Pharmaceutical composition capable of improving living body availability rate of oral statins and application of pharmaceutical composition

Abstract

The invention relates to a pharmaceutical composition capable of improving the bioavailable rate of oral statins and application of the pharmaceutical composition, and the pharmaceutical composition comprises statins, a pH value regulator, a metabolic enzyme safety inhibitor and a modified release coating or coating, the pH value regulator can regulate the pH value of the gastrointestinal tract absorbing the medicine, so that the living body availability of the medicine composition is improved, the variation of the concentration in blood in the body caused by individual difference is small, the variation range of the increase of the medicine absorption amount is reduced, the serious side effects of the medicine, such as the serious side effects of rhabdomyolysis and even the lethal side effects, are reduced, and the curative effect of the medicine is improved. The medicine safety is improved; the design of the special dosage form not only reduces the serious side effects which may cause death, but also prolongs the action time, reduces the administration frequency, and can greatly reduce the treatment failure caused by the fact that a patient forgets to take the medicine.

Description

[0001] This application is a divisional application of Chinese patent application No. 201810283391.0, filed on April 2, 2018. Technical Field

[0002] The present invention relates to the field of medicine, and in particular to a pharmaceutical composition capable of improving the bioavailability of oral statins and a use thereof. Background Art

[0003] High blood lipids are a problem for patients with slow metabolism, overeating or family cardiovascular disease. Due to the high calorie diet, the incidence of obesity, coronary atherosclerosis, heart disease and other diseases in European and American countries is higher than in other countries. In the past decade, cardiovascular disease has also been one of the top ten causes of death in the United States. In recent years, the number of deaths due to stroke or heart disease in Taiwan, China has also been rising. Therefore, lowering blood lipids is very important for health.

[0004] Statins (HMG-CoA reductase inhibitors) are commonly used lipid-lowering drugs that can inhibit the synthesis of cholesterol precursor mevalonate, which is the rate-limiting step in cholesterol synthesis. Therefore, they are often used to treat hypercholesterolemia and prevent cardiovascular disease. Atorvastatin (trade name: ), synthesized by Pfizer in 1985, was the best-selling prescription drug in history in 2003. In addition to lowering blood lipids, statins can also inhibit vascular inflammation, becoming a widely used drug, even replacing the former universal drug aspirin.

[0005] The metabolic pathway of atorvastatin (pKa = 4.46) includes Phase I and Phase II. The parent drug atorvastatin is metabolized by CYP3A4 to form active metabolites 2-hydroxyatorvastatin acid (2-OHatorvastatin acid) and 4-hydroxyatorvastatin acid (4-OH atorvastatin acid), or metabolized by CYP3A4, UGT1A1 and UGT1A3 to form inactive pharmacologically active atorvastatin lactone (atorvastatin lactone), 2-hydroxyatorvastatin lactone (2-OH atorvastatin lactone) and 4-hydroxyatorvastatin lactone (4-OHatorvastatin lactone) (see Figure 1). About 70% of the total active metabolites in the body will inhibit HMG-CoA reductase to produce therapeutic effects, and the active metabolites 2-hydroxyatorvastatin acid and 4-hydroxyatorvastatin acid have been shown in in vitro experiments to have an inhibitory effect on HMG-CoA reductase equivalent to the prototype drug of atorvastatin. There are also literature reports that the metabolites of atorvastatin are also pH-dependent compounds, because in the gastrointestinal environment, it will undergo non-enzymatic conversion between the acid form and the lactone form. Silybin, a currently known UGT enzyme inhibitor, belongs to the flavonoids class and is often used clinically as an antioxidant, anticancer agent, or even as a hepatoprotectant. There are also literature reports that Silybin can produce drug interactions with both Phase I and Phase II drug metabolizing enzymes. In vitro, Silybin can inhibit a series of UGT enzymes such as UGT 1A6 and UGT1A9, and has a high inhibitory effect on UGT 1A1.

[0006] The problem to be solved by the present invention is how to reduce the conversion of atorvastatin into inactive atorvastatin lactone, 2-hydroxy atorvastatin lactone and 4-hydroxy atorvastatin lactone by adding a UGT inhibitor, thereby increasing the effective concentration and bioavailability in the body.

[0007] Common side effects of statins are related to myotoxicity, such as fatal rhabdomyolysis. In Japan, more than 20 people died due to side effects of statins. The cause of the side effects is excessively high blood drug concentrations. There are two reasons for the high blood drug concentrations: 1) Clinically, statins are taken orally together with the cholesterol-lowering drug gemfibrozil. Because of drug-drug interactions, the risk of myotoxicity may be increased; 2) Due to individual differences, the drug metabolizing enzyme genotypes in the body are divided into normal metabolic drug enzyme types (extensive metabolizers), intermediate metabolizers, and extreme metabolic enzyme types (ultrarapid metabolizers) and poor metabolizers. The amount of drug absorption also varies from person to person.

[0008] The bioavailability of statins is not high, among which the absolute bioavailability of atorvastatin is 14%. Due to the low bioavailability, a large amount of drugs needs to be taken to reach the effective concentration in the body. The possibility of serious or even fatal side effects such as rhabdomyolysis due to differences in drug absorption between individuals increases, and high blood concentrations need to be avoided to reduce the occurrence of side effects. If the bioavailability of statins can be improved, such as increasing the bioavailability from 14% to 98%, the difference in drug absorption between individuals will be reduced from 7.14 times (14% to 100%) to 1.02 times (98% to 100%). Since the bioavailability is very high, the possibility of serious or even fatal side effects such as rhabdomyolysis due to high blood drug concentrations caused by differences in drug absorption between individuals will be greatly reduced.

[0009] Although previous literature has reported that the metabolites of atorvastatin are also pH-dependent compounds and pH adjustment is used to improve the stability of atorvastatin, there is currently no successful research case of successfully improving the bioavailability of atorvastatin by pH adjustment.

[0010] The US invention (US20040138290) discloses a pharmaceutical preparation, which contains atorvastatin calcium as an active ingredient and a pH adjusting substance, characterized in that the atorvastatin calcium contains micronized amorphous atorvastatin calcium and is dissolved in 900 ml of a liquid aqueous medium with a pH of 3. When the pharmaceutical preparation increases the pH of the medium to a pH equal to or greater than the pKa+1 of atorvastatin calcium, the solubility and dissolution rate of atorvastatin in the aqueous solution are increased by the pharmaceutical preparation containing an alkalizing agent or a buffer substance to improve the bioavailability of atorvastatin. The previous case discloses that the drug has a high solubility when the pH value is pKa+1, that is, the pH value is 5.5. Although the previous case specification mentions that the bioavailability can be increased by increasing the solubility, there is no example of increasing the bioavailability in the specification.

