicine, d: physical mixture of atorvastatin and naringenin (molar ratio 1: 1), e: atorvastatin-naringenin co-amorphous complex;
fig. 3 is a differential scanning calorimetry plot characterizing the starting material employed in example 3 and the co-amorphous composite prepared, wherein a: sodium lauryl sulfate, b: atorvastatin drug substance, c: hesperetin raw material medicine, d: physical mixture of atorvastatin and hesperetin (molar ratio 1: 1), e: atorvastatin-hesperetin co-amorphous complex;
FIG. 4 is a graph of the dissolution profile of atorvastatin, apigenin bulk drug, prepared atorvastatin-apigenin amorphous complex in dissolution medium pH7.4, used in example 1; wherein: a apigenin; apigenin (amorphous complex) [ i.e. apigenin in the atorvastatin-apigenin amorphous complex ]; c atorvastatin; d atorvastatin (amorphous complex) [ i.e. atorvastatin in atorvastatin-apigenin amorphous complex ];
FIG. 5 is a graph of the dissolution profiles of atorvastatin, naringenin bulk drug, naringenin in an atorvastatin-naringenin amorphous complex, and atorvastatin in an atorvastatin-naringenin amorphous complex in dissolution media pH7.4, as used in example 2; wherein: a naringenin; b atorvastatin; c naringenin (amorphous complex) [ i.e. naringenin in the atorvastatin-naringenin amorphous complex ]; d atorvastatin (amorphous complex) [ i.e. atorvastatin in atorvastatin-naringenin amorphous complex ];
FIG. 6 is a graph of the dissolution profiles of atorvastatin, hesperetin as a bulk drug, hesperetin as an amorphous complex of atorvastatin-hesperetin and atorvastatin as an amorphous complex of atorvastatin-hesperetin as employed in example 3 in a dissolution medium at pH 7.4; wherein, a is hesperetin; b atorvastatin; c hesperetin (amorphous complex) [ i.e. hesperetin in atorvastatin-hesperetin amorphous complex ]; d atorvastatin (amorphous complex) [ i.e. atorvastatin in atorvastatin-hesperetin amorphous complex ];
figure 7 is the atorvastatin plasma drug concentration-time curve of example 6; wherein (a) atorvastatin (10mg/kg) group; (b) atorvastatin (10mg/kg) -apigenin (60mg/kg) co-amorphous complex group; (c) atorvastatin (10mg/kg) -apigenin (150mg/kg) co-amorphous complex group; (d) atorvastatin (10mg/kg) -apigenin (300mg/kg) co-amorphous complex group;
figure 8 is the atorvastatin plasma drug concentration-time curve of example 7; wherein (a) atorvastatin (10mg/kg) group; (b) atorvastatin (10mg/kg) -naringenin (60mg/kg) co-amorphous complex group; (c) atorvastatin (10mg/kg) -naringenin (150mg/kg) co-amorphous complex group; (d) atorvastatin (10mg/kg) -naringenin (300mg/kg) co-amorphous complex group;
figure 9 is the atorvastatin plasma drug concentration-time curve of example 8; wherein (a) atorvastatin (10mg/kg) group; (b) atorvastatin (10mg/kg) -hesperetin (60mg/kg) co-amorphous complex group; (c) atorvastatin (10mg/kg) -hesperetin (150mg/kg) co-amorphous complex group; (d) atorvastatin (10mg/kg) -hesperetin (300mg/kg) co-amorphous complex group.
The specific implementation mode is as follows:
the present invention will be described in further detail with reference to examples.
The following examples serve to further illustrate the invention, but in no way limit its scope, and further illustrate the beneficial effects of the pharmaceutical compositions of the present invention by the following tests.
In the following examples, the ultrasonic power used was 20-30 KHZ; apigenin has chemical formula of C15H10O5Yellow needle crystal which is almost insoluble in water and has purity more than or equal to 97 percent; naringenin has a molecular formula of C15H12O5White needle crystal which is almost insoluble in water and has purity more than or equal to 97 percent; hesperetin has chemical formula of C20H20O7White crystal, almost insoluble in water, purity more than or equal to 97%.
