Telmisartan pharmaceutical composition and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations for treating cardiovascular system diseases, and relates to a telmisartan pharmaceutical composition and a preparation method thereof. The telmisartan pharmaceutical composition disclosed by the invention is prepared from telmisartan, phospholipid, cholesterol, creatinine and carboxymethyl chitosan and is prepared by adopting a film dispersion method. The liposome material is optimized, in the hydration process, a liposome film interacts with creatinine and carboxymethyl chitosan dissolved in a buffer solution, a more stable liposome structure is formed, the stability of the liposome is enhanced, and the drug loading capacity and the encapsulation efficiency of the liposome are improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations for treating cardiovascular diseases, and particularly relates to a telmisartan pharmaceutical composition and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Hypertension is one of the most common chronic diseases in the world. Long-term hypertension not only increases the risk of heart disease, stroke, kidney disease and other diseases, but also significantly affects the quality of life of patients. In order to control the occurrence and development of hypertension, many antihypertensive drugs are widely used in clinical treatment. Among them, angiotensin II receptor antagonists have become one of the commonly used drugs for the treatment of hypertension due to their good antihypertensive effect, low side effects and good tolerance.

[0004] Telmisartan is a new type of angiotensin II receptor antagonist, which is widely used in the treatment of hypertension. Telmisartan inhibits the action of angiotensin II by binding to angiotensin II receptors, reduces the resistance of peripheral blood vessels, and thus achieves the effect of lowering blood pressure. Telmisartan has shown good antihypertensive effect in clinical practice and has fewer side effects. However, telmisartan has many defects due to its poor water solubility. (1) The poor water solubility of telmisartan will lead to its slow dissolution rate in the gastrointestinal tract, thereby reducing the amount of drug entering the blood circulation, which ultimately manifests as low bioavailability. (2) Poor water solubility may slow the dissolution and absorption process of telmisartan in the body, resulting in a slower onset of action. This means that patients may need longer to experience the effects of the drug, especially in cases where blood pressure control is urgently needed. (3) Due to the poor solubility of telmisartan, the degree of drug absorption may vary greatly among different individuals, which will lead to unstable drug efficacy. Some patients may have incomplete absorption, resulting in too low drug concentration in the body and unsatisfactory treatment effects. (4) Although studies have shown that telmisartan can remain relatively stable under certain conditions, in a high temperature and high humidity environment, telmisartan may undergo changes such as crystallization and degradation, affecting the quality and efficacy of the drug.

[0005] Chinese patent publication number CN102133189A discloses a telmisartan liposome solid preparation. Telmisartan, dipalmitoylphosphatidylcholine, octadecylamine, sodium taurocholate and poloxamer 188 are first prepared into liposomes, and then conventional excipients for preparing solid preparations in medicine are added and mixed to obtain the telmisartan liposome solid preparation.

[0006] The Chinese patent with publication number CN106822122A discloses a telmisartan solid lipid nanoparticle, wherein telmisartan, lecithin and sodium cholate are added to ethanol, heated to 60°C, stirred and dissolved as an organic phase; poloxamer and polyethylene glycol are added to purified water, preheated to 60°C, stirred and dissolved as an aqueous phase. The preheated aqueous phase is added to a high-pressure homogenizer, stirring is turned on and the preheated organic phase is slowly injected into the aqueous phase under high-speed stirring to form colostrum, and then high-pressure emulsification is homogenized for 2 hours, and ethanol is removed under reduced pressure to obtain a telmisartan liposome solution. However, the encapsulation efficiency is low, between 48% and 73%, which may lead to insufficient drug release, poor drug stability, increased drug dosage or frequency, and increased patient burden.

[0007] Therefore, the present invention is committed to developing a new telmisartan liposome composition and preparation to meet the clinical needs of patients with hypertension, which has important significance and broad market prospects. Summary of the invention

[0008] In order to overcome the deficiencies of the prior art, the present invention designs an innovative liposome material and provides a telmisartan pharmaceutical composition and preparation thereof with high drug loading and high encapsulation rate.

