Process for the preparation of pimavanserin solid formulations

Abstract

A preparation method of a solid preparation of pimavanserin, which improves the flowability of pimavanserin powder in the preparation process, improves the stability of the active ingredient content in the solid preparation, and has the characteristics of rapid dissolution and release and good compression molding.

Description

Technical Field

[0001] This invention relates to a method for preparing pimova serline solid dosage form. This method improves the flowability of pimova serline powder during the preparation process, enhances the stability of the active ingredient content in the solid dosage form, and has the characteristics of rapid dissolution and release and good compressibility. Background Technology

[0002] Pimavanserin, with the structure shown below, is a selective serotonin 2A / 2C receptor inverse agonist, described in international patent application PCT / US2004 / 001234. Its tartrate salt, pimavanserin tartrate, received marketing approval from the US FDA on April 29, 2016. It is used for mental disorders (hallucinations and delusions) that are complications of Parkinson's disease.

[0003]

[0004] Pimovanserine is typically formulated into solid dosage forms such as tablets and capsules. For example, pimovaserine tartrate, marketed in the United States, is available in tablet and capsule form. The preparation of such solid dosage forms usually involves mixing the active ingredient with appropriate excipients to form granules, which are then compressed (to form tablets) or filled into capsules (to form capsules). In the industrial production of solid dosage forms, to ensure a uniform and stable content of the active ingredient in the granules and the resulting tablets or capsules, it is necessary to improve the flowability of the powder during the mixing process of the active ingredient and excipients.

[0005] It is well known to those skilled in the art that particle size has a significant impact on the flowability of powders during the preparation of solid dosage forms. Larger particle sizes generally result in smaller angles of repose and higher flowability. Typically, if the particle size is less than 200 μm, the particles tend to aggregate and exhibit adhesion (see *Pharmaceutics*, edited by Zhang Qiang and Wu Fenglan, 1st edition, Peking University Medical Press, 2005). However, due to the unique inherent properties of pimova serine tartrate, the flowability of its active ingredient powder is extremely poor. Even with commonly used techniques in the field, such as increasing particle size and adding lubricants, it is difficult to produce particles with uniform content. Consequently, the resulting solid dosage forms have low content stability, making it difficult to ensure accurate dosage in clinical applications.

[0006] Besides needing to improve powder flowability, solid dosage forms also require a certain degree of dissolution of the active ingredient to ensure absorption. Furthermore, in the case of tablet preparation, the compressed tablets should be easy to compress and not easily broken, thus facilitating production and transportation and maintaining stable drug quality. Most existing pimovasselin tartrate solid dosage forms do not yet achieve satisfactory levels in terms of dissolution and compressibility.

[0007] In summary, there is an urgent need in the art for a new method for preparing solid dosage forms of pimova serline (especially pimova serline tartrate) to improve the powder flowability of pimova serline during formulation, as well as to improve dissolution and compressibility. Summary of the Invention

[0008] Through extensive and in-depth research on pimovarserin, particularly pimovarserin tartrate solid dosage forms, the inventors of this invention unexpectedly discovered that, contrary to the commonly used method of increasing powder particle size in the prior art, further pulverizing the pimovarserin raw material powder to control its particle size below 178 μm (equivalent to an 80-mesh sieve) can significantly improve powder flowability during granulation, improve the content stability of the formulation, improve the compressibility of the formulation, and increase the dissolution rate of the active ingredient, thus completing this invention.

[0009] Therefore, the present invention relates to a method for preparing a pimozantrone solid dosage form, which includes the following steps:

[0010] (1) Pulverize the pimozantrone raw material to a particle size of less than 178 μm;

[0011] (2) Mix the pulverized pimozantrine raw material with a pharmaceutically acceptable excipient;

[0012] (3) Dry granulation of the mixed powder;

[0013] (4) Compress the obtained granules into tablets or fill them into capsules.

[0014] In a preferred embodiment, the pimovanserin is pimovanserin tartrate. In another preferred embodiment, the pimovanserin is pimovanserin in crystalline form.

[0015] In a preferred embodiment, the particle size is represented by D90, preferably D95, and more preferably D98.

