CN105997887A - Tolterodine sustained release microsphere preparation containing small molecular additive and preparation method thereof - Google Patents

Abstract

The invention provides a tolterodine sustained-release microsphere preparation containing a small molecule additive and a preparation method thereof, wherein tolterodine, the small molecule additive and polylactide-glycolide are weighed and added to 0.2-5ml of dichloromethane Dissolve it in the medium, inject it into the aqueous solution under homogeneous conditions, keep the above homogeneous conditions for 5 minutes, then evaporate the solvent with stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry. The present invention uses fatty acids or fatty acid esters as additives for biological sustained-release microsphere preparations, so that the drug can be released for nearly a month, greatly reducing the number of medications, improving the bioavailability and therapeutic effect of the drug, and reducing toxic and side effects, thereby greatly reducing the pain of the majority of patients. pain and improve their quality of life. The polylactide-glycolide encapsulates the tolterodine, delays the release of the tolterodine, and plays a slow-release effect. The addition of small molecular additives changes the existence and distribution of tolterodine inside the microspheres, further delays the release of tolterodine, and increases the drug loading.

Description

A kind of tolterodine sustained-release microsphere preparation containing small molecule additive and preparation method thereof

technical field

The invention provides a tolterodine sustained-release microsphere preparation containing a small molecular additive, and also provides a preparation method thereof, which belongs to the technical field of pharmaceutical preparation.

Background technique

Tolterodine belongs to 3,3-diphenylpropylamine muscarinic receptor antagonists, and its oral efficacy is low and its side effects are large, such as dry mouth, constipation, indigestion, headache, dizziness, dry eyes, and urinary retention. The unabsorbed part will produce systemic side effects or interactions (EP1077912), and the hepatic first-pass effect also leads to decreased drug efficacy and increased side effects. Although it can be administered by ordinary injection, for the long-term treatment of urinary incontinence patients, one or more injections per day will increase the pain and discomfort of the patient.

Contents of the invention

The invention provides a tolterodine slow-release microsphere preparation containing a small molecular additive, which has a high drug loading capacity and can be released for nearly one month, greatly reduces the number of times of medication, and improves the bioavailability and therapeutic effect of the drug.

The present invention further provides a preparation method of tolterodine sustained-release microsphere preparation containing small molecular additives, which is suitable for industrial production.

A kind of tolterodine slow-release microsphere reagent containing small molecular additive of the present invention is characterized in that it is made by the following medicines in parts by weight:

1%-20% tolterodine, 0.1%-10% small molecular additives, and the balance is biodegradable pharmaceutical polymer excipients.

in,

The small molecule additive is a small molecular fatty acid or a small molecular fatty acid ester with a molecular weight of less than 500 Daltons.

The small molecular fatty acid is one of stearic acid, palmitic acid and myristic acid.

The biodegradable pharmaceutical polymer material is from one of polylactide-glycolide, polylactic acid, polycaprolactone, polyhydroxybutyrate-hydroxyvalerate copolymer or a mixture of two of them ( 1:9-9:1), its molecular weight is 3000-50000 Daltons

A kind of preparation method of the tolterodine slow-release microsphere preparation containing small molecule additive of the present invention, comprises the following steps:

Weigh tolterodine, small molecule additives and polylactide-glycolide according to the above ratio, add them into 0.2-5 ml dichloromethane and dissolve them, and inject them into 0.3-3 In the aqueous solution of %PVA (w/w), keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry.

The tolterodine slow-release microsphere preparation containing small molecular additives prepared by the invention has a particle diameter of 50-300 μm and an encapsulation rate of 40-90%.

The positive effects of the present invention are: using fatty acids or fatty acid esters as additives for biological sustained-release microsphere preparations, so that the drug can be released for nearly a month, greatly reducing the number of medications, improving the bioavailability and therapeutic effect of the drug, and reducing toxic and side effects, thereby extremely Dadi relieves the pain of the majority of patients and improves their quality of life. The polylactide-glycolide encapsulates the tolterodine, delays the release of the tolterodine, and plays a slow-release effect. The addition of small molecular additives changes the existence and distribution of tolterodine inside the microspheres, further delays the release of tolterodine, and increases the drug loading.

