CN102993348B - Sevelamer niacin, preparation method and application - Google Patents

Abstract

The invention provides a nicotinic acid sevelamer and its preparation method and application. The Ram of the present invention has the following structural formula I; wherein, in the structural formula I, (a+b):c is 45:1 to 2:1, m represents a non-zero or negative integer, and each x is independently represents 0 or 1, and each x is not 0 at the same time; and the specific gravity of the nicotinic acid sevelamer is 2.00-2.50. The nicotinic acid sevelamer of the present invention can still achieve a therapeutic effect similar to that of the sevelamer hydrochloride when the dosage is only half of the sevelamer hydrochloride.

Description

A kind of nicotinic acid sevelamer and its preparation method and application

technical field

The invention relates to the field of biomedicine, in particular to a preparation method of nicotinic acid sevelamer and nicotinic acid sevelamer, the use of nicotinic acid sevelamer in preparing medicines for treating hyperphosphatemia, and nicotinic acid sevelamer Use of Vilamer in the preparation of medicines for lowering blood lipids.

Background technique

Niacin and its derivatives, such as nicotinic acid esters, can not only reduce the levels of triglycerides, very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoproteins in plasma, but also effectively increase the level of high-density lipoprotein cholesterol. Recent studies It was found that niacin and its derivatives can effectively reduce the blood phosphorus level of hemodialysis patients with hyperphosphatemia.

Sevelamer salt is a new generation drug approved by the U.S. Food and Drug Administration. It is mainly used as a phosphorus binder. It is a new drug in pharmacological classification. It is characterized by no aluminum, no calcium, and no For polymers containing any metal components, the patient takes three meals at the same time with the drug. It adsorbs phosphoric acid in the intestinal tract in a manner similar to resin ion exchange, and then excretes it through the feces after being combined. Sevelamer is available commercially mainly in the form of its hydrochloride and carbonate salts. These sevelamer salts have a common shortcoming: the dose is large, and the daily dose should reach 2-3g. Due to the large dose, it often causes symptoms such as constipation and vitamin deficiency in the user.

Therefore, it is necessary to improve the existing sevelamer salt, so that good pharmaceutical effects can still be achieved under the condition of reducing the dose of sevelamer salt.

Contents of the invention

An object of the present invention is to provide a sevelamer salt, which has a lower dosage than the existing sevelamer hydrochloride and sevelamer carbonate, but still has good pharmaceutical effects.

Another object of the present invention is to provide the preparation method of the sevelamer salt of the present invention.

Another object of the present invention is to provide the use of the sevelamer salt of the present invention.

One aspect of the present invention provides a kind of nicotinic acid sevelamer, which has the following structural formula I:

Formula I

In said structural formula I, (a+b):c is 45:1 to 2:1, m represents a non-zero or negative integer, each x independently represents 0 or 1, and each x is not 0 at the same time; and The specific gravity of the nicotinic acid sevelamer is 2.00-2.50.

Preferably, the specific gravity of the niacin sevelamer is 2.10-2.25.

More preferably, the specific gravity of the niacin sevelamer is 2.15-2.20.

Preferably, in the structural formula I, (a+b):c is in the range of 20:1 to 4:1.

Preferably, more than 90% of the sevelamer niacin is particles with a particle size below 400 μm.

Preferably, more than 90% of the sevelamer niacin is particles with a particle size below 300 μm.

Another aspect of the present invention also provides a method for preparing sevelamer nicotinate of the present invention, the method comprising the following steps:

a) making Sevelamer hydrochloride react with an alkali to obtain basic Sevelamer;

b) reacting the basic sevelamer with niacin to obtain niacin sevelamer.

Preferably, in the step a), the aqueous dispersion of sevelamer hydrochloride and the aqueous alkali solution are mixed and stirred at 25-35° C. for 30 minutes to 1 hour to react; preferably Alternatively, the base is NaOH.

Preferably, in the step a), the reaction product obtained from the reaction of the sevelamer hydrochloride and the base is filtered, washed with water, and collected to obtain the basic sevelamer.

