CN111821277A

CN111821277A - Pimavanserin nanocrystalline capsule and preparation method thereof

Info

Publication number: CN111821277A
Application number: CN201910327848.8A
Authority: CN
Inventors: 李春; 王宇杰
Original assignee: Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Current assignee: Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Priority date: 2019-04-23
Filing date: 2019-04-23
Publication date: 2020-10-27

Abstract

The invention belongs to the field of medicinal preparations, and particularly relates to a pimavanserin nanocrystal capsule and a preparation method thereof; the preparation method comprises the following steps: 1) adding pimavanserin and poloxamer 188 into water, and mixing to obtain a mixed solution; 2) homogenizing the mixed solution for 3 times to obtain suspension; 3) spray drying the suspension in a spray dryer; 4) mixing with other adjuvants, and encapsulating. The pimavanserin capsule preparation prepared by the invention can obviously increase the dissolution rate, thereby improving the bioavailability of the medicament in vivo.

Description

Pimavanserin nanocrystalline capsule and preparation method thereof

Technical Field

The invention relates to the technical field of medicinal preparations, in particular to a pimavanserin nanocrystal capsule and a preparation method thereof.

Background

Pimavanserin (Pimavanserin), chemical name, 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea, formerly known as acadia pharmaceutical. The pimavanserin has high targeting and specificity for the reverse and antagonism of the 5-HT2A receptor, and the selectivity is 40 times of that of the 5-HT2C receptor and the dopamine receptor. Good curative effect, good specificity, no deterioration of muscle movement, and less side effects. The FDA was awarded a breakthrough therapeutic position title on day 2 and 9 in 2014, and FDA approved for the treatment of parkinson's hallucinations and delusions on month 2016, 29, the first of which is currently the only drug approved for the treatment of parkinson's disease.

However, the pimavanserin oral solid preparation has poor in vitro dissolution rate and low in vivo bioavailability, and through the research of the applicant in the prior art, the applicant surprisingly discovers that the pimavanserin oral solid preparation is prepared into a nanocrystalline suspension, and the nanocrystalline suspension is mixed with other auxiliary materials through spray drying and then is filled into capsules, so that the in vitro dissolution rate can be remarkably improved, and the in vivo bioavailability can be improved.

Disclosure of Invention

The invention aims to solve the technical problems of poor dissolution rate and low bioavailability of pimavanserin and provides a pimavanserin nanocrystal capsule and a preparation method thereof. The capsule serving as an oral preparation remarkably improves the in-vitro dissolution rate of the pimavanserin, improves the oral bioavailability of the pimavanserin and has good application prospect.

The invention also provides a preparation method of the pimavanserin nanocrystalline capsule, which comprises the following steps:

(1) adding pimavanserin and poloxamer 188 into water, and mixing to obtain a mixed solution; wherein the mass ratio of pimavanserin to poloxamer 188 is 1: 3-1: 6.

(2) Homogenizing the mixed solution for 3 times to obtain suspension; wherein the homogenizing temperature is 30-40 ℃, and the homogenizing pressure is 500-1000 Bar; the particle size of the pimavanserin nanocrystal suspension is 300-500 nm;

(3) spray drying the suspension in a spray dryer; wherein the air inlet temperature of the spray drying is 120-180 DEG C

(4) Mixing with other adjuvants, and encapsulating.

In the step (1), the mass-to-volume ratio of pimavanserin to water is 1g: 30mL-1g is 100 mL; the pimavanserin accounts for less than 25%, and the poloxamer 188 accounts for 75% -86%; the percentages are mass percentages of the pimavanserin nanocrystalline powder.

In the step (1), the mass-to-volume ratio of pimavanserin to water is 1g:65 mL; the pimavanserin accounts for 17% -20%; the poloxamer 188 accounts for 80% -83%.

In the step (1), the mass ratio of pimavanserin to poloxamer 188 is 1: 4-1: 5.

In the step (2), the homogenizing device is a high-pressure homogenizer; the homogenization temperature is 35 ℃; the homogenizing pressure is 750 Bar; the particle size of the pimavanserin nanocrystal suspension is 350-450 nm.

In the step (2), the particle size of the pimavanserin nanocrystal suspension is 400 nm.

In the step (3), the spray drying is carried out by adopting a spray dryer, and the air inlet temperature is 140-160 ℃.

In the step (4), the other auxiliary materials are microcrystalline cellulose, spray-dried lactose and magnesium stearate.

Detailed Description

To more clearly illustrate the advantages and features of the present invention, the following detailed description of the present invention is given by way of example only, and it should be understood by those skilled in the art that the following detailed description is given by way of illustration and not limitation, and the scope of the present invention should not be limited thereby.