[0016] In a preferred embodiment, in step (1), the pimovaserine raw material is pulverized to a particle size of less than 170 μm, less than 160 μm, or less than 150 μm.

[0017] In a preferred embodiment, the excipient comprises a filler and a lubricant. In a more preferred embodiment, the filler is microcrystalline cellulose. In an even more preferred embodiment, the lubricant is magnesium stearate.

[0018] In a more preferred embodiment, the mass ratio of the pimovaserine raw material, filler, and lubricant is (20-60):(40-80):(0.1-5), preferably (30-50):(50-70):(0.2-2), and more preferably about 40:59:(0.5-1).

[0019] In a preferred embodiment, the mixing is performed using a mixer. In a more preferred embodiment, the mixer is a three-dimensional mixer, a V-type mixer, a trough mixer, or a square cone hopper mixer, and more preferably a hopper mixer.

[0020] In a more preferred embodiment, the mixer rotates at a speed of about 1 to 100 rpm, preferably 2 to 50 rpm, more preferably about 5 to 20 rpm (e.g., about 10 rpm); and the mixing time is about 1 to 60 minutes, preferably 2 to 30 minutes, more preferably about 5 to 20 minutes (e.g., about 10 minutes).

[0021] In a preferred embodiment, the dry granulation is performed using a dry granulator with a granulation pressure of approximately 1–100 bar, preferably 20–80 bar, more preferably 40–60 bar, and particularly preferably approximately 50 bar.

[0022] In a preferred embodiment, the following step (3') is performed after step (3):

[0023] (3'): The obtained granules are mixed with a second pharmaceutically acceptable excipient, the second pharmaceutically acceptable excipient comprising a second lubricant (e.g., magnesium stearate), wherein the mass ratio of pimovaserine active pharmaceutical ingredient to the second lubricant is (20-60):(0.1-5), preferably (30-50):(0.2-2), more preferably about 40:59:0.5.

[0024] In a preferred embodiment, the particle size D90 of the prepared particles is 100–1000 μm, preferably 200–800 μm, and more preferably 300–600 μm.

[0025] In a preferred embodiment, the solid dosage form is in the form of tablets or capsules, preferably capsules, characterized in that the capsule shell is preferably made from gelatin capsules, potato capsules, plant (hydroxypropyl methylcellulose) capsules, sodium alginate capsules, and more preferably plant (hydroxypropyl methylcellulose) capsules.

[0026] The method of this invention improves the flowability of pimozantrone powder during solid dosage form preparation, enhances the stability of the active ingredient content in solid dosage forms, and exhibits rapid dissolution and release as well as good compressibility. Therefore, the formulations and methods of this invention are not only suitable for operation and control in large-scale industrial production, but also significantly improve the stability of the dosage and facilitate the efficacy of the active ingredient, thereby benefiting patients. In particular, the method of this invention does not have special requirements for the density and particle size of excipients; conventional microcrystalline cellulose and magnesium stearate are sufficient as fillers and lubricants, respectively, greatly reducing the cost of the formulation. Furthermore, the method of this invention has higher process durability and reproducibility, significantly reducing the requirements for production equipment and process control, exhibiting better equipment applicability, and greatly reducing the risks associated with process parameter control. Attached Figure Description

[0027] Figure 1 Dissolution curve of pimozantrone tartrate capsules prepared according to the method of the present invention in 0.1 mol / L hydrochloric acid solution.

[0028] Figure 2 Dissolution curve of pimova serine tartrate capsules prepared according to the method of the present invention in a pH 4.5 acetic acid-sodium acetate buffer solution.

[0029] Figure 3 Dissolution curve of pimova serine tartrate capsules prepared according to the method of the present invention in water.

[0030] Figure 4 Dissolution curve of pimova serine tartrate capsules prepared according to the method of the present invention in phosphate buffer solution at pH 6.8.

[0031] Figure 5 Marketed drugs Dissolution curve in 0.1 mol / L hydrochloric acid solution. Detailed Implementation

[0032] The term “about” as used in the context of this specification means a range of approximately 10% above or below the corresponding value. For example, if the concentration of a component is about 5 mM, it indicates that its concentration is 4.5-5.5 mM; if the concentration range of a component is about 5-10 mM, it indicates that its concentration range is 4.5-11 mM.

