METHOD FOR PREPARING SOLID FORMULATION OF PIMAVANSERIN

Abstract

A method for a pimavanserin solid preparation. The method improves the fluidity of pimavanserin powder during preparation, can improve the stability of the content of an active ingredient in the solid preparation, and has the characteristics of rapid dissolution and release and good compression moldability.

Claims

1. A method for preparing a pimavanserin solid preparation, the method comprising the following steps: (1) crushing the bulk drug pimavanserin into a particle size of 178 μm or less; (2) mixing the crushed bulk drug pimavanserin with a pharmaceutically acceptable excipient; (3) dry granulating the mixed powder; and (4) pressing the prepared granules into tablets or filling the prepared granules into capsules.

2. The method according to claim 1, wherein the pimavanserin is pimavanserin tartrate.

3. The method according to claim 1, wherein the particle size is expressed as D90, preferably D95, more preferably D98.

4. The method according to claim 1, wherein in step (1), the bulk drug pimavanserin is crushed into a particle size of 170 μm or less, 160 μm or less, or 150 μm or less.

5. The method according to claim 1, wherein the excipient includes a filler (such as microcrystalline cellulose) and a lubricant (such as magnesium stearate).

6. The method according to claim 5, wherein the mass ratio of the bulk drug pimavanserin to the filler to the lubricant is (20-60):(40-80):(0.1-5), preferably (30-50):(50-70):(0.2-2), more preferably about 40:59:1.

7. The method according to claim 1, wherein the mixing is carried out using a mixer (such as a hopper mixer).

8. The method according to claim 7, wherein the rotational speed of the mixer is about 1-100 rpm, and the mixing time is about 1-60 minutes.

9. The method according to claim 1, wherein the dry granulation is carried out using a dry granulator, and the granulation pressure is about 1-100 bar, preferably 20-80 bar, more preferably 40-60 bar, and particularly preferably about 50 bar.

10. The method according to claim 1, wherein after step (3), the following step (3′) is carried out: (3′) mixing the prepared granules with a second portion of pharmaceutically acceptable excipient, wherein the second portion of pharmaceutically acceptable excipient comprises a second portion of lubricant (such as magnesium stearate).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1: a dissolution curve of the pimavanserin tartrate capsules prepared according to the method of the present invention in 0.1 mol/L hydrochloric acid solution.

[0027] FIG. 2: a dissolution curve of the pimavanserin tartrate capsules prepared according to the method of the present invention in pH 4.5 acetic acid-sodium acetate buffer solution.

[0028] FIG. 3: a dissolution curve of the pimavanserin tartrate capsules prepared according to the method of the present invention in water.

[0029] FIG. 4: a dissolution curve of the pimavanserin tartrate capsules prepared according to the method of the present invention in pH 6.8 phosphate buffer solution.

[0030] FIG. 5: dissolution curve of the commercial drug Nuplazid® in 0.1 mol/L hydrochloric acid solution.

DETAILED DESCRIPTION OF EMBODIMENTS

[0031] The term “about” used in the context of the description represents a range of 10% fluctuation from the corresponding value. For example, if the concentration of a certain ingredient is about 5 mM, the concentration thereof is indicated to be 4.5-5.5 mM; and if the concentration range of a certain ingredient is about 5-10 mM, the concentration range thereof is indicated to be 4.5-11 mM.

[0032] Unless otherwise specified, the term “active ingredient” in the context of the description refers to pimavanserin, especially pimavanserin tartrate.

[0033] The term “particle size” used in the context of the description generally refers to the particle size with a particle cumulative distribution of 90%, i.e., “D90”. For example, the expression “particle size is 178 μm or less” in the context of the description generally means that “D90 is 178 μm or less”. Preferably, the term “particle size” refers to the particle size with a particle cumulative distribution of 95%, i.e., “D95”; more preferably, the term “particle size” refers to the particle size with a particle cumulative distribution of 98%, i.e., “D98”.

[0034] The term “bulk drug” used in the context of the description refers to the raw material of pimavanserin, which has not been prepared into a preparation, the form of which includes but is not limited to amorphous powder and crystal powder, and the purity of which meets the requirements of pharmacopoeia or other normative documents or meets the general requirements in the pharmaceutical field for bulk drugs. The source thereof is commercially available or obtained by chemical synthesis by researchers themselves.