Preferably, said step b) comprises the following steps:

d) dispersing the alkaline sevelamer in water to obtain an aqueous dispersion of alkaline sevelamer;

e) making the nicotinic acid aqueous solution;

f) mixing the aqueous solution of nicotinic acid and the aqueous dispersion of alkaline sevelamer, and stirring at 20-40°C for 8-12 hours to react to obtain a reaction product;

g) The reaction product obtained in step f) is filtered, washed with water, and collected to obtain the sevelamer nicotinate.

Preferably, step d) precedes or follows step e).

Preferably, the concentration of the aqueous dispersion of sevelamer hydrochloride is 0.06-0.20 mg/ml, and the aqueous alkali solution is an aqueous sodium hydroxide solution with a concentration of 0.04 mg/ml.

Preferably, the mass ratio of the sevelamer hydrochloride to the NaOH is 4:1 to 8:1.

Preferably, in the step b), the mass ratio of the basic sevelamer to the niacin is 1:1 to 1:1.5.

Another aspect of the present invention provides the use of the nicotinic acid sevelamer of the present invention in the preparation of medicaments for treating and/or preventing hyperphosphatemia.

In one aspect, the present invention provides the use of the nicotinic acid sevelamer of the present invention in the preparation of a drug for lowering blood lipid.

The beneficial effect of the present invention is that compared with the existing sevelamer hydrochloride, the sevelamer niacin provided by the present invention overcomes the shortcoming that sevelamer hydrochloride may cause excessive chloride ion content in the human body , and when its effective dose is only half the weight of the existing sevelamer hydrochloride and sevelamer carbonate, it can achieve similar pharmaceutical effects, thus greatly reducing the dosage of patients.

The existing sevelamer hydrochloride and sevelamer carbonate will cause symptoms of malnutrition in patients after taking them for a long time because they absorb vitamins in the body. Yet nicotinic acid sevelamer of the present invention supplements vitamin B from molecule itself, so even if take medicine for a long time, also can not cause the lack of vitamin B of taking medicine, and the dosage of nicotinic acid sevelamer of the present invention is few, so The side effects of vitamin deficiency in patients are not obvious.

In addition, Sevelamer hydrochloride and Sevelamer carbonate will cause adverse symptoms such as vomiting, nausea, diarrhea, indigestion and constipation in the course of taking. Taking it for a long time, the above side effects were not found in patients.

In addition, during the course of taking niacin as a lipid-lowering drug, patients will experience mild to moderate symptoms of flushing, burning and itching on the face, neck, and limbs 2-5 hours after taking the drug. Niacin sevelamer, these symptoms are not obvious.

The preparation method of the nicotinic acid sevelamer of the present invention is simple and easy to implement, has few reaction impurities and high reaction product yield, and the yield of the reaction product is greater than 80% relative to the basic sevelamer.

Detailed ways

The present invention will be further described below through the description of specific embodiment, but this is not limitation to the present invention, those skilled in the art can make various modifications or improvements according to the basic idea of the present invention, but as long as not departing from the basic principle of the present invention Thoughts are all within the scope of the present invention.

In this article, unless otherwise stated, "Sevelamer hydrochloride" herein is also referred to as the hydrochloride salt of Sevelamer, and its chemical name is: polymer salt of 2-propen-1-amine and epichlorohydrin acid salt, CAS number is 152751-57-0, and the structural formula is the following formula II:

Formula II

Wherein (a+b):c is 45:1 to 2:1, and m represents a non-zero or negative integer. The structure of Sevelamer Hydrochloride and its preparation method can be found in Chinese Patent Application No.99813175.x.

As used herein, unless otherwise stated, "nicotinic acid" herein refers to pyridine 3-carboxylic acid, which is a B vitamins, the molecular formula is C ₆ H ₅ NO ₂ , and the structural formula is the following formula III:

Formula III

The content of the present invention is further explained or illustrated by examples below, but these examples should not be construed as limiting the protection scope of the present invention.

In the following example:

Sevelamer hydrochloride is prepared according to the method described in Production Example 1 in Chinese Patent Application No.99813175.x. Niacin was purchased from Wuhan Jinnuo Chemical Co., Ltd.

