WO2016161683A1 - Statin pharmaceutical composition, and capsule formulation and preparation method thereof - Google Patents

Abstract

Disclosed is a statin pharmaceutical composition, comprising components of the following mass fractions: 0.1-10% of statins, 0.01-5% colchicine and 85-98% polyethylene glycol 1000 vitamin E succinate. In the statin pharmaceutical composition, polyethylene glycol 1000 vitamin E succinate can inhibit P-glycoproteins in advance, and can prevent statins from interacting with colchicine by affecting P-glycoproteins, thereby reducing the gastrointestinal toxicity of colchicine and other toxicities. At the same time, polyethylene glycol 1000 vitamin E succinate improves the bioavailability of colchicine, reduces the therapeutically effective dose of colchicine, and further reduces the toxicity of colchicine.

Description

Statin composition and capsule preparation, and preparation method thereof

The present application claims priority to Chinese Patent Application No. 201510167319.8, entitled "A statin composition and a capsule preparation, a preparation method thereof", which is filed on April 9, 2015, the entire contents of which are incorporated herein by reference. This is incorporated herein by reference.

Technical field

The invention belongs to the technical field of medicine, and in particular relates to a statin pharmaceutical composition and a capsule preparation, and a preparation method thereof.

Background technique

Cardiovascular diseases generally refer to ischemic or hemorrhagic diseases of the heart and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, and hypertension. It is a common disease that seriously threatens the health of human beings, especially middle-aged and older people over the age of 50. The number of people who die of cardiovascular and cerebrovascular diseases every year in the world is as high as 15 million, ranking first in all causes of death.

Statins are commonly used drugs for the treatment of cardiovascular diseases, but existing statins do not specifically address the occurrence and development of cardiovascular disease inflammation. Atherosclerotic plaques are prone to damage, making neutrophils easy to infiltrate, which in turn causes an aggressive inflammatory response, leading to plaque instability, increasing the risk of plaque enlargement and rupture, thus increasing clinical cardiovascular disease. risk. Therefore, targeted inhibition of neutrophil function in plaque can increase the stability of plaque, thereby reducing the incidence of cardiovascular disease.

Colchicine is widely used in the treatment of gout, and it has a unique anti-inflammatory effect, including inhibition of neutrophil function by inhibiting tubulin.

Although the combination of colchicine and statin can enhance the effect of treating stable coronary heart disease, the therapeutic index of colchicine is narrower, and the effective concentration (0.3-4 ng/mL) is lower than the toxicity concentration (>5 ng/mL). Small, and, colchicine itself is a substrate for P-glycoprotein, which can significantly increase its blood in combination with P-glycoprotein inhibitors (including erythromycin, cyclosporine A, verapamil, etc.). The concentration in the medium reaches a toxic concentration, which induces serious adverse reactions, and even certain foods (such as grapefruit juice) also have this effect. More importantly, amiodarone, simvastatin and atorvastatin calcium all inhibited P-glycoprotein, which significantly increased the concentration of colchicine in the body, which in turn significantly enhanced the muscle toxicity of colchicine. Therefore, when statin is combined with colchicine for long-term use, it is a particularly important issue to ensure the safety of the combination.

Summary of the invention

The object of the present invention is to provide a statin composition and a capsule preparation, and a preparation method thereof, and the statin composition provided by the invention has low toxicity.

The present invention provides a statin composition comprising the following mass fractions of components:

0.1 to 10% statin, 0.01 to 5% colchicine and 85 to 98% polyethylene glycol 1000 vitamin E succinate.

Preferably, the statin comprises one or more of simvastatin, atorvastatin calcium, pravastatin calcium and rosuvastatin calcium.

Preferably, the statin comprises one or more of simvastatin, atorvastatin calcium and rosuvastatin calcium;

The mass fraction of the statin is from 1 to 8%.

Preferably, the colchicine has a mass fraction of 0.02 to 3%.

Preferably, the polyethylene glycol 1000 vitamin E succinate has a mass fraction of 90 to 97%.

The present invention provides a capsule formulation comprising a content comprising the above-described statin composition and adjuvant.

