CN113933472B

CN113933472B - Dissolution medium for determining dissolution rate of telmisartan solid preparation and application thereof

Info

Publication number: CN113933472B
Application number: CN202010605133.7A
Authority: CN
Inventors: 李自毅; 赵寅; 李谦; 王松笛; 张晓毅; 毛善圆; 王亚军
Original assignee: Wuhan Wuyao Science & Technology Co ltd
Current assignee: Wuhan Wuyao Science & Technology Co ltd
Priority date: 2020-06-29
Filing date: 2020-06-29
Publication date: 2024-07-09
Anticipated expiration: 2040-06-29
Also published as: CN113933472A

Abstract

The invention provides a dissolution medium for determining dissolution rate of a telmisartan solid preparation and application thereof, wherein the dissolution medium comprises the following components: at least one of citric acid-phosphate buffer solution and hydrochloric acid, wherein the pH of the dissolution medium is 1.8-3.2. The dissolution medium can effectively simulate the dissolution process of the telmisartan solid preparation in gastric juice, has good dissolution effect, and has high dissolution distinction degree of the telmisartan solid preparation, and the measured dissolution degree has small batch-to-batch difference.

Description

Dissolution medium for determining dissolution rate of telmisartan solid preparation and application thereof

Technical Field

The invention relates to the field of biological medicine, in particular to a dissolution medium for measuring the dissolution rate of a telmisartan solid preparation and application thereof, and more particularly relates to a method for measuring the dissolution rate of the telmisartan solid preparation.

Background

Telmisartan (TELMISARTAN, TELM) is a highly specific non-peptide angiotensin II receptor (subtype AT 1) antagonist, has high affinity for the ATl subtype, inhibits angiotensin II by selectively binding to ATl, reduces blood pressure by lowering blood aldosterone levels, and selectively activates the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) to produce an anti-atherosclerosis effect. Hydrochlorothiazide is a thiazide diuretic for treating hypertension. The antihypertensive effect is mild and durable, and is suitable for treating mild and moderate hypertension, especially senile systolic hypertension and heart failure with hypertension.

After the diuretic is singly used by a hypertensive patient, the blood pressure can be reduced only to a certain extent, because the diuretic activates a neurohumoral mechanism and stimulates the release of renin, thereby antagonizing the antihypertensive effect of the diuretic; and it is also common clinically that many patients with mild to moderate hypertension do not reach the target blood pressure with telmisartan alone. After hydrochlorothiazide and telmisartan are combined, the latter antagonizes the activity of neurohormone, and can make up for some adverse effects of hydrochlorothiazide, and the compound preparation of the hydrochlorothiazide and telmisartan can further improve the antihypertensive effect, reduce the side effect of the medicine and improve the compliance of patients.

Telmisartan hydrochlorothiazide tablets were first marketed in the united states in 2001 by the company bologilyohn, germany under the trade nameHCT is a double-layer tablet preparation, most of oral solid preparations can be taken after being absorbed into blood after being administrated and reach a certain blood concentration, so that the dissolution or release of the preparation is a key factor affecting the absorption of the medicine in vivo, and the in-vitro dissolution curve of the solid preparation can be used as one of the quality evaluation indexes of the preparation.

Therefore, it is necessary to develop a reasonable dissolution rate measurement method and dissolution medium for telmisartan solid preparation.

Disclosure of Invention

The present application has been made based on the findings and knowledge of the inventors of the following problems:

the inventor finds that the existing dissolution rate measuring method has low dissolution rate of telmisartan in the telmisartan hydrochlorothiazide double-layer tablet, the auxiliary materials are changed, the dissolution curve of telmisartan is not changed obviously, and the quality judgment of the researcher on the prepared product can be seriously influenced.

Based on the problems and analysis, the application develops a dissolution rate determination method which has high dissolution rate differentiation degree for telmisartan, changes auxiliary materials, changes the dissolution curve of telmisartan, and can effectively simulate the in-vivo environment.

In a first aspect of the present invention, the present invention proposes a dissolution medium for determining the dissolution rate of a solid preparation of telmisartan. According to an embodiment of the invention, the dissolution medium comprises: at least one of citric acid-phosphate buffer and hydrochloric acid, wherein the phosphate comprises at least one of hydrogen phosphate and dihydrogen phosphate, and the pH of the dissolution medium is 1.8-3.2. According to the embodiment of the invention, the raw materials of the dissolution medium are easy to obtain, the pH value is stable, the pH value of gastric acid after meals is effectively simulated, technicians can conveniently and effectively simulate the dissolution environment of a telmisartan solid preparation in vivo in vitro, and the measured dissolution rate of the telmisartan solid preparation is more similar to the dissolution rate of telmisartan in vivo.

According to an embodiment of the present invention, the dissolution medium may further include at least one of the following additional technical features:

According to an embodiment of the present invention, the dissolution medium includes: citric acid-phosphate buffer; and a surfactant in an amount of 0.01w/v% to 0.5w/v%, preferably 0.05w/v% to 0.35w/v%, more preferably 0.15w/v% to 0.21w/v%. For example ,0.01w/v％、0.02w/v％、0.03w/v％、0.04w/v％、0.05w/v％、0.06w/v％、0.07w/v％、0.08w/v％、0.09w/v％、0.1w/v％、0.11w/v％、0.12w/v％、0.13w/v％、0.14w/v％、0.15w/v％、0.16w/v％、0.17w/v％、0.18w/v％、0.19w/v％、0.2w/v％、0.21w/v％、0.22w/v％、0.23w/v％、0.24w/v％、0.25w/v％、0.26w/v％、0.27w/v％、0.28w/v％、0.29w/v％、0.3w/v％、0.31w/v％、0.32w/v％、0.33w/v％、0.34w/v％、0.35w/v％、0.36w/v％、0.37w/v％、0.38w/v％、0.39w/v％、0.4w/v％、0.41w/v％、0.42w/v％、0.43w/v％、0.44w/v％、0.45w/v％、0.46w/v％、0.47w/v％、0.48w/v％、0.49w/v％、0.5w/v％. the dissolution medium according to embodiments of the present invention can significantly improve the detection effect of telmisartan dissolution, reduce RSD of dissolution between samples, and can improve the differentiation of dissolution curves between different telmisartan sample preparations.

