CN119818489A - Telmisartan pharmaceutical composition and preparation method thereof - Google Patents
Telmisartan pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN119818489A CN119818489A CN202510049721.XA CN202510049721A CN119818489A CN 119818489 A CN119818489 A CN 119818489A CN 202510049721 A CN202510049721 A CN 202510049721A CN 119818489 A CN119818489 A CN 119818489A
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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 provided by the invention consists of telmisartan, phospholipid, cholesterol, creatinine and carboxymethyl chitosan, and is prepared by a film dispersion method. The liposome material is optimized, and in the hydration process, the liposome film interacts with creatinine and carboxymethyl chitosan dissolved in the buffer solution to form a more stable liposome structure, so that the stability of the liposome is enhanced, and the drug loading rate and encapsulation rate of the liposome are improved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations for treating cardiovascular system diseases, and particularly relates to a telmisartan pharmaceutical composition and a preparation method thereof.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Hypertension is one of the chronic diseases which are commonly present in the world, and long-term hypertension not only increases the risk of heart disease, stroke, kidney disease and other diseases, but also can significantly affect 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, wherein angiotensin II receptor antagonists are one of the common drugs for treating hypertension due to their good antihypertensive effect, lower side effects and better tolerability.
Telmisartan is a novel angiotensin II receptor antagonist and is widely used in the treatment of hypertension. Telmisartan is combined with an angiotensin II receptor to inhibit the action of angiotensin II and reduce the resistance of peripheral blood vessels, so that the effect of reducing blood pressure is achieved. Telmisartan has a clinically good antihypertensive effect and has fewer side effects. However, telmisartan has various drawbacks due to its poor water solubility. (1) Poor water solubility of telmisartan results in slow dissolution in the gastrointestinal tract, resulting in reduced amounts of drug entering the blood circulation, which ultimately manifest as low bioavailability. (2) Poor water solubility may slow the dissolution and absorption of losartan in the body, resulting in a slower onset of action. This means that the patient may take longer to experience the effect of the drug, especially in situations where control of blood pressure is urgently needed. (3) Due to the poor solubility of losartan, there may be a large difference in the degree of absorption of the drug among individuals, which may lead to instability in the therapeutic effect of the drug. Some patients may have poor therapeutic effects due to insufficient absorption, resulting in too low in-vivo drug concentrations. (4) Although research shows that telmisartan can be kept relatively stable under certain conditions, telmisartan can be crystallized, degraded and the like under high-temperature and high-humidity environments, and the quality and the curative effect of the medicine are affected.
The Chinese patent with publication number CN102133189A discloses a telmisartan liposome solid preparation, which is prepared by firstly preparing telmisartan, dipalmitoyl phosphatidylcholine, octadecylamine, sodium taurocholate and poloxamer 188 into a liposome, adding conventional excipients for preparing the solid preparation in pharmacy, and mixing.
Chinese patent publication No. CN106822122a discloses a telmisartan solid lipid nanoparticle, which is prepared by adding telmisartan, lecithin, sodium cholate into ethanol, heating to 60 ℃, stirring to dissolve, as an organic phase, adding poloxamer and polyethylene glycol into purified water, preheating to 60 ℃, stirring to dissolve, and as a water phase. Adding the preheated aqueous phase into a high-pressure emulsion homogenizer, starting stirring, slowly injecting the preheated organic phase into the aqueous phase under high-speed stirring to form colostrum, emulsifying and homogenizing for 2 hours under high pressure, and evaporating ethanol under reduced pressure to obtain telmisartan liposome solution. However, the encapsulation efficiency is low, and the problems of insufficient drug release, poor drug stability, increased drug dosage or frequency, increased patient burden and the like can be caused between 48% and 73%.
Therefore, the invention aims at developing a novel telmisartan liposome composition and preparation to meet the clinical requirements of patients with hypertension, and has important significance and broad market prospect.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention designs and innovates liposome materials, and provides a telmisartan pharmaceutical composition with high drug loading and high encapsulation efficiency and a preparation thereof.
