WO2022042646A1 - Lurasidone hydrochloride composition and preparation method therefor - Google Patents

Abstract

A lurasidone hydrochloride composition and a preparation method therefor. The lurasidone hydrochloride composition comprises a lurasidone hydrochloride particle composition and a lubricant. The lurasidone hydrochloride particle composition comprises: lurasidone hydrochloride, croscarmellose sodium, silica, pre-gelatinized starch, a filler, and a binder.

Description

Lurasidone hydrochloride composition and preparation method thereof

This application claims the priority of the Chinese patent application filed on August 26, 2020 with the application number 202010867062.8 and the invention titled "An oral preparation of lurasidone hydrochloride and its preparation method", the entire contents of which are passed Reference is incorporated in this application.

technical field

The invention belongs to the technical field of medicine, and relates to a lurasidone hydrochloride composition and a preparation method thereof.

Background technique

Lurasidone is an atypical antipsychotic. Its structural formula is as follows:

Chinese patent CN201010564784.2 discloses a lurasidone instant tablet and a preparation method thereof. The method achieves the effect of improving the dissolution rate by making the content of pregelatinized starch by weight 10-50% of the weight of the preparation.

Chinese patent CN201410602319.1 discloses the use of a mixture of low-substituted hydroxypropyl cellulose and croscarmellose sodium, the low-substituted hydroxypropyl cellulose is 5-20% of the weight of the preparation, and the The mixture is 1-5% of the weight of the preparation, the weight ratio of low-substituted hydroxypropyl cellulose and croscarmellose sodium is 4-6:1, and the effect of improving the dissolution rate is achieved by using two disintegrants .

Bioavailability is the rate at which a drug enters a target organ or tissue and the extent to which it is utilized by the target organ. Lurasidone is a poorly soluble drug and has bioavailability problems when administered orally. Because the drug bioavailability test is more complicated than the in vitro dissolution test, in practice, the in vivo bioavailability of poorly soluble drugs can generally be predicted by measuring the in vitro dissolution rate, but there is also the possibility of poor in vitro and in vivo correlation.

SUMMARY OF THE INVENTION

The present invention provides a lurasidone hydrochloride composition and a preparation method thereof. The lurasidone hydrochloride composition can comprehensively improve the dissolution effect of lurasidone hydrochloride and simultaneously improve the bioavailability.

In one aspect, the present invention provides a lurasidone hydrochloride granular composition, the granular composition comprising the following components: lurasidone hydrochloride, croscarmellose sodium, silicon dioxide, pregelatinized starch , fillers and adhesives.

The granular composition of the present invention refers to the product after granulation. Granulation is the operation of processing powder and other materials into granules with a certain shape and size. Granulation, as a processing process of particles, is related to almost all solid preparations. The granulate may be the final product or an intermediate, eg in capsules the granules are the product and in the production of tablets the granules are the intermediate.

Preferably, the present invention provides a lurasidone hydrochloride granular composition, the lurasidone hydrochloride granular composition comprising the following components: by weight, 20-45wt% lurasidone hydrochloride, 0.5-5.0 wt% croscarmellose sodium, 0.25-4.0 wt% silicon dioxide, greater than 0 wt% and less than 10 wt% pregelatinized starch, fillers and binders.

Further preferably, the lurasidone hydrochloride granule composition of the present invention comprises 0.5-3.0wt% of croscarmellose sodium, particularly preferably 1.5-2.5wt% of croscarmellose sodium, preferably 0.5-1.5 wt % silica, particularly preferably 0.5-1 wt % silica, and/or preferably greater than 0 wt % and less than or equal to 9.0 wt % pregelatinized starch.

Further preferably, the lurasidone hydrochloride granular composition of the present invention comprises 30-80wt% filler, preferably 40-70wt% filler, more preferably 55-60wt% filler, particularly preferably 56-60wt% filler .

Further preferably, the lurasidone hydrochloride granule composition of the present invention comprises 0.5-20wt% binder, preferably 0.5-8wt% binder, particularly preferably 4.0-5.0wt% binder.

