CN110833532A

CN110833532A - Rapidly-released lurasidone hydrochloride tablet and preparation process thereof

Info

Publication number: CN110833532A
Application number: CN201911317450.2A
Authority: CN
Inventors: 王慧; 段培锋; 张延蕊; 崔晴晴; 赵洁
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-12-19
Filing date: 2019-12-19
Publication date: 2020-02-25

Abstract

The invention relates to a lurasidone hydrochloride tablet which is used for treating major depression related to bipolar I disorder of pediatric patients and can realize quick and complete release of medicine, and a preparation process thereof. The invention obtains the lurasidone hydrochloride tablet by dissolving the medicine and part of the diluent in the mixed solvent of the organic solvent and water, then mixing with the rest auxiliary materials at high speed, drying, granulating and tabletting. Compared with the prior art, the preparation method has the advantages of simple preparation process, low energy consumption, rapid release, good release reproducibility and stable preparation after accelerated test.

Description

Rapidly-released lurasidone hydrochloride tablet and preparation process thereof

Technical Field

The invention relates to the field of medicaments, in particular to lurasidone hydrochloride tablets capable of realizing quick and complete drug release and used for treating major depression related to bipolar I disorder of pediatric patients and a preparation process thereof.

Background

Lurasidone Hydrochloride (Lurasidone Hydrochloride) is an atypical antipsychotic drug developed by Sumitomo pharmaceutical (Sumitomo) corporation. It was approved by the FDA for first line treatment of schizophrenia on day 28 of 10 months 2010 under the trade name Latuda and was formulated as a tablet. As 8 months of 2019, there are 44 records on the drug in the american orange book; in addition, the drug was FDA approved for the treatment of bipolar I disorder-associated major depressive disorder in pediatric patients on 3/1 in 2019. It follows that even after the last 9 years of marketing, the drug still has great potential in the field of psychiatric subdivision. At present, many pharmaceutical enterprises or research institutes such as Sumitomo pharmaceutical (Suzhou) Co., Ltd, Harbin Tri-drug industry Co., Ltd, Shanghai pharmaceutical industry research institute, Shanghai Mingkude New drug development Co., Ltd, Chenxin pharmaceutical industry Co., Ltd have submitted the drug review of lurasidone hydrochloride tablets in China, and some have obtained the lot. This also shows the viability and potential of the "old" drug for its exchange.

However, the lurasidone hydrochloride has poor water solubility, and after the lurasidone hydrochloride is prepared into tablets, the initial release speed is slow, and the lurasidone hydrochloride is accumulated and incompletely released, so that the bioavailability is poor, and the drug effect is not high. In order to overcome the problems, patent CN201210241053.3 discloses an orally disintegrating tablet of lurasidone hydrochloride, which can be rapidly disintegrated by controlling the particle size of the raw material drug below 75 microns and screening the types of the auxiliary materials, wherein the dissolution rate in 15min is up to 85% or more, however, although the dissolution rate is improved, the particle size of the raw material drug needs to be controlled, the pharmaceutical cost is increased, the commonly used physical pulverization has high energy consumption, dust needs to be strictly controlled, and the orally disintegrating tablet has potential safety risks, and after the orally disintegrating tablet rapidly releases the drug, the blood concentration is easily and rapidly increased after the orally disintegrating tablet is absorbed by oral mucosa and gastrointestinal tract. Patent CN201711358052.6 discloses a lurasidone hydrochloride dispersible tablet and a preparation method thereof, which essentially controls the particle size of lurasidone hydrochloride by crushing and sieving with a 200-mesh sieve, and a disintegrating agent is added by an internal and external method, and then the dissolution is realized for 15min to be more than 85 percent, and the problem similar to the orally disintegrating tablet still exists. Patent CN201710830387.7 discloses a preparation method of lurasidone hydrochloride tablets, wherein raw materials and a filler are micronized in a micronization mode and then wet granulation is carried out, the 15-min dissolution rate can reach 90%, and 45% of the dissolution rate can be close to complete dissolution. However, compared with the above-mentioned pulverizing and sieving method, micronization has the disadvantages of higher energy consumption, higher risk, and poor powder flowability, and limits that only wet granulation can be adopted, and the steps are complicated. In addition, the above patents only focus on dissolution of the formulation, but none focus on formulation stability of lurasidone hydrochloride.