According to an embodiment of the present invention, the surfactant includes at least one of sodium dodecyl sulfate and hydroxypropyl β -cyclodextrin, wherein the content of sodium dodecyl sulfate is 0.04w/v% to 0.3w/v%, preferably 0.05w/v% to 0.2w/v%, more preferably 0.1w/v%, and the content of hydroxypropyl β -cyclodextrin is 0.01w/v% to 0.2w/v%, preferably 0.01w/v% to 0.1w/v%, more preferably 0.05w/v%.

According to an embodiment of the present invention, the surfactant includes: 0.04w/v% -0.3 w/v% sodium dodecyl sulfate and 0.01w/v% -0.2 w/v% hydroxypropyl beta-cyclodextrin. According to the embodiment of the invention, the dissolution medium is added with sodium dodecyl sulfate and hydroxypropyl beta-cyclodextrin simultaneously, so that the detection effect of the dissolution rate of telmisartan can be improved, the distinction degree of dissolution curves among different telmisartan sample preparations can be improved, and the RSD of the dissolution rate among samples can be reduced.

According to an embodiment of the present invention, the surfactant includes: 0.05w/v% -0.2 w/v% sodium dodecyl sulfate and 0.01w/v% -0.1 w/v% hydroxypropyl beta-cyclodextrin. According to the embodiment of the invention, the dissolution medium is added with sodium dodecyl sulfate hydroxypropyl beta-cyclodextrin simultaneously, so that the detection effect of the dissolution rate of telmisartan can be improved, the distinction degree of dissolution curves among different telmisartan sample preparations is improved, and the RSD of the dissolution rate among samples is reduced.

According to an embodiment of the invention, the pH of the dissolution medium is 2.8-3.2, preferably the pH of the dissolution medium is 3.0. The pH of the dissolution medium is 2.8-3.2, and the pH of gastric acid after meals in the body can be effectively simulated, so that the measured dissolution rate of the telmisartan solid preparation is more similar to the dissolution rate of telmisartan in the body.

According to an embodiment of the invention, the phosphate is a potassium or sodium salt, preferably disodium hydrogen phosphate.

According to a specific embodiment of the invention, the phosphate is disodium hydrogen phosphate or phosphate with functions and properties similar to those of disodium hydrogen phosphate.

According to the embodiment of the invention, the mass ratio of the sodium dodecyl sulfate to the hydroxypropyl beta-cyclodextrin is (0.2-37.5): 1, and preferably (0.5-20): 1. According to the dissolution medium provided by the embodiment of the invention, when the proportion of the sodium dodecyl sulfate and the hydroxypropyl beta-cyclodextrin is consistent, the distinction of dissolution curves among different telmisartan sample preparations can be obviously improved, the RSD of the dissolution rate among samples can be reduced, and the dissolution effect can be improved.

According to an embodiment of the present invention, the telmisartan solid formulation is at least one of a tablet, a bilayer tablet and a capsule formulation, and the bilayer tablet is a telmisartan-hydrochlorothiazide bilayer tablet according to an embodiment of the present invention. The dissolution medium provided by the embodiment of the invention is particularly suitable for effectively detecting the dissolution rate of telmisartan in a hydrochlorothiazide-containing double-layer tablet, so that the obtained telmisartan dissolution rate is higher in distinction degree and is closer to the actual dissolution rate.

In a second aspect of the invention, the invention proposes the use of the dissolution medium as described previously for determining the dissolution rate of a telmisartan solid formulation. The dissolution medium according to the embodiment of the invention can be used for simulating the dissolution process of the telmisartan solid preparation in gastric acid in vivo, so that a detector can obtain the telmisartan dissolution rate closer to an in-vivo scene in vitro, the dissolution medium has high differentiation degree on different telmisartan solid preparations, the RSD of the dissolution rate between batches is small, and the detected telmisartan dissolution rate is more accurate.

In a third aspect of the invention, the invention provides a method for detecting the dissolution rate of a telmisartan solid preparation. According to an embodiment of the invention, the method comprises: mixing the dissolution medium with the telmisartan solid preparation so as to obtain a pharmaceutical solution; the amount of telmisartan in the pharmaceutical solution is determined at a plurality of time points after the mixing in order to determine the dissolution rate of the telmisartan solid formulation. According to the detection method provided by the embodiment of the invention, the operation is simple, the detection effect of the telmisartan dissolution rate can be obviously improved, the RSD of the dissolution rate between samples is reduced, and the distinction degree of the dissolution curve between different telmisartan sample preparations can be improved. According to the method of the embodiment of the invention, the multiple time points can be 5min, 10min, 15min, 20min, 30min, 45min, 60min, 90min and the like.

According to an embodiment of the present invention, the above method may further include at least one of the following additional technical features:

According to an embodiment of the invention, the mixing is carried out with stirring at 50 rpm. The inventors found that the release of telmisartan was smoother and more simulated in vivo release process at 50rpm of stirring and mixing.

In a fourth aspect of the invention, the invention provides a method for detecting the dissolution rate of a telmisartan solid preparation. According to a specific embodiment of the invention, the method comprises the following: 900mL of citric acid-disodium hydrogen phosphate buffer solution with the pH of 3.0 is taken as a dissolution medium, a telmisartan solid preparation is added, 0.1w/v% of Sodium Dodecyl Sulfate (SDS) and 0.05w/v% of hydroxypropyl beta-cyclodextrin are added, the solution is mixed and stirred at the rotation speed of 50 revolutions per minute, 5mL of solution is respectively taken at 5, 10, 15, 20, 30, 45, 60 and 90min (5 mL of dissolution medium with the same temperature is added after each sampling), filtration is carried out by a 0.45 mu m microporous filter membrane, 1mL of continuous filtrate is precisely measured, and the solution is placed in a 10mL measuring flask, diluted to a scale by the dissolution medium and shaken uniformly to be taken as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, the telmisartan reference substance is placed in a 25mL measuring flask, a proper amount of methanol is added, 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, the telmisartan is dissolved by ultrasound, methanol is added to dilute to a scale, shaking is carried out, and then the telmisartan reference substance is taken in a1 mL-20 mL volumetric flask, diluted to the scale by a dissolution medium to serve as a reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point.

Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Drawings

The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:

Fig. 1 is a 90% confidence interval distribution of telmisartan C _max、AUC_0-48 and AUC _0-∞ for 12 subjects of the present invention after oral administration of sample T of experimental group 1 of example 1 with commercial product R.

Detailed Description

Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to like or similar elements or elements having like or similar functions throughout. The embodiments described below by referring to the drawings are illustrative and intended to explain the present invention and should not be construed as limiting the invention.