[0011] The U.S. invention (US20080138429) discloses a granule composition, wherein the granules contain an active ingredient, which is an HMG-CoA reductase inhibitor, and a coating, wherein the coating comprises: (a) a protective film-forming substance selected from the group consisting of polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxyethyl cellulose and combinations thereof and (b) at least one pharmaceutical excipient selected from the group consisting of a buffer, an alkalizer and a surfactant, wherein the alkalizer and the coating are added to increase drug stability.

[0012] The US invention (US20110165239) discloses a pharmaceutical composition, comprising atorvastatin and a group consisting of L-arginine and sodium bicarbonate, wherein the atorvastatin is an alkalizing agent selected from the free acid or pharmaceutically acceptable salt of atorvastatin, and wherein the ratio of the alkalizing additive to atorvastatin is 1:1 to 6:1, and the alkalizing additive can improve the stability of atorvastatin.

[0013] Although the above-mentioned prior cases used pH adjusters (alkaline agents), their purpose was to act as drug stabilizers or to increase drug solubility. There was no disclosure of using pH adjusters to increase the bioavailability of atorvastatin. Furthermore, the prior cases disclosed that the content of pH adjusters had a wide range or was not specifically limited. However, since oral drugs first pass through the acidic stomach and then the alkaline intestines, the drugs require a certain amount of pH adjusters to adjust the pH of the stomach and intestines to a pH environment that can increase the bioavailability of atorvastatin. Too much or too little pH adjusters cannot achieve this.

[0014] Modified release drugs can change the release time in the body. Currently, no one has revealed that a specific pH value can increase bioavailability. The total drug amount of modified release dosage forms is high. Statins such as atorvastatin have low bioavailability, and there are large differences between people, resulting in some people having higher absorption rates or stronger responsiveness to the drug. Therefore, it is necessary to increase the bioavailability, reduce individual differences after patients take the drug, reduce the degree of inconsistent blood concentrations, increase the average safety and efficacy of the drug, and increase patient compliance with the drug, and reduce the chance of serious or even fatal side effects such as rhabdomyolysis when atorvastatin is made into a controlled-release drug.

[0015] Therefore, how to develop a new dosage form of statins with high bioavailability, increase the bioavailability, reduce the inconsistency of blood concentration caused by individual differences among patients after taking the medicine, and reduce serious or even fatal side effects such as rhabdomyolysis, and use a modified release dosage form to allow the drug components to safely pass through the destruction of gastric acid and smoothly reach the intestines before release to increase drug stability and absorption rate, and better control the release time in the body to reduce treatment failure caused by patients forgetting to take the medicine, which has become an important issue that the present invention aims to solve. Summary of the invention

[0016] The object of the present invention is to provide a pharmaceutical composition capable of improving the bioavailability of oral statins and its use. The pharmaceutical composition comprises a statin and a substance for improving the bioavailability, wherein the substance for improving the bioavailability comprises: 1) a pH regulator and a modified release formulation, or / and 2) a metabolic enzyme inhibitor, wherein the pH regulator can adjust the pH value of the intestine, and the modified release formulation can enable the active ingredient to safely pass through the destruction of gastric acid and smoothly reach the intestinal part.

[0017] To achieve the aforementioned purpose of the invention, the pH regulator can adjust the intestinal pH value to 4.9-8.5.

[0018] To achieve the aforementioned purpose of the invention, the pH regulator can adjust the intestinal pH value to 5.8-7.8.

[0019] To achieve the aforementioned object of the invention, the pH value adjuster comprises sodium carbonate, sodium bicarbonate, sodium hydroxide, boric acid, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium phosphate, glycine, ammonia, ammonium lactate, ammonium bicarbonate, ammonium hydroxide, ammonium phosphate dibasic, monoethanolamine, diethanolamine, triethanolamine, trihydroxymethylaminomethane, ethylenediamine, N-methyl glucamide, 6N-methyl glucamide, glucamine), meglucamine, L-lysine and 2-amino-2-(hydroxymethyl)-1,3-propanediol or any combination thereof.

[0020] To achieve the aforementioned object of the invention, the weight of the pH adjuster is 200-11800 mg.

[0021] To achieve the aforementioned object of the invention, the mass of the pH adjuster is 20-90% (w / w) of the pharmaceutical composition.

[0022] To achieve the aforementioned purpose of the invention, the statin is selected from the group consisting of atorvastatin, pravastatin, simvastatin, lovastatin, mevastatin, compactin, fluvastatin, cerivastatin, rosuvastatin, and pitavastatin.

[0023] To achieve the aforementioned purpose of the invention, the UGT1A3 inhibitor comprises sodium lauryl sulfate (SLS), acesulfame potassium, colloidal silicon dioxide (Aerosil200), apigenin, baicalin, benzoic acid (Benzyl alcohol), benzyl benzoate (Benzylbenzoate), butylated anisole (BHA), polyethylene glycol cetyl ether (Brij 58), polyoxyethylene 10 stearyl ether (Brij76), cherry flavor (Cherry), citric acid (Citric acid), croscarmellosesodium (Croscarmellosesodium), dextrates (Dextrates), ethylenediaminetetraacetic acid disodium (EDTA2Na), glycerin (Glycerin), glycyrrhizin (Glycyrrhizin), hydroxypropyl cellulose (Hydroxypropyl cellulose), hydroxypropyl methylcellulose phthalate (Hydroxypropyl methylcellulose), polyvinylrolidone (kollidon VA64), lactose, lactose monohydrate, lactose S.G, lemon oil, locust, low-substituted hydroxypropylcellulose, maltodextrin, mannitol, methyl paraben, menthol, myri 52, methyl cellulose, NF hydrate, β-naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG 2000), polyethylene glycol 4000 (PEG4000), poloxamer 188 (Pluronic F68), poloxamer 407 (Pluronic F127), polyoxyl 40 hydrogenated castor oil (RH 40), propylparaben, polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin, sodium cyclamate, sodium starch glycolate, sodium benzoate, sorbic acid, sorbitol solution, sorbitan monostearate (Span 60), sorbitan monooleate 80 (Span 80), sucralose, starch acetate, trans-aconitic acid, triethyl citrate, trisodium citrate, polysorbate 20 (Tween 20, TW20), polysorbate 40 (Tween 40, TW40), polysorbate 80 (Tween 80, TW80), ursolic acid, sodium dihydrogen phosphate (sodium dihydrogenphosphate), Dicalcium phosphate dihydrate, Dextrates, NF hydrate, and Cholic acid, or any combination thereof.