Fillers suitable for the lurasidone hydrochloride granular composition of the present invention include, but are not limited to: mannitol, lactose, microcrystalline cellulose, xylitol, silicified microcrystalline cellulose, starch, sucrose, glucose, maltitol, One or any combination of fructose, sorbitol, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium silicate, etc., preferably mannitol and microcrystalline cellulose, more preferably mannitol.

Adhesives suitable for the lurasidone hydrochloride granule composition of the present invention include but are not limited to: hypromellose, hypromellose, methylcellulose, copovidone, povidone, polyvinyl alcohol, etc. , preferably hypromellose and polyvinyl alcohol, more preferably hypromellose.

The silicon dioxide described in the present invention is colloidal silicon dioxide.

In another aspect, the present invention provides a lurasidone hydrochloride pharmaceutical composition, the pharmaceutical composition comprising the above-mentioned lurasidone hydrochloride granular composition and a lubricant, and the pharmaceutical composition is preferably a tablet agent.

Lubricants suitable for the lurasidone hydrochloride pharmaceutical composition of the present invention include but are not limited to: stearic acid, magnesium stearate, sodium stearyl fumarate, talc, etc., preferably magnesium stearate, stearic acid Sodium fumarate; more preferably sodium stearyl fumarate.

Further, the lurasidone hydrochloride pharmaceutical composition of the present invention contains 0.1-5wt% lubricant, preferably 0.5%-2wt%, more preferably 0.75-2wt%, particularly preferably 0.75-1wt%.

Further, the particle size of lurasidone hydrochloride in the lurasidone hydrochloride granular composition or pharmaceutical composition of the present invention is preferably D90 of 1-25 μm, more preferably D90 of 6-25 μm, particularly preferably D90 of 6-16 μm.

Further, the particle size D50 of lurasidone hydrochloride in the lurasidone hydrochloride granule composition or pharmaceutical composition of the present invention is 2-9 μm, particularly preferably D50 is 2.5-8 μm.

On the other hand, the present invention also provides a preparation method of lurasidone hydrochloride granule composition, the method comprises the following steps:

1) lurasidone hydrochloride, pregelatinized starch, filler, and croscarmellose sodium are mixed to obtain a mixture;

2) The mixture obtained in 1) is wet granulated by using a binder and silica, and dried to obtain a lurasidone hydrochloride granule composition.

In another aspect, the present invention also provides a method for preparing a lurasidone hydrochloride pharmaceutical composition, the method comprising adding a lubricant to the lurasidone hydrochloride granule composition, selectively adding an external disintegrant, etc. The pharmaceutical composition is obtained by processing, such as tableting to obtain tablets, and encapsulation to obtain capsules.

Preferably, the lurasidone hydrochloride pharmaceutical composition obtained above may optionally be film-coated, if desired.

If necessary, the lurasidone hydrochloride pharmaceutical composition provided by the present invention may further comprise a dosage form such as a granule, a tablet or a capsule after being mixed with external adjuvants. Optionally additional excipients include additional disintegrants and the like. The added disintegrant includes but is not limited to: crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, etc., preferably crospovidone.

Further, the percentage of the additional disintegrant in the weight of the preparation is 1-4 wt %, preferably 1.5-3 wt %.

In the lurasidone hydrochloride pharmaceutical composition provided by the present invention, additives can be optionally added, and the additives include colorants, coating agents, flavoring agents, surfactants, plasticizers, fragrances or polishing agents Wait.

The lurasidone hydrochloride composition provided by the present invention improves the dissolution rate and/or bioavailability of lurasidone hydrochloride. In some cases, there may be an incomplete correlation between the in vivo bioavailability test and the in vitro dissolution test. At the same time, the preparation method of the lurasidone hydrochloride composition of the present invention is easy to operate, has good reproducibility, and is suitable for large-scale industrial production.

Description of drawings

In order to illustrate the embodiments of the present invention and the technical solutions of the prior art more clearly, the following briefly introduces the drawings required in the embodiments and the prior art. Obviously, the drawings in the following description are only the For some embodiments of the invention, those of ordinary skill in the art can also obtain other drawings according to these drawings.