Specifically, the scheme is as follows:
The telmisartan pharmaceutical composition comprises telmisartan, phospholipid, cholesterol, creatinine and carboxymethyl chitosan, wherein the weight ratio of the telmisartan to the phospholipid to the cholesterol to the creatinine to the carboxymethyl chitosan is 15:15-25:5-15:0.5-2:2-5, and the phospholipid is egg yolk phospholipid or/and soybean phospholipid.
The preparation method of the telmisartan pharmaceutical composition comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in an organic solvent, and performing reduced pressure rotary evaporation in a water bath at 35 ℃ plus or minus 5 ℃ to obtain a liposome film;
(2) Dissolving creatinine and carboxymethyl chitosan in buffer solution, adding into liposome film for hydration, steaming in water bath at 40+ -5deg.C under reduced pressure, and homogenizing under high pressure.
Further, 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 with a volume ratio of 2-4:1 or a mixed solvent of chloroform and ethanol with a volume ratio of 2-4:1, the buffer solution is one selected from a phosphate buffer solution, a citrate buffer solution and a carbonate buffer solution, and the pH=5.2-6.2 of the buffer solution.
The invention also provides a preparation consisting of the telmisartan pharmaceutical composition and auxiliary materials.
Compared with the prior art, the invention has the technical effects that:
According to the invention, liposome materials are optimized, a certain proportion of creatinine and carboxymethyl chitosan are added into aqueous-phase liposome materials, and in the hydration process, a liposome film interacts with creatinine and carboxymethyl chitosan dissolved in a buffer solution to form a more stable liposome structure, so that the stability of the liposome is enhanced, and the drug loading rate and encapsulation rate of the liposome are improved. In addition, compared with the telmisartan preparation on the market, the preparation prepared by using the telmisartan pharmaceutical composition has high stability and low content of related substances in an acceleration experiment.
Drawings
Fig. 1 shows the drug loading and encapsulation rates of the telmisartan pharmaceutical compositions of examples 1 to 5 and the telmisartan pharmaceutical compositions of comparative examples 1 to 4.
Fig. 2 shows the change of impurity I content of telmisartan tablets of examples 6 to 8 in an acceleration test.
Detailed Description
The present invention will be further described with reference to examples for the purpose of making the objects and technical aspects of the present invention more apparent, but the scope of the present invention is not limited to these examples, which are only for explaining the present invention. It will be understood by those skilled in the art that variations or equivalent substitutions that do not depart from the spirit of the invention are intended to be included within the scope of the invention.
Example 1 telmisartan pharmaceutical composition
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in 150ml of mixed solvent of chloroform and methanol with the volume ratio of 3:1, and performing reduced pressure rotary evaporation in a water bath at 35 ℃ to obtain a liposome film;
(2) Dissolving creatinine and carboxymethyl chitosan in 100ml phosphate buffer solution with pH=5.8, adding into liposome film for hydration, steaming under reduced pressure in water bath at 40deg.C for 10min, and homogenizing under high pressure (1500 bar, passing times 5 times, flow rate 25ml/min, and temperature 35 deg.C).
Example 2 telmisartan pharmaceutical compositions
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in 150ml of a mixed solvent of chloroform and methanol in a volume ratio of 2:1, and performing reduced pressure rotary evaporation in a water bath at 35 ℃ to obtain a liposome film;
(2) Dissolving creatinine and carboxymethyl chitosan in 100ml buffer solution of pH=5.6 citrate, adding into liposome film for hydration, steaming under reduced pressure in water bath at 40deg.C for 10min, homogenizing under high pressure (1500 bar, passing times 5 times, flow rate 25ml/min, and temperature 35 deg.C).
Example 3 telmisartan pharmaceutical compositions
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in 150ml of mixed solvent of chloroform and methanol with the volume ratio of 4:1, and performing reduced pressure rotary evaporation in a water bath at 35 ℃ to obtain a liposome film;
(2) Dissolving creatinine and carboxymethyl chitosan in 100ml buffer solution of pH=6.0 citrate, adding into liposome film for hydration, steaming under reduced pressure in water bath at 40deg.C for 10min, homogenizing under high pressure (1500 bar, passing times 5 times, flow rate 25ml/min, and temperature 35 deg.C).