Description of drawings

Fig. 1 is the morphological photograph under the scanning electron microscope of the obtained microsphere of embodiment 4;

Fig. 2 is the line graph of the cumulative release rate of the microspheres obtained in embodiment 1, embodiment 2, embodiment 3, embodiment 4, embodiment 5 in simulated release liquid;

Fig. 3 is the line graph of the cumulative release rate of the microspheres obtained in embodiment 6, embodiment 7, embodiment 8, embodiment 9, embodiment 10 in the simulated release liquid;

Fig. 4 is the broken line graph of the cumulative release rate of the microspheres obtained in embodiment 11, embodiment 12, embodiment 13, embodiment 14, embodiment 15 in simulated release liquid;

Fig. 5 is the line graph of the cumulative release rate of the microspheres obtained in embodiment 16, embodiment 17, embodiment 18, embodiment 19, embodiment 20, embodiment 21, embodiment 22 in the simulated release liquid;

Fig. 6 is embodiment 4, the curve of the microsphere of embodiment 23 gained medicine in the Beagle dog body;

Figure 7 is a line graph of the cumulative release rate of sustained-release microspheres in Beagle dogs.

Specific embodiments

The following examples will further illustrate the preparation method and sustained release effect of a tolterodine sustained-release microsphere containing a small molecule additive according to the present invention, but the following examples do not constitute any limitation to the present invention. The particle diameter of microsphere adopts the L2000 that those skilled in the art are familiar with in the following examples A fully automatic laser particle size analyzer (Beckman Coulter Company) was used for the determination. The content is determined by high-performance liquid chromatography (HPLC), and the method is according to the literature method, for example, it can be disclosed according to the Chinese Journal of New Drugs, 2012, 21 (23). Blood drug concentration is determined by LC-MS-MS method, for example, according to Journal of China Pharmaceutical University, 2005, 36(6):546-550.

Example 1

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, the above weighed material was added to 0.5 ml of dichloromethane to dissolve, and injected into 50 ml under homogeneous (6000-8000rpm) conditions In an aqueous solution of 0.5% PVA (w/w), keep the above homogeneous conditions for 5 minutes, then stir at 1000rpm to evaporate the solvent for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 8.6% drug were prepared, the embedding rate was 57%, and the measured particle size was 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 2.

Example 2

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 0.3 mg stearic acid, add the above weighed material into 0.5 ml dichloromethane to dissolve, inject it into 50 ml 0.5%PVA (w/w) under homogeneous (6000-8000rpm) conditions In the aqueous solution, keep the above homogeneous condition for 5 minutes, then evaporate the solvent by stirring at 1000rpm for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 9.4% drug were prepared, the embedding rate was 63%, and the measured particle size was 50-300μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 2.

Example 3

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 1.5 mg butyl stearate, add the above weighed material into 0.5 ml dichloromethane to dissolve, and inject it into 50 ml 0.5%PVA (w/ In the aqueous solution of w), keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry. Prepared with 10.3% drug The microspheres have an embedding rate of 68.7% and a measured particle size of 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 2.

Example 4

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 3 mg butyl stearate, add the above weighed material into 0.5 ml dichloromethane to dissolve, and inject it into 50 ml 0.5%PVA (w/ In the aqueous solution of w), keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry. Prepared to contain 13.3% of the drug The microspheres have an embedding rate of 89%, and the measured particle size is 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 2. The curve of sustained-release microspheres in Beagle dogs is shown in Figure 6. The line graph of the cumulative release rate of the sustained-release microspheres in Beagle dogs is shown in Figure 7. The scanning electron micrographs of the slow-release microspheres are shown in Figure 1.

Example 5

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 30 mg butyl stearate, add the above weighed material into 0.5 ml dichloromethane and dissolve it, inject it into 50 ml 0.5%PVA (w/ In the aqueous solution of w), keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry. Prepared to contain 10.5% of the drug The microspheres have an embedding rate of 70% and a measured particle size of 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 2.

Example 6

Weigh 52.9mg tolterodine, 300.0 mg 5050 5E PLGA, add the above weighed substance into 0.5 ml dichloromethane and dissolve it, inject it into 50 ml under homogeneous (6000-8000rpm) In an aqueous solution of 0.5% PVA (w/w), keep the above homogeneous conditions for 5 minutes, then stir at 1000rpm to evaporate the solvent for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. Microspheres containing 7.8% drug were prepared, the embedding rate was 52%, and the measured particle size was 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 3.