Preferably, the excipient comprises lauric acid polyethylene glycol glyceride, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, ethanol, propylene glycol and caprylic acid phthalic acid polyethylene One or more of the alcohol glycerides;

The mass fraction of the excipient in the content is 5 to 19%.

Preferably, the auxiliary material comprises one or more of polyethylene glycol 200, propylene glycol and polyglycol phthalate of caprylic acid;

The mass fraction of the excipient in the content is 8 to 15%.

The invention provides a preparation method of a capsule preparation, comprising the following steps:

A) mixing 80-90% of polyethylene glycol 1000 vitamin E succinate and auxiliary materials by mass fraction to obtain mixed auxiliary materials.

B) mixing 0.1 to 10% of the statin, 0.01 to 5% of colchicine, and the mixed adjuvant obtained in the step A) by mass fraction to obtain a content;

C) The contents obtained in the step B) are filled into capsules to obtain a capsule preparation.

Preferably, the temperature of the mixing in the step A) is 38 to 80 ° C;

The temperature of mixing in the step B) is 38 to 80 °C.

The present invention provides a statin composition comprising the following components in mass fraction: 0.1 to 10% statin, 0.01 to 5% colchicine, and 85 to 98% polyethylene glycol 1000 vitamin E Succinate. In the statin composition provided by the invention, the polyethylene glycol 1000 vitamin E succinate can inhibit the P-glycoprotein in advance, and can prevent the statin from interacting with the colchicine by affecting the P-glycoprotein, thereby Reduces gastrointestinal toxicity and other toxicity of colchicine. At the same time, polyethylene glycol 1000 vitamin E succinate increased the bioavailability of colchicine, reduced the therapeutic effective dose of colchicine, and further reduced the toxicity of colchicine.

detailed description

The present invention provides a statin composition comprising the following components in mass fraction: 0.1 to 10% statin, 0.01 to 5% colchicine, and 85 to 98% polyethylene glycol 1000 vitamin E Succinate.

The polyethylene glycol 1000 vitamin E succinate in the statin composition provided by the invention can prevent the statin from interacting with colchicine by affecting the P-glycoprotein, thereby reducing the gastrointestinal of the colchicine Toxicity and other toxicities.

The statin composition provided by the present invention comprises a statin, and the statin preferably comprises one or more of simvastatin, atorvastatin calcium, pravastatin calcium and rosuvastatin calcium, and more Preferably, one or more of simvastatin, atorvastatin calcium and rosuvastatin calcium are included, most preferably including simvastatin and/or atorvastatin calcium; said statin is in said statin The mass fraction in the pharmaceutical composition is from 0.1 to 10%, preferably from 1 to 8%, more preferably from 2 to 6%.

The statin composition provided by the present invention comprises colchicine, and the colchicine has a mass fraction of 0.01 to 5%, preferably 0.02 to 3%, more preferably 0.03 to 1 in the statin composition. %.

The statin composition provided by the present invention comprises polyethylene glycol 1000 vitamin E succinate, and the mass fraction of the polyethylene glycol 1000 vitamin E succinate in the statin composition is 85 to 98%. It is preferably 90 to 97%, more preferably 93 to 96%. In the present invention, the polyethylene glycol 1000 vitamin E succinate can be converted into a vitamin after being absorbed into the body. E, supplementation with a certain amount of vitamin E is beneficial for patients with stable coronary heart disease.

The present invention also provides a capsule preparation comprising a content prepared from the statin composition and the adjuvant described in the above technical solution, wherein the statin composition is a statin as described in the above technical solution. The pharmaceutical composition will not be described here.

In the present invention, the excipients include glycerol laurate, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, ethanol, propylene glycol, and caprylic acid phthalic acid. One or more of ethylene glycol glycerides, preferably one or more of polyethylene glycol 200, propylene glycol, and polyglycolic acid decanoic acid glyceride, more preferably polyethylene glycol 200 and / Or propylene glycol; the mass fraction of the adjuvant in the content is preferably from 5 to 19%, more preferably from 8 to 15%, most preferably from 9 to 13%. The invention adopts the above-mentioned ratio of excipients combined with polyethylene glycol 1000 vitamin E succinate to obtain a temperature-sensitive capsule preparation, so that the capsule contents are presented in a solid form at room temperature, in the human gastrointestinal tract, The conversion of the contents of the capsule into a liquid state facilitates the stability and uniformity of the contents of the capsule and also facilitates the preparation of the capsule. Ultimately, capsule preparations are safer and more effective in treating stable coronary heart disease.