Example 4 telmisartan pharmaceutical compositions
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in 100ml of mixed solvent of chloroform and ethanol with volume ratio of 2:1, and performing reduced pressure rotary evaporation in a water bath at 30 ℃ to obtain a liposome film;
(2) Dissolving creatinine and carboxymethyl chitosan in 80ml buffer solution of pH=5.2 citrate, adding into liposome film for hydration, steaming under reduced pressure in water bath at 35deg.C for 5min, homogenizing under high pressure (pressure 1500bar, passing times 5 times, flow rate 25ml/min, and temperature 35 deg.C).
Example 5 Telmisartan pharmaceutical composition
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in 200ml of mixed solvent of chloroform and ethanol with the volume ratio of 4:1, and performing reduced pressure rotary evaporation in a water bath at 40 ℃ to obtain a liposome film;
(2) Dissolving creatinine and carboxymethyl chitosan in 120ml of carbonate buffer solution with pH=6.2, adding into liposome film for hydration, steaming in 45 deg.C water bath under reduced pressure for 12min, and homogenizing under high pressure (1500 bar, passing times 5 times, flow rate 25ml/min, and temperature 35 deg.C).
Comparative example 1 telmisartan pharmaceutical composition
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in 150ml of a mixed solvent of chloroform and methanol in a volume ratio of 3:1, and performing reduced pressure rotary evaporation in a water bath at 35 ℃ to obtain a liposome film;
(2) Dissolving carboxymethyl chitosan in 100ml phosphate buffer solution with pH=5.8, adding into liposome film for hydration, steaming under reduced pressure in water bath at 40deg.C for 10min, homogenizing under high pressure (1500 bar, passing times 5 times, flow rate 25ml/min, and temperature 35 deg.C).
Comparative example 2 telmisartan pharmaceutical composition
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in 150ml of a mixed solvent of chloroform and methanol in a volume ratio of 3:1, and performing reduced pressure rotary evaporation in a water bath at 35 ℃ to obtain a liposome film;
(2) Dissolving creatinine in 100ml phosphate buffer solution with pH=5.8, adding into liposome film for hydration, steaming under reduced pressure in water bath at 40deg.C for 10min, homogenizing under high pressure (1500 bar, passing times of 5 times and flow rate of 25ml/min, and temperature of 35deg.C).
Comparative example 3 telmisartan pharmaceutical composition
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in 150ml of a mixed solvent of chloroform and methanol in a volume ratio of 3:1, and performing reduced pressure rotary evaporation in a water bath at 35 ℃ to obtain a liposome film;
(2) Dissolving creatinine and poloxamer 188 in 100ml phosphate buffer solution with pH=5.8, adding into liposome film for hydration, steaming under reduced pressure in water bath at 40deg.C for 10min, and homogenizing under high pressure (pressure 1500bar, passing times 5 times, flow rate 25ml/min, and temperature 35 deg.C).
Comparative example 4 telmisartan pharmaceutical composition
The formula comprises the following components:
the preparation method comprises the following steps:
(1) Dissolving telmisartan, phospholipid and cholesterol in 150ml of a mixed solvent of chloroform and methanol in a volume ratio of 3:1, and performing reduced pressure rotary evaporation in a water bath at 35 ℃ to obtain a liposome film;
(2) Dissolving creatinine and carboxymethyl chitosan in 100ml phosphate buffer solution with pH=5.8, adding into liposome film for hydration, steaming under reduced pressure in water bath at 40deg.C for 10min, and homogenizing under high pressure (1500 bar, passing times 5 times, flow rate 25ml/min, and temperature 35 deg.C).
Example 6 telmisartan tablets (100 tablets)
The formula comprises the following components:
| Quality (g) | |
| Example 1 telmisartan pharmaceutical composition | 20.6 |
| Starch | 20 |
| Microcrystalline cellulose | 8 |
| Carboxymethyl starch sodium | 4 |
| Magnesium stearate | 0.5 |
The preparation method comprises the steps of wet granulation and tabletting.