[0024] To achieve the aforementioned purpose of the invention, the UGT1A1 inhibitor comprises sodium lauryl sulfate (SLS), acesulfame potassium, colloidal silicon dioxide (Aerosil200), apigenin, baicalin, benzoic acid (Benzyl alcohol), benzyl benzoate (Benzylbenzoate), butylated anisole (BHA), polyethylene glycol cetyl ether (Brij 58), polyoxyethylene 10 stearyl ether (Brij76), cherry flavor (Cherry), citric acid (Citric acid), croscarmellosesodium, dextrates, disodium ethylenediaminetetraacetate (EDTA2Na), glycerin (Glycerin), glycyrrhizin (Glycyrrhizin), hydroxypropyl cellulose (Hydroxypropyl cellulose), hydroxypropyl methylcellulose phthalate (Hydroxypropyl cellulose). methylcellulose), polyvinylrolidone (kollidon VA64), lactose, lactose monohydrate, lactose S.G, lemon oil, locust, low-substituted hydroxypropylcellulose, maltodextrin, mannitol, methyl paraben, menthol, myri 52, methyl cellulose, NF hydrate, β-naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG 2000), polyethylene glycol 4000 (PEG4000), poloxamer 188 (Pluronic F68), poloxamer 407 (Pluronic F127), polyoxyl 40 hydrogenated castor oil (RH 40), propylparaben, polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin, sodium cyclamate, sodium starch glycolate, sodium benzoate, sorbic acid, sorbitol solution, sorbitan monostearate (Span 60), sorbitan monooleate 80 (Span 80), sucralose, starch acetate, trans-aconitic acid, triethyl citrate, trisodium citrate, polysorbate 20 (Tween 20, TW20), polysorbate 40 (Tween 40, TW40), polysorbate 80 (Tween 80, TW80), ursolic acid, sodium dihydrogen phosphate (sodium dihydrogenphosphate), Dicalcium phosphate dihydrate, Dextrates, NF hydrate, and Cholic acid, or any combination thereof.

[0025] To achieve the aforementioned object of the invention, the modified release dosage form may further comprise a delayed release effect.

[0026] To achieve the aforementioned purpose of the invention, the pharmaceutical composition is in the form of tablets, granules, capsules, powders or other pharmaceutically acceptable dosage forms.

[0027] In order to achieve the aforementioned object of the invention, the pharmaceutical composition may further contain excipients.

[0028] To achieve the aforementioned purpose of the invention, the excipient may be a diluent, a filler, a binder, a disintegrant, a lubricant or other pharmaceutically acceptable excipients.

[0029] Another object of the present invention is to provide a composition for improving the bioavailability of statins, the composition comprising: 1) a pH regulator and a modified release formulation, or / and 2) a metabolic enzyme inhibitor, the modified release formulation can enable the active ingredients of the statin to safely pass through the destruction of gastric acid and smoothly reach the intestine, and the pH regulator can adjust the intestinal pH to improve the drug stability and absorption rate.

[0030] To achieve the aforementioned object of the invention, the pH value adjuster comprises sodium carbonate, sodium bicarbonate, sodium hydroxide, boric acid, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium phosphate, glycine, ammonia, ammonium lactate, ammonium bicarbonate, ammonium hydroxide, ammonium phosphate dibasic, monoethanolamine, diethanolamine, triethanolamine, trihydroxymethylaminomethane, ethylenediamine, N-methyl glucamide, 6N-methyl glucamide, glucamine), meglucamine, L-lysine and 2-amino-2-(hydroxymethyl)-1,3-propanediol or any combination thereof.

[0031] To achieve the aforementioned purpose of the invention, the UGT1A3 inhibitor comprises sodium lauryl sulfate (SLS), acesulfame potassium, colloidal silicon dioxide (Aerosil200), apigenin, baicalin, benzoic acid (Benzyl alcohol), benzyl benzoate (Benzylbenzoate), butylated anisole (BHA), polyethylene glycol cetyl ether (Brij 58), polyoxyethylene 10 stearyl ether (Brij76), cherry flavor (Cherry), citric acid (Citric acid), croscarmellosesodium (Croscarmellosesodium), dextrates (Dextrates), ethylenediaminetetraacetic acid disodium (EDTA2Na), glycerin (Glycerin), glycyrrhizin (Glycyrrhizin), hydroxypropyl cellulose (Hydroxypropyl cellulose), hydroxypropyl methylcellulose phthalate (Hydroxypropyl methylcellulose), polyvinylrolidone (kollidon VA64), lactose, lactose monohydrate, lactose S.G, lemon oil, locust, low-substituted hydroxypropylcellulose, maltodextrin, mannitol, methyl paraben, menthol, myri 52, methyl cellulose, NF hydrate, β-naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG 2000), polyethylene glycol 4000 (PEG4000), poloxamer 188 (Pluronic F68), poloxamer 407 (Pluronic F127), polyoxyl 40 hydrogenated castor oil (RH 40), propylparaben, polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin, sodium cyclamate, sodium starch glycolate, sodium benzoate, sorbic acid, sorbitol solution, sorbitan monostearate (Span 60), sorbitan monooleate 80 (Span 80), sucralose, starch acetate, trans-aconitic acid, triethyl citrate, trisodium citrate, polysorbate 20 (Tween 20, TW20), polysorbate 40 (Tween 40, TW40), polysorbate 80 (Tween 80, TW80), ursolic acid, sodium dihydrogen phosphate (sodium dihydrogenphosphate), Dicalcium phosphate dihydrate, Dextrates, NF hydrate, and Cholic acid, or any combination thereof.

[0032] To achieve the aforementioned purpose of the invention, the UGT1A1 inhibitor comprises sodium lauryl sulfate (SLS), acesulfame potassium, colloidal silicon dioxide (Aerosil200), apigenin, baicalin, benzoic acid (Benzyl alcohol), benzyl benzoate (Benzylbenzoate), butylated anisole (BHA), polyethylene glycol cetyl ether (Brij 58), polyoxyethylene 10 stearyl ether (Brij76), cherry flavor (Cherry), citric acid (Citric acid), croscarmellosesodium, dextrates, disodium ethylenediaminetetraacetate (EDTA2Na), glycerin (Glycerin), glycyrrhizin (Glycyrrhizin), hydroxypropyl cellulose (Hydroxypropyl cellulose), hydroxypropyl methylcellulose phthalate (Hydroxypropyl cellulose). methylcellulose), polyvinylrolidone (kollidon VA64), lactose, lactose monohydrate, lactose S.G, lemon oil, locust, low-substituted hydroxypropylcellulose, maltodextrin, mannitol, methyl paraben, menthol, myri 52, methyl cellulose, NF hydrate, β-naphthoflavone, polyethylene glycol 400 (PEG400), polyethylene glycol 2000 (PEG 2000), polyethylene glycol 4000 (PEG4000), poloxamer 188 (Pluronic F68), poloxamer 407 (Pluronic F127), polyoxyl 40 hydrogenated castor oil (RH 40), propylparaben, polyoxyl 40 hydrogenated castor oil (PVP K90F), saccharin, sodium cyclamate, sodium starch glycolate, sodium benzoate, sorbic acid, sorbitol solution, sorbitan monostearate (Span 60), sorbitan monooleate 80 (Span 80), sucralose, starch acetate, trans-aconitic acid, triethyl citrate, trisodium citrate, polysorbate 20 (Tween 20, TW20), polysorbate 40 (Tween 40, TW40), polysorbate 80 (Tween 80, TW80), ursolic acid, sodium dihydrogen phosphate (sodium dihydrogenphosphate), Dicalcium phosphate dihydrate, Dextrates, NF hydrate, and Cholic acid, or any combination thereof.