The capsule preparation provided by the present invention further comprises a capsule coated with a content, the capsule may be a hard capsule or a soft capsule, preferably a hard capsule, and the capsule is preferably of the type 000, 00 or 0.

The invention also provides a preparation method of a capsule preparation, comprising the following steps:

A) 80 to 90% of polyethylene glycol 1000 vitamin E succinate and 5 to 19% of auxiliary materials are mixed in a mass fraction to obtain a mixed auxiliary.

The excipients include glycerol laurate, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, ethanol, propylene glycol, and polyglycolic acid decanoic acid glyceride One or several of them;

B) mixing 0.1 to 10% of the statin, 0.01 to 5% of colchicine, and the mixed adjuvant obtained in the step A) by mass fraction to obtain a content;

C) The contents obtained in the step B) are filled into capsules to obtain a capsule preparation.

In the present invention, 80 to 90% of polyethylene glycol 1000 vitamin E succinate and 5 to 19% of an auxiliary material are mixed to obtain a mixed auxiliary material, and the polyethylene glycol 1000 vitamin E amber is preferably used in the present invention. The acid ester is heated to a liquid state, and then the liquid polyethylene glycol 1000 vitamin E The succinate is mixed with the auxiliary material to obtain a mixed auxiliary. The invention combines polyethylene glycol 1000 vitamin E succinate and auxiliary materials in a certain ratio to prepare a temperature sensitive capsule preparation, so that the capsule contents are presented in solid form at room temperature, in the human stomach. In the channel, the contents of the capsule are converted into a liquid state; it is advantageous for the stability and uniformity of the contents of the capsule, and is also convenient for the preparation of the capsule.

In the present invention, the source of the polyethylene glycol 1000 vitamin E succinate is consistent with the source of the polyethylene glycol 1000 vitamin E succinate in the above technical solution, and will not be described herein; the type of the auxiliary material and The source is the same as the adjuvant in the capsule preparation described in the above technical scheme, and will not be described herein. In the present invention, the polyethylene glycol 1000 vitamin E succinate has a mass fraction of 80 to 90%, preferably 82 to 88%, more preferably 83 to 86%; and the mass fraction of the auxiliary material is 5 to 19%, preferably 8 to 15%, more preferably 9 to 13%.

In the present invention, the heating temperature of the polyethylene glycol 1000 vitamin E succinate is preferably 38 to 80 ° C, more preferably 40 to 70 ° C, and most preferably 50 to 60 ° C; The heating time of the diol 1000 vitamin E succinate is not particularly limited, and it can be melted to a liquid state; the temperature at which the polyethylene glycol 1000 vitamin E succinate is mixed with the auxiliary material is preferably 38 to 80 ° C, It is preferably 40 to 70 ° C, and most preferably 50 to 60 ° C. The time for mixing the polyethylene glycol 1000 vitamin E succinate and the auxiliary material in the present invention is not particularly limited, and the two can be uniformly mixed.

After obtaining the mixed auxiliary material, the present invention mixes 0.1 to 10% of the statin and 0.01 to 5% of the colchicine with the mixed adjuvant obtained in the step A) in terms of mass fraction to obtain a content, and the present invention preferably The statin and the colchicine are separately pulverized, and then mixed with the obtained mixed auxiliary material to obtain a content. In the present invention, the types and sources of the statins and colchicine are the same as those of the statins and colchicines in the above technical solutions, and will not be described herein. In the present invention, the mass fraction of the statin is 0.1 to 10%, preferably 1 to 9%, more preferably 2 to 6%; and the mass fraction of the colchicine is 0.01 to 5%, preferably 0.02 to 1%, more preferably 0.03 to 0.2%. The method and the particle size of the statin and colchicine pulverization of the present invention are not particularly limited, and a pulverization method commonly used by those skilled in the art may be employed.