[0009] Specifically, the plan is as follows:

[0010] The telmisartan pharmaceutical composition of the present invention consists of telmisartan, phospholipid, cholesterol, creatinine and carboxymethyl chitosan; the weight ratio of the telmisartan, phospholipid, cholesterol, creatinine and carboxymethyl chitosan is 15:15-25:5-15:0.5-2:2-5; the phospholipid is egg yolk phospholipid and / or soybean phospholipid.

[0011] The preparation method of the telmisartan pharmaceutical composition of the present invention is:

[0012] (1) dissolving telmisartan, phospholipids and cholesterol in an organic solvent, and performing vacuum rotary evaporation in a water bath at 35°C±5°C to obtain a liposome film;

[0013] (2) Dissolve creatinine and carboxymethyl chitosan in a buffer solution, add the solution to the liposome film for hydration, and perform vacuum rotary evaporation in a water bath at 40°C ± 5°C, and homogenize under high pressure to obtain the liposome film.

[0014] Furthermore, the organic solvent is a mixed solvent of chloroform and methanol or a mixed solvent of chloroform and ethanol. Preferably, the organic solvent is a mixed solvent of chloroform and methanol in a volume ratio of 2 to 4:1 or a mixed solvent of chloroform and ethanol in a volume ratio of 2 to 4:1; the buffer solution is selected from one of a phosphate buffer solution, a citrate buffer solution, and a carbonate buffer solution; the pH of the buffer solution is 5.2 to 6.2.

[0015] The present invention also provides a preparation consisting of the telmisartan pharmaceutical composition and auxiliary materials.

[0016] Compared with the prior art, the technical effects of the present invention are:

[0017] The present invention optimizes the liposome material, adds a certain proportion of creatinine and carboxymethyl chitosan to the aqueous phase liposome material, and during the hydration process, the liposome film interacts with the creatinine and carboxymethyl chitosan dissolved in the buffer solution to form a more stable liposome structure, thereby enhancing the stability of the liposome and improving the drug loading and encapsulation rate of the liposome. In addition, compared with the commercially available telmisartan preparation, the preparation prepared by the telmisartan pharmaceutical composition of the present invention has high stability and low content of related substances in the accelerated experiment. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : Drug loading and encapsulation efficiency of the telmisartan pharmaceutical compositions of Examples 1 to 5 and Comparative Examples 1 to 4.

[0019] Figure 2 : The change diagram of impurity I content in Telmisartan tablets of Examples 6 to 8 and commercially available Telmisartan tablets in the accelerated test. DETAILED DESCRIPTION

[0020] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0021] Example 1 Telmisartan pharmaceutical composition

[0022] formula:

[0023]

[0024]

[0025] Preparation method:

[0026] (1) Telmisartan, phospholipids and cholesterol were dissolved in 150 ml of a mixed solvent of chloroform and methanol in a volume ratio of 3:1, and the mixture was subjected to vacuum rotary evaporation in a water bath at 35° C. to obtain a liposome film;

[0027] (2) Dissolve creatinine and carboxymethyl chitosan in 100 ml of pH 5.8 phosphate buffer solution, add the solution to the liposome film for hydration, and perform vacuum rotary evaporation in a 40° C. water bath for 10 min. High pressure homogenization (pressure 1500 bar, 5 passes, flow rate 25 ml / min, temperature 35° C.) to obtain the liposome film.

[0028] Example 2 Telmisartan pharmaceutical composition

[0029] formula:

[0030]

[0031] Preparation method:

[0032] (1) Telmisartan, phospholipids and cholesterol were dissolved in 150 ml of a mixed solvent of chloroform and methanol in a volume ratio of 2:1, and vacuum evaporated in a water bath at 35° C. to obtain a liposome film;

[0033] (2) Dissolve creatinine and carboxymethyl chitosan in 100 ml of pH 5.6 citrate buffer solution, add the solution to the liposome film for hydration, evaporate under reduced pressure in a 40° C. water bath for 10 min, and homogenize under high pressure (pressure 1500 bar, 5 passes, flow rate 25 ml / min, temperature 35° C.) to obtain the product.