In order to overcome the defects of complicated preparation process and high energy consumption of the prior art and improve the release speed and the release degree of the lurasidone hydrochloride preparation, the invention provides the lurasidone hydrochloride tablet capable of releasing the drug rapidly.

Disclosure of Invention

The technical scheme of the invention is realized by the following steps:

(1) preparing a mixed solvent of an organic solvent and water, adding the medicine and part of the filler into the solvent, and stirring to form a uniform and clear single-phase system A;

(2) adding the adhesive and the rest of the filler into a high-speed mixing granulator and uniformly mixing to obtain a mixture B;

(3) and (2) adding the single-phase system A in the step (1) into the high-speed mixing granulator in the step (2), and discharging dry granules after high-speed mixing and cutting.

(4) And (4) directly tabletting the dry particles obtained in the step (3) to obtain the lurasidone hydrochloride tablet.

Wherein the organic solvent is one or more of ethanol, acetone and isopropanol; preferably isopropanol; the filler is one or two of lactose and mannitol; preferably mannitol; the adhesive is PVPK 30;

further, the mass ratio of the drug to the total filler is 1: 5-20, preferably 1: 8-12;

further, the mass ratio of the filler to the adhesive is 4-6: 1;

further, the volume ratio of the organic solvent to the water in the step (1) is 1-3:1, preferably 2: 1;

further, the amount of part of the filler in the step (1) is 1/2-1/10, preferably 1/4-1/5;

still further, the dosage ratio (volume/mass ratio) of the mixed solvent and the drug in the step (1) is 6-12:1, preferably 8-9: 1.

Drawings

FIG. 1 is a dissolution profile of tablets prepared in examples 1-5 of the present invention.

Detailed Description

1. Preliminary experiment of preparation process

Generally, there are two ways to increase drug solubility, one is from large to small, such as micronization; the other is from small to large, for example, nanocrystalline is precipitated after dissolution. The micronization has less influence on the chemical stability of the active ingredient due to less parameter selection and no additional addition of other solvents, but the prepared powder has poor flowability, high energy consumption in the preparation process and potential dust pollution and explosion risks. The solvent rule needs to select a proper solvent, and different solvents have great influence on the stability of the preparation and the physical properties of the tablet. The present invention adopts a solvation method to increase the stability of the drug and attempts to simplify the preparation process by optimizing the solvent. Ethanol is the most common, safe and nontoxic organic solvent in the medicament, can dissolve lurasidone hydrochloride, is selected for preliminary experiments, and in addition, the most common lactose is selected as a filling agent, PVPK30 is selected as a binding agent, and a lubricant and a disintegrating agent are considered to be adopted to control the tabletting performance and dissolution.

However, in preliminary experiments, two problems are found when the medicine is directly mixed with tablet auxiliary materials for tabletting after being dissolved in an organic solvent, and one is that the friability of the tablets is not easy to be qualified; secondly, after the tablet is qualified by adding a high amount of adhesive, the 5min accumulated dissolution rate is only about 30 percent, which is lower than the dissolution rate close to 50 percent disclosed by the prior art such as CN201710830387.7, and the 45min dissolution rate in a preliminary experiment is only 80 percent.

After a plurality of attempts, the inventor finds that the dissolution of the obtained tablet can be obviously increased by dissolving the medicine and part of lactose together and then mixing the medicine and the rest of lactose and the bonding agent, and the friability index of the tablet is improved to a certain extent. Therefore, the basic process is determined by mixing and dissolving the medicine and part of the filling agent in advance and then mixing the medicine and the rest auxiliary materials.

2. Selection of solvents and adjuvants

Because ethanol, acetone and isopropanol are all organic solvents which are usually involved in the preparation of lurasidone hydrochloride or related preparations thereof, the three organic solvents are selected as solvents for dissolving the medicine; considering that water has a high viscosity and thus the tablet molding rate can be increased and the friability can be reduced, the effects of the use of an organic solvent alone or the mixing of water at a certain ratio on the compressibility, flowability, and the like of the preparation granules were also examined. Because the solubility of the lurasidone hydrochloride is poor, and the filling agent needs to select auxiliary materials with good water solubility, the lactose and the mannitol are selected as the filling agents of the preparation. In addition, a binder is additionally added to adjust the compressibility of discharged particles, and the binder is selected from the commonly used PVPK 30.