Example 7

Weigh 52.9mg tolterodine, 300.0 mg 5050 5E PLGA, 0.3 mg butyl stearate, add the above weighed material into 0.5 ml dichloromethane to dissolve, and inject it into 50 ml 0.5%PVA (w/ In the aqueous solution of w), keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry. Microspheres containing 7.2% drug were prepared, the embedding rate was 48%, and the measured particle size was 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 3.

Example 8

Weigh 52.9mg tolterodine, 300.0 mg, 5050 5E PLGA, 1.5 mg butyl stearate, add the above weighed material to 0.5 ml of dichloromethane, inject it into 50 ml of 0.5% PVA (w/w) aqueous solution under homogeneous (6000-8000rpm) conditions, keep the above homogeneous conditions for 5 minutes, and then stir at 1000rpm to evaporate the solvent 4 hours, filter through sieves with pore size of 25 μm and 125 μm, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 8.1% drug were prepared, the embedding rate was 54%, and the measured particle size was 50-300μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 3.

Example 9

Weigh 52.9mg tolterodine, 300.0 mg 5050 5E PLGA, 3 mg butyl stearate, add the above weighed substances into 0.5 ml dichloromethane to dissolve, and inject it into 50 ml 0.5%PVA (w/ In the aqueous solution of w), keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 9.3% drug were prepared, the embedding rate was 62%, and the measured particle size was 50-300μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 3.

Example 10

Weigh 52.9mg tolterodine 300.0 mg, 5050 5E PLGA, 30 mg butyl stearate, the above weighed material was added to 0.5 ml of dichloromethane, inject it into 50 ml of 0.5% PVA (w/w) aqueous solution under homogeneous (6000-8000rpm) conditions, keep the above homogeneous conditions for 5 minutes, and then stir at 1000rpm to evaporate the solvent 4 hours, filter through sieves with pore size of 25 μm and 125 μm, wash the microspheres with distilled water three times, and freeze-dry. Prepared with 10.7% drug The microspheres have an embedding rate of 71%, and the measured particle size is 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 3.

Example 11

Weigh 52.9mg tolterodine, 300.0 mg 5050 4.5A PLGA, add the above weighed material into 0.5 ml dichloromethane to dissolve, inject it into 50 ml under homogeneous (6000-8000rpm) conditions In an aqueous solution of 0.5% PVA (w/w), keep the above homogeneous conditions for 5 minutes, then stir at 1000rpm to evaporate the solvent for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 9.5% drug were prepared, the embedding rate was 634%, and the measured particle size was 50-300μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 4.

Example 12

Weigh 52.9mg tolterodine, 300.0 mg 5050 4.5A PLGA, 0.3 mg isopropyl palmitate, add the above weighed material into 0.5 ml dichloromethane to dissolve, inject it into 50 ml 0.5%PVA (w /w) in the aqueous solution, keep the above homogeneous condition for 5 minutes, then volatile solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and lyophilize. The microspheres containing 9.1% drug were prepared, the embedding rate was 61%, and the measured particle size was 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 4.

Example 13

Weigh 52.9mg tolterodine, 300.0 mg 5050 4.5A PLGA, 3 mg isopropyl palmitate, add the above weighed material into 0.5 ml dichloromethane to dissolve, and inject it into 50 ml 0.5%PVA (w /w) in the aqueous solution, keep the above homogeneous condition for 5 minutes, then volatile solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and lyophilize. The microspheres containing 8.4% drug were prepared, the embedding rate was 56%, and the measured particle size was 50-300μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 4.

Example 14

Weigh and weigh 52.9mg tolterodine, 300.0 mg 5050 4.5A PLGA, 30mg isopropyl palmitate, add the above weighed material into 0.5 ml dichloromethane to dissolve, and inject it into 50 ml 0.5%PVA (w/ In the aqueous solution of w), keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 8.6% drug were prepared, the embedding rate was 57%, and the measured particle size was 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 4.

Example 15

Weigh and weigh 52.9mg tolterodine, 300.0 mg 5050 4.5A PLGA, 10mg butyl stearate, add the above weighed material into 0.5 ml dichloromethane to dissolve, and inject it into 50 ml 0.5%PVA (w/ In the aqueous solution of w), keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 7.9% drug were prepared, the embedding rate was 53%, and the measured particle size was 50-300μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 4.