Example 1
The preparation method of the atorvastatin-apigenin co-amorphous compound comprises the following steps:
(1) weighing atorvastatin and apigenin according to the mass ratio of 1:6/1:15 and 1:30, carrying out parallel experiments, and respectively ultrasonically dissolving the atorvastatin and the apigenin in methanol to respectively obtain a solution A-1, a solution A-2 and a solution A-3;
(2) dissolving sodium dodecyl sulfate in distilled water to obtain solution B with the concentration of 5 mM/L;
(3) and adding the organic phase into the aqueous phase, wherein the mass ratio of the atorvastatin to the sodium dodecyl sulfate in the solution A-1 is 1:1, the mass ratio of atorvastatin to sodium dodecyl sulfate in the solution A-2 is 1: 5, the mass ratio of the atorvastatin to the sodium dodecyl sulfate in the solution A-3 is 1: 10, fully and uniformly mixing to obtain mixed liquor M1, M2 and M3;
(4) performing ultrasonic treatment for 15min in ice bath;
(5) and (3) carrying out reduced pressure rotary evaporation to remove the organic solvent, and freeze-drying to obtain atorvastatin-apigenin co-amorphous compounds A1, A2 and A3.
The measurement result of the equilibrium solubility shows that the solubilities of atorvastatin and apigenin in the atorvastatin-apigenin co-amorphous compound A1 are respectively improved by 1.5 times and 1.8 times, the solubilities of atorvastatin-apigenin co-amorphous compound A2 atorvastatin and apigenin are respectively improved by 1.8 times and 2.1 times, and the solubilities of atorvastatin-apigenin co-amorphous compound A3 atorvastatin and apigenin are respectively improved by 2.0 times and 2.2 times.
Example 2
The preparation method of the atorvastatin-naringenin co-amorphous compound comprises the following steps:
(1) weighing atorvastatin and naringenin, carrying out parallel experiments according to the mass ratio of 1:6/1:15 and 1:30, and respectively ultrasonically dissolving the atorvastatin and naringenin in methanol to obtain a solution A-4, a solution A-5 and a solution A-6;
(2) dissolving sodium dodecyl sulfate in distilled water to obtain solution B with the concentration of 5 mM/L;
(3) and adding the organic phase into the aqueous phase, wherein the mass ratio of the atorvastatin to the sodium dodecyl sulfate in the solution A-4 is 1:1, the mass ratio of atorvastatin to sodium dodecyl sulfate in the solution A-5 is 1: 5, the mass ratio of the atorvastatin to the sodium dodecyl sulfate in the solution A-6 is 1: 10, fully and uniformly mixing to obtain mixed liquor M4, M5 and M6;
(4) performing ultrasonic treatment for 15min in ice bath;
(5) and (3) carrying out reduced pressure rotary evaporation to remove the organic solvent, and freeze-drying to obtain atorvastatin-naringenin co-amorphous compounds A4, A5 and A6.
The measurement result of the equilibrium solubility shows that the solubilities of atorvastatin and naringenin in the atorvastatin-naringenin co-amorphous compound A4 are respectively improved by 1.6 times and 1.5 times, the solubilities of atorvastatin-naringenin co-amorphous compound A5 atorvastatin and naringenin are respectively improved by 1.8 times and 1.9 times, and the solubilities of atorvastatin-naringenin co-amorphous compound A6 atorvastatin and naringenin are respectively improved by 2.1 times and 2.3 times.
Example 3
The preparation method of the atorvastatin-hesperetin co-amorphous compound comprises the following steps:
(1) weighing atorvastatin and hesperetin, performing parallel experiments according to the mass ratio of 1:6/1:15 and 1:30, and respectively performing ultrasonic dissolution in methanol to obtain a solution A-7, a solution A-8 and a solution A-9;
(2) dissolving sodium dodecyl sulfate in distilled water to obtain solution B with the concentration of 5 mM/L;
(3) and adding the organic phase into the aqueous phase, wherein the mass ratio of the atorvastatin to the sodium dodecyl sulfate in the solution A-7 is 1:1, the mass ratio of atorvastatin to sodium dodecyl sulfate in the solution A-8 is 1: 5, the mass ratio of the atorvastatin to the sodium dodecyl sulfate in the solution A-9 is 1: 10, fully and uniformly mixing to obtain mixed liquor M7, M8 and M9;
(4) performing ultrasonic treatment for 15min in ice bath;
(5) and (3) carrying out reduced pressure rotary evaporation to remove the organic solvent, and freeze-drying to obtain the atorvastatin-hesperetin co-amorphous compound.