[0033] Unless otherwise specified, “active ingredient” in the context of this specification refers to pimova serine, particularly pimova serine tartrate.

[0034] As used in this specification, the term "particle size" generally refers to the particle size at which the cumulative particle distribution is 90%, i.e., "D90". For example, "particle size of 178 μm or less" as used in this specification generally means "D90 is 178 μm or less". Preferably, the term "particle size" refers to the particle size at which the cumulative particle distribution is 95%, i.e., "D95"; more preferably, the term "particle size" refers to the particle size at which the cumulative particle distribution is 98%, i.e., "D98".

[0035] As used in this specification, the term "active pharmaceutical ingredient" refers to pimovaserine raw material not formulated into a pharmaceutical preparation, in forms including but not limited to amorphous powder and crystalline powder, with purity meeting the requirements of pharmacopoeia or other regulatory documents, or meeting the general requirements for active pharmaceutical ingredients in the pharmaceutical industry. It may be obtained commercially or chemically synthesized by the researcher.

[0036] The terms "above" and "below" used in the context of this specification include the stated number. For example, "particle size below 178 μm" has the same meaning as "particle size less than or equal to 178 μm".

[0037] One specific embodiment of the present invention relates to a method for preparing a pimozantrone solid dosage form, which includes the following steps:

[0038] (1) Pulverize the pimova serine tartrate raw material to a D90 (preferably D95, more preferably D98) of less than 178 μm (for example, pass the pimova serine tartrate raw material through an 80 mesh sieve);

[0039] (2) The pulverized pimova serine tartrate raw material is mixed with a pharmaceutically acceptable excipient using a hopper mixer. The pharmaceutically acceptable excipient comprises microcrystalline cellulose and magnesium stearate, and the mass ratio of pimova serine raw material, microcrystalline cellulose and magnesium stearate is (20-60):(40-80):(0.1-5), preferably (30-50):(50-70):(0.2-2), more preferably about 40:59:(0.5-1). The speed of the mixer is about 1 to 100 rpm, preferably 2 to 50 rpm, more preferably about 5 to 20 rpm (e.g., about 10 rpm). The mixing time is about 1 to 60 minutes, preferably 2 to 30 minutes, more preferably about 5 to 20 minutes (e.g., about 10 minutes).

[0040] (3) The mixed powder is granulated by a dry granulator, wherein the granulation pressure of the dry granulator is about 1 to 100 bar, preferably 20 to 80 bar, more preferably 40 to 60 bar, and particularly preferably about 50 bar;

[0041] (3') Optionally, the obtained granules are mixed with the second part of magnesium stearate, wherein the mass ratio of pimozantrone raw material to the second part of magnesium stearate is (20-60):(0.1-5), preferably (30-50):(0.2-2), and more preferably about 40:59:0.5;

[0042] (4) Compress the obtained granules into tablets or fill them into capsules.

[0043] More specific embodiments of the present invention will be illustrated by the following examples, but it should be understood that the examples are not intended to limit the scope of the invention.

[0044] Example 1: Capsule Preparation Process 1

[0045] Pimovanserine tartrate active pharmaceutical ingredient (API) was prepared according to the method described in international patent application PCT / US2004 / 001234. The API was passed through an 80-mesh sieve to control its particle size to below D90 of 178 μm. The API was then weighed according to the formulation amounts shown in Table 1 below.

[0046] Table 1: Formulation amount for preparation process 1

[0047] prescription Dosage (mg / capsule) effect Pimovanseline tartrate 40 Active ingredients microcrystalline cellulose 59 filler magnesium stearate 1 lubricant

[0048] Add pimova serine tartrate, microcrystalline cellulose, and magnesium stearate in the above proportions to a hopper mixer, set the speed to 10 rpm and the time to 10 minutes, and start the mixer to mix. After mixing, add the mixed powder to a dry granulator for dry granulation, setting the granulation pressure to 50 bar. After granulation, fill the granules into No. 3 plant capsules, preparing a total of 5000 capsules.

[0049] Example 2: Capsule Preparation Process 2

[0050] Pimovanserine tartrate raw material was passed through an 80-mesh sieve to control its particle size to below D90 of 178 μm. Then, it was weighed according to the prescribed amounts shown in Table 2 below.