Figure 1 shows the results of intra-batch differences in cumulative dissolution of lurasidone hydrochloride tablets prepared according to Example 1 and Comparative Examples 1-2 of the present invention;

Figure 2 shows the comparative results of cumulative dissolution of lurasidone hydrochloride tablets prepared according to Examples 1-4 of the present invention;

Figure 3 shows the comparative results of cumulative dissolution of lurasidone hydrochloride tablets prepared according to Examples 1 to 5-7 of the present invention.

detailed description

In order to make the objectives, technical solutions, and advantages of the present invention more clear, the present invention will be described in further detail below with reference to the accompanying drawings and embodiments. Obviously, the described embodiments are only some, but not all, embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention fall within the protection scope of the present invention.

The preparation of lurasidone hydrochloride tablet used in the embodiment of the present invention, the concrete method is as follows:

1) Pulverize the crude drug of lurasidone hydrochloride, and control its particle size D90 to be 6-24 μm for later use.

2) Preparation of the binder/silicon dioxide suspension: Dissolve the binder (the amount of the binder is 0.5-20 wt %, preferably 0.5-8 wt %, particularly preferably 4.0-5.0 wt % based on the weight of the oral preparation) pure water, and then adding silicon dioxide (the amount of silicon dioxide is 0.25-4.0 wt % of the weight of the oral preparation, preferably 0.5-1.5 wt %, particularly preferably 1.5-2.5 wt %) to prepare the prepared adhesive/di Silicon oxide suspension, wherein the binder can be used such as hypromellose or polyvinyl alcohol, the concentration of the binder aqueous solution is preferably 1-15wt%, preferably 2-8wt%, more preferably 5wt%.

3) Preparation of granules containing lurasidone hydrochloride: adding lurasidone hydrochloride, mannitol, croscarmellose sodium and pregelatinized starch into the fluidized bed and mixing uniformly. Add the binder/silicon dioxide suspension prepared in (2) to make soft material, and adopt fluidized bed granulation or direct high shear granulation.

4) Drying: The granules obtained above are dried in a fluidized bed. The criterion for drying is loss on drying, eg, within 3 wt%, preferably 1-2 wt%.

5) A lubricant is added to the dried granules in (4) above, and mixed to obtain a mixture. Agitators, for example of the diffusion mixer type, can be used. In particular, a V mixer, a double cone mixer, a hopper mixer, or the like is used.

6) Compression and coating: the above mixture is compressed, and the plain tablet is optionally coated with Opadry to obtain the final coated tablet. The coating material is a film coating premix. The equipment used for coating may be a coating pan type equipment or the like. The coating weight gain is selected to be about 1-5 wt%, preferably 2-4 wt%.

One, embodiment 1-3 and comparative example 1 and 2:

The raw materials and proportions of Examples 1-3 and Comparative Examples 1 and 2 are shown in Table 1:

Table 1

	Example 1 (g)	Comparative Example 1 (g)	Comparative Example 2 (g)
lurasidone hydrochloride	40	40	40
Mannitol	90.4	72	132
pregelatinized starch	14.4	14.4	14.4
Croscarmellose sodium	4	4	4
low substituted hydroxypropyl cellulose	-	20	-
Hydroxypropylmethylcellulose	8	8	8
silica	1.6	-	-
Magnesium stearate	1.6	1.6	1.6

test:

a. Dissolution test: The formulation prepared by the present invention is subjected to a dissolution test. Measurement conditions include: test solution; pH 1.2 hydrochloric acid solution; method: slurry method; rotational speed: 50 rpm; volume of dissolution medium: 900 mL.

b. Similarity of dissolution properties

The similarity factor f ₂ is used here as an indicator for evaluating the similarity of the dissolution properties. The f ₂ value was calculated by the following formula. It was determined that each formulation prepared in the present invention had similar dissolution characteristics if f2 calculated from the dissolution rate of each _formulation was _{50≤f2≤100} . After the start of the experiment, the dissolution rates at three time points, such as at 10 minutes, 15 minutes and ₂₀ minutes, were used to calculate f2 values. The calculation _formula of the similarity factor f2 is as follows:

In the above formula, Ti and Ri are the dissolution percentages at each time point, and n is the number of points to be compared. The results are shown in Table 2 and Figure 1.