Example 1

Preparation of basic sevelamer

First 80mg of Sevelamer hydrochloride is dispersed in 500ml pure water, then the aqueous solution 0.04mg/ml of preparation sodium hydroxide, in the aqueous solution of Sevelamer hydrochloride, add the sodium hydroxide solution of 500ml, mixed solution is warmed up to Stir at 35°C for 30 minutes, filter, collect the filter cake, wash the filter cake 3 times with pure water, and then dry the wet cake obtained after washing at 80°C for 5 hours to obtain basic sevelamer. Sevelamer was analyzed and identified.

Example 2

Analysis of Basic Sevelamer

Part of the sample obtained in the basic sevelamer obtained in Example 1 was dissolved in water, stirred, and silver nitrate solution was added to the solution, and no precipitation occurred. It shows that the chloride ions in the basic sevelamer have been completely removed.

Example 3

Analysis of Basic Sevelamer

The basic sevelamer prepared in Example 1 was subjected to infrared spectroscopic analysis, and the infrared spectrometer was a Varian640 Fourier transform infrared spectrometer produced by Varian Corporation of the United States. Characterization of the results: the peak at 3380.6cm ^-1 is the peak of -OH group and -NH group overlap; the peak at 2920.4cm ^-1 and 2851.4cm ^-1 is considered to be the peak of -CH ₂ -; The peak at 1580.1cm ^-1 is considered to be the stretching vibration peak of NH; the peak at 1310.1cm ^-1 is considered to be the bending vibration peak of CN; the peak at 1461.2cm ^-1 and 1380cm ^-1 is considered to be -CH ₃ and -CH ₂ - peaks; the peak at 1310.1cm ^-1 is considered to be the stretching vibration peak of CO. The combination of this embodiment and the detection method in Example 2 proves that basic sevelamer has been obtained.

Example 4

Preparation of Niacin Sevelamer

Take 10 g of basic sevelamer prepared according to the method described in Example 1 and disperse it in 50000 ml of pure water, then dissolve 15 g of niacin in 500 ml of aqueous solution to make a niacin solution, add the niacin solution to In alkaline sevelamer solution, stirred at 30° C. for 8 hours, filtered the obtained reaction product, collected the filter cake, washed the filter cake with pure water for 5 times, and freeze-dried the filter cake.

Example 5

Infrared Spectrum Analysis of Niacin Sevelamer

Get the filter cake that a small amount of embodiment 4 obtains, carry out infrared analysis, and infrared spectrometer is the Varian640 Fourier transform infrared spectrometer that U.S. Varian Company produces. Characterization of the results: the peak at 3410.6cm ^-1 is the peak of -OH group and -NH group overlap; the peak at 2922.4cm ^-1 and 2850.4cm ^-1 is considered to be the peak of -CH ₂ -; The peak at 1710.3cm ^-1 is considered to be the C=O peak in niacin; the peak at 1670cm ^-1 is considered to be the peak of C=N; the peak at 1580.1cm ^-1 is considered to be the stretching vibration peak of NH ; The peaks at 1570.5cm ^-1 and 1470.6cm ^-1 are considered to be the peaks of the C=C double bond of the pyridine skeleton, and the peaks at 1310.1cm ^-1 are considered to be the bending vibration peaks of CN; 1461.2cm ^-1 , 1380cm ^- The peak at ¹ is considered to be the peak of -CH ₃ and -CH ₂ -; the peak at 1310.1cm ^-1 is considered to be the stretching vibration peak of CO. Since the reaction raw material nicotinic acid is soluble in water, nicotinic acid has been washed and removed in the preparation of Example 4, so the filter cake used for testing does not contain nicotinic acid. C=O peaks, C=N peaks, and pyridine skeleton C=C double bond peaks were detected by infrared spectroscopy, so it can be considered that the nicotinic acid sevelamer was obtained.

Example 6

The nicotinic acid sevelamer prepared in Example 4 was tested using an ultrafine particle size analyzer (model: N5) from Beckman Coulter, USA. The particle size of 92% of sevelamer nicotinate is less than 300 μm. The density of the nicotinic acid sevelamer was tested by a DH-300 density meter of DAHO company, and the density of the prepared nicotinic acid sevelamer was 2.12 g/cm ³ . Elemental analysis was carried out, and the results were C=65.04%, N=16.6%, O=9.0%, H=11.2%.