The results of the equilibrium solubility measurements show that the solubilities of atorvastatin and hesperetin in the atorvastatin-hesperetin co-amorphous complex a7 are respectively improved by 1.3 times and 2.1 times, the solubilities of atorvastatin-hesperetin co-amorphous complex A8 atorvastatin and hesperetin are respectively improved by 1.8 times and 2.3 times, and the solubilities of atorvastatin-hesperetin co-amorphous complex a9 atorvastatin and hesperetin are respectively improved by 2.3 times and 2.4 times.
Example 4
Characterization of Co-amorphous complexes of atorvastatin and flavonoids
The atorvastatin-apigenin co-amorphous complex, the atorvastatin-naringenin co-amorphous complex, and the atorvastatin-hesperetin co-amorphous complex prepared in examples 1-3 were characterized by Differential Scanning Calorimetry (DSC), respectively, and the experimental results are shown in fig. 1, 2, and 3.
As shown in figure 1, sodium dodecyl sulfate has no obvious endothermic peak, atorvastatin bulk drug has a characteristic endothermic peak at 157.5 ℃, apigenin bulk drug has a characteristic endothermic peak at 355.2 ℃, the characteristic endothermic peaks of atorvastatin and apigenin also exist in two physical mixtures at the same time, which indicates that the physical mixtures are only the mixture of drugs and do not form amorphous compounds; in the amorphous compound, the endothermic peaks of atorvastatin and apigenin shift to 132.2 ℃ and 342.3 ℃ respectively, which indicates that the atorvastatin and the apigenin form a new amorphous compound.
As can be seen from the attached figure 2, sodium dodecyl sulfate has no obvious endothermic peak, atorvastatin bulk drug has a characteristic endothermic peak at 157.5 ℃, naringenin bulk drug has a characteristic endothermic peak at 258.3 ℃, the characteristic endothermic peaks of atorvastatin and naringenin also exist in two physical mixtures at the same time, which indicates that the physical mixtures are only the mixture of drugs, but no amorphous compound is formed; in the amorphous compound, the endothermic peaks of atorvastatin and naringenin respectively shift to 128.8 ℃ and 233.4 ℃, which indicates that atorvastatin and naringenin generate a new amorphous compound.
As shown in fig. 3, sodium dodecyl sulfate has no obvious endothermic peak, atorvastatin bulk drug has a characteristic endothermic peak at 157.5 ℃, hesperetin bulk drug has a characteristic endothermic peak at 154.6 ℃, and the characteristic endothermic peaks of atorvastatin and hesperetin also exist in two physical mixtures at the same time, which indicates that the physical mixtures are only the mixtures of drugs and do not form amorphous compounds; in the amorphous compound, the endothermic peaks of atorvastatin and hesperetin shift to 152.2 ℃ and 151.3 ℃ respectively, which indicates that atorvastatin and hesperetin form a new amorphous compound.
Example 5:
determination of dissolution
Respectively and precisely weighing appropriate amounts of atorvastatin, apigenin, naringenin and hesperetin raw material medicines, an atorvastatin-apigenin amorphous compound, an atorvastatin-naringenin amorphous compound and an atorvastatin-hesperetin amorphous compound prepared in examples 1-3 (containing the same mass as the raw material medicines), referring to 2015 version Chinese pharmacopoeia dissolution method (appendix XC second method), taking phosphate aqueous solution with pH7.4 as a dissolution medium, rotating at 75 revolutions per minute, operating according to the method, sampling for 5mL, 10 μm, 15, 20, 30, 45, 60, 90 and 120min, filtering by a 0.45 μm filter membrane, discarding the previous 2mL of primary filtrate, taking the subsequent filtrate for determination, and calculating the accumulated dissolution according to an external standard method, wherein the initial filtrate is shown in figures 4-6. As can be seen from the figure, the dissolution rate of the atorvastatin-apigenin amorphous compound, the atorvastatin-naringenin amorphous compound and the atorvastatin-tangeretin amorphous compound prepared by the invention under the condition of a pH7.4 medium is obviously higher than that of atorvastatin, apigenin, naringenin and tangeretin bulk drugs.