Table 2

As shown in Table 2 and Figure 1, the dissolution of Example 1 reaches more than 85% in 15 minutes, and can be rapidly dissolved, and basically completely dissolves and reaches more than 99% in 20 minutes. In Comparative Example 2, when croscarmellose sodium is used alone, the dissolution of the sample in a pH 1.2 hydrochloric acid solution is too slow, and it is not similar to Example 1. Although the disintegrant of Comparative Example 1 was used in combination with L-HPC and croscarmellose sodium, the dissolution rate was improved, but the dissolution characteristics were not similar to those of Example 1. In Example 1, the dissolution reached more than 85% in 15 minutes, and the dissolution was rapid, and the dissolution was basically complete and reached more than 99% in 20 minutes.

Two, embodiment 1-4:

(1) embodiment 1-4 raw material and proportioning are as shown in table 3:

table 3

(1) Test:

The dissolution results of Examples 1-4 are shown in Table 4 and Figure 2.

Table 4

As shown in Table 4 and Figure ₂ , the f2 values in Examples 2-4 show similarities to Example 1. That is, as shown in Table 4 and FIG. 2 , in Examples 1-4, the f ₂ value representing the similarity of the dissolution characteristics was in the range of 50≦f ₂ ≦100, and preparations having similar dissolution characteristics were obtained.

Three, embodiment 1,5-7:

(1) In Examples 1, 5-7, lurasidone hydrochloride-containing tablets were prepared by using lurasidone hydrochloride powders having different particle size distributions (Table 5). :

table 5

(2) embodiment 1,5-7 raw material and proportioning are as shown in table 6:

Table 6

(3) Test:

The dissolution results of Examples 1 and 5-7 are shown in Table 7 and Figure 3 .

Table 7

As shown in Table 7 and Figure ₃ , the f2 values in Examples 5-6 show similarities to Example 1. That is, formulations prepared by using lurasidone hydrochloride powder exhibit similar dissolution characteristics, preferably wherein the powder has a 50% particle size distribution D50 of 2-9 μm and a 90% particle size distribution D90 of 24 μm or less.

4. Embodiment 1, 8-10

1) Example 1, 8-10 raw materials and proportions are as shown in Table 8:

Table 8

Embodiment 8-10 adopts the same production batch of lurasidone hydrochloride raw material to test, and the particle size distribution of described lurasidone hydrochloride is as follows in Table 9:

Table 9

2) Test:

Embodiment 1, 8-10, comparative example 3 (trade name:

Specification: 40mg) The dissolution results are shown in Table 10.

Table 10

The results show that the f2 values in Examples 1, 8-10 show that Examples 1, 8-10 and Comparative Example 3 have similar dissolution rates.

V. Pharmacokinetic test of Example 10 and Comparative Example 3

The purpose of this test is to study the pharmacokinetic characteristics of Example 10 after a single oral dose, and compare it with Comparative Example 3 (trade name:

Specification: 40 mg) as a comparison, the pharmacokinetic parameters of the two preparations were compared, and the differences in the absorption rate and extent of Example 10 and Comparative Example 3 in healthy subjects were preliminarily evaluated.

This study was a randomized, open-label, two-cycle crossover, single-dose, fasting trial. 16 healthy subjects were randomly divided into 2 groups. Under fasting conditions, oral administration of Comparative Example 3 (R) Lurasidone Hydrochloride Tablets (40 mg) or Example 10 (T) Lurasidone Hydrochloride Tablets (40 mg) was performed according to the random grouping table. Before administration (0h) and after administration at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 36, 48, 3 mL of venous blood was collected at 72 h. The drug concentration of lurasidone in plasma was determined using a validated analytical method. Pharmacokinetic parameters were calculated from the plasma concentration data, and the results were determined by double-sided t-test.

A total of 34 subjects were screened in this trial, 16 subjects were enrolled, 1 subject voluntarily withdrew, and 15 subjects completed the trial. No incident occurred during the trial, which had an impact on the safety and rights of subjects and the scientific evaluation of data. deviation or violation of the plan. According to the measured plasma lurasidone plasma concentration-time data, the statistical analysis software Winnonlin 8.3.1 was used to calculate the pharmacokinetic parameters of Comparative Example 3 and Example 10. A comparison of the calculated fasting mean pharmacokinetic parameters is shown in Table 11.