Interpretation of the terms

The terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated unless otherwise specified. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In the description of the present invention, the meaning of "plurality" means at least two, for example, two, three, etc., unless specifically defined otherwise.

As used herein, F2 (similarity factor) refers to the similarity of dissolution rates of different telmisartan solid formulations, and FDA and EMEA specify: a reference formulation is considered similar if the F2 value between the dissolution curves of the test formulation and the reference formulation is not less than 50.

It should be noted that BE (bioequivalency) as used herein refers to a bioequivalence test, and the statistical difference between the absorption degree and the absorption rate of the drug between the test preparation and the control standard preparation under the same test conditions.

In the examples, commercial products are used as reference preparations, and the commercial products are: the company Boringer John (Boehringer Ingelheim) in the United statesThe HCT specification is 40mg/12.5mg telmisartan hydrochlorothiazide tablet.

The invention will now be described with reference to specific examples, which are intended to be illustrative only and not limiting in any way.

Example 1

The following experimental group is the preparation of telmisartan hydrochlorothiazide double-layer tablet:

Experiment group 1:

preparation of telmisartan sodium salt: 400g of telmisartan, 34g of sodium hydroxide, 120g of meglumine, 120g of povidone are dissolved in 1600g of water, and the materials are added while stirring until the solution is clear. And (3) spray-drying the solution at 200 ℃ of air inlet and 15000RPM of atomization rotating speed to obtain telmisartan sodium.

Tablet formulation (1000 formulation unit amounts):

telmisartan layer prescription: 68 parts of telmisartan sodium, 134 parts of sorbitol, 29 parts of crospovidone and 9 parts of magnesium stearate.

Hydrochlorothiazide layer prescription: 12.5 parts of hydrochlorothiazide, 108 parts of lactose, 61 parts of microcrystalline cellulose, 12 parts of carboxymethyl starch sodium, 6 parts of starch and 0.5 part of magnesium stearate.

The preparation process comprises the following steps:

Step 1: telmisartan sodium is sieved by a 100-mesh pharmacopoeia sieve;

Step 2: and weighing the prescription amount of telmisartan sodium, sorbitol, crosslinked povidone and magnesium stearate, and uniformly mixing in a mixing tank to obtain telmisartan layer mixed powder.

Step 3: the starch is prepared into starch slurry for standby.

Step 4: adding hydrochlorothiazide, lactose, microcrystalline cellulose and carboxymethyl starch sodium into a wet granulating pot, mixing, adding starch slurry, wet granulating, oven drying, adding magnesium stearate, and mixing to obtain hydrochlorothiazide layer granule

Step 5: the telmisartan layer particles and the hydrochlorothiazide particles are pressed into a double-layer tablet.

Experiment group 2:

telmisartan sodium salt preparation method as in experimental group 1;

Tablet formulation (1000 formulation unit amounts):

Telmisartan layer prescription: 68 parts of telmisartan sodium, 124 parts of sorbitol, 39 parts of crospovidone and 9 parts of magnesium stearate.

The preparation process is as in experiment 1.

Experiment group 3:

Telmisartan sodium salt was prepared as in experiment group 1.

Tablet formulation (1000 formulation unit amounts):

telmisartan layer prescription: 68 parts of telmisartan sodium, 124 parts of microcrystalline cellulose, 39 parts of crospovidone and 9 parts of magnesium stearate.

The preparation process is as in experiment 1.

Experiment group 4:

Telmisartan sodium salt was prepared as in experiment group 1.

Tablet formulation (1000 formulation unit amounts):

Telmisartan layer prescription: 68 parts of telmisartan sodium, 67 parts of microcrystalline cellulose, 67 parts of sorbitol, 39 parts of crospovidone and 9 parts of magnesium stearate.

The preparation process is as in experiment 1.

Experimental group 5:

Telmisartan sodium salt was prepared as in experiment group 1.

Tablet formulation (1000 formulation unit amounts):

telmisartan layer prescription: 68 parts of telmisartan sodium, 82 parts of microcrystalline cellulose, 42 parts of sorbitol, 39 parts of crospovidone and 9 parts of magnesium stearate.

The preparation process is as in experiment 1.

Example 2

Taking a commercially available product, a sample of an experiment group 1 of the example 1, a sample of an experiment group 2 of the example 1, a sample of an experiment group 3 of the example 1 and a sample of an experiment group 4 of the example 1, and respectively taking six samples for detection according to a dissolution rate measurement method (a second method of an annex XC of a second edition of Chinese pharmacopoeia 2010). Taking 900mL of hydrochloric acid aqueous solution with pH of 2.0 as a dissolution medium, rotating at 50rpm per minute, performing normal operation, taking 5mL of solution at 5, 10, 15, 20, 30, 45, 60 and 90min respectively (adding 5mL of dissolution medium with the same temperature after each sampling), filtering with a 0.45 mu m microporous filter membrane, precisely measuring 1mL of the continuous filtrate, placing in a10 mL measuring flask, diluting to a scale with the dissolution medium, shaking uniformly, and taking the filtrate as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 1 (six samples were taken for each batch and the RSD values were calculated).

Table 1: cumulative dissolution and RSD at various time points when aqueous hydrochloric acid solution of pH2.0 in example 2 was used as dissolution medium

The results show that when the aqueous hydrochloric acid solution with the pH of 2.0 is taken as a dissolution medium in the embodiment, the degree of distinction between different telmisartan solid preparations is higher, and part of telmisartan solid preparations can be distinguished. In this example, the dissolution rate of telmisartan from the aqueous hydrochloric acid solution with pH of 2.0 is mild, and is close to that of the in vivo gastric acid environment, and the dissolution rate is complete, wherein 45min is more than 80%, and RSD of dissolution rate of telmisartan preparations in different batches is approximately 20% or less than 20% within 10 min.

Example 3

The commercially available products, the sample of example 1 experiment group 1, the sample of example 1 experiment group 3 and the sample of example 1 experiment group 4 were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, according to the law, 5mL of solution is respectively taken at 5, 10, 15, 20, 30, 45, 60 and 90min (5 mL of dissolution medium with the same temperature is added after each sampling), a microporous filter membrane with 0.45 mu m is used for filtering, 1mL of the continuous filtrate is precisely measured and placed in a 10mL measuring flask, the dissolution medium is used for dilution to scale, and shaking is carried out uniformly to obtain a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 2 (six samples were taken for each batch and the RSD values were calculated).