[0033] To achieve the aforementioned object of the invention, the statin is selected from the group consisting of atorvastatin, pravastatin, simvastatin, lovastatin, mevastatin, compactin, fluvastatin, cerivastatin, rosuvastatin and pitavastatin.

[0034] To achieve the aforementioned object of the invention, the modified release dosage form may further comprise a delayed release effect.

[0035] In summary, the novel dosage form of statins of the present invention has the following advantages:

[0036] (1) Using special doses of pH regulators to adjust the intestinal pH value to increase the bioavailability of statins such as atorvastatin.

[0037] (2) Metabolic enzyme inhibitors are used to reduce the metabolism of atorvastatin and its active metabolites 2-hydroxyatorvastatin acid and 4-hydroxyatorvastatin acid into pharmacologically inactive atorvastatin lactone, 2-hydroxyatorvastatin lactone and 4-hydroxyatorvastatin lactone, thereby increasing the bioavailability.

[0038] (3) In order to release the drug in an environment with the most appropriate pH value and not in gastric juice, a modified release dosage form is used to encapsulate the drug so that the drug will pass through the stomach and dissolve in the intestines. This allows the drug to carry enough alkaline agents to change the intestinal tract to an appropriate pH value that can increase bioavailability, thereby further increasing bioavailability.

[0039] (4) As the bioavailability of the drug increases, the occurrence of serious or even fatal side effects such as rhabdomyolysis caused by individual absorption differences is reduced, the drug safety is increased, and the safety of high-dose modified release dosage forms is further guaranteed. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The metabolic pathway of atorvastatin in the organism.

[0041] Figure 2A The in vitro penetration efficiency of atorvastatin through the rat intestinal wall at different pH conditions and at different time points.

[0042] Figure 2BThe in vitro penetration efficiency of atorvastatin through the rat intestinal wall at 5 hours under different pH conditions.

[0043] Figure 3A Oral administration of SD rats Lipitor (water, n = 8), atorvastatin (pH 7.4, n = 11), experimental group atorvastatin (atorvastatin) and HUEXC41 (pH 7.4, n = 6), the time-dependent changes in the blood concentration of the parent drug and the sum of two active metabolites (AT+2AT+4AT).

[0044] Figure 3B Oral administration to SD rats Time-dependent changes in the blood concentration of the active metabolite (2AT) in the experimental group of Lipitor (water, n=8), atorvastatin (pH 7.4, n=11), and atorvastatin combined with HUEXC41 (pH 7.4, n=6).

[0045] Figure 4A Oral administration to SD rats Time-dependent changes in blood concentrations of Lipitor (water, n=8), atorvastatin (pH 7.4, n=11), and the experimental group of atorvastatin and HUEXC85 (pH 6.8, n=6), the sum of the parent drug and two active metabolites (AT+2AT+4AT).

[0046] Figure 4B Oral administration to SD rats Time-dependent changes in the blood concentration of the active metabolite (2AT) of Lipitor (water, n=8), atorvastatin (pH 7.4, n=11), and the experimental group of atorvastatin and HUEXC85 (pH 7.4, n=6).

[0047] Figure 5A Oral administration to SD rats Time-dependent changes in blood concentrations of Lipitor (water, n=8), atorvastatin (water, n=11), experimental group atorvastatin (pH 7.4, n=11), parent drug and the sum of two active metabolites (AT+2AT+4AT).

[0048] Figure 5B Oral administration to SD rats Time-dependent changes in blood concentrations of Lipitor (water, n=8), atorvastatin (water, n=11), experimental group atorvastatin (pH 7.4, n=11), and active metabolite (2AT). DETAILED DESCRIPTION

[0049] The present invention is illustrated by the following examples, but the present invention is not limited by the following examples.

[0050] The novel compound statin with high bioavailability provided by the present invention takes atorvastatin as an example, but statin drugs are not limited thereto.

[0051] In vitro penetration experimental device and method

[0052] A vertical diffusion cell was used as the in vitro penetration test. It is a cylindrical glass container that can be separated from top to bottom. The upper end is a cylindrical double-layer glass diffusion tank, which is mainly used to store penetrating drugs and is called the donor end. The lower end is a cylindrical glass tube with a contact surface at the bottom, which can collect the content of percutaneous absorption of the penetrant, called the receptor end. The penetration barrier used in the experimental design can be fixed between the upper and lower glass containers. This part is mainly based on the SD rat duodenum intestinal membrane as its barrier, and the outer layer of glass is mainly used as the circulating water flow filled in the water bath, and the temperature is controlled at 37°C. When the upper and lower ends are tightly combined, the inner cross-sectional area is 0.785cm 2 (The actual penetration area). In this experiment, the space inside the upper end was filled with 1 ml of atorvastatin solution 0.5 mg / ml prepared with phosphate buffers of different pH values, and the space inside the lower end was filled with 6 ml of pH 7.4 phosphate buffer. A magnetic stirring stone was placed at the bottom of the lower end, and it was placed on a multi-point stirrer and stirred at a speed of 600 rpm. 0.5 ml of the drug solution was extracted at different time points of 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 5 hours, and then 0.5 ml of pH 7.4 phosphate buffer was injected into the drug receiving end (simulating the pH value in blood) to maintain a fixed capacity. The cumulative penetration of the drug at the drug receiving end was analyzed by high performance liquid chromatography, and the Student's t test was used to analyze whether there was a statistical difference between the different groups and the control group.

[0053] In vitro screening reagents and methods

[0054] Liver microsomal enzyme preparation

[0055] Male rats weighing 250-300g were used as the source of liver microsomal enzymes (microsomes). Rats that had fasted for more than 16 hours were sacrificed, the livers were removed, and then washed with ice KCl (1.15%) 34 and weighed (and the weight was recorded). After the liver was chopped, ice KCl was added at a weight ratio (liver: KCl = 1:4), and the liver was completely homogenized with a homogenizer. The homogenized liver liquid was placed in a high-speed centrifuge tube (about 15ml per tube). The high-speed centrifuge was centrifuged at 9000rpm (gravitational acceleration 12500g) for 20 minutes at 4°C. After the centrifugation was completed, the supernatant was removed and placed in an ultra-high-speed centrifuge, and centrifuged at 40000rpm (100,000g) for 2 hours at 4°C. After the centrifugation was completed, the supernatant was discarded, the precipitated fragments in the tube were scraped, and KH was added with an equal weight to the liver. 2 PO 4 (pH 7.4) buffer, homogenize and dispense into 2 ml centrifuge tubes, and store them in a -80°C refrigerator.