Example 7 telmisartan tablets (100 tablets)
The formula comprises the following components:
| Quality (g) | |
| Example 2 telmisartan pharmaceutical compositions | 21.5 |
| Starch | 18 |
| Dextrin | 8 |
| Mannitol (mannitol) | 5 |
| Low substituted hypromellose | 3 |
| Micro powder silica gel | 0.3 |
The preparation method comprises the steps of wet granulation and tabletting.
Example 8 telmisartan tablets (100 tablets)
The formula comprises the following components:
| Quality (g) | |
| Example 3 telmisartan pharmaceutical compositions | 22.4 |
| Starch | 22 |
| Lactose and lactose | 5 |
| Crosslinked povidone | 2 |
| Talc powder | 1 |
The preparation method comprises the steps of wet granulation and tabletting.
Telmisartan pharmaceutical composition mass evaluation
The drug loading and encapsulation efficiency of the liposome are important indexes for measuring the quality of the liposome preparation. The drug loading rate refers to the amount of the drug loaded in the liposome, and the encapsulation rate refers to the proportion of the drug encapsulated in the liposome to the total amount of the drug. And (3) measuring the drug loading and encapsulation efficiency of the telmisartan pharmaceutical compositions of examples 1-5 and the telmisartan pharmaceutical compositions of comparative examples 1-4 by adopting a high performance liquid chromatography and a microcolumn centrifugation method.
Fig. 1 shows the drug loading and encapsulation rates of telmisartan pharmaceutical compositions of examples 1 to 5 and of telmisartan pharmaceutical compositions of comparative examples 1 to 4. The data show that the telmisartan pharmaceutical composition of the embodiments 1-5 has higher drug-loading rate and encapsulation rate, and the higher drug-loading rate means that more telmisartan can be carried in the liposome with unit volume or mass, so that the treatment effect of telmisartan is improved, the administration times of patients are reduced, the drugs can be more effectively utilized, and the waste of the drugs is reduced. The higher encapsulation efficiency means that telmisartan can be effectively wrapped inside, and contact between telmisartan and the external environment is reduced, so that stability is improved.
Accelerated test to verify the stability of telmisartan formulations
Examples 6-8 telmisartan tablets were packaged on the market, and the tablets were placed at 40.+ -. 2 ℃ and 75%.+ -. 5% relative humidity for 6 months with the commercial telmisartan tablets (national drug standard J20180016), and samples were taken at the ends of 1 st month, 2 months, 3 months and 6 months, respectively, during the test, and the substances were examined.
The related substances are measured by high performance liquid chromatography according to the edition 2020 of Chinese pharmacopoeia. The sample solution is prepared by dissolving a proper amount of the sample in 100 μl of 1mol/L sodium hydroxide solution, and diluting with methanol to obtain a solution containing about 0.5mg per 1 ml. The control solution is prepared by precisely measuring 1ml of the sample solution, placing the sample solution in a 100ml measuring flask, diluting the sample solution to a scale with methanol, and shaking the sample solution uniformly. The system applicability solution is prepared by taking a proper amount of telmisartan and an impurity I reference substance respectively, adding methanol for dissolving and diluting to prepare a mixed solution containing about 10 mug of each 1 ml. The chromatographic conditions were octadecylsilane chemically bonded silica as filler, methanol 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) as mobile phase B, gradient elution according to the following table, detection wavelength of 230nm, flow rate of 1.0ml per minute (flow rate adjusted as necessary), system applicability solution injection volume of 10. Mu.l, and other solution injection volume of 20. Mu.l.
TABLE 1 gradient elution procedure
The system applicability requires that the retention time of the telmisartan peak in the system applicability solution chromatogram is 17-20 minutes, the tailing factor is not more than 2.0, and the separation degree between the telmisartan peak and the impurity I peak meets the requirement. The measuring method comprises precisely measuring the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatograms.
Fig. 2 is a graph of the impurity I content change of the telmisartan tablets of examples 6 to 8 and the commercial telmisartan tablets in an acceleration test, which shows that the telmisartan tablets of examples 6 to 8 have low impurity content and high stability.
Claims (10)
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