Table 11

The results show that compared with Comparative Example 3, Example 10 has a T/R of _Cmax =121.89, which shows that Example 10 has better bioavailability than Comparative Example 3.

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection of the present invention. within the range.

Claims (11)

1. A lurasidone hydrochloride granular composition comprising the following components: lurasidone hydrochloride, croscarmellose sodium, silicon dioxide, pregelatinized starch, filler and binding agent agent.
2. The lurasidone hydrochloride granular composition according to claim 1, wherein the lurasidone hydrochloride granular composition comprises the following components: by weight, 20-45wt% lurasidone hydrochloride; 0.5-5.0wt% croscarmellose sodium, more preferably 0.5-3.0wt% croscarmellose sodium, particularly preferably 1.5-2.5wt% croscarmellose sodium; 0.25 -4.0wt% silica, further preferably 0.5-1.5wt% silica, particularly preferably 0.5-1wt% silica; greater than 0wt% and less than 10wt% pregelatinized starch, preferably greater than 0wt% and Less than or equal to 9 wt% pregelatinized starch; fillers and binders.
3. The lurasidone hydrochloride granular composition according to claim 1, wherein the lurasidone hydrochloride granular composition comprises: 30-80wt% filler, preferably 40-70wt% filler, More preferred is 55-60 wt% filler, particularly preferred 56-60 wt% filler.
4. The lurasidone hydrochloride granular composition according to claim 1, wherein the lurasidone hydrochloride granular composition comprises: 0.5-20wt% binder, preferably 0.5-8wt% binder, 4.0-5.0 wt% binder is particularly preferred.
5. The lurasidone hydrochloride granular composition according to claim 1, wherein the filler is selected from the group consisting of mannitol, lactose, microcrystalline cellulose, xylitol, silicified microcrystalline cellulose, starch, sucrose, One or any combination of glucose, maltitol, fructose, sorbitol sugar, dibasic calcium phosphate, dibasic calcium phosphate and calcium silicate, preferably mannitol and microcrystalline cellulose, more preferably mannitol.
6. The lurasidone hydrochloride granular composition according to claim 1, wherein the binder is selected from the group consisting of hypromellose, hypromellose, methyl cellulose, copovidone, polyvinyl Ketone and polyvinyl alcohol, preferably hypromellose and polyvinyl alcohol, more preferably hypromellose, the percentage of the binder in the weight of the preparation is 0.5-20wt%, preferably 0.5-8wt%, particularly preferably 4.0 -5.0 wt%.
7. A lurasidone hydrochloride pharmaceutical composition, the pharmaceutical composition comprising the lurasidone hydrochloride granular composition and lubricant described in any one of the above claims 1-6, the pharmaceutical composition Tablets are preferred.
8. lurasidone hydrochloride pharmaceutical composition according to claim 7, is characterized in that, described lubricant is selected from stearic acid, magnesium stearate, sodium stearyl fumarate and talc, preferably magnesium stearate , sodium stearyl fumarate; more preferably sodium stearyl fumarate, the percentage of lubricant in the weight of the preparation is 0.1-5wt%, preferably 0.5%-2wt%, more preferably 0.75-2wt%, particularly preferably 0.75-1wt% .
9. The lurasidone hydrochloride granular composition according to any one of claims 1-6 or the lurasidone hydrochloride pharmaceutical composition according to any one of claims 7-8, wherein the hydrochloric acid The particle size D90 of lurasidone is 1-25 μm, preferably D90 is 6-25 μm, particularly preferably D90 is 6-16 μm; the particle size D50 of lurasidone hydrochloride is 2-9 μm, particularly preferably D50 is 2.5-8 μm.
10. The preparation method of lurasidone hydrochloride granular composition as claimed in claim 1, is characterized in that described method comprises the following steps:

    1) lurasidone hydrochloride, pregelatinized starch, filler, and croscarmellose sodium are mixed to obtain a mixture;

    2) The mixture obtained in 1) is wet granulated by using a binder and silicon dioxide, and dried to obtain a lurasidone hydrochloride granule composition.
11. The preparation method of the lurasidone hydrochloride pharmaceutical composition according to claim 7, the method comprises adding a lubricant to the lurasidone hydrochloride granule composition, selectively adding an external disintegrant for further processing to obtain medicinal combination.

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