Table 2: cumulative dissolution and RSD at different time points with pH3.0 in example 3 in citric acid-disodium hydrogen phosphate buffer as dissolution medium

The result shows that when the citric acid-disodium hydrogen phosphate buffer solution with the pH value of 3.0 is taken as a dissolution medium, the distinguishing degree of the citric acid-disodium hydrogen phosphate buffer solution on different telmisartan solid preparations is higher, and part of telmisartan solid preparations can be distinguished.

Example 4

The commercially available products, the sample of example 1 experiment group 1, the sample of example 1 experiment group 2, the sample of example 1 experiment group 3 and the sample of example 1 experiment group 4 were taken according to the dissolution rate measurement method (second method of the appendix XC of the second edition 2010 edition of chinese pharmacopoeia). 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, 0.1w/v% of Sodium Dodecyl Sulfate (SDS) is added, 5mL of solution is respectively taken at 5, 10, 15, 20, 30, 45, 60 and 90min according to the normal operation (5 mL of dissolution medium with the same temperature is added after each sampling), 0.45 mu m microporous filter membrane is used for filtering, 1mL of the subsequent filtrate is precisely measured and placed in a 10mL measuring flask, the dissolution medium is used for dilution to scale, and shaking is carried out uniformly to obtain a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 3 (six samples were taken for each batch and the RSD values were calculated).

Table 3: cumulative dissolution and RSD at different time points when Sodium Dodecyl Sulfate (SDS) was added to a ph3.0 citric acid-disodium hydrogen phosphate buffer as a dissolution medium

The results show that the dissolution medium in this example has a high degree of differentiation between different telmisartan solid formulations, and that the F2 similarity factor is less than 50, while having significant advantages in both the telmisartan dissolution effect, the RSD between batches of dissolution and the differentiation of the dissolution profile compared to the dissolution medium without Sodium Dodecyl Sulfate (SDS) addition in example 3. The dissolution medium in this example has a better dissolution effect on telmisartan than the hydrochloric acid solution at pH 1.0 in comparative example 1 and the acetate buffer at pH 4.5 in comparative example 2; the dissolution medium in this example is effective to mimic the gastric acid environment in vivo, with more moderate dissolution of telmisartan relative to the phosphate buffer at pH 6.8 in comparative example 3 and the phosphate buffer at pH 7.5 in comparative example 4; more importantly, the degree of distinction between different telmisartan solid formulations is significantly higher than that of the comparative examples.

Example 5

The commercially available products, the sample of example 1 experiment group 1, the sample of example 1 experiment group 2, the sample of example 1 experiment group 3 and the sample of example 1 experiment group 4 were taken according to the dissolution rate measurement method (second method of the appendix XC of the second edition 2010 edition of chinese pharmacopoeia). 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, 0.05w/v% hydroxypropyl beta-cyclodextrin is added, according to the normal operation, 5mL of solution is respectively taken at 5,10, 15, 20, 30, 45, 60 and 90min (5 mL of dissolution medium with the same temperature is added after each sampling), 0.45 mu m microporous filter membrane is used for filtering, 1mL of the subsequent filtrate is precisely measured and placed in a 10mL measuring flask, the dissolution medium is used for dilution to scale, and shaking is carried out uniformly to obtain a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 4 (six samples were taken for each batch and the RSD values were calculated).

Table 4: cumulative dissolution and RSD at different time points when hydroxypropyl beta-cyclodextrin was added to the dissolution medium in citric acid-disodium hydrogen phosphate buffer at ph3.0 of example 5

The results show that the dissolution rate of the dissolution medium in this example for the telmisartan formulations of different batches has a RSD of less than 20% within 10min, less than 10% from 10min to 90min, and a small RSD between batches. Meanwhile, compared with the dissolution medium without adding hydroxypropyl beta-cyclodextrin in the embodiment 3, the method has obvious advantages in the dissolution effect, the dissolution degree of telmisartan and the distinction degree of the dissolution curve between the batch RSD and the dissolution curve, especially the dissolution degree of the batch RSD.

Example 6

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, 0.1w/v% of Sodium Dodecyl Sulfate (SDS) and 0.05w/v% of hydroxypropyl beta-cyclodextrin are added, according to the normal operation, 5mL of solution (5 mL of dissolution medium with the same temperature is added after each sampling) is respectively taken at 5, 10, 15, 20, 30, 45, 60 and 90min, 1mL of the continuous filtrate is placed in a10 mL measuring flask, diluted to the scale by the dissolution medium, and uniformly shaken to be taken as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 5 (six samples were taken for each batch and the RSD values were calculated).

Table 5: the cumulative dissolution rate and RSD at different time points when two surfactants were added to the dissolution medium in citric acid-disodium hydrogen phosphate buffer at ph3.0 of example 6

The result shows that the dissolution rate of the dissolution medium in the embodiment on telmisartan is mild, is close to that of the dissolution medium in the gastric acid environment in the body, and is complete, the dissolution rate is nearly 80% or more in 45min, the RSD of the dissolution rate of the telmisartan preparations in different batches is less than 20% within 10min, the RSD in batches is less than 10% in 10min to 90min, the differentiation rate on the solid preparations of different telmisartan is high, and the F2 similarity factor is less than 50; meanwhile, compared with the dissolution medium without adding hydroxypropyl beta-cyclodextrin and Sodium Dodecyl Sulfate (SDS) in the embodiment 3, the method has obvious advantages in the dissolution effect of telmisartan, the batch-to-batch RSD of the dissolution rate and the distinction degree of the dissolution curve; the dissolution effect and the RSD between batches of the dissolution rate were further improved compared to that of example 4 in which Sodium Dodecyl Sulfate (SDS) was added alone; compared to the dissolution medium of hydroxypropyl beta-cyclodextrin alone in example 5, it further improved the inter-batch RSD of the dissolution profile, dissolution effect and dissolution rate between different telmisartan solid formulations.

Example 7

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, 0.05w/v percent of Sodium Dodecyl Sulfate (SDS) and 0.1w/v percent of hydroxypropyl beta-cyclodextrin are added, according to the normal operation, 5mL of solution (5 mL of dissolution medium with the same temperature is added after each sampling) is respectively taken at 5, 10, 15, 20, 30, 45, 60 and 90min, 1mL of continuous filtrate is measured by a precision quantity, the solution is placed in a10 mL measuring flask, diluted to a scale by the dissolution medium, and uniformly shaken to be taken as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 6 (six samples were taken for each batch and the RSD values were calculated).