[0051] Table 2: Formulation amount for preparation process 2

[0052] prescription Dosage (mg / capsule) effect Pimovanseline tartrate 40 Active ingredients microcrystalline cellulose 59 filler Magnesium stearate (added internally) 0.5 lubricant Magnesium stearate (added) 0.5 lubricant

[0053] Add pimova serine tartrate, microcrystalline cellulose, and magnesium stearate (internal addition) in the above proportions to a hopper mixer. Set the speed to 10 rpm and the time to 10 minutes, and start the mixer to mix. After mixing, add the above mixed powder to a dry granulator for dry granulation. Set the granulation pressure of the dry granulator to 50 bar. After granulation, add the obtained granules and magnesium stearate (external addition) at a rate of 0.5 mg / capsule to a mixer. Set the speed to 10 rpm and the time to 10 minutes, and start the mixer to mix evenly. Then fill the mixture into No. 3 plant capsules.

[0054] Example 3: Evaluation of particle flowability and particle size distribution

[0055] The angle of repose, loose density, and tap density of the capsule particles from Example 2 were measured. The measurement methods are as follows, and the results are shown in Table 3.

[0056] Angle of repose: Fix the funnel at a certain height above the coordinate paper, add material from the funnel until the bottom of the resulting accumulation cone just touches the bottom of the funnel, measure the diameter of the cone, and use the ratio of the height of the funnel bottom to the radius of the cone as the tangent value to calculate the angle of repose (measured in three parallel steps).

[0057] Bulk density: Add about 100g of uncompacted sample to a dry 250ml graduated cylinder (readable to 2mL), weigh to an accuracy of 0.1%, carefully level the sample, do not compact it, and read the initial volume V0, i.e. the most recent scale value. Bulk density (g / ml) is calculated using the formula: m / V0 (three parallel determinations).

[0058] Tapped density: Fix the graduated cylinder to the support. Tap the cylinder 10, 500, and 1250 times, and record the corresponding volumes V10, V500, and V1250 to the nearest graduation. When the difference between V500 and V1250 is less than or equal to 2 ml, V1250 is the tapped volume VF. When the difference between V500 and V1250 exceeds 2 ml, continue tapping 1250 times until the difference between the measurements is less than or equal to 2 ml; the volume recorded is the final tapped volume VF. Calculation formula: m / VF (three parallel measurements).

[0059] Table 3: Results of Capsule Flowability Measurement

[0060] Test number Angle of repose (°) <![CDATA[Bulk density (g / cm 3 )]]> <![CDATA[Tap density (g / cm 3 )]]> 1 30.2 0.50 0.58 2 31.5 0.49 0.58

[0061] In addition, to evaluate the particle size distribution of the prepared capsule particles, they were sieved using different sieves, and the results are shown in Table 4:

[0062] Table 4: Particle size distribution of capsule particles

[0063] Aperture (μm) Percentage (by weight) 20 mesh 850 0.24 30 mesh 600 56.5 45 mesh 355 27.1 60 mesh 250 11.3

[0064] The above shows that the particles prepared in Examples 1 and 2 have good flowability and a more reasonable particle size distribution, making them suitable for capsule filling. This ensures the stability of the filling dosage and also ensures the stability of the uniformity of the active pharmaceutical ingredient content during material transfer and continuous filling processes in production, ultimately ensuring the accuracy of the therapeutic dosage.

[0065] Example 4: Evaluation of Content Uniformity

[0066] Ten capsules obtained in Example 2 were randomly selected and numbered 1-10. The relative content of the active ingredients in each capsule was determined, with 40 mg as 100%. As shown in Table 5, the distribution of the active ingredients was well uniform, indicating that the content was stable.

[0067] Table 5:

[0068]

[0069]

[0070] Example 5: Dissolution Evaluation

[0071] Dissolution rate was determined for the capsules of Example 2:

[0072] The basket method was used, with experiments conducted at 100 rpm in 900 ml of dissolution media, including 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate-sodium acetate buffer solution, water, and pH 6.8 phosphate buffer solution. Each dissolution medium was tested in parallel six times, following the method described in the FDA review (NDA210793 Product Quality Review). Dissolution was measured at 5, 10, 15, 20, 30, and 45 minutes after the start of the experiment, and the results are shown in […]. Figures 1-5 And in Tables 6-10.