[0035] The terms “or more” and “or less” used in the context of the description are inclusive. For example, “particle size is 178 μm or less” and “particle size is less than or equal to 178 μm” have the same meaning.

[0036] One specific embodiment of the present invention relates to a method for preparing a pimavanserin solid preparation, the method comprising the following steps: [0037] (1) crushing a tartrate of the bulk drug pimavanserin into a D90 (preferably D95, more preferably D98) of 178 μm or less (for example, by passing the tartrate of the bulk drug pimavanserin through an 80-mesh sieve); [0038] (2) mixing the crushed tartrate of the bulk drug pimavanserin with a pharmaceutically acceptable excipient using a hopper mixer, wherein the pharmaceutically acceptable excipient includes microcrystalline cellulose and magnesium stearate; the mass ratio of the bulk drug pimavanserin to microcrystalline cellulose to 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 rotational speed of the mixer is about 1-100 rpm, preferably 2-50 rpm, more preferably about 5-20 rpm (for example, about 10 rpm); and the mixing time is about 1-60 minutes, preferably 2-30 minutes, and more preferably about 5-20 minutes (for example, about 10 minutes); [0039] (3) dry granulating the mixed powder using a dry granulator, wherein the granulation pressure of the dry granulator is about 1-100 bar, preferably 20-80 bar, more preferably 40-60 bar, and particularly preferably about 50 bar; [0040] (3′) optionally mixing the prepared granules with a second portion of magnesium stearate, wherein the mass ratio of the bulk drug pimavanserin to the second portion of magnesium stearate is (20-60):(0.1-5), preferably (30-50):(0.2-2), more preferably about 40:59:0.5; and [0041] (4) pressing the prepared granules into tablets or filling the prepared granules into capsules.

[0042] The more specific embodiments of the present invention will be explained and described in an illustrative manner by the following examples; however, it should be recognized that the examples are not intended to limit the scope of the present invention.

Example 1: Capsule Preparation Process 1

[0043] The tartrate of the bulk drug pimavanserin was prepared according to the method described in International Patent Application PCT/US2004/001234. The bulk drug was passed through an 80-mesh sieve to control the particle size (D90) thereof to be 178 μm or less. It was then weighed on a proportional basis according to the prescribed amounts shown in Table 1 below.

TABLE-US-00001 TABLE 1 Prescribed amounts for preparation process 1 Prescription Amount (mg/capsule) Function Pimavanserin tartrate 40 Active ingredient Microcrystalline 59 Filler cellulose Magnesium stearate 1 Lubricant

[0044] Pimavanserin tartrate, microcrystalline cellulose, and magnesium stearate, which satisfied the above ratio, were added to a hopper mixer; with the rotating speed being set to 10 rpm and the time to 10 minutes, the mixer was started for mixing. After the mixing was complete, the mixed powder was added to a dry granulator for dry granulation, wherein the granulation pressure of the dry granulator was set to 50 bar. After granulation, the granules were filled into size 3 plant capsules, and a total of 5000 capsules were prepared.

Example 2: Capsule Preparation Process 2

[0045] The tartrate of the bulk drug pimavanserin was passed through an 80-mesh sieve to control the particle size (D90) thereof to be 178 μm or less. It was then weighed on a proportional basis according to the prescribed amounts shown in Table 2 below.

TABLE-US-00002 TABLE 2 Prescribed amounts for preparation process 2 Prescription Amount (mg/capsule) Function Pimavanserin tartrate 40 Active ingredient Microcrystalline cellulose 59 Filler Magnesium stearate 0.5 Lubricant (added internally) Magnesium stearate 0.5 Lubricant (added externally)

[0046] Pimavanserin tartrate, microcrystalline cellulose, and magnesium stearate (added internally), which satisfied the above ratio, were added to a hopper mixer; with the rotating speed set to 10 rpm and the time to 10 minutes, the mixer was started for mixing. After the mixing was complete, the mixed powder was added to a dry granulator for dry granulation, wherein the granulation pressure of the dry granulator was set to 50 bar. After granulation, the prepared granules and magnesium stearate (added externally) at 0.5 mg/capsule were added to the mixer; and with the rotation speed being set to 10 rpm and the time to 10 minutes. the mixer was started for mixing until uniform, and the mixed material was filled into size 3 plant capsules.