Example 16

Weigh and weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 10mg butyl stearate, add the above weighed material into 0.5 ml dichloromethane to dissolve, and inject it into 50 ml 0.5%PVA (w/w) under homogeneous (6000-8000rpm) conditions ) in the aqueous solution, keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with 25μm and 125μm sieves, wash the microspheres with distilled water three times, and freeze-dry. Prepared to contain 12.4% of the drug The microspheres have an embedding rate of 82%, and the measured particle size is 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 5.

Example 17

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 3 mg tetradecanoic acid, the above weighed material was added to 0.5 ml dichloromethane to dissolve, and injected into 50 ml 0.5%PVA (w/w) under homogeneous (6000-8000rpm) conditions In the aqueous solution, keep the above homogeneous condition for 5 minutes, then evaporate the solvent by stirring at 1000rpm for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 7.7% drug were prepared, the embedding rate was 51%, and the measured particle size was 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 5.

Example 18

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 10 mg tetradecanoic acid, add the above weighed material into 0.5 ml dichloromethane to dissolve, inject it into 50 ml 0.5%PVA (w/w) under homogeneous (6000-8000rpm) conditions In the aqueous solution, keep the above homogeneous condition for 5 minutes, then evaporate the solvent by stirring at 1000rpm for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. Microspheres containing 7.2% drug were prepared, the embedding rate was 48%, and the measured particle size was 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 5.

Example 19

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 3 mg stearic acid, add the above weighed material into 0.5 ml dichloromethane to dissolve, inject it into 50 ml 0.5%PVA (w/w) under homogeneous (6000-8000rpm) conditions In the aqueous solution, keep the above homogeneous condition for 5 minutes, then evaporate the solvent by stirring at 1000rpm for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 7.3% drug were prepared, the embedding rate was 49%, and the measured particle size was 50-300μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 5.

Example 20

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 10 mg stearic acid, add the above weighed material into 0.5 ml dichloromethane to dissolve, inject it into 50 ml 0.5%PVA (w/w) under homogeneous (6000-8000rpm) conditions In the aqueous solution, keep the above homogeneous condition for 5 minutes, then evaporate the solvent by stirring at 1000rpm for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 8.5% drug were prepared, the embedding rate was 57%, and the measured particle size was 50-300μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 5.

Example twenty one

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 3 mg palmitic acid, the above weighed material was added to 0.5 ml dichloromethane to dissolve, and it was injected into 50 ml 0.5%PVA (w/w) under homogeneous (6000-8000rpm) conditions In the aqueous solution, keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 8.2% drug were prepared, the embedding rate was 55%, and the measured particle size was 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 5.

Example twenty two

Weigh 52.9mg tolterodine, 300.0 mg 7525 7E PLGA, 10 mg palmitic acid, the above weighed material was added to 0.5 ml of dichloromethane to dissolve, and injected into 50 ml of 0.5% PVA (w/w) under homogeneous (6000-8000rpm) conditions In the aqueous solution, keep the above homogeneous condition for 5 minutes, then volatile the solvent by stirring at 1000rpm for 4 hours, filter with a 25μm and 125μm sieve, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 7.9% drug were prepared, the embedding rate was 52%, and the measured particle size was 50-300 μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 5.

Example twenty three

Weigh 52.9mg tolterodine, 300.0 mg 503H PLGA, 3 mg butyl stearate, the above weighed material was added to 0.5 ml of dichloromethane, inject it into 50 ml of 0.5% PVA (w/w) aqueous solution under homogeneous (6000-8000rpm) conditions, keep the above homogeneous conditions for 5 minutes, and then stir at 1000rpm to evaporate the solvent 4 hours, filter through sieves with pore size of 25 μm and 125 μm, wash the microspheres with distilled water three times, and freeze-dry. The microspheres containing 6.2% drug were prepared, the embedding rate was 41%, and the measured particle size was 50-300μm. The line graph of the cumulative release rate of the sustained-release microspheres in the simulated release solution is shown in Figure 4. The line graph of the cumulative release rate of the sustained-release microspheres in Beagle dogs is shown in Figure 6. The line graph of the cumulative release rate of the sustained-release microspheres in Beagle dogs is shown in Figure 7.

Prove positive effect of the present invention by following experimental example:

The release of tolterodine long-acting sustained-release microsphere preparation with small molecular fatty acid ester and fatty acid as additives and drug loading of 15% is more stable, and the release period is extended from the original two weeks to 40 days.