[0034] Example 3 Telmisartan pharmaceutical composition

[0035] formula:

[0036]

[0037]

[0038] Preparation method:

[0039] (1) Telmisartan, phospholipids and cholesterol were dissolved in 150 ml of a mixed solvent of chloroform and methanol in a volume ratio of 4:1, and the mixture was subjected to vacuum rotary evaporation in a water bath at 35° C. to obtain a liposome film;

[0040] (2) Dissolve creatinine and carboxymethyl chitosan in 100 ml of pH 6.0 citrate buffer solution, add the solution to the liposome film for hydration, evaporate under reduced pressure in a 40° C. water bath for 10 min, and homogenize under high pressure (pressure 1500 bar, 5 passes, flow rate 25 ml / min, temperature 35° C.) to obtain the product.

[0041] Example 4 Telmisartan pharmaceutical composition

[0042] formula:

[0043]

[0044] Preparation method:

[0045] (1) dissolving telmisartan, phospholipids and cholesterol in 100 ml of a mixed solvent of chloroform and ethanol in a volume ratio of 2:1, and performing vacuum rotary evaporation in a 30° C. water bath to obtain a liposome film;

[0046] (2) Dissolve creatinine and carboxymethyl chitosan in 80 ml of pH 5.2 citrate buffer solution, add the solution to the liposome film for hydration, and perform vacuum rotary evaporation in a 35° C. water bath for 5 min. Perform high pressure homogenization (pressure 1500 bar, 5 passes, flow rate 25 ml / min, temperature 35° C.) to obtain the liposome film.

[0047] Example 5 Telmisartan pharmaceutical composition

[0048] formula:

[0049]

[0050]

[0051] Preparation method:

[0052] (1) dissolving telmisartan, phospholipids and cholesterol in 200 ml of a mixed solvent of chloroform and ethanol in a volume ratio of 4:1, and performing vacuum rotary evaporation in a 40° C. water bath to obtain a liposome film;

[0053] (2) Dissolve creatinine and carboxymethyl chitosan in 120 ml of carbonate buffer solution with a pH of 6.2, add the solution to the liposome film for hydration, evaporate under reduced pressure in a water bath at 45° C. for 12 min, and homogenize under high pressure (pressure 1500 bar, 5 passes, flow rate 25 ml / min, temperature 35° C.) to obtain the liposome film.

[0054] Comparative Example 1 Telmisartan Pharmaceutical Composition

[0055] formula:

[0056]

[0057] Preparation method:

[0058] (1) Telmisartan, phospholipids and cholesterol were dissolved in 150 ml of a mixed solvent of chloroform and methanol in a volume ratio of 3:1, and the mixture was subjected to vacuum rotary evaporation in a 35° C. water bath to obtain a liposome film;

[0059] (2) Dissolve carboxymethyl chitosan in 100 ml of pH 5.8 phosphate buffer solution, add it to the liposome film for hydration, and evaporate it in a water bath at 40° C. for 10 min under reduced pressure. High-pressure homogenization (pressure 1500 bar, number of passes 5 times, flow rate 25 ml / min, temperature 35° C.) is performed.

[0060] Comparative Example 2 Telmisartan Pharmaceutical Composition

[0061] formula:

[0062]

[0063]

[0064] Preparation method:

[0065] (1) Telmisartan, phospholipids and cholesterol were dissolved in 150 ml of a mixed solvent of chloroform and methanol in a volume ratio of 3:1, and the mixture was subjected to vacuum rotary evaporation in a 35° C. water bath to obtain a liposome film;

[0066] (2) Dissolve creatinine in 100 ml of pH 5.8 phosphate buffer solution, add it to the liposome film for hydration, and evaporate it in a 40°C water bath under reduced pressure for 10 min. High-pressure homogenization (pressure 1500 bar, 5 passes, flow rate 25 ml / min, temperature 35°C) is performed to obtain the liposome film.