In the present invention, the temperature at which the statin, the colchicine, and the mixed auxiliary are mixed Preferably, it is 38 to 80 ° C, more preferably 40 to 70 ° C, and most preferably 50 to 60 ° C; the present invention has no particular limitation on the time of mixing the statin, colchicine and the mixed adjuvant, and can The above materials can be mixed evenly.

After the content is obtained, the present invention fills the content into a capsule to obtain a capsule preparation. In the present invention, the type and model of the capsule are the same as those of the above-mentioned technical solution, and will not be described herein. In the present invention, the obtained content is preferably filled in a capsule, and then cooled to room temperature to obtain a capsule preparation. The capsule preparation provided by the invention has a solid content in the capsule under the condition of room temperature (25 ° C), but under the condition of human body temperature (37 ° C), the content is in a liquid state, which is favorable for the stability and uniformity of the contents of the capsule. It is also convenient for the preparation of capsules.

The present invention provides a statin composition comprising the following components in mass fraction: 0.1 to 10% statin, 0.01 to 5% colchicine, and 85 to 98% polyethylene glycol 1000 vitamin E Succinate. In the statin composition provided by the invention, the polyethylene glycol 1000 vitamin E succinate can inhibit the P-glycoprotein in advance, and can prevent the statin from interacting with the colchicine by affecting the P-glycoprotein, thereby Reduces gastrointestinal toxicity and other toxicity of colchicine. At the same time, polyethylene glycol 1000 vitamin E succinate increased the bioavailability of colchicine, reduced the therapeutic effective dose of colchicine, and further reduced the toxicity of colchicine.

Further, since the statin and the colchicine, which are active ingredients for treating coronary heart disease, are not changed in the statin composition provided by the present invention, the statin composition provided by the present invention reduces the colchicine. At the same time of toxicity, it maintains a good therapeutic effect on coronary heart disease.

The invention also provides a preparation method of a capsule preparation and a capsule preparation, wherein the polyethylene glycol 1000 vitamin E succinate and the auxiliary material are combined in a certain ratio to prepare a temperature sensitive capsule preparation, thereby making The contents of the capsule are presented in solid form at room temperature. When in the gastrointestinal tract of the human body, the contents of the capsule are converted into a liquid state; the stability and uniformity of the contents of the capsule are facilitated, and the preparation of the capsule is also facilitated. The capsule preparation provided by the invention can also increase the compliance and tolerance of the medication, and ultimately safe and effective treatment for patients with stable coronary heart disease.

In order to further illustrate the present invention, a statin pharmaceutical composition and a capsule preparation provided by the present invention and a preparation method thereof are described in detail below with reference to examples, but it should not be construed as The scope of protection of the present invention is limited.

Example 1 Pharmacokinetic Experiment 1

Female rat pharmacokinetic experiments were carried out according to the formulation in Table 1, and Table 1 is the ratio of the raw materials and the amount of the drug in the first embodiment of the present invention. The experimental animals were female rats (180 g to 200 g), with 6 rats in each group. 0.3 ml blood samples were collected at the time points of 15 min, 30 min, 45 min, 1 h, 1.5 h, 3 h, 4 h, 6 h and 24 h after administration of the test solution. Anticoagulation), the concentration of colchicine in plasma was determined by HPLC, and the pharmacokinetic parameters were calculated. The experimental results are shown in Table 2. Table 2 shows the results of the pharmacokinetic experiments of Example 1 of the present invention, and the data shown in Table 2 is the mean value ± standard deviation of each set of experimental data.

Table 1 Raw material ratio and dosage of Example 1 of the present invention

Table 2 Results of pharmacokinetic experiments of Example 1 of the present invention (comparison of colchicine concentration)

Group t _max (h) C _max (ng/ml) AUC (h·ng/ml) Group 1 0.25±0.01 36.9 ± 7.5 30.5±6.5 Group 2 0.33±0.13 72.9±9.8** 65.4±11.2** Group 3 0.25±0.01 46.5±6.9* 39.4±5.3* Group 4 0.29±0.10 77.9±7.9** 70.4±12.4*

Note: * indicates p value <0.05, ** indicates p value <0.01, that is, compared with group 1, the difference between the two is statistically significant.