Table 6: the cumulative dissolution rate and RSD at different time points when two surfactants were added to the dissolution medium in citric acid-disodium hydrogen phosphate buffer at ph3.0 of example 7

The result shows that the dissolution rate of the dissolution medium in the embodiment on telmisartan is mild, is close to that of the dissolution medium in the gastric acid environment in the body, and is complete, the dissolution rate is nearly 80% or more in 45min, the RSD of the dissolution rate of the telmisartan preparations in different batches is less than 20% within 10min, the RSD in batches is less than 10% in 10min to 90min, the differentiation rate on the solid preparations of different telmisartan is high, and the F2 similarity factor is less than 50; meanwhile, compared with the dissolution medium without adding hydroxypropyl beta-cyclodextrin and Sodium Dodecyl Sulfate (SDS) in the embodiment 3, the method has obvious advantages in the dissolution effect of telmisartan, the batch-to-batch RSD of the dissolution rate and the distinction degree of the dissolution curve; the dissolution effect and the batch-to-batch RSD of the dissolution effect and the dissolution rate thereof were further improved as compared with the addition of Sodium Dodecyl Sulfate (SDS) alone in example 4; the distinction of dissolution profile, dissolution effect and RSD between batches of different telmisartan solid formulations is further improved compared to the dissolution medium of hydroxypropyl β -cyclodextrin alone in example 5.

Example 8

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, 0.2w/v percent of Sodium Dodecyl Sulfate (SDS) and 0.01w/v percent of hydroxypropyl beta-cyclodextrin are added, according to the normal operation, 5mL of solution (5 mL of dissolution medium with the same temperature is added after each sampling) is respectively taken at 5, 10, 15, 20, 30, 45, 60 and 90min, 1mL of continuous filtrate is measured by a precision quantity, the solution is placed in a10 mL measuring flask, diluted to a scale by the dissolution medium, and the solution is uniformly shaken to be taken as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 7 (six samples were taken for each batch and the RSD values were calculated).

Table 7: the cumulative dissolution rate and RSD at different time points when two surfactants were added to the dissolution medium in citric acid-disodium hydrogen phosphate buffer at ph3.0 of example 8

The result shows that the dissolution rate of the dissolution medium in the embodiment on telmisartan is mild, is close to that of the dissolution medium in the gastric acid environment in the body, and is complete, the dissolution rate is nearly 80% or more in 45min, the RSD of the dissolution rate of the telmisartan preparations in different batches is less than 20% within 10min, the RSD in batches is less than 10% in 10min to 90min, the differentiation rate on the solid preparations of different telmisartan is high, and the F2 similarity factor is less than 50; meanwhile, compared with the dissolution medium without adding hydroxypropyl beta-cyclodextrin and Sodium Dodecyl Sulfate (SDS) in the embodiment 3, the method has obvious advantages in the dissolution effect of telmisartan, the batch-to-batch RSD of the dissolution rate and the distinction degree of the dissolution curve; the dissolution effect and the batch-to-batch RSD of the dissolution effect and the dissolution rate thereof were further improved as compared with the addition of Sodium Dodecyl Sulfate (SDS) alone in example 4; the degree of distinction, dissolution effect and the RSD between batches of dissolution of different telmisartan solid formulations are further improved compared to the dissolution medium of hydroxypropyl β -cyclodextrin alone in example 5.

Example 9

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, 0.3w/v percent of Sodium Dodecyl Sulfate (SDS) and 0.008w/v percent of hydroxypropyl beta-cyclodextrin are added, according to the normal operation, 5mL of solution (5 mL of dissolution medium with the same temperature is added after each sampling) is respectively taken at 5, 10, 15, 20, 30, 45, 60 and 90min, 1mL of continuous filtrate is measured by a precision quantity, the solution is placed in a 10mL measuring flask, diluted to a scale by the dissolution medium, and uniformly shaken to be taken as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 6 (six samples were taken for each batch and the RSD values were calculated).

Table 8: cumulative dissolution and RSD at different time points when two surfactants were added to the dissolution medium in citric acid-disodium hydrogen phosphate buffer at ph3.0 of example 9

Example 10

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, 0.04w/v percent of Sodium Dodecyl Sulfate (SDS) and 0.2w/v percent of hydroxypropyl beta-cyclodextrin are added, according to the normal operation, 5mL of solution (5 mL of dissolution medium with the same temperature is added after each sampling) is respectively taken at 5, 10, 15, 20, 30, 45, 60 and 90min, 1mL of continuous filtrate is measured by a precision quantity, the solution is placed in a10 mL measuring flask, diluted to a scale by the dissolution medium, and uniformly shaken to be taken as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 6 (six samples were taken for each batch and the RSD values were calculated).

Table 9: cumulative dissolution and RSD at different time points when two surfactants were added to the dissolution medium in citric acid-disodium hydrogen phosphate buffer at ph3.0 of example 10

The experimental results of examples 9 to 10 show that when the amount or ratio of the surfactant in the dissolution medium is changed, the RSD between batches of the telmisartan solid formulation in this example is slightly increased compared to examples 6, 7 and 8, and the degree of distinction between the different telmisartan solid formulations by the dissolution medium in this example is slightly deteriorated compared to examples 6, 7 and 8.

Example 11

The commercial product was taken and subjected to dissolution measurement (second method of appendix XC of second edition 2010 of Chinese pharmacopoeia). 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, 0.1w/v% of Sodium Dodecyl Sulfate (SDS) and 0.05w/v% of hydroxypropyl beta-cyclodextrin are added, the solution is respectively taken for 5mL (5 mL of dissolution medium with the same temperature is added after each sampling) at the rotation speed of 50 revolutions per minute, 75 revolutions per minute and 100 revolutions per minute according to the law, 0.45 mu m microporous filter membrane is used for filtering, the continuous filtrate is precisely measured for 1mL, and the solution is placed in a 10mL measuring flask, diluted to a scale by the dissolution medium and shaken uniformly to be taken as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The results of the experiment are shown in Table 8 (six samples were taken for each batch and the RSD values were calculated).

Table 10: cumulative dissolution and RSD results for commercial products at different time points at three rotational speeds

The results show that: the dissolution rates of the samples are about 76%, 93% and 97% after 45min under the conditions of 50rpm, 75rpm and 100rpm, the dissolution process is more intense under the conditions of 75rpm and 100rpm, and the dissolution process of the samples reaches a release platform basically after 5min, so that 50rpm is selected, and the release of the samples is more gentle under the conditions, and the dissolution process of telmisartan in vivo can be more simulated.