[0056] Protein content determination

[0057] The protein concentration of the prepared liver microsomal enzymes was quantified using the Roche protein quantification method. This method has a medium sensitivity and a detection limit of approximately 0.05 to 0.5 mg / ml. It is currently a widely used and credible method.

[0058] In vitro metabolic assay

[0059] The model drugs are midazolam, estradiol and chenodeoxycholic acid, which correspond to enzymes CYP3A4, UGT1A1 and UGT 1A3 respectively. The experimental groups include positive control, negative control and experimental groups. Each sample in each group has n=3, and the matrix added is KH 2 PO 4 (pH 7.4) 53 mM, MgCl 2 5mM, NADPH, UDPGA. Model drug midazolam 1.65μg / ml, estradiol 0.24mM and chenodeoxycholic acid 0.24mM. Inhibitors ketoconazole 0.03mM and silybin 0.075mM. Liver microsomal enzyme 0.5mg / ml is used to start the reaction [Table 8-9]. After adding the reagents to each sample, shake it with an oscillator for 10 seconds and then place it in a 37℃ water bath for 1 hour.

[0060] The matrix added to the experimental group was the same as that of the control group, but no inhibitor was added and it was replaced by the excipient of the drug to be screened. The concentrations of the added excipients were 33.3, 16.7, and 3.33 mg / ml from high to low, and the reaction concentrations were 0.033, 0.0167, and 0.003 μg / ml. After adding the reagent to each sample, it was shaken on an oscillator for 10 seconds and then placed in a 37°C water bath for 1 hour.

[0061] After the test sample was incubated in a water bath for 1 hour, 1 ml of acetonitrile (Acetonitrile) containing the internal standard 1'-hydroxy-midazolam-D4 was added to terminate the reaction. The total volume of 1.5 ml of the sample was transferred to a 2 ml tube and centrifuged at 15000 rpm for 10 minutes. After centrifugation, 0.2 ml of the test sample supernatant was taken out for analysis. The analysis results were substituted into the formula to calculate the generation rate, the percentage relative to the control group (% control) and the inhibition percentage (% inhibition). The in vitro screening was divided into 13 batches, and the control group (control) and the positive control group (positive control) of each batch had statistically significant differences (P<0.05).

[0062] Preparation of calibration curve for in vitro metabolic assay

[0063] This experiment analyzed three metabolites, so three calibration lines were prepared, namely, 1'-hydroxy-midazolam (CYP3A4) concentration range from low to high 16.7, 33, 83, 167, 330, 830, 1670ng / ml, QC points are 50, 750, 1500ng / ml. Similarly, the concentration range of B-estradiol 3-(BD-glucuronide)*sodium and CDCA24-acyl-β-D-glucuronide (UGT 1A1 & UGT1A3) is from low to high 16.7, 33, 83, 167, 330, 830, 1670ng / ml, QC points are 50, 750, 1500ng / ml.

[0064] Calculation formula:

[0065] I. Generation rate V (pmol / min / mg) = (generation amount (ng / mL) / molecular weight) * 0.0005L / 60min / 0.5mg protein * 1000000

[0066] II. % control = (measured metabolite concentration / average concentration of control group) * 100

[0067] III.%inhibition=100-%control

[0068] IV. In vitro screening concentration conversion:

[0069] Oral dose for a 60kg healthy adult (mg) / 3000ml (liver and intestine volume)*100% = in vitro screening dose (mg)

[0070] Preparation of rat liver microsomal enzymes

[0071]

[0072]

[0073] Protein content determination

[0074]

[0075] Preparation of animal test samples

[0076] The pharmacokinetic test was conducted on SD rats, and blood samples were collected at 0min, 10min, 20min, 40min, 1hr, 2hr, 4hr, 6hr, 8hr, 12hr, and 24hr after oral administration. The metabolites of the test samples in this experiment were extracted using a solid phase extraction kit (HLB), and the entire preparation process of the test samples was performed on ice.

[0077] The present invention analyzes a total of 6 metabolites, namely atorvastatin acid (AT), 2-hydroxy-atorvastatin acid (2AT), 4-hydroxy-atorvastatin acid (4AT), atorvastatin lactone (AT-lactone), 2-hydroxy-atorvastatin lactone (2AT-lactone), and 4-hydroxy-atorvastatin lactone (4AT-lactone).

[0078] The calibration concentration ranges of atorvastatin acid and 2-hydroxy-atorvastatin acid are 0.25, 0.5, 1, 5, 10, 20, 50, 100 ng / ml, and the QC concentration range is 0.75, 45, 90 ng / ml. The calibration concentration ranges of atorvastatin lactone, 2-hydroxy-atorvastatin lactone and 4-hydroxy-atorvastatin lactone are 0.25, 0.5, 1, 2, 5, 10, 15, 25 ng / ml, and the QC concentration range is 0.75, 9, 20 ng / ml.

[0079] Solid Phase Extraction Box (HLB) Animal Sample Preparation Process:

[0080]

[0081]

[0082] Example 1 Effect of pH on the in vitro penetration efficiency of atorvastatin

[0083] In order to improve the formulation of atorvastatin, the drug penetration efficiency was evaluated under different environmental pH conditions. Therefore, human stem cells (Franz-cell) were used to conduct in vitro penetration experiments. In vitro penetration experiment of atorvastatin through Franz-cell and rat duodenal membrane: Figure 2A As a result, the concentration of atorvastatin penetrated at each time point showed that the difference in penetration caused by pH value increased significantly after 2 hours. The experimental results showed that atorvastatin had good penetration efficiency for the duodenal membrane of SD rats under the conditions of pH 5.8**, pH 6.3*, pH 6.8**, pH 7.4***, pH 7.8*, pH 8.0*** and pH 8.5**, and the best penetration effect was achieved at pH 7.4 at each time point. Figure 2B As a result, the penetration concentration of atorvastatin reached the highest at pH 7.4 at 5 hours, and The results of Lipitor gastrointestinal pH value (pH4.5) were significantly different; (*P<0.05; **P<0.01; ***P<0.001). Atorvastatin (pKa=4.46) is a class II acidic drug in the BCS system. Its physicochemical properties are low solubility and high permeability. Therefore, from the results of the in vitro rat intestinal membrane penetration experiment, it can be seen that when the environmental pH value is greater than the pKa value of the drug itself, its permeability will increase until the environmental pH=7.4 reaches the highest penetration concentration. It has also been verified in animal experiments that the lipophilic drug atorvastatin can increase the degree of dissociation at pH7.4, and enable the metabolites of atorvastatin to smoothly penetrate the gastrointestinal cell membrane (mucosa), resulting in an increase in the drug concentration in the blood.