Example 6
Pharmacokinetic experiment for improving bioavailability of atorvastatin by atorvastatin-apigenin co-amorphous compound
The experimental scheme is as follows: SD rats, 240-300 g, male, were randomly divided into atorvastatin group and atorvastatin-apigenin co-amorphous complex group, 6 rats each, and the administration mode of intragastric administration of two groups of rats was as follows:
atorvastatin group: atorvastatin (10mg/kg) was administered alone.
Atorvastatin-apigenin co-amorphous complex group:
combination administration 1 group: atorvastatin (10mg/kg) -apigenin (60mg/kg) co-amorphous complex.
Combination 2 groups: atorvastatin (10mg/kg) -apigenin (150mg/kg) co-amorphous complex.
Combination administration 3 groups: atorvastatin (10mg/kg) -apigenin (300mg/kg) co-amorphous complex.
After oral administration, 0.3ml of blood is taken at 0.083h,0.167h,0.25h,0.5h,1h,2h,5h,8h,12h and 24h respectively, the upper plasma is taken by centrifugation, the blood concentration of atorvastatin is detected, and the area under the drug concentration-time curve and the relative bioavailability are calculated.
The experimental results are as follows:
the corresponding atorvastatin plasma drug concentration-time curve according to the pharmacokinetic experiment results is shown in figure 7.
The pharmacokinetic parameters for atorvastatin group and atorvastatin-apigenin co-amorphous complex were as follows:
t1/2: biological half life: t ismax: time to peak; cmax: maximum blood concentration; AUC: area under the drug-time curve; RB%: relative bioavailability.
It can be seen that the oral absorption of atorvastatin can be significantly improved by the co-amorphous compound of apigenin and atorvastatin through combined oral administration, and the oral relative bioavailability of atorvastatin in the combined administration groups 1, 2 and 3 is respectively improved by 4.29 times, 7.04 times and 10.79 times.
Example 7
Pharmacokinetic experiment for improving bioavailability of atorvastatin by atorvastatin-naringenin co-amorphous compound
The experimental scheme is as follows: SD rats, 240-300 g, male, were randomly divided into atorvastatin group and atorvastatin-naringenin co-amorphous complex group, 6 rats each, and the administration mode of gastric lavage of two groups of rats was as follows:
atorvastatin group: atorvastatin (10mg/kg) was administered alone.
Atorvastatin-naringenin co-amorphous complex group:
combination administration 1 group: atorvastatin (10mg/kg) -naringenin (60mg/kg) co-amorphous complex.
Combination 2 groups: atorvastatin (10mg/kg) -naringenin (150mg/kg) co-amorphous complex.
Combination administration 3 groups: atorvastatin (10mg/kg) -naringenin (300mg/kg) co-amorphous complex.
After oral administration, 0.3ml of blood is taken at 0.083h,0.167h,0.25h,0.5h,1h,2h,5h,8h,12h and 24h respectively, the upper plasma is taken by centrifugation, the blood concentration of atorvastatin is detected, and the area under the drug concentration-time curve and the relative bioavailability are calculated.
The experimental results are as follows:
the corresponding atorvastatin plasma drug concentration-time curve according to the pharmacokinetic experiment results is shown in figure 8.
The pharmacokinetic parameters for the atorvastatin group and the atorvastatin-naringenin co-amorphous complex group were as follows:
t1/2: biological half-life: t ismax: time to peak; cmax: maximum blood concentration; AUC: area under the drug-time curve; RB%: relative bioavailability.
It can be seen that the oral absorption of atorvastatin can be significantly improved by the co-amorphous compound of naringenin and atorvastatin through combined oral administration, and the oral relative bioavailability of atorvastatin in the combined administration groups 1, 2 and 3 is respectively improved by 1.93 times, 3.14 times and 5.55 times.