Comparative example 1: 0.1mol/L HCl aqueous solution is taken as dissolution medium

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. Taking 900mL of 0.1mol/L HCl aqueous solution as a dissolution medium, rotating at 50 revolutions per minute, performing normal operation, taking 5mL of solution (5 mL of dissolution medium with the same temperature is added after each sampling) at 5, 10, 15, 20, 30, 45, 60 and 90min respectively, filtering with a 0.45 mu m microporous filter membrane, precisely measuring 1mL of subsequent filtrate, placing in a10 mL measuring flask, diluting to a scale with the dissolution medium, shaking uniformly, and taking the diluted filtrate as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The experimental results are shown in table 11.

Table 11: cumulative dissolution results at various time points when 0.1M aqueous hydrochloric acid was used as dissolution medium

Experimental results show that compared with the experimental results of example 2, the hydrochloric acid solution with the pH of 1 has poor dissolution effect on telmisartan, the dissolution effect is far less than that of the hydrochloric acid solution with the pH of 2.0, and F2 in the experimental results of the comparative example is also higher, so that the degree of distinction of different telmisartan preparations is not high; the F2 is significantly increased in the results of this comparative example relative to the results of example 3, and the F2 of each of the four experimental samples is much higher than 50, indicating that the dissolution medium of this example is not highly differentiated from the different telmisartan formulations, and therefore the hydrochloric acid solution with pH 1.0 of this comparative example is not suitable as the dissolution medium for the telmisartan solid formulation.

Comparative example 2: acetate buffer with pH of 4.5 as dissolution medium

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. Taking 900mL of acetate buffer solution with pH of 4.5 as a dissolution medium, rotating at 50 revolutions per minute, performing normal operation, taking 5mL of solution (5 mL of dissolution medium with the same temperature is added after each sampling) at 5, 10, 15, 20, 30, 45, 60 and 90min respectively, filtering with a microporous filter membrane with the thickness of 0.45 mu m, precisely measuring 1mL of the subsequent filtrate, placing in a measuring flask with the thickness of 10mL, diluting to a scale with the dissolution medium, and shaking uniformly to obtain a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The experimental results are shown in table 12.

Table 12: cumulative dissolution results at different time points at pH4.5 in dissolution medium

The experimental results show that, compared with the experimental results of example 2 and example 3, the dissolution effect of the dissolution medium of this comparative example on telmisartan is poor, the dissolution rate is only about 40% at 45min, which is far less than that of the hydrochloric acid solution with pH of 2.0, and the F2 in the results of this example is also high, about 70, and the degree of distinction between different telmisartan preparations is not high, so that the dissolution medium of this comparative example is not suitable as the dissolution medium of telmisartan solid preparations.

Comparative example 3: phosphate buffer solution with pH of 6.8 as dissolution medium

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. Taking 900mL of phosphate buffer solution with pH of 6.8 as a dissolution medium, rotating at 50 revolutions per minute, performing normal operation, taking 5mL of solution (5 mL of dissolution medium with the same temperature is added after each sampling) at 5, 10, 15, 20, 30, 45, 60 and 90min respectively, filtering with a microporous filter membrane with the thickness of 0.45 mu m, precisely measuring 1mL of the subsequent filtrate, placing in a measuring flask with the thickness of 10mL, diluting to a scale with the dissolution medium, and shaking uniformly to obtain a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The experimental results are shown in table 13.

Table 13: cumulative dissolution results at different time points at pH6.8 in dissolution medium

The experimental results show that, compared with the results of examples 2 to 8, the dissolution reaction of the dissolution medium with a pH close to neutral in the present comparative example is too strong, namely 80% at 15min, the gastric acid environment in the body cannot be simulated, the difference between the dissolution process of telmisartan in the body is large, the F2 in the present comparative example is also more than 70, the degree of distinction of the dissolution curves of different telmisartan preparations is low, and in conclusion, the dissolution medium in the present comparative example is not suitable as the dissolution medium of the telmisartan solid preparation.

Comparative example 4: phosphate buffer with pH7.5 as dissolution medium

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. Taking 900mL of phosphate buffer solution with pH of 7.5 as a dissolution medium, rotating at 50 revolutions per minute, performing normal operation, taking 5mL of solution (5 mL of dissolution medium with the same temperature is added after each sampling) at 5, 10, 15, 20, 30, 45, 60 and 90min respectively, filtering with a microporous filter membrane with the thickness of 0.45 mu m, precisely measuring 1mL of the subsequent filtrate, placing in a measuring flask with the thickness of 10mL, diluting to a scale with the dissolution medium, and shaking uniformly to obtain a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The experimental results are shown in table 14.

Table 14: cumulative dissolution results at different time points in the dissolution medium at pH7.5

The experimental results show that the dissolution reaction of the dissolution medium with a pH close to neutral in this comparative example is too strong, i.e., 80% at 15min, which is greatly different from the dissolution process of telmisartan in vivo, and the dissolution profile of the different telmisartan preparations is less differentiated by F2 of this comparative example being 70 or more, compared to the results of examples 2 to 8, and therefore the dissolution medium of this comparative example is not suitable as the dissolution medium of the telmisartan solid preparation.

Comparative example 5: water is used as dissolution medium

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. 900mL of water is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, the operation is carried out according to law, 5mL of solution is taken respectively at 5, 10, 15, 20, 30, 45, 60 and 90min (5 mL of dissolution medium with the same temperature is added after each sampling), a 0.45 mu m microporous filter membrane is used for filtering, 1mL of continuous filtrate is measured accurately, the filtrate is placed in a 10mL measuring flask, diluted to a scale by the dissolution medium, and the sample solution is uniformly shaken; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The experimental results are shown in table 15.

Table 15: cumulative dissolution results at different time points in water-soluble medium

The results show that: compared with the results of examples 2 to 10, the dissolution reaction of the dissolution medium with a pH close to neutral in the present comparative example is too strong, namely 80% at 15min, the gastric acid environment in vivo cannot be simulated, the dissolution process of telmisartan in vivo is greatly different from that of telmisartan, and the degree of distinction of the dissolution curves of different telmisartan preparations is low because the F2 of the present comparative example is also above 70, so the dissolution medium of the present comparative example is not suitable as the dissolution medium of a telmisartan solid preparation.