Example 7

Preparation of basic sevelamer

First disperse 300mg of Sevelamer hydrochloride in 2700ml pure water, then prepare an aqueous solution of sodium hydroxide 0.04mg/ml, add 1000ml of sodium hydroxide solution to the aqueous solution of Sevelamer hydrochloride, and control the temperature of the mixed solution to 30° C., stirred for 45 minutes, filtered, and the filter cake was collected. The filter cake was washed 4 times with pure water, and the filter cake was collected to obtain basic sevelamer.

Example 8

Preparation of Niacin Sevelamer

The basic sevelamer prepared according to the method described in Example 7 was dispersed in pure water to prepare a solution with a concentration of 0.10 mg/ml, and 750 ml of niacin at 1 mg/ml was added to 5000 ml of the solution, and Stir at 20°C for 12 hours. After the reaction, filter the reaction product, wash the filtered filter cake with pure water 4 times, collect the filter cake, and obtain sevelamer nicotinic acid with a specific gravity of 2.22.

Example 9

Preparation of basic sevelamer

First 400mg of Sevelamer hydrochloride is dispersed in 6000ml of pure water, then prepare the aqueous solution of sodium hydroxide 0.04mg/ml, add the sodium hydroxide solution of 1250ml in the aqueous solution of Sevelamer hydrochloride, the mixed solution temperature is controlled to 25° C., stirred for 1 hour, filtered, and the filter cake was collected. The filter cake was washed 4 times with pure water, and the filter cake was collected to obtain basic sevelamer.

Example 10

Preparation of Niacin Sevelamer

The basic sevelamer prepared according to the method described in Example 9 was dispersed in pure water to prepare a solution with a concentration of 0.15 mg/ml, and 750 ml of niacin at 1 mg/ml was added to 5000 ml of the solution. Stir at 40°C for 10 hours. After the reaction, filter the reaction product and wash the filtered filter cake with pure water 5 times. Collect the filter cake. After inspection, sevelamer nicotinate is obtained with a specific gravity of 2.50.

Example 11

Pharmacological Experiment of Niacin Sevelamer in Lowering Serum Phosphorus

Materials and Methods

1. Animal selection and feeding: 8-week-old male clean-grade SD rats, weighing 190-200 g, were used, and each 3 rats were raised in a cage. Natural light, about 55% relative humidity, free diet, specially prepared high-phosphorus (containing 1.20% by mass percentage of P, 1.6% by mass of Ca, VitD3 1000U/kg) rat feed. The food intake and body weight of the rats were measured once a week.

2. Animal model making and grouping: Animals were randomly divided into 4 groups (6 for each): sham operation group, chronic renal failure group, sevelamer hydrochloride (purchased from Wuhan Meitang Pharmaceutical Co., Ltd.) group (100mg/kg ), the nicotinic acid sevelamer group (50mg/kg) prepared in Example 4, the latter two groups of test substances sevelamer hydrochloride and nicotinic acid sevelamer were added to the feed respectively. The rat model of chronic renal failure was established by classical subtotal nephrectomy. In the sham operation group, only the renal capsule was peeled off. Before modeling, each group was fed with commercially available normal rat feed containing (0.9% by mass percentage of P, 1.42% by mass of Ca), and high-phosphorus feed was given after modeling. Blood was collected from the orbits of the rats at 2 and 7 days after the second operation; blood was collected from the orbits of the rats after 24 hours of urine was collected on the 14th day.

3. Biochemical indicators: Serum calcium (SCa), serum phosphorus (SP), serum creatinine (SCr), urine phosphorus and urine creatinine were measured with Hitachi automatic biochemical analyzer. Fractional phosphorus excretion (FEp) was calculated by the standard formula (urine P×SCr)/(SP×urine Cr). Serum parathyroid hormone (iPTH) was determined by chemiluminescent enzyme immunoassay (IMMULITE instrument).

result

1. Changes in blood phosphorus, calcium, and calcium-phosphorus product (see Tables 1 and 2): During the experiment, blood phosphorus in the sham operation group was consistently lower than that in the chronic renal failure group; It was lower than that of the chronic renal failure group on the 2nd day after operation, and there was a significant difference on the 7th and 14th day (P<0.05). P<0.05). There was no significant difference in serum calcium among the groups. The calcium and phosphorus products of the sevelamer hydrochloride group and the nicotinic acid sevelamer group were significantly lower than those of the chronic renal failure group on the 7th and 14th day, and the nicotinic acid sevelamer group was lower than that of the sevelamer hydrochloride group on the 7th and 14th day. Significant difference (P<0.05).