Example 8
Pharmacokinetic experiment for improving bioavailability of atorvastatin by atorvastatin-hesperetin co-amorphous compound
The experimental scheme is as follows: SD rats, 240-300 g, male, were randomly divided into atorvastatin group and atorvastatin-hesperetin co-amorphous complex group, 6 rats each, and the administration mode of intragastric administration of two groups of rats was as follows:
atorvastatin group: atorvastatin (10mg/kg) was administered alone.
Atorvastatin-hesperetin co-amorphous complex group:
combination administration 1 group: atorvastatin (10mg/kg) -hesperetin (60mg/kg) co-amorphous complex.
Combination administration 2 groups: atorvastatin (10mg/kg) -hesperetin (150mg/kg) co-amorphous complex.
Combination administration 3 groups: atorvastatin (10mg/kg) -hesperetin (300mg/kg) co-amorphous complex.
After oral administration, 0.3ml of blood is taken at 0.083h,0.167h,0.25h,0.5h,1h,2h,5h,8h,12h and 24h respectively, the upper plasma is taken by centrifugation, the blood concentration of atorvastatin is detected, and the area under the drug concentration-time curve and the relative bioavailability are calculated.
The experimental results are as follows:
the corresponding atorvastatin plasma drug concentration-time curve according to the pharmacokinetic experiment results is shown in fig. 9.
The pharmacokinetic parameters for the atorvastatin group and the atorvastatin-hesperetin co-amorphous complex group were as follows:
t1/2: biological half-life: t ismax: time to peak; cmax: maximum blood concentration; AUC: area under the drug-time curve; RB%: relative bioavailability.
It can be seen that the co-amorphous compound of hesperetin and atorvastatin which are taken orally in combination can obviously improve the oral absorption of atorvastatin, and the oral relative bioavailability of atorvastatin in the combined administration of 1 group, 2 groups and 3 groups is respectively improved by 1.15 times, 1.55 times and 2.76 times.
In conclusion, the flavonoid compounds apigenin, naringenin, hesperetin and atorvastatin are orally taken together to form the amorphous compound, so that the bioavailability of atorvastatin can be remarkably improved.
Experimental embodiment of the distribution of atorvastatin in vivo in the liver of the target organ:
example 9
Liver drug concentration determination of combined administration of apigenin and atorvastatin
The experimental scheme is as follows: SD rats, 240-300 g, male, were randomly divided into atorvastatin group and atorvastatin-apigenin co-amorphous complex group, 6 rats each, and the administration mode of intragastric administration of two groups of rats was as follows:
atorvastatin group: atorvastatin (10mg/kg) was administered alone.
Atorvastatin-apigenin co-amorphous complex group:
combination administration 1 group: atorvastatin (10mg/kg) -apigenin (60mg/kg) co-amorphous complex.
Combination administration 2 groups: atorvastatin (10mg/kg) -apigenin (150mg/kg) co-amorphous complex.
Combination administration 3 groups: atorvastatin (10mg/kg) -apigenin (300mg/kg) co-amorphous complex.
Rats were anesthetized with isoflurane 30min after dosing. After the head is cut off, taking the liver, weighing, shearing into pieces, and mixing according to the weight ratio of 1: 10(g/ml) of physiological saline was added, and the tissue homogenate was cooled in ice. Taking tissue homogenate, adding 10 μ L internal standard solution (500mg/mL daidzein), 10 μ L methanol, vortexing for 1min, and centrifuging for 10min (13000 r.min)-1) Taking the supernatant, centrifuging at 13000rpm for 5min, taking the supernatant, and carrying out liquid quality quantitative determination on the concentration of the atorvastatin by injecting 5 mu L of the supernatant. Calculating the concentration of the atorvastatin drug in the liver.
The experimental results show that the concentration of the intra-hepatic drug of atorvastatin alone is 2765.91 +/-121.73 ng/g, the concentration of the intra-hepatic drug of the combined administration group 1 is 9287.10 +/-378.64 ng/g, the concentration of the intra-hepatic drug of the combined administration group 2 is 15788.07 +/-542.78 ng/g, the concentration of the intra-hepatic drug of the combined administration group 3 is 23217.75 +/-616.43 ng/g, and the intra-hepatic drug of the target organ is respectively increased by 3.36 times, 5.71 times and 8.39 times after the combined administration.