Comparative examples 1 to 5 selected dissolution media with the best telmisartan preparation effect measured in the prior art, and the dissolution media of other telmisartan preparations measured in the prior art were inferior to comparative examples 1 to 5 in the distinction of dissolution curves of different telmisartan preparations, in the RSD between batches and in the cumulative dissolution amount, however, comparative examples 1 to 5 were inferior in the distinction of dissolution curves of different telmisartan preparations, which means that the dissolution media of the telmisartan preparations measured in the prior art are not suitable as dissolution media of telmisartan solid preparations.

Comparative example 6: acetate buffer at pH3.0 as dissolution medium

The commercially available products, the example 1 experiment group 1 sample, the example 1 experiment group 2 sample, the example 1 experiment group 3 sample, and the example 1 experiment group 4 sample were taken and subjected to dissolution measurement (second method of the second appendix XC of the 2010 edition of chinese pharmacopoeia) respectively. Taking 900mL of acetate buffer solution with pH of 3.0 as a dissolution medium, rotating at 50 revolutions per minute, taking 5mL of solution respectively at 5, 10, 15, 20, 30, 45, 60 and 90min (adding 5mL of dissolution medium with the same temperature after each sampling), filtering with a 0.45 mu m microporous filter membrane, precisely measuring 1mL of the subsequent filtrate, placing in a 10mL measuring flask, diluting to a scale with the dissolution medium, shaking uniformly, and taking the diluted solution as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The experimental results are shown in table 16.

Table 16: acetate buffer at pH3.0 as dissolution medium, cumulative dissolution and RSD at different time points

The experimental results show that the acetate buffer with pH3.0 in this example has too low dissolution effect compared with the citric acid-disodium hydrogen phosphate buffer with the same pH in example 3, and in this comparative example, the dissolution rate of telmisartan is only 7% -26% at 45min, and RSD is too large between batches, reaching 20% or more within 10min, and 10 min-90 min being close to 20% or more, so that it is not suitable as dissolution medium for solid preparation of telmisartan.

Comparative example 7: the citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is used as a dissolution medium, and the added surfactant is Tween-80

The commercially available products, the sample of example 1 experiment group 1, the sample of example 1 experiment group 2, the sample of example 1 experiment group 3 and the sample of example 1 experiment group 4 were taken according to the dissolution rate measurement method (second method of the appendix XC of the second edition 2010 edition of chinese pharmacopoeia). 900mL of citric acid-disodium hydrogen phosphate buffer solution with pH of 3.0 is taken as a dissolution medium, the rotating speed is 50 revolutions per minute, 0.1% Tween-80 is added, according to the law, 5mL of solutions are respectively taken for 5, 10, 15, 20, 30, 45, 60 and 90min (5 mL of dissolution medium with the same temperature is added after each sampling), 0.45 mu m microporous filter membrane is used for filtering, 1mL of the continuous filtrate is precisely measured and placed in a 10mL measuring flask, the dissolution medium is used for dilution to scale, and shaking is carried out uniformly, and the solution is taken as a sample solution; in addition, about 20mg of telmisartan reference substance is precisely weighed, placed in a 25mL measuring flask, a proper amount of methanol is added, then 1.25mL of sodium hydroxide solution (0.1 mol/L) is added, ultrasonic treatment is carried out to dissolve telmisartan, then methanol is added to dilute to a scale, shaking is carried out, then 1mL to 20mL volumetric flask is taken, and dissolution medium is used to dilute to the scale to serve as reference substance solution. And (3) measuring the content of telmisartan in the sample solution and the reference solution by using an HPLC (high performance liquid chromatography) external standard method, and further calculating the accumulated dissolution amount of telmisartan at each time point. The commercial product has the commodity nameTelmisartan hydrochlorothiazide bilayer tablet of HCT. The experimental results are shown in table 17. (six samples were taken for each batch and their RSD values were calculated)

Table 17: cumulative dissolution and RSD at different time points when tween-80 was added to the dissolution medium in citric acid-disodium hydrogen phosphate buffer at ph3.0

Experimental results show that when tween-80 is used as a surfactant in the comparative example, the degree of distinction, telmisartan dissolution effect and RSD among batches of dissolution rate of telmisartan solid preparations are not improved, meanwhile, the tween-80 in comparative example 7 is replaced by surfactants such as poloxamer 188, sorbic acid, polyvinyl alkyl ether, docusate sodium and the like, other conditions are unchanged, and the results are similar, and the degree of distinction, telmisartan dissolution effect and RSD among batches of dissolution rate of telmisartan solid preparations are not improved.

Verification experiment

The following experiments were performed to compare the in vitro and in vivo elution results of the samples of experimental group 1 and experimental group 5 of example 1.

Example 1 experimental group 1 samples, experimental group 5 samples and commercially available layers of telmisartan in vitro dissolution experimental results are shown in table 18.

Table 18: example 1 experimental group 1 samples, experimental group 5 samples and commercial telmisartan layer in vitro dissolution experimental results:

Dissolution conditions	Experimental group 1 sample and commercial F2 value	Experimental group 5 sample and commercial F2 value
			Conditions described in comparative example 1	60	62
Comparative example 2 conditions	74	80
			Comparative example 3 conditions	74	82
Conditions described in comparative example 4	76	67
			Conditions described in comparative example 5	62	63
Example 2 conditions	54	73
			Example 6 conditions	47	79

Table 18 shows the comparison of the F2 values of the factors similar to those of commercially available telmisartan hydrochlorothiazide double-layer tablets obtained by measuring the dissolution medium and conditions of the samples of the experimental group 1 and the experimental group 5 of the example 1 according to the comparative examples 1, 2, 3, 4, 5, 2 and 6.

As is clear from Table 18, the similarity factor (F2) between the sample in the experimental group 1 and the commercial product in the ordinary dissolution medium is 50 or more, which indicates that the sample in the experimental group 1 of example 1 and the commercial product are in vitro consistent in dissolution in the ordinary dissolution medium, whereas the sample in the experimental group 1 and the commercial product are respectively detected by using the specific dissolution medium in the invention, and the similarity factor between the sample in the experimental group 1 of example 1 and the commercial product is 50 or less, which indicates that the sample in the specific dissolution medium in the invention is not in vitro consistent in the experimental group 1 of example 1 and the commercial product; for example 1, test group 5, the similarity factor between the sample of example 1, test group 5 and the commercial product in each of the ordinary dissolution medium and the specific medium was 50 or more, which indicates that the sample of example 1, test group 5 and the commercial product in each of the ordinary dissolution medium and the specific dissolution medium showed in vitro agreement.

Example 1 experimental group 5 samples and the first pre-BE results of the commercially available telmisartan layer are shown in table 16.