Example 3: Evaluation of Fluidity and Particle Size Distribution of Granules

[0047] The angle of repose, bulk density, and tap density of the capsule granules of Example 2 were measured. The determination method was as follows, and the results were as shown in Table 3.

[0048] Angle of repose: A funnel was fixed at a certain height above a piece of graph paper, and a material was added from the funnel until the bottom of the formed accumulated cone just came into contact with the bottom of the funnel, the diameter of the cone was measured, and the angle of repose was calculated by taking the ratio of the height of the bottom of the funnel to the radius of the cone as the tangent value (measured in parallel three times).

[0049] Bulk density: About 100 g of the uncompacted material to be measured was added to a dry 250 ml measuring cylinder (readable to 2 mL), with the weighing accuracy being 0.1%, and the sample was carefully scraped flat without compaction; and the initial volume VO was read, i.e., to the nearest calibration value, and the packing density (g/ml) was obtained. The calculation formula was m/V0 (measured three times in parallel).

[0050] Tap density: The measuring cylinder was fixed on a bracket. It was tapped 10, 500, and 1250 times, and the corresponding volumes V10, V500 and V1250 were read to the nearest calibration values. When the difference between V500 and V1250 was less than or equal to 2 ml, V1250 was the tap volume VF. When the difference between V500 and V1250 exceeded 2 ml, it was tapped 1250 times until the difference between the measured values was less than or equal to 2 ml, and the read volume was the final tap volume VF. The calculation formula was m/VF (measured three times in parallel).

TABLE-US-00003 TABLE 3 Measurement results of the fluidity of capsule granules Angle of repose Bulk density Tap density Test No. (°) (g/cm.sup.3) (g/cm.sup.3) 1 30.2 0.50 0.58 2 31.5 0.49 0.58

[0051] In addition, in order to evaluate the particle size distribution of the prepared capsule granules, different sieves were used for sieving, and the results thereof were as shown in Table 4:

TABLE-US-00004 TABLE 4 Particle size distribution of capsule granules Aperture (μm) Proportion (wt %) 20 mesh 850 0.24 30 mesh 600 56.5 45 mesh 355 27.1 60 mesh 250 11.3

[0052] From the above, it was indicated that the granules prepared in Examples 1 and 2 had better fluidity and also more rational particle size distribution, and were suitable for capsule filling. The stability of the filling dose could be ensured, and during the continuous processing of material transfer and filling in production, the stability of the content uniformity of the bulk drug could also be ensured, and the accuracy of therapeutic dose was finally ensured.

Example 4: Evaluation of Content Uniformity

[0053] 10 capsules obtained in Example 2 were randomly selected and numbered 1-10 respectively, and the relative value of the content of the active ingredient therein was determined, with 40 mg as 100%. As shown in Table 5, the distribution of the active ingredient had good uniformity, indicating that the content was stable.

TABLE-US-00005 TABLE 5 Capsule No. Content (%) RSD (%) 1 87.5 1.7% 2 90.6 3 99.5 4 99.9 5 101.2 6 100 7 99.2 8 93.8 9 89.1 10 88.9

Example 5: Evaluation of Dissolution

[0054] The dissolution of the capsules of Example 2 was determined:

[0055] Experiments were carried out in 900 ml dissolution media at a speed of 100 rpm by a basket method. The dissolution media were respectively 0.1 mol/L hydrochloric acid solution, pH 4.5 acetic acid-sodium acetate buffer solution, water, and pH 6.8 phosphate buffer solution. Six experiments were conducted in parallel for each dissolution medium according to 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 were separately as shown in FIGS. 1-5 and Tables 6-10.

[0056] For comparison, FIG. 5 and Table 10 showed the dissolution test results of Nuplazid®, a commercially available pimavanserin tartrate capsule as mentioned in the above FDA review, and the dissolution medium used was 0.1 mol/L hydrochloric acid solution.