The results show that the Group 1 (distilled water as a solvent) compared to Group 2 and Group 4 (10% polyethylene glycol 1000 succinate of vitamin E as a solvent) of colchicine were increased C _max and AUC About 100%; and although atorvastatin calcium significantly increased the _Cmax and AUC (about 30%) of colchicine, when using 10% polyethylene glycol 1000 vitamin E succinate as a solvent, this Significant increase has disappeared. It shows that 10% polyethylene glycol 1000 vitamin E succinate not only significantly increases the bioavailability of colchicine (so that the therapeutically effective dose is reduced), but also prevents the interaction of atorvastatin with colchicine (drug generation). Dynamics).

Example 2 Pharmacokinetic Experiment 2

The experimental animals were 350 g to 400 g male rats, 5 rats in each group, and the bile duct cannulation and carotid artery cannulation were performed under anesthesia (the anesthesia state was maintained during the experiment), and the four groups of drugs as shown in Table 3 were used respectively. Injection into the tail vein. The specific administration method is as follows: firstly, administration of polyethylene glycol 1000 vitamin E succinate (using physiological saline containing 50% concentration of propylene glycol as a solvent), and then giving colchicine after 30 minutes (using a physiological saline containing 50% concentration of propylene glycol) For the solvent). Bile and blood were collected every 10 minutes after administration of colchicine (12 times in total), the concentration of colchicine in bile and plasma was measured, and the pharmacokinetic parameters were calculated. The results are shown in Table 4. Table 4 is a pharmacokinetic parameter of colchicine in rat bile and plasma according to Example 2 of the present invention. The results shown in Table 4 indicate that polyethylene glycol 1000 vitamin E succinate significantly reduced the secretion of colchicine in bile in a dose-dependent manner with a maximum reduction of approximately 75%.

Table 3 The administration formula and dosage of Example 2 of the present invention

Group Test article dose 1 Colchicine 10mg/kg 2 Colchicine + Polyethylene Glycol 1000 Vitamin E Succinate 10mg/kg+2mg/kg 3 Colchicine + Polyethylene Glycol 1000 Vitamin E Succinate 10mg/kg+10mg/kg 4 Colchicine + Polyethylene Glycol 1000 Vitamin E Succinate 10mg/kg+50mg/kg

Table 4 Pharmacokinetic parameters of colchicine in rat bile and plasma according to Example 2 of the present invention

Note: CL indicates the clearance rate, ** indicates that the p value is <0.01 compared to group 1.

Example 3 Rat Diarrhea Experiment

The experimental animals were 300 g to 350 g male rats, 5 in each group, and administered according to the dosing schedule in Table 5. Table 5 shows the administration formula and the administration amount of Example 3 of the present invention. The specific administration method is as follows: first injection of polyethylene glycol 1000 vitamin E succinate (using physiological saline containing 50% concentration of propylene glycol as a solvent), and then administering colchicine (containing 50%) after 10 minutes. The physiological saline of the concentration of propylene glycol is a solvent).

The fecal shape of the rats was recorded and scored before administration and the day after administration, and the evaluation criteria for diarrhea were evaluated. For: 0 (normal stool); 1 (mild, wet stool); 2 (moderate, unformed liquid feces with small stool particles); 3 points (severe, unformed liquid feces, not seen Small stool particles, perianal stained with stool color).

The results are shown in Table 6, which is the diarrhea score of the rat in Example 3 of the present invention. As shown in Table 6, the results showed that the diarrhea score of the polyethylene glycol 1000 vitamin E succinate-administered group was dose-dependently reduced compared with colchicine alone, with a maximum reduction of about 50%. , from severe to light to moderate.

Table 5 Administration Formulation and Dosage of Example 3 of the Invention

Group Test article dose 1 Colchicine 0.7mg/kg 2 Colchicine + Polyethylene Glycol 1000 Vitamin E Succinate 0.7mg/kg+5mg/kg 3 Colchicine + Polyethylene Glycol 1000 Vitamin E Succinate 0.7mg/kg+20mg/kg 4 Colchicine + Polyethylene Glycol 1000 Vitamin E Succinate 0.7mg/kg+80mg/kg

Table 6 Rat diarrhea score in Example 3 of the present invention

Before administration The second day after administration Group 1 0 3±0 Group 2 0 2.8±0.45 Group 3 0 2.2±0.45** Group 4 0 1.4±0.55**

Note: ** indicates that the p value is <0.01 compared to group 1.