[0073] In contrast. Figure 5 Table 10 lists the commercially available pimova serine tartrate capsules described in the aforementioned FDA review. The dissolution rate was determined using a 0.1 mol / L hydrochloric acid solution as the dissolution medium.

[0074] Table 6: Dissolution curves of pimozantrone tartrate capsules in 0.1 mol / L hydrochloric acid solution

[0075]

[0076] Table 7: Dissolution curves of pimozantrone tartrate capsules in pH 4.5 acetate-sodium acetate buffer solution

[0077]

[0078] Table 8: Dissolution curves of pimozantrone tartrate capsules in water

[0079]

[0080] Table 9: Dissolution curves of pimozide vanserine capsules in pH 6.8 phosphate buffer solution

[0081]

[0082]

[0083] Table 10: Dissolution curve in 0.1 mol / L hydrochloric acid solution (literature data)

[0084]

[0085] N / A: Not determined

[0086] Experimental results show that, in all the various dissolution media tested, the formulations prepared by the method of this invention achieved almost complete dissolution within 5 minutes; while, according to the aforementioned literature, in 0.1 mol / L hydrochloric acid solution, commercially available pimozide tartaric acid capsules... Dissolution of more than 90% was not achieved until 30 minutes. This indicates that the solid dosage form prepared by the method of the present invention has achieved a significant improvement in dissolution compared to commercially available original drugs.

Claims

1. A method for preparing a pimovaserine solid dosage form, comprising the following steps: (1) The pimovaserine raw material is pulverized to a particle size of 160 μm to 178 μm, wherein the particle size is expressed as D90; (2) The pulverized pimova serine raw material is mixed with a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient consists of a filler and a lubricant, wherein the filler is microcrystalline cellulose and the lubricant is magnesium stearate, and the mass ratio of the pimova serine raw material, the filler and the lubricant is (30-50):(50-70):(0.2-2); (3) Dry granulation of the mixed powder; (4) Compress the obtained granules into tablets or fill them into capsules.

2. The method of claim 1, wherein pimovaserin is pimovaserin tartrate.

3. The method of claim 1 or 2, wherein the particle size is expressed as D95.

4. The method of claim 1 or 2, wherein the particle size is expressed as D98.

5. The method of claim 1 or 2, wherein the mass ratio of the pimovaserine active pharmaceutical ingredient, the filler, and the lubricant is about 40:59:

1.

6. The method of claim 1 or 2, wherein the mixing is performed using a mixer.

7. The method of claim 6, wherein the mixing is performed using a hopper mixer.

8. The method of claim 6, wherein the mixer rotates at a speed of about 1 to 100 rpm and the mixing time is about 1 to 60 minutes.

9. The method of claim 1 or 2, wherein the dry granulation is performed using a dry granulator and the granulation pressure is approximately 1 to 100 bar.

10. The method of claim 9, wherein the granulation pressure is 20 to 80 bar.

11. The method of claim 9, wherein the granulation pressure is 40 to 60 bar.

12. The method of claim 9, wherein the granulation pressure is approximately 50 bar.

13. The method of claim 1 or 2, wherein the following step (3') is performed after step (3): (3') The obtained granules are mixed with a second pharmaceutically acceptable excipient, the second pharmaceutically acceptable excipient comprising a second lubricant, which is magnesium stearate.

14. The method according to claim 1 or 2, wherein the particle size D90 of the particles prepared in step (3) is 100 to 1000 μm.

15. The method of claim 14, wherein the particle size D90 of the particles prepared in step (3) is 200 to 800 μm.

16. The method of claim 14, wherein the particle size D90 of the particles prepared in step (3) is 300-600 μm.

17. The method of claim 1 or 2, wherein the solid dosage form is a capsule.

18. The method of claim 17, wherein the capsule shell of the capsule is selected from gelatin capsule shells, potato capsule shells, plant capsule shells, and sodium alginate capsule shells.

19. The method of claim 17, wherein the capsule shell of the capsule is selected from hydroxypropyl methylcellulose capsule shells.

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