[0067] Comparative Example 3 Telmisartan Pharmaceutical Composition

[0068] formula:

[0069]

[0070] Preparation method:

[0071] (1) Telmisartan, phospholipids and cholesterol were dissolved in 150 ml of a mixed solvent of chloroform and methanol in a volume ratio of 3:1, and the mixture was subjected to vacuum rotary evaporation in a 35° C. water bath to obtain a liposome film;

[0072] (2) Dissolve creatinine and poloxamer 188 in 100 ml of pH 5.8 phosphate buffer solution, add the solution to the liposome film for hydration, and perform vacuum rotary evaporation in a 40° C. water bath for 10 min. High pressure homogenization (pressure 1500 bar, 5 passes, flow rate 25 ml / min, temperature 35° C.) to obtain the liposome film.

[0073] Comparative Example 4 Telmisartan Pharmaceutical Composition

[0074] formula:

[0075]

[0076]

[0077] Preparation method:

[0078] (1) Telmisartan, phospholipids and cholesterol were dissolved in 150 ml of a mixed solvent of chloroform and methanol in a volume ratio of 3:1, and the mixture was subjected to vacuum rotary evaporation in a 35° C. water bath to obtain a liposome film;

[0079] (2) Dissolve creatinine and carboxymethyl chitosan in 100 ml of pH 5.8 phosphate buffer solution, add the solution to the liposome film for hydration, and perform vacuum rotary evaporation in a 40° C. water bath for 10 min. High pressure homogenization (pressure 1500 bar, 5 passes, flow rate 25 ml / min, temperature 35° C.) to obtain the liposome film.

[0080] Example 6 Telmisartan Tablets (100 tablets)

[0081] formula:

[0082] Mass(g) Example 1 Telmisartan pharmaceutical composition 20.6 starch 20 Microcrystalline Cellulose 8 Sodium starch glycolate 4 Magnesium Stearate 0.5

[0083] Preparation method: wet granulation tableting method.

[0084] Example 7 Telmisartan Tablets (100 tablets)

[0085] formula:

[0086] Mass(g) Example 2 Telmisartan pharmaceutical composition 21.5 starch 18 dextrin 8 Mannitol 5 Low substituted Hydroxypropyl Methylcellulose 3 Micro powder silica gel 0.3

[0087] Preparation method: wet granulation tableting method.

[0088] Example 8 Telmisartan Tablets (100 tablets)

[0089] formula:

[0090] Mass(g) Example 3 Telmisartan pharmaceutical composition 22.4 starch 22 lactose 5 Crospovidone 2 talcum powder 1

[0091] Preparation method: wet granulation tableting method.

[0092] Quality evaluation of telmisartan pharmaceutical composition

[0093] The drug loading and encapsulation efficiency of liposomes are important indicators for measuring the quality of liposome preparations. The drug loading refers to the amount of drug loaded in the liposomes; the encapsulation efficiency refers to the proportion of the drug encapsulated in the liposomes to the total amount of the drug input. The drug loading and encapsulation efficiency of the telmisartan pharmaceutical compositions of Examples 1 to 5 and the telmisartan pharmaceutical compositions of Comparative Examples 1 to 4 were determined by high performance liquid chromatography and microcolumn centrifugation.

[0094] Figure 1The drug loading and encapsulation efficiency of the telmisartan pharmaceutical compositions of Examples 1 to 5 and the telmisartan pharmaceutical compositions of Comparative Examples 1 to 4 are shown. The data show that the telmisartan pharmaceutical compositions of Examples 1 to 5 of the present invention have higher drug loading and encapsulation efficiency. A higher drug loading means that more telmisartan can be carried in a unit volume or mass of liposomes, thereby improving the therapeutic effect of telmisartan, reducing the number of drug administrations for patients, and more effectively utilizing drugs to reduce drug waste. A higher encapsulation efficiency means that telmisartan can be effectively wrapped inside, reducing the contact of telmisartan with the external environment, thereby improving stability.

[0095] Accelerated test to verify the stability of telmisartan preparations

[0096] Telmisartan tablets of Examples 6 to 8 were packaged as sold in the market and placed together with commercially available telmisartan tablets (National Medicine Standard No. J20180016) at a temperature of 40±2°C and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the first, second, third and sixth months of the test period to inspect related substances.