Example 4 Preparation of Capsule Formulation

Table 7 Formulation of the capsule preparation in Example 4 of the present invention

Colchicine 0.3g Atorvastatin calcium 40g Polyethylene glycol 1000 vitamin E succinate 850g Propylene glycol 100g

First melt the polyethylene glycol 1000 vitamin E succinate at 60 ° C, then add propylene glycol, mix for 10 min (at 60 ° C), then add colchicine and atorvastatin calcium (pre-crushed) It was mixed for 30 min (in a liquid state at 60 ° C), and finally filled into a No. 000 hard capsule to prepare 1000 capsules, and the contents of the capsule were solid when cooled to room temperature.

Example 5 Preparation of Capsule Formulation

Table 8 Formulation of the capsule preparation in Example 5 of the present invention

Colchicine 0.3g Rosuvastatin calcium 20g

Polyethylene glycol 1000 vitamin E succinate 850g Polyethylene glycol 200 100g

First melt the polyethylene glycol 1000 vitamin E succinate at 60 ° C, then add polyethylene glycol 200, mix for 10 min (at 60 ° C), then add colchicine and rosuvastatin calcium ( It was pulverized beforehand and mixed for 30 min (in a liquid state at 60 ° C), and finally filled into a No. 000 hard capsule to prepare 1000 capsules, and the contents of the capsule were solid when cooled to room temperature.

Example 6 Preparation of colchicine simvastatin compound capsule

Table 9 Formulation of the capsule preparation in Example 6 of the present invention

Colchicine 0.3g Simvastatin 40g Polyethylene glycol 1000 vitamin E succinate 800g Octanoic acid phthalate 150g

First melt the polyethylene glycol 1000 vitamin E succinate at 60 ° C, then add glyceryl phthalate phthalate, mix for 10 min (at 60 ° C), then add colchicine and simva The statin (pre-crushed) was mixed for 30 min (in a liquid state at 60 ° C), and finally filled into a No. 000 hard capsule to make 1000 capsules, and the contents of the capsule were solid when cooled to room temperature.

The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

Claims (10)

A statin composition comprising the following mass fractions of components: 0.1 to 10% statin, 0.01 to 5% colchicine and 85 to 98% polyethylene glycol 1000 vitamin E succinate. The statin composition according to claim 1, wherein the statin comprises one or more of simvastatin, atorvastatin calcium, pravastatin calcium and rosuvastatin calcium. . The statin composition according to claim 1 or 2, wherein the statin comprises one or more of simvastatin, atorvastatin calcium and rosuvastatin calcium; The mass fraction of the statin is from 1 to 8%. The statin composition according to claim 1 or 2, wherein the colchicine has a mass fraction of 0.02 to 3%. The statin composition according to claim 1 or 2, wherein the polyethylene glycol 1000 vitamin E succinate has a mass fraction of 90 to 97%. A capsule preparation comprising a content comprising the statin pharmaceutical composition according to any one of claims 1 to 5 and an adjuvant. The capsule preparation according to claim 6, wherein the adjuvant comprises glycerol laurate, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600 One or more of ethanol, propylene glycol and polyglycolic acid decanoic acid glyceride; The mass fraction of the excipient in the content is 5 to 19%. The capsule preparation according to claim 6, wherein the adjuvant comprises one or more of polyethylene glycol 200, propylene glycol, and polyglycol phthalate; The mass fraction of the excipient in the content is 8 to 15%. A method for preparing a capsule preparation, comprising the steps of: A) mixing 80-90% of polyethylene glycol 1000 vitamin E succinate and auxiliary materials by mass fraction to obtain mixed auxiliary materials. B) 0.1 to 10% statin, 0.01 to 5% colchicine by mass fraction Mixing with the mixed auxiliary material obtained in the step A) to obtain a content; C) The contents obtained in the step B) are filled into capsules to obtain a capsule preparation. The capsule preparation according to claim 9, wherein the temperature in the step A) is 38 to 80 ° C; The temperature of mixing in the step B) is 38 to 80 °C.