Example 10
Intrahepatic drug concentration determination of combined administration of naringenin and atorvastatin
The experimental scheme is as follows: SD rats, 240-300 g, male, were randomly divided into atorvastatin group and atorvastatin-naringenin co-amorphous complex group, 6 rats each, and the administration mode of gastric lavage of two groups of rats was as follows:
atorvastatin group: atorvastatin (10mg/kg) was administered alone.
Atorvastatin-naringenin co-amorphous complex group:
combination administration 1 group: atorvastatin (10mg/kg) -naringenin (60mg/kg) co-amorphous complex.
Combination administration 2 groups: atorvastatin (10mg/kg) -naringenin (150mg/kg) co-amorphous complex.
Combination administration 3 groups: atorvastatin (10mg/kg) -naringenin (300mg/kg) co-amorphous complex.
Rats were anesthetized with isoflurane 30min after dosing. After the head is cut off, taking the liver, weighing, shearing into pieces, and cutting into pieces according to the weight ratio of 1: 10(g/ml) of physiological saline was added, and the tissue homogenate was cooled in ice. Taking tissue homogenate, adding 10 μ L internal standard solution (500mg/mL daidzein), 10 μ L methanol, vortexing for 1min, and centrifuging for 10min (13000 r.min)-1) Taking the supernatant, centrifuging at 13000rpm for 5min, taking the supernatant, and carrying out liquid quality quantitative determination on the concentration of the atorvastatin by injecting 5 mu L of the supernatant. Calculating the concentration of the atorvastatin drug in the liver.
The experimental results show that the concentration of the intra-hepatic drug of the atorvastatin single administration is 2765.91 +/-121.73 ng/g, the concentration of the intra-hepatic drug of the combined administration group 1 is 7127.08 +/-276.39, the concentration of the intra-hepatic drug of the combined administration group 2 is 12116.03 +/-499.27 ng/g, and the concentration of the intra-hepatic drug of the combined administration group 3 is 17817.70 +/-637.79 ng/g. The intrahepatic drug concentrations in the target organs increased 2.58-fold, 4.38-fold and 6.44-fold, respectively, after the combination administration.
Example 11
Method for determining concentration of drug in liver by combined administration of hesperetin and atorvastatin
The experimental scheme is as follows: SD rats, 240-300 g, male, were randomly assigned to atorvastatin-hesperetin co-amorphous complex groups of 6 rats each, and the gastric lavage was administered to the two groups of rats as follows:
atorvastatin group: atorvastatin (10mg/kg) was administered alone.
Atorvastatin-hesperetin co-amorphous complex group:
combination administration 1 group: atorvastatin (10mg/kg) -hesperetin (60mg/kg) co-amorphous complex.
Combination administration 2 groups: atorvastatin (10mg/kg) -hesperetin (150mg/kg) co-amorphous complex.
Combination administration 3 groups: atorvastatin (10mg/kg) -hesperetin (300mg/kg) co-amorphous complex.
Rats were anesthetized with isoflurane 30min after dosing. After the head is cut off, taking the liver, weighing, shearing into pieces, and mixing according to the weight ratio of 1: 10(g/ml) of physiological saline was added, and the tissue homogenate was cooled in ice. Taking tissue homogenate, adding 10 μ L internal standard solution (500mg/mL daidzein), 10 μ L methanol, vortexing for 1min, and centrifuging for 10min (13000 r.min)-1) Taking the supernatant, centrifuging at 13000rpm for 5min, taking the supernatant, and carrying out liquid quality quantitative determination on the concentration of the atorvastatin by injecting 5 mu L of the supernatant. Calculating the concentration of the atorvastatin drug in the liver.