[0097] The relevant substances were determined by high performance liquid chromatography according to the 2020 edition of the Chinese Pharmacopoeia. Test solution: Take an appropriate amount of this product, add an appropriate amount of methanol and 100μl of 1mol / L sodium hydroxide solution to dissolve it, and dilute it with methanol to make a solution containing about 0.5mg per 1ml. Control solution: Accurately measure 1ml of the test solution, place it in a 100ml volumetric flask, dilute it to the scale with methanol, and shake well. System suitability solution: Take an appropriate amount of telmisartan and impurity I reference substance, dissolve them in methanol and dilute them to make a mixed solution containing about 10μg of each per 1ml. Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; methanol was used as mobile phase A, 0.1% potassium dihydrogen phosphate solution-methanol (35:65, containing 0.2% triethylamine, pH adjusted to 5.0 with phosphoric acid) was used as mobile phase B, and gradient elution was performed according to the table below; the detection wavelength was 230 nm; the flow rate was 1.0 ml per minute (the flow rate was adjusted if necessary); the injection volume of the system suitability solution was 10 μl, and the injection volume of other solutions was 20 μl.

[0098] Table 1 Gradient elution program

[0099]

[0100] System suitability requirements: In the system suitability solution chromatogram, the retention time of the telmisartan peak is 17-20 minutes; the tailing factor should be no greater than 2.0; the separation between the telmisartan peak and the impurity I peak should meet the requirements. Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0101] Figure 2The graph is a change chart of the impurity I content of the telmisartan tablets of Examples 6 to 8 and commercially available telmisartan tablets in an accelerated test, which shows that the telmisartan tablets of Examples 6 to 8 of the present invention have low impurity content and high stability.

Claims

1. A telmisartan pharmaceutical composition, characterized in that: The telmisartan medicinal composition consists of telmisartan, phospholipid, cholesterol, creatinine and carboxymethyl chitosan.

2. The telmisartan pharmaceutical composition according to claim 1, characterized in that: The phospholipids are egg yolk phospholipids and / or soybean phospholipids. Preferably, the phospholipids are egg yolk phospholipids and soybean phospholipids.

3. The telmisartan pharmaceutical composition according to claim 1, characterized in that: The weight ratio of telmisartan, phospholipid, cholesterol, creatinine and carboxymethyl chitosan is 15:15-25:5-15:0.5-2:2-5.

4. The telmisartan pharmaceutical composition according to claim 1, characterized in that: The weight ratio of telmisartan, phospholipid, cholesterol, creatinine and carboxymethyl chitosan is 15:20:10:1:

4.

5. A method for preparing the telmisartan pharmaceutical composition according to claim 1, characterized in that: The preparation method is: (1) dissolving telmisartan, phospholipids and cholesterol in an organic solvent, and performing vacuum rotary evaporation in a water bath at 35°C±5°C to obtain a liposome film; (2) Dissolve creatinine and carboxymethyl chitosan in a buffer solution, add the solution to the liposome film for hydration, and perform vacuum rotary evaporation in a water bath at 40°C ± 5°C, and homogenize under high pressure to obtain the liposome film.

6. The preparation method according to claim 5, characterized in that: The organic solvent is a mixed solvent of chloroform and methanol or a mixed solvent of chloroform and ethanol.

7. The preparation method according to claim 5, characterized in that: The organic solvent is a mixed solvent of chloroform and methanol in a volume ratio of 2 to 4:1 or a mixed solvent of chloroform and ethanol in a volume ratio of 2 to 4:1; preferably, the organic solvent is a mixed solvent of chloroform and methanol in a volume ratio of 3:

1.

8. The preparation method according to claim 5, characterized in that: The buffer solution is selected from one of a phosphate buffer solution, a citrate buffer solution and a carbonate buffer solution. Preferably, the buffer solution is a phosphate buffer solution.

9. The preparation method according to claim 5, characterized in that: The pH of the buffer solution is 5.2-6.2, and preferably, the pH of the buffer solution is 5.

8.

10. A preparation, characterized in that The preparation consists of the telmisartan pharmaceutical composition according to claim 1 and excipients.

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