In vitro release test of tolterodine microspheres prepared with 7525 7E PLGA as matrix and added with butyl stearate by emulsification solvent evaporation method, using the microspheres of Examples 1-5 and Example 16 to release by simulating in vivo conditions Test, see accompanying drawing 2 and accompanying drawing 5.

The in vitro release test of tolterodine microspheres with 5050 5E PLGA as the matrix and added butyl stearate prepared by the emulsification solvent volatilization method adopts the microspheres of Examples 6-10 to carry out the release test by simulating the in vivo conditions, see the attached image 3.

The in vitro release test of tolterodine microspheres with 5050 4.5A PLGA prepared by the emulsification solvent evaporation method, adding isopropyl palmitate or adding butyl stearate, using the microspheres of embodiments 11-15, by simulating The release test was carried out under in vivo conditions, as shown in Figure 4.

The in vitro release test of tolterodine microspheres prepared with 7525 7E PLGA as a matrix and added with myristic acid or stearic acid or palmitic acid by the emulsification solvent evaporation method, using the microspheres of Examples 17-22, carried out by simulating in vivo conditions Release test, see accompanying drawing 5.

The beagle dog in vivo experiment of tolterodine microspheres adopts Examples 4 and 23, and it can be concluded that the main reason for the different in vivo release behaviors of the two batches of microspheres is that the PLGA model is different, and the secondary reason is that the additives are different. Figure 6 and Figure 7.

According to the research of the present inventors, using a buffer solution (phosphate buffer solution) with a certain pH value (pH 7.4), the drug release behavior is similar to that in the body, so although the environment is not exactly the same as the environment in the human body, it is generally believed that In vivo release pattern.

Experimental equipment: constant temperature oscillator, centrifuge.

Experimental conditions: temperature: 37±0.5°C, rotation speed: 120rpm.

Experimental method: Accurately weigh about 1.5 ㎎ of the experimental sample, put it in a plastic centrifuge tube with a cap with a volume of 50 ml, add 40 ml of release medium (pH=7.4 Phosphate buffer solution) placed in a constant temperature shaker, maintaining a certain temperature and rotation speed, and sampling according to time points.

Sampling method: centrifuge the centrifuge tube at 4500 rpm for 5 minutes, accurately draw 20 ml of the solution, and at the same time add 20 ml of release medium to the centrifuge tube, and take out the liquid for detection by HPLC.

Sampling time point (day): 0, 0.125, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 38, 42 , 46, 50 where Day 0 refers to the drug concentration before administration on the day of administration.

Conclusion: The invention of this experiment uses fatty acids or fatty acid esters as additives for biological sustained-release microsphere preparations, so that the drug can be released for nearly a month, greatly reducing the number of medications, improving the therapeutic effect, and reducing toxic and side effects, thereby greatly reducing the number of patients. pain and improve their quality of life.

Claims (2)

1. a tolterodine slow-release microsphere reagent containing small molecule additive, is characterized in that being made by following medicine by weight and number ratio: 1%-20% tolterodine, 0.1%-10% small molecular additives, and the balance is biodegradable pharmaceutical polymer excipients; The small-molecule additive is a small-molecule fatty acid or a small-molecule fatty acid ester with a molecular weight of less than 500 Daltons; The small molecular fatty acid is one of stearic acid, palmitic acid and myristic acid; The biodegradable pharmaceutical polymer material is from one of polylactide-glycolide, polylactic acid, polycaprolactone, polyhydroxybutyrate-hydroxyvalerate copolymer or a mixture of two of them ( 1:9-9:1), its molecular weight is 3000-50000 Daltons. 2. the preparation method of a kind of tolterodine slow-release microsphere preparation containing small molecule additive described in claim 1, comprises the following steps: Weigh tolterodine, small molecule additives and polylactide-glycolide according to the above ratio and add to 0.2-5 ml Dissolve in dichloromethane, inject it into 0.3-3% PVA (w/w) aqueous solution under homogeneous (6000-8000rpm) conditions, keep the above homogeneous conditions for 5 minutes, and then stir at 1000rpm The solvent was evaporated for 4 hours, filtered through a sieve with a pore size of 25 μm and 125 μm, the microspheres were washed three times with distilled water, and freeze-dried.