[0084] Example 2 Effects of Commonly Used Excipients or Pure Chinese Medicine Ingredients on the Activity of Atorvastatin Metabolizing Enzymes

[0085] The protein content of liver microsomal enzymes (microsomes) purified from the liver of SD rats weighing 250-300g was determined according to the Roche protein quantification method, and the absorbance value (OD 550) was measured by UV spectrophotometer and finally compared with protein standards (BSA). The calibration line concentration of the standard was 5, 10, 20, 30, 40 mg / ml. The average concentration of liver microsomal enzymes measured was about 10 mg / ml. The results in Tables 1 to 14 show the effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4. The main enzymes screened were CYP3A4, UGT1A1 and UGT1A3, and the screening concentrations of the excipients were 33.3, 16.7 and 3.33 mg / ml, respectively. The inhibitors affected the degree of metabolism of liver microsomal enzymes, and the ranking was mainly based on UGT1A3 because it was the main force involved in the glucuronidation reaction of the active metabolite of atorvastatin, followed by UGT1A1. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3, and ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4 (*p<0.05, **p<0.01, ***p<0.001). The present invention needs to find safe compounds that can inhibit UGT1A1 and UGT1A3 but not CYP3A4 to improve the bioavailability of statins.

[0086] Table 1 Effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4

[0087]

[0088]

[0089] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3; b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0090] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0091] Table 2 Effects of commonly used excipients or pure components of traditional Chinese medicine on the activities of UGT1A3, UGT1A1 and CYP3A4

[0092]

[0093] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3;

[0094] b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0095] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0096] Table 3 Effects of commonly used excipients or pure components of traditional Chinese medicine on the activities of UGT1A3, UGT1A1 and CYP3A4

[0097]

[0098] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3;

[0099] b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0100] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0101] Table 4 Effects of commonly used excipients or pure components of traditional Chinese medicine on the activities of UGT1A3, UGT1A1 and CYP3A4

[0102]

[0103]

[0104] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3;

[0105] b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0106] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0107] Table 5 Effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4

[0108]

[0109]

[0110] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3; b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0111] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0112] Table 6 Effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4

[0113]

[0114] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3; b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0115] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0116] Table 7 Effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4

[0117]

[0118]

[0119] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3; b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0120] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0121] Table 8 Effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4

[0122]

[0123]

[0124] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3; b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0125] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0126] Table 9 Effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4

[0127]

[0128] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3; b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0129] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0130] Table 10 Effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4

[0131]

[0132] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3; b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0133] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0134] Table 11 Effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4

[0135]

[0136]

[0137] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3; b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0138] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0139] Table 12 Effects of commonly used excipients on the activities of UGT1A3, UGT1A1 and CYP3A4

[0140]

[0141]

[0142] a. Silybin (0.036 μg / ml) was used as the positive control group for UGT1A1 / UGT1A3; b. Ketoconazole (0.016 μg / ml) was used as the positive control group for CYP3A4;

[0143] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0144] Table 13 Ranking of the effects of commonly used excipients on UGT1A1 activity

[0145]

[0146]

[0147] a.0.033μg / ml, b.0.167μg / ml, c.0.003μg / ml

[0148] Statistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0149] Table 14 Ranking of the effects of commonly used excipients on UGT1A3 activity

[0150]

[0151]

[0152] a.0.033μg / ml, b.0.167μg / ml, c.0.003μg / mlStatistical method: two-way test. *p<0.05, **p<0.01, ***p<0.001 compared with the control group.

[0153] Table 13 shows the ranking of UGT1A1 inhibition rate. The top five inhibitors are HUEXC40 (Sodium lauryl sulfate, SLS), HUEXC07 (Brij 76), HUEXC14 (Span 80), HUEXC77 (Polyoxyl 40 hydrogenated castor oil, RH 40) and HUEXC85 (Trans-Aconitic acid). However, the strongest inhibitory effect is HUEXC40 (Sodium lauryl sulfate, SLS) at a concentration of 0.01667 μg / ml, with an inhibition rate of 84.4%; followed by HUEXC07 (Brij 76) at a concentration of 0.03334 μg / ml, with an inhibition rate of 52.1%. Table 14 shows that the top four UGT1A3 inhibitors screened out in vitro are HUEXC40 (sodium lauryl sulfate, SLS), HUEXC32 (propyl paraben), HUEXC01 (polysorbate 20, Tween20, TW20) and HUEXC33 (methyl paraben). When the inhibitor concentration is 0.01667 μg / ml, the inhibition rate of UGT1A3 is about 50%. In the results of in vitro screening of inhibitors, the types with the best inhibitory effect are mostly surfactants, but the opposite effect is obtained in animal experiments. The possible reason is that surfactants easily cause diarrhea in experimental animals, resulting in poor absorption of oral drugs.

[0154] Example 3 Effects of pH Value and Common Excipients on the Bioavailability of Atorvastatin

[0155] Figure 3A SD rats oral Time-dependent changes in blood concentrations of Lipitor (water, n=8), atorvastatin (pH 7.4, n=11), and the experimental group of atorvastatin plus HUEXC41 (pH 7.4, n=6), parent drug and the sum of two active metabolites (AT+2AT+4AT). Figure 3B SD Rat oral Lipitor (water, n = 8), atorvastatin (pH 7.4, n = 11), experimental group atorvastatin and HUEXC41 (pH 7.4, n = 6), active metabolite (2AT) time versus blood concentration over time. Table 15 shows that the experimental group atorvastatin 1mg / kg and inhibitor HUEXC41 10mg / kg (in pH7.4) and the control group Lipitor (in water) for comparison, AUC ∞ Increased by 3.79 times (P<0.001), AUC t increased by 3.56 times (P<0.001), C max Increased by 3.38 times (P=0.001).

[0156] Table 15 Pharmacokinetic parameters and statistical analysis of animals orally administered atorvastatin and vehicle (HUEXC41).

[0157]

[0158]

[0159]

[0160] Statistical methods: one-way test. ANOVA

[0161] *p<0.05, **p<0.01, ***p<0.001

[0162] Figure 4A Indicates SD Rat oral Time-dependent changes in blood concentrations of Lipitor (water, n=8), atorvastatin (pH 7.4, n=11), and the experimental group of atorvastatin plus HUEXC85 (pH 7.4, n=6), parent drug and the sum of two active metabolites (AT+2AT+4AT). Figure 4B SD rats oral Lipitor (water, n = 8), atorvastatin (pH 7.4, n = 11), experimental group atorvastatin and HUEXC85 (pH 7.4, n = 6), active metabolite (2AT) time versus blood concentration. Table 16 shows that if the inhibitor HUEXC85 6mg / kg (inpH7.4) is taken together, compared with the control group Lipitor (in water) for comparison, AUC ∞ Increased by 3.8 times (P<0.001), AUC t increased by 3.74 times (P<0.001), C max Increased by 3.21 times (P=0.001).