Respectively dissolving the medicines in three pure organic solvents of ethanol, acetone and isopropanol and three mixed solvents of ethanol-water, acetone-water and isopropanol-water (volume ratio is 2:1) to obtain 6 solutions, and testing the content of a lurasidone hydrochloride related substance A and the total impurities in the 6 solutions after storing for one week at 40 ℃; in addition, lactose and mannitol which are respectively 10 times of the lurasidone hydrochloride are added into the 6 solutions which are prepared in addition, a uniform system is formed by stirring, and the lurasidone hydrochloride related substance A and the total impurity content in the 6 solutions are tested after the lurasidone hydrochloride related substance A and the mannitol are stored for one week at the temperature of 40 ℃. The results are shown in table 1:

TABLE 1 compatibility test of solvents and adjuvants

As can be seen from Table 1, the increase of the content of the substances after one week of storage was not significant when water was not added, whereas the increase of the content of the substances after one week of storage was significant when water was added to form a mixed solvent; in addition, the results of the intermediate time period (1-6 days) show that the content of impurities increases with the time, wherein the increase of the content of impurities is not obvious within 24 hours, so that the subsequent preparation needs to ensure that the mixing system is completely mixed with other auxiliary materials within 24 hours, and the prepared granules are dried, so that the stability of the dried granules is improved. The influence effect of lactose and mannitol in the content of related substances has no significant difference.

3. Particle flowability and compressibility tests.

Based on preliminary experiments, compressibility, friability, were the focus of the study. Therefore, whether the tablets prepared by adopting different auxiliary materials/parameters meet the basic requirements of the dosage form is tested. The process used in this test section was as follows: (1) preparing an organic solvent or a mixed solvent (the ratio is 2:1) of the organic solvent and water, dissolving a medicine (the mass ratio of the medicine to the solvent is 1:10) in the solvent, adding 1/5 filler (the mass ratio of the medicine to the total amount of the filler is 1:10), and stirring to form a uniform and clear single-phase system A; (2) adding the optional adhesive and the rest filler into a high-speed mixing granulator and uniformly mixing to obtain a mixture B; (3) and (3) adding the single-phase system A in the step (1) into the high-speed mixing granulator in the step (2), mixing, cutting and discharging dry granules. Sampling the granules to test the angle of repose, directly tabletting the granules, sampling tablets, and testing the friability of the tablets after tabletting according to a friability inspection method of 0923 tablets in 2015 edition of Chinese pharmacopoeia, wherein the weight loss is more than 1%, and the tablets which are broken, cracked and crushed are judged to be unqualified in friability.

TABLE 2 sheeting test

As can be seen from table 2, when the drug and a part of the filler were dissolved by using only an organic solvent, the flowability of the obtained granules was extremely excellent, but the friability of the tablets did not meet the requirement even when the tablets were compressed after PVPK30 was added, and thus tablets meeting the basic compression requirements could not be obtained by using only an organic solvent. The flowability of the granules generally decreases slightly after the addition of water, but is still in a good range, and the friability of the resulting tablets is satisfactory due to the addition of water having a relatively high viscosity during mixing.

4. Dissolution test

The 6 groups of tablets in test 3, which were of acceptable friability, were tested directly for cumulative dissolution within 45min, with the following results:

TABLE 3 dissolution Table

5min

10min

15min

25min

35min

45min

Group 1: ethanol/water + lactose/PVP group

42.1％

63.2％

80.8％

88.6％

91.6％

92.2％

Group 2: acetone/water + lactose/PVP group

45.5％

64.5％

87.3％

91.7％

95.5％

96.9％

Group 3: isopropyl alcohol/water + lactose/PVP group

46.3％

65.1％

86.6％

90.2％

96.3％

96.2％

Group 4: ethanol/Water + mannitol/PVP group

47.2％

70.6％

87.3％

91.5％

96.5％

97.0％

Group 5: acetone/water + mannitol/PVP group

52.6％

78.3％

92.9％

93.6％

97.8％

98.1％

Group 6: isopropyl alcohol/water + mannitol/PVP group

55.3％

79.5％

91.6％

95.3％

98.5％

98.2％

As can be seen from Table 3, the dissolution effects in groups 1-6 were all good, and most of them had a dissolution rate of 90% or more at 25 min. Wherein the overall effect of the lactose group is slightly inferior to that of the mannitol group; the dissolution effect of using isopropyl alcohol and water and using acetone and water as a mixed dissolution solvent is more excellent than that of the ethanol and water group; especially the combination of isopropanol/water and mannitol, the dissolution rate is the best. However, since acetone has high toxicity and the influence of acetone on the stability of the drug is large in a compatibility test, a mixed solvent of isopropanol and water is selected as a solvent in the preparation of the tablet.

Specific preparation examples

Example 1:

(1) weighing 20g of lurasidone hydrochloride and 200g of mannitol for later use;

(2) weighing 120mL of isopropanol and 60mL of water, mixing, and dissolving lurasidone hydrochloride and 40g of mannitol in the mixed solution to obtain a uniform and clear single-phase system A;

(3) adding 40g of PVPK30 and the rest of filler into a high-speed mixing granulator and uniformly mixing to obtain a mixture B;

(4) adding the single-phase system A in the step (2) into the high-speed mixing granulator in the step (3), mixing, cutting and drying, and then discharging dry granules;

(5) and directly tabletting to obtain 1000 tablets in total.

Example 2:

the specific procedure was the same as in example 1 except that the total amount of mannitol was 160 g;

example 3:

the specific steps are the same as example 1, except that the amount of water is 50 mL;

example 4:

the specific steps are the same as example 1, except that the total amount of mannitol is 180g, the dosage of isopropanol is 100mL, and the dosage of PVP is 30 g;

example 5:

the specific steps are the same as example 1, except that the total amount of mannitol is 180g, and the consumption of PVP is 30 g;

the tablets of examples 1-5 were each tested for dissolution within 45min, see table 4;

TABLE 4 dissolution of the examples

5min

10min

15min

25min

35min

45min

Example 1

53.4％

81.1％

92.6％

95.1％

99.1％

99.2％

Example 2

51.8％

78.8％

92.1％

94.4％

99.0％

99.1％

Example 3

52.9％

79.6％

92.5％

94.5％

99.0％

Example 4

50.3％

77.2％

90.6％

93.5％

98.2％

98.6％

Example 5

51.3％

76.5％

91.3％

93.7％

98.9％

The result shows that the tablet prepared by the method has stable release rate and high release speed. In addition, the stability of the tablet of example 1 was tested under the accelerated condition of 6 months, and the results showed that the total impurity content of the tablet was 0.03% and the impurity a content was 0.02% under the accelerated condition of 6 months, which met the formulation stability requirements.

Claims

1. A preparation process of a rapid-release lurasidone hydrochloride tablet is characterized by comprising the following steps:

(3) and (3) adding the single-phase system A in the step (1) into the high-speed mixing granulator in the step (2), and discharging dry granules after high-speed mixing and cutting.

2. The process of claim 1, wherein: the organic solvent is one or more of ethanol, acetone and isopropanol; isopropyl alcohol is preferred.

3. The process according to claim 1, wherein the filler is one or both of lactose and mannitol; mannitol is preferred.

4. The process of claim 1, wherein the binder is PVPK 30.

5. The process according to claim 1, wherein the mass ratio of the drug to the total filler is 1: 5-20, preferably 1: 8-12.

6. The process according to claim 1, wherein the mass ratio of the filler to the binder is 4-6: 1.

7. The process according to claim 1, wherein the volume ratio of the organic solvent to water in step (1) is 1-3:1, preferably 2: 1.

8. The process according to claim 1, wherein the amount of the filler used in step (1) is 1/2-1/10, preferably 1/4-1/5, based on the total amount of the filler.

9. The process according to claim 1, wherein the amount ratio (volume/mass ratio) of the mixed solvent to the drug in the step (1) is 6 to 12:1, preferably 8 to 9: 1.

10. The lurasidone hydrochloride tablet capable of releasing the drug rapidly is prepared by the preparation process of any one of claims 1 to 9.