Table 1 Changes of blood phosphorus in each group (mmol/L)

mock surgical group Chronic renal failure group Sevelamer hydrochloride group Niacin Sevelamer Group 2d 2.91±0.22 4.21±0.31 3.89±0.29 3.76±0.34 7d 3.01±0.28 4.26±0.38 3.23±0.26 3.01±0.16 14d 2.89±0.23 4.33±0.34 3.12±0.29 2.97±0.18

Table 2 Changes of calcium and phosphorus products in each group (mmol ² /L ² )

Chronic renal failure group Sevelamer hydrochloride group Niacin Sevelamer Group 2d 12.04±1.34 11.03±1.01 10.96±1.23 7d 11.98±1.41 9.88±0.99 9.08±0.91 14d 12.01±1.38 8.93±0.89 8.34±0.78

2. Phosphorus excretion fraction (see Table 3): the chronic renal failure group was significantly higher than the sham operation group, the sevelamer hydrochloride group, and the nicotinic acid sevelamer group; the nicotinic acid sevelamer group was lower than the sevelamer hydrochloride group Mu group had significant difference (P<0.05).

Table 3 Phosphorus excretion fraction changes in each group (%, X±S)

mock surgical group Chronic renal failure group Sevelamer hydrochloride group Niacin Sevelamer Group 14d 20.63±5.70 37.98±4.58 22.36±5.42 20.68±4.01

3. Serum parathyroid hormone (see Table 4): the chronic renal failure group was significantly higher than that of the sham operation group, the sevelamer hydrochloride group, and the nicotinic acid sevelamer group, but the sevelamer hydrochloride group, the nicotinic acid sevelamer group There was no significant difference between the Vilamer group and the sham group.

Table 4 Changes of serum parathyroid hormone in each group (pg/ml)

mock surgical group Chronic renal failure group Sevelamer hydrochloride group Niacin Sevelamer Group 2d 33.58±3.85 68.21±6.45 30.19±3.23 29.89±3.07 7d 34.01±3.72 68.46±6.18 29.97±3.42 28.94±3.21 14d 33.78±3.21 68.18±6.29 29.76±3.37 28.56±3.17

Conclusion: It can be seen that the sevelamer niacin in the present invention has almost the same effect on treating hyperphosphatemia as that of sevelamer hydrochloride when the dosage is half that of sevelamer hydrochloride.

Example 12

Pharmacological Test of Niacin Sevelamer in Lowering Blood Lipid

For the body weight of nutritionally obese rats, establish a high-fat feed feeding "nutritive Obesity Rat Model", observe that Sevelamer hydrochloride (purchased from Wuhan Meitang Pharmaceutical Co., Ltd.) and Sevelamer nicotinate (from the same source as in Example 11) with different ratios and different dosages have a greater effect on the nutritional obesity model. Effects of total cholesterol in serum, total triglyceride in serum, low-density lipoprotein, high-density lipoprotein (TC, TG, LDL-c, HDL-c) in mice.

experimental drug

Sevelamer hydrochloride group: dosage 100mg/kg

Nicotinic acid sevelamer group: dosage 50mg/kg

Normal control group: the group fed with conventional feed

Positive control drug: orlistat (Roche); 120 mg/tablet; dosage: 36 mg/kg.

Experimental animal: same as embodiment 11

Experimental method: the rats were randomly divided into two groups, the first group of 10 rats was the conventional diet group; the other group of 110 rats was the model group. After being fed with nutritious feed for 12 weeks, the model rats were randomly divided into 10 groups and given different test drugs, 10 in each group, namely: (1) model control group; (2) orlistat positive control group; 3) Sevelamer hydrochloride group alone (100mg/kg); (4) Sevelamer nicotinic acid group alone (50mg/kg); the normal group and the model group were given distilled water at 5mL/kg·d, and the positive control drug 5 mL/kg·d and 10 mL/kg·d drug suspensions were administered into the stomach, respectively, for 12 weeks, and the indicators were determined.