Table 19: example 1 experiment group 5 sample T and commercial product R pharmacokinetic parameters 90% confidence interval

As can BE seen from Table 19, the 90% confidence interval of the pharmacokinetic parameters of sample T and commercial product R in experiment group 5 of example 1 falls completely within the equivalent interval, which indicates that the samples and commercial products in experiment group 5 of example 1 are equivalent to commercial products in BE experiments, and that the specific dissolution medium and the common dissolution medium of the present invention are consistent with the results of the first pre-BE experiment.

Example 1 experimental group 1 samples and the second pre-BE results of the commercially available telmisartan layer are shown in table 17.

Table 20: example 1 test group 1 pharmacokinetic parameters 90% confidence interval for sample T and commercial product R

Referring to fig. 1, the 90% confidence interval distribution of telmisartan C _max、AUC_0-48 and AUC _0-∞ after oral administration of sample T of experimental group 1 of example 1 to commercial product R was 12 subjects.

From the above results, the 90% confidence interval of the pharmacokinetic parameters of the sample T and the commercial product R in the experimental group 1 of example 1 does not completely fall within the equivalent interval, which indicates that the sample and the commercial product in the experimental group 1 of example 1 are not equivalent to the commercial product in the BE experiment, so that the specific dissolution medium of the invention corresponds to the second pre-BE result, which indicates that the specific dissolution medium of the invention can more accurately simulate the in vivo dissolution process of telmisartan, and the common dissolution medium is different from the second pre-BE result, which indicates that the common dissolution medium cannot objectively simulate the in vivo dissolution process of telmisartan.

As is clear from tables 18 to 20, the samples of experiment group 5 of example 1 showed in vitro agreement with the commercial products in each of the ordinary medium and the specific medium, the similarity factor was 50 or more, and the BE test was further conducted at this time, and the BE result showed that the samples of example 5 were in vivo equivalent to the commercial products, so that the ordinary dissolution medium was similar in effect to the specific dissolution medium with respect to experiment group 5 of example. The sample of the experiment group 1 of the example 1 is obtained by changing the auxiliary material type and the content of the sample of the experiment group 5 of the example 1 to adjust the prescription process, the sample of the experiment group 1 of the example 1 and the commercial product show in vitro consistency in a common medium, but show inequality with the commercial product in BE experiment, the sample of the experiment group 1 of the example 1 and the commercial product respectively detected by using the specific dissolution medium of the invention show in vitro inconsistency, and the similarity factor is below 50, so that the specific dissolution medium of the invention can effectively distinguish the dissolution rates of the experiment group 1 of the example 1 and the commercial product in vitro and is consistent with the in vivo BE experiment, and the common dissolution medium cannot distinguish the dissolution rates of the experiment group 1 of the example 1 and the commercial product, thereby misjudgment is caused. In conclusion, the dissolution rate measuring method provided by the invention can objectively simulate the dissolution and absorption process of the telmisartan layer in the telmisartan hydrochlorothiazide tablet in a human body, can effectively distinguish samples with different qualities, and improves the success rate of bioequivalence tests.

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

1. A dissolution medium for determining dissolution similarity of telmisartan solid formulation, comprising:

Citric acid-phosphate buffer, and surfactant,

Wherein the pH of the dissolution medium is 2.8-3.2;

The surfactant comprises at least one of sodium dodecyl sulfate and hydroxypropyl beta-cyclodextrin;

the content of the surfactant is 0.01w/v% -0.5 w/v%;

The phosphate is hydrogen phosphate.

2. The dissolution medium according to claim 1, wherein the pH of the dissolution medium is 3.0.

3. The dissolution medium according to claim 1, wherein the phosphate is a potassium or sodium salt.

4. A dissolution medium according to claim 3, characterised in that the phosphate is disodium hydrogen phosphate.

5. The dissolution medium according to claim 1, wherein the surfactant is present in an amount of 0.05w/v% to 0.35w/v%.

6. The dissolution medium according to claim 5, wherein the content of the surfactant is 0.15w/v% to 0.21w/v%.

7. A dissolution medium according to claim 1, wherein,

The content of the sodium dodecyl sulfate is 0.04w/v percent to 0.3w/v percent, and the content of the hydroxypropyl beta-cyclodextrin is 0.01w/v percent to 0.2w/v percent.

8. The dissolution medium according to claim 7, wherein the content of sodium dodecyl sulfate is 0.05w/v% to 0.2w/v%, and the content of β -cyclodextrin is 0.01w/v% to 0.1w/v%.

9. The dissolution medium according to claim 8, wherein the content of sodium dodecyl sulfate is 0.1w/v% and the content of β -cyclodextrin is 0.05w/v%.

10. The dissolution medium according to claim 1, wherein the surfactant comprises: 0.04w/v% -0.3 w/v% sodium dodecyl sulfate and 0.01w/v% -0.2 w/v% hydroxypropyl beta-cyclodextrin.

11. The dissolution medium according to claim 10, wherein the surfactant comprises: 0.05w/v% -0.2 w/v% sodium dodecyl sulfate and 0.01w/v% -0.1 w/v% hydroxypropyl beta-cyclodextrin.

12. The dissolution medium according to claim 10, wherein the mass ratio of sodium dodecyl sulfate to hydroxypropyl β -cyclodextrin is (0.2 to 37.5): 1.

13. The dissolution medium according to claim 12, wherein a mass ratio of the sodium dodecyl sulfate to the hydroxypropyl β -cyclodextrin is (0.5 to 20): 1.

14. The dissolution medium according to claim 1, wherein the telmisartan solid formulation is at least one of a tablet, a bilayer tablet and a capsule formulation.

15. The dissolution medium according to claim 14, wherein the bilayer tablet is a telmisartan hydrochlorothiazide bilayer tablet.

16. Use of the dissolution medium according to any one of claims 1 to 15 for determining the dissolution similarity of a telmisartan solid formulation.

17. A method for determining dissolution similarity of telmisartan solid preparation, comprising:

mixing the dissolution medium of any one of claims 1 to 15 with the telmisartan solid formulation so as to obtain a pharmaceutical solution;

Determining the amount of telmisartan in said drug solution at a plurality of time points after said mixing, so as to determine the dissolution rate of said telmisartan solid formulation;

and determining the dissolution similarity of the telmisartan solid preparation based on the dissolution of the telmisartan solid preparation.

18. The method of claim 17, wherein the mixing is performed with stirring at 50 rpm.