[0163] Animals were given oral administration of an improved formulation of atorvastatin combined with an inhibitor, and Lipitor (in water) was compared with the total T of atorvastatin and two active metabolites (AT / 2AT / 4AT). max =1~1.94hr, C max =0.11~0.12μmol / L, AUC ∞ =0.66hr*μmol / L. Its individual active metabolite atorvastatin acid (AT) T max =0.61~0.69hr,C max =6.23~11.43ng / ml, AUC ∞ =23.97~28.92hr*ng / ml; 2OH-atorvastatin acid (2AT) T max =1~2hr, C max =67.17~70.55ng / ml, AUC ∞ =383.62~406.06ng / ml. It was found that improving the drug formulation of atorvastatin and combining inhibitors can increase the concentration of active metabolites in the blood and prolong the drug action time (duration).

[0164] Table 16 Pharmacokinetic parameters and statistical analysis of animals orally administered atorvastatin and excipient (HUEXC85).

[0165]

[0166]

[0167]

[0168] Statistical methods: one-way test. ANOVA

[0169] *p<0.05, **p<0.01, ***p<0.001

[0170] The present invention improves the formula of atorvastatin, uses appropriate pH and enzyme inhibitors to synergistically promote the solubility and absorption of the drug in the gastrointestinal tract, facilitates penetration into the blood circulation, and prolongs the drug's residence time in the body. Animal experiment results of Lipitor showed that the addition of UGT1A1 / UGT1A3 inhibitors to the formula increased the AUC of atorvastatin. ∞ Increased by 3.79 to 3.8 times, C max It can further increase by 3.21 to 3.38 times and significantly increase the bioavailability of atorvastatin.

[0171] Example 4 Effect of pH Value on Bioavailability of Atorvastatin

[0172] Rats were orally administered Lipitor or atorvastatin 1 mg / kg dissolved in pure water and pH 7.4 buffer. Lipitor (in water), atorvastatin (in water), and atorvastatin (in pH 7.4 buffer). Figure 5A Indicates SD Rat oral Time-dependent changes in blood concentrations of Lipitor (water, n=8), atorvastatin (water, n=11), experimental group atorvastatin (pH 7.4, n=11), parent drug and the sum of two active metabolites (AT+2AT+4AT). Figure 5B SD rats oral Lipitor (water, n = 8), atorvastatin (water, n = 11), experimental group atorvastatin (pH 7.4, n = 11), active metabolite (2AT) time versus blood concentration over time. Experimental results show (Table 17) The pharmacokinetic results of Lipitor (in water) and atorvastatin (in water) were similar, while the pharmacokinetic results of atorvastatin (in pH 7.4 buffer) and Lipitor (in water) for comparison, AUC ∞ Increased by 3.39 times (P<0.001), AUC t increased by 3.02 times (P<0.001), C max Increased by 1.77 times (P = 0.002). After oral administration of Lipitor to animals, the total T of atorvastatin and its two active metabolites (AT / 2AT / 4AT) max =0.58hr, C max =0.03 μmol / L, AUC ∞

[0173] =0.17hr*μmol / L. Its individual active metabolite atorvastatin acid (AT) T max =0.54hr,

[0174] C max =11.99 ng / ml, AUC ∞ =30.91hr*ng / ml; 2OH-atorvastatin acid (2AT) T max =1hr,

[0175] C max =16.07ng / ml, AUC ∞ =91.04hr*ng / ml.

[0176] Table 17 Pharmacokinetic parameters and statistical analysis of oral administration of atorvastatin in animals after adjustment of gastrointestinal pH.

[0177]

[0178]

[0179]

[0180] Statistical methods: one-way test. ANOVA

[0181] *p<0.05, **p<0.01, ***p<0.001

[0182] Example 5: Feasibility Study of pH Regulators for Adjusting Intestinal pH

[0183] The above examples confirm that the permeability and bioavailability of atorvastatin are optimal at pH 7.4, so this example further explores the feasibility of adding a pH regulator to the pharmaceutical composition to adjust the intestinal pH.

[0184] 80 mg of atorvastatin powder (the daily dose of atorvastatin is about 10-80 mg) was added to 150 ml of artificial intestinal fluid (pH 4.5, according to the USP 39 formula) and the pH value was measured first, and then the volume of buffer solution was determined to maintain the pH value of the gastrointestinal tract at pH 7.4. Table 18 attempts to use various alkaline buffers to adjust the pH value of artificial intestinal fluid from pH 4.5 to pH 7.4, and calculates the required buffer and the dosage of various salts therein. The buffer Na 2 CO 3 / NaHCO 3 (pH8.6~pH10.1), NaHCO 3 / NaOH, alkaline borate (boric acid / KCL / NaOH) (pH10) only needs to use 236-826 mg of buffer salts to successfully adjust the pH of artificial intestinal fluid from 4.5 to pH 7.4, and because the dosage of the buffer salt used is less than 1 gram, it is feasible to add a pH regulator to the pharmaceutical composition to adjust the intestinal pH. In addition, it can be found that the higher the original pH of the buffer, the smaller the dosage required to adjust the artificial intestinal fluid from pH 4.5 to pH 7.4.

[0185] Table 18 Estimates of the amount of alkalizing agent required to maintain the intestinal pH at 7.4 based on 150 ml simulated intestinal fluid (pH 4.5)

[0186]

[0187]

[0188] The above results confirm that the pharmaceutical composition of statins of the present invention utilizes:

[0189] 1) Special dosage of pH regulator and use of enteric film to coat the drug, so that the oral drug will dissolve in the intestine and adjust the intestinal pH; or

[0190] 2) Combined use of metabolic enzyme inhibitors to reduce the metabolism of atorvastatin and its active metabolites 2-OH atorvastatin acid and 4-OH atorvastatin acid into pharmacologically inactive atorvastatin lactone, 2-OH atorvastatin lactone and 4-OH atorvastatin lactone;

[0191] In order to increase the bioavailability of statins such as atorvastatin, the increased bioavailability of the drug reduces the occurrence of serious or even fatal side effects such as rhabdomyolysis caused by individual absorption differences, thereby increasing drug safety. Therefore, the pharmaceutical composition of the statin can be prepared into a modified release dosage form.

[0192] The present invention has been described above in detail and fully disclosed the relevant technical contents through the preferred embodiments. However, those skilled in the art should understand that the embodiments are only used to describe the present invention and should not be used to limit the patent scope of the present invention. Those skilled in the art can change and modify the present invention after understanding the spirit and principles of the present invention to achieve equivalent purposes, and such changes and modifications should all be included in the scope defined by the scope of the patent application as described below.