TABLE-US-00006 TABLE 6 Dissolution curve of pimavanserin tartrate capsules in 0.1 mol/L hydrochloric acid solution Dissolution (%) No. 5 min 10 min 15 min 20 min 30 min 45 min 1 105.68 104.69 104.02 104.43 103.54 102.94 2 100.85 100.99 100.77 100.98 101.17 99.95 3 102.96 101.98 101.42 101.57 100.65 100.22 4 103.81 103.15 103.23 103.30 101.74 102.37 5 99.23 99.48 99.11 99.17 98.26 98.60 6 100.51 99.29 98.88 100.28 99.70 99.99 Mean (%) 102.7 101.59 101.24 101.62 100.84 100.68 RSD (%) 2.3 2.1 2.1 1.9 1.8 1.6

TABLE-US-00007 TABLE 7 Dissolution curve of pimavanserin tartrate capsules in pH 4.5 acetic acid-sodium acetate buffer solution Dissolution (%) No. 5 min 10 min 15 min 20 min 30 min 45 min 1 103.76 106.21 106.12 106.36 106.27 106.91 2 115.42 110.78 110.87 110.80 110.82 110.93 3 101.95 105.59 106.13 106.10 105.96 105.92 4 107.06 110.29 110.73 111.04 110.95 110.49 5 102.62 105.10 105.86 106.21 105.94 106.00 6 100.74 105.89 106.50 106.26 106.17 106.28 Mean (%) 105.26 107.70 107.80 107.80 107.68 107.75 RSD (%) 5.2 2.4 2.2 2.2 2.3 2.2

TABLE-US-00008 TABLE 8 Dissolution curve of pimavanserin tartrate capsules in water Dissolution (%) No. 5 min 10 min 15 min 20 min 30 min 45 min 1 98.96 103.04 103.70 103.88 103.45 103.33 2 93.29 100.57 100.09 100.88 100.46 100.65 3 99.61 102.74 102.80 103.40 103.23 102.53 4 101.85 105.73 105.42 105.45 105.97 105.45 5 98.35 100.87 101.23 99.80 100.97 101.27 6 95.30 101.38 101.99 101.65 101.67 102.22 Mean (%) 97.89 102.39 102.54 102.51 102.63 102.58 RSD (%) 3.2 1.9 1.8 2.0 2.0 1.7

TABLE-US-00009 TABLE 9 Dissolution curve of pimavanserin tartrate capsules in pH 6.8 phosphate buffer solution Dissolution (%) No. 5 min 10 min 15 min 20 min 30 min 45 min 1 93.70 101.34 102.08 101.22 102.20 102.13 2 96.09 102.13 102.75 103.52 102.89 101.31 3 93.30 101.77 102.28 101.96 101.73 101.24 4 94.98 103.88 104.06 104.10 104.17 104.03 5 93.70 102.46 102.81 103.00 103.46 102.66 6 95.94 103.77 104.06 105.01 104.55 103.72 Mean (%) 94.62 102.56 103.00 103.13 103.17 102.52 RSD (%) 1.3 1.0 0.8 1.3 1.1 1.2

TABLE-US-00010 TABLE 10 Dissolution curve of Nuplazid ® in 0.1 mol/L hydrochloric acid solution (literature data) Dissolution (%) No. 5 min 10 min 15 min 20 min 30 min 45 min 1 0 23 67 94 94 N/A 2 0 37 82 88 85 N/A 3 0 32 86 88 86 N/A 4 0 40 84 84 83 N/A 5 0 37 85 92 93 N/A 6 0 51 86 92 92 N/A Mean (%) 0 36.7 81.7 89.7 88.8 N/A RSD (%) N/A 4.0 11.1 24.4 18.9 N/A N/A: Not determined

[0057] The experimental results indicated that in these test dissolution media, the preparations prepared by the method of the present invention all realized almost complete dissolution within 5 minutes; whereas, according to the description in the above-mentioned documents, Nuplazid®, a commercially available pimavanserin tartrate capsule, failed to achieve no less than 90% dissolution in 0.1 mol/L hydrochloric acid solution by 30 minutes. This indicated that the dissolution of the solid preparation prepared by the method of the present invention was significantly improved compared with the innovator drug on the market in terms of dissolution.