Determination of serum TC, TG, LDL-C and HDL-C: all adopt enzymatic method. The kit is a product of Shanghai Biochemical Pharmaceutical Factory No. 1 Branch.

Experimental results: see Table 5 below.

Table 5 Effects of different drugs on total cholesterol in serum, total triglyceride in serum, low-density lipoprotein, high-density lipoprotein (TC, TG, LDL-c, HDL-c)

Conclusion: It can be seen that the Sevelamer niacin in the present invention has almost the same effect of treating hyperlipidemia as Sevelamer Hydrochloride at half the dosage of Sevelamer Hydrochloride. The nicotinic acid sevelamer prepared by the method of invention embodiment 8 and embodiment 10 can also obtain the above pharmaceutical effects: that is: in the case of taking half of the dose of sevelamer hydrochloride, the same amount as that of sevelamer hydrochloride is obtained. Almost equivalent to the effect of treating hyperlipidemia.

Claims (17)

1. A nicotinic acid sevelamer, which has the following structural formula I: Wherein, in the structural formula I, (a+b):c is 45:1 to 2:1, m represents a non-zero or negative integer, each x independently represents 0 or 1, and each x is not 0 at the same time ;and The specific gravity of the nicotinic acid sevelamer is 2.00-2.50. 2. The nicotinic acid sevelamer according to claim 1, wherein the specific gravity of the nicotinic acid sevelamer is 2.10-2.25. 3. The nicotinic acid sevelamer according to claim 1 or 2, wherein the specific gravity of the nicotinic acid sevelamer is 2.15-2.20. 4. The nicotinic acid sevelamer according to claim 1, wherein (a+b):c is 20:1 to 4:1. 5. The nicotinic acid sevelamer according to claim 1, wherein the nicotinic acid sevelamer accounting for more than 90% by volume is particles with a particle diameter of less than 400 μm. 6. The nicotinic acid sevelamer according to claim 1, wherein the nicotinic acid sevelamer which accounts for more than 90% by volume is particles with a particle diameter of less than 300 μm. 7. A method for preparing sevelamer niacin described in any one of claims 1-6, the method comprising the following steps: a) making Sevelamer hydrochloride react with an alkali to obtain basic Sevelamer; b) reacting the basic sevelamer with niacin to obtain niacin sevelamer. 8. The method according to claim 7, wherein, in the step a), the aqueous dispersion of the sevelamer hydrochloride and the aqueous solution of the alkali are mixed, and stirred at 25-35°C for 30 Minutes - 1 hour for reaction. 9. The method of claim 8, wherein the base is NaOH. 10. The method according to claim 7 or 8, wherein, in said step a), the reaction product obtained by the reaction of said sevelamer hydrochloride and said alkali is filtered, washed with water, and collected, Obtain the basic sevelamer. 11. method according to claim 7, wherein, described step b) comprises the following steps: d) dispersing the alkaline sevelamer in water to obtain an aqueous dispersion of alkaline sevelamer; e) making the nicotinic acid aqueous solution; f) mixing the aqueous solution of nicotinic acid and the aqueous dispersion of alkaline sevelamer, and stirring at 20-40°C for 8-12 hours to react to obtain a reaction product; g) The reaction product obtained in step f) is filtered, washed with water, and collected to obtain the sevelamer nicotinate. 12. The method of claim 11, wherein said step d) precedes or follows said step e). 13. The method according to claim 8, wherein, the concentration of the aqueous dispersion of the described sevelamer hydrochloride is 0.06-0.20mg/ml, and the aqueous solution of the alkali is that the concentration is 0.04mg/ml Aqueous sodium hydroxide solution. 14. The method according to claim 9, wherein the mass ratio of the Sevelamer Hydrochloride to the NaOH is 4:1 to 8:1. 15. The method according to claim 7, wherein, in the step b), the mass ratio of the basic sevelamer to the niacin is 1:1 to 1:1.5. 16. Use of the nicotinic acid sevelamer described in any one of claims 1-6 in the preparation of a medicament for treating and/or preventing hyperphosphatemia. 17. Use of the nicotinic acid sevelamer according to any one of claims 1-6 in the preparation of a medicament for lowering blood lipid.