The experimental results show that: the concentration of the atorvastatin single-administrated intrahepatic drugs is 2765.91 +/-121.73 ng/g, the concentration of the atorvastatin combined-administrated intrahepatic drugs in the group 1 is 4643.49 +/-48.65 ng/g, the concentration of the atorvastatin combined-administrated intrahepatic drugs in the group 2 is 6675.01 +/-297.46 ng/g, and the concentration of the atorvastatin combined-administrated intrahepatic drugs in the group 3 is 14510.90 +/-512.98 ng/g. The intrahepatic drug concentrations in the target organs increased 1.68-fold, 2.41-fold and 5.25-fold, respectively, after the combination administration.
In conclusion, the co-amorphous compound delivery system consisting of the flavonoid compounds apigenin, naringenin, hesperetin and atorvastatin can obviously improve the concentration of atorvastatin target organs in the liver and can obviously improve the blood fat reducing effect of atorvastatin.
Claims (7)
1. The atorvastatin-flavonoid compound co-amorphous compound is characterized by comprising the following components in percentage by mass: and (3) flavonoid compounds: surfactant 1: (6-30): (1-10), wherein the flavonoid compound is one or a mixture of several of apigenin, naringenin or hesperetin, and the mixing ratio is any ratio.
2. The atorvastatin-flavonoid co-amorphous complex of claim 1, wherein said surfactant is sodium lauryl sulfate or cyclodextrin.
3. The atorvastatin-flavonoid co-amorphous complex of claim 1, wherein the ratio by mass of atorvastatin: flavonoid compound ═ 1: (15-30).
4. The method of preparing the atorvastatin-flavonoid co-amorphous complex of claim 1, comprising the steps of:
(1) according to the mass ratio, atorvastatin: and (3) flavonoid compounds: surfactant 1: (6-30): (1-10), respectively weighing atorvastatin, a flavonoid compound and a surfactant, adding the atorvastatin and the flavonoid compound into an organic solvent, and performing ultrasonic dissolution to obtain a solution A;
(2) dissolving a surfactant in distilled water to obtain a solution B;
(3) adding the solution A into the solution B, and fully and uniformly mixing;
(4) and (3) after ultrasonic treatment in ice bath, carrying out reduced pressure rotary evaporation to remove the organic solvent, and freeze-drying to prepare the atorvastatin-flavonoid compound co-amorphous compound.
5. The method for preparing the atorvastatin-flavonoid co-amorphous complex according to claim 4, wherein in the step (1), the organic solvent is any one of methanol, ethanol or dimethyl sulfoxide.
6. The method for preparing the atorvastatin-flavonoid co-amorphous complex of claim 4, wherein in step (2), the surfactant is present in solution B at a molar concentration of 0.1 to 10 mM/L.
7. The method for preparing the atorvastatin-flavonoid co-amorphous complex according to claim 4, wherein in the step (4), the ultrasound time is 10-50min and the ultrasound power is 20-30 KHZ.
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Citations (4)
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|---|---|---|---|---|
| US20080095838A1 (en) * | 2002-06-25 | 2008-04-24 | Cll Pharma | Solid pharmaceutical composition containing a lipophilic active principle and preparation method thereof |
| US20080269314A1 (en) * | 2004-10-28 | 2008-10-30 | Antone John Debetten-Court | Process for Forming Amorphous Atorvastatin |
| US20110312985A1 (en) * | 2008-10-08 | 2011-12-22 | The General Hospital Corporation | Naringenin complexes and methods of use thereof |
| CN110339365A (en) * | 2018-04-02 | 2019-10-18 | 强生化学制药厂股份有限公司 | A kind of medical composition and application thereof that oral statins bioavailability can be improved |
-
2022
- 2022-03-10 CN CN202210238496.0A patent/CN114569605A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080095838A1 (en) * | 2002-06-25 | 2008-04-24 | Cll Pharma | Solid pharmaceutical composition containing a lipophilic active principle and preparation method thereof |
| US20080269314A1 (en) * | 2004-10-28 | 2008-10-30 | Antone John Debetten-Court | Process for Forming Amorphous Atorvastatin |
| US20110312985A1 (en) * | 2008-10-08 | 2011-12-22 | The General Hospital Corporation | Naringenin complexes and methods of use thereof |
| CN110339365A (en) * | 2018-04-02 | 2019-10-18 | 强生化学制药厂股份有限公司 | A kind of medical composition and application thereof that oral statins bioavailability can be improved |
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