[0193] In summary, the pharmaceutical composition of the oral statin with high bioavailability of the present invention is not only innovative in formulation, but also has multiple functions such as increasing bioavailability and reducing serious or even fatal side effects such as rhabdomyolysis, which is indeed practical. The application of its technical means is undoubtedly novel, and the efficacy is indeed consistent with the design purpose, which can be regarded as a reasonable progress.

Claims

1. A pharmaceutical composition capable of improving the bioavailability of oral statins, characterized in that: The pharmaceutical composition comprises a statin and a substance that improves bioavailability, wherein the substance that improves bioavailability comprises: A pH adjuster and a modified release dosage form, wherein the mass of the pH adjuster is 20-90% (w / w) of the pharmaceutical composition, and the pH adjuster comprises sodium bicarbonate, boric acid, potassium chloride, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium phosphate, glycine, ammonia, ammonium lactate, ammonium bicarbonate, ammonium hydroxide, ammonium phosphate dibasic, monoethanolamine, diethanolamine, triethanolamine, trihydroxymethylaminomethane, ethylenediamine, N-methyl glucamide, 6N-methyl glucamide, glucamine), meglucamine, L-lysine and 2-amino-2-(hydroxymethyl)-1,3-propanediol, or any combination thereof; The pH regulator can adjust the pH value of the gastrointestinal tract for drug absorption, and the modified release dosage form can enable the effective ingredients to safely pass through the stomach and smoothly reach the intestinal tract.

2. The pharmaceutical composition according to claim 1, characterized in that The pH value regulator can adjust the intestinal pH value to 4.9-8.

5.

3. The pharmaceutical composition according to claim 1, characterized in that The pH value regulator can adjust the intestinal pH value to 5.8-7.

8.

4. The pharmaceutical composition according to claim 1, characterized in that The weight of the pH regulator is 200 to 1180 mg.

5. The pharmaceutical composition according to claim 1, characterized in that The statin is selected from the group consisting of atorvastatin, pravastatin, simvastatin, lovastatin, mevastatin, compactin, fluvastatin, cerivastatin, rosuvastatin and pitavastatin.

6. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises a metabolic enzyme inhibitor, wherein the metabolic enzyme inhibitor is at least one of a UGT1A1 inhibitor and a UGT1A3 inhibitor or any combination thereof.

7. The pharmaceutical composition according to claim 6, characterized in that The metabolic enzyme inhibitors include colloidal silicon dioxide (Aerosil 200), apigenin, baicalin, butylated anisole (BHA), polyethylene glycol cetyl ether (Brij 58), cherry flavor (Cherry), croscarmellosesodium, dextrates, glycerin, glycyrrhizin, lactose S.G, lemon oil (Lemon oil), locust (Locust), mannitol, methyl paraben (Methyl paraben), menthol (Menthol), myri 52 stearate (Myri 52), methyl cellulose (Methyl cellulose), NF hydrate (NF hydrate), β-naphthoflavone (β-Naphthoflavone, polyethylene glycol 400 (PEG400), polyoxyl 40 hydrogenated castor oil (RH 40), Propyl paraben, Polyoxyethylene 40 hydrogenated castor oil (PVP K90F), saccharin, Sorbic acid, Sorbitol solution, Span 60, Sucralose, Starch acetate, Trans-Aconitic acid, triethylcitrate, Polysorbate 40 (Tween 40, TW40), Ursolic Acid, Sodium dihydrogen phosphate, Dextrates, NF hydrate and Cholic acid or any combination thereof.

8. The pharmaceutical composition according to claim 1, characterized in that The modified release dosage form also comprises a delayed release effect.

9. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition is in the form of tablets, granules, capsules, powders or other pharmaceutically acceptable dosage forms.

10. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises an excipient.

11. The pharmaceutical composition according to claim 10, characterized in that The excipient may be a diluent, a filler, a binder, a disintegrant, a lubricant or other pharmaceutically acceptable excipients.

12. A composition for improving the bioavailability of statins, the composition comprising: pH adjusters and modified release dosage forms. The modified release dosage forms can allow the active ingredients of statins to safely pass through the destruction of gastric acid and smoothly reach the intestinal tract. The pH adjusters can adjust the pH value of the intestinal tract to improve the stability and absorption rate of the drug. The pH adjusters include sodium carbonate, sodium bicarbonate, sodium hydroxide, boric acid, potassium chloride, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium phosphate, glycine, ammonia, ammonium lactate, ammonium bicarbonate, ammonium hydroxide, and ammonium phosphate. The invention can be used in combination with at least one of dibasic, monoethanolamine, diethanolamine, triethanolamine, trihydroxymethylaminomethane, ethylenediamine, N-methyl glucamide, 6N-methyl glucamine, meglucamine, L-lysine and 2-amino-2-(hydroxymethyl)-1,3-propanediol or any combination thereof.

13. The use according to claim 12, characterized in that The composition further comprises a metabolic enzyme inhibitor, which is at least one of a UGT1A1 inhibitor and a UGT1A3 inhibitor or any combination thereof.

14. The use according to claim 13, characterized in that The metabolic enzyme inhibitors include colloidal silicon dioxide (Aerosil 200), apigenin, baicalin, butylated anisole (BHA), polyethylene glycol cetyl ether (Brij 58), cherry flavor (Cherry), croscarmellose sodium (Croscarmellose sodium), dextrates (Dextrates), glycerin (Glycerin), glycyrrhizin (Glycyrrhizin), polyvinylrolidone (kollidon VA64), lactose SG, lemon oil (Lemon oil), locust (Locust), mannitol (Mannitol), methyl paraben (Methyl paraben), menthol (Menthol), polyoxyethylene tetradecyl stearate (Myri 52), methyl cellulose (Methyl cellulose), NF hydrate (NF hydrate), β-naphthoflavone (β-Naphthoflavone, polyethylene glycol 400 (PEG400), polyoxyethylene 40 hydrogenated castor oil (polyoxyl 40hydrogenated castor oil, RH 40), propyl paraben, polyoxyethylene 40 hydrogenated castor oil (PVP K90F), saccharin, sorbic acid, sorbitol, sorbitan monostearate (Span 60), sucralose, starch acetate, trans-aconitic acid, triethyl citrate, polysorbate 40 (Tween 40, TW40), ursolic acid, sodium dihydrogen phosphate, Dextrates, NFhydrate and cholic acid or any combination thereof.

15. The use according to claim 12, characterized in that The statin is selected from the group consisting of atorvastatin, pravastatin, simvastatin, lovastatin, mevastatin, compactin, fluvastatin, cerivastatin, rosuvastatin and pitavastatin.

16. The use according to claim 12, characterized in that The modified release dosage form also comprises a delayed release effect.

17. The pharmaceutical composition according to claim 1, characterized in that The pH adjuster further includes sodium carbonate or sodium hydroxide.

18. The pharmaceutical composition according to claim 13, characterized in that The metabolic enzyme inhibitor also includes polyvinylrolidone (kollidon VA64).

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