Example 1

Adding 2g of pimavanserin and 6g of poloxamer 188 into 60mL of water, and uniformly stirring by magnetic force; adding the mixed solution into a high-pressure homogenizer, controlling the temperature in the preparation process at 35 ℃, and circularly homogenizing for 3 times under the pressure of 750Bar to obtain pimavanserin nanocrystal suspension; putting the pimavanserin nanocrystal suspension into a spray dryer for spray drying, wherein the inlet temperature of spray drying is 120 ℃, and obtaining a pimavanserin nanocrystal spray-dried product; and (3) sieving the pimavanserin nanocrystal spray-dried product by using a 80-mesh sieve, mixing the product with spray-dried lactose, microcrystalline cellulose and magnesium stearate according to the prescription amount, and filling the mixture into capsules to obtain the pimavanserin nanocrystal capsules.

Example 2

Adding 2g of pimavanserin and 12g of poloxamer 188 into 200mL of water, and uniformly stirring by magnetic force; adding the mixed solution into a high-pressure homogenizer, controlling the temperature in the preparation process at 35 ℃, and circularly homogenizing for 3 times under the pressure of 750Bar to obtain pimavanserin nanocrystal suspension; putting the pimavanserin nanocrystal suspension into a spray dryer for spray drying, wherein the inlet temperature of spray drying is 150 ℃, and obtaining a pimavanserin nanocrystal spray-dried product; and (3) sieving the pimavanserin nanocrystal spray-dried product by using a 80-mesh sieve, mixing the product with spray-dried lactose, microcrystalline cellulose and magnesium stearate according to the prescription amount, and filling the mixture into capsules to obtain the pimavanserin nanocrystal capsules.

Example 3

Adding 2g of pimavanserin and 8g of poloxamer 188 into 100mL of water, and uniformly stirring by magnetic force; adding the mixed solution into a high-pressure homogenizer, controlling the temperature in the preparation process at 35 ℃, and circularly homogenizing for 3 times under the pressure of 750Bar to obtain pimavanserin nanocrystal suspension; putting the pimavanserin nanocrystal suspension into a spray dryer for spray drying, wherein the inlet temperature of spray drying is 150 ℃, and obtaining a pimavanserin nanocrystal spray-dried product; and (3) sieving the pimavanserin nanocrystal spray-dried product by using a 80-mesh sieve, mixing the product with spray-dried lactose, microcrystalline cellulose and magnesium stearate according to the prescription amount, and filling the mixture into capsules to obtain the pimavanserin nanocrystal capsules.

Example 4

Adding 2g of pimavanserin and 10g of poloxamer 188 into 100mL of water, and uniformly stirring by magnetic force; adding the mixed solution into a high-pressure homogenizer, controlling the temperature in the preparation process at 35 ℃, and circularly homogenizing for 3 times under the pressure of 750Bar to obtain pimavanserin nanocrystal suspension; putting the pimavanserin nanocrystal suspension into a spray dryer for spray drying, wherein the inlet temperature of spray drying is 150 ℃, and obtaining a pimavanserin nanocrystal spray-dried product; and (3) sieving the pimavanserin nanocrystal spray-dried product by using a 80-mesh sieve, mixing the product with spray-dried lactose, microcrystalline cellulose and magnesium stearate according to the prescription amount, and filling the mixture into capsules to obtain the pimavanserin nanocrystal capsules.

Comparative example 1

Taking 2g of pimavanserin, sieving with a 80-mesh sieve, mixing with spray-dried lactose, microcrystalline cellulose and magnesium stearate according to the prescription amount, and filling into capsules to obtain the pimavanserin common capsules.

Examples 1-4 and comparative example 1 pmodanserin nanocrystals and pmodanserin size detection results.

In vitro dissolution test of pimavanserin formulations obtained in examples 1-4 and comparative example 1 in Ph4.5 medium, the dissolution test is performed in pH4.5 medium according to 50 rotations of the second method of slurry 0931 in the fourth part of the Chinese pharmacopoeia 2015 edition, and the dissolution test results are shown in the following table.

Time of day	Example 1	Example 2	Example 3	Example 4	Comparative example 1
						15min/%	73.9	68.5	75.1	64.5	56.5
30min/%	95.6	90.4.	98.4	89.2	79.6

。

Claims

1. A pimavanserin nanocrystal capsule and a preparation method thereof are characterized by comprising the following steps:

Homogenizing the mixed solution for 3 times to obtain suspension; wherein the homogenizing temperature is 30-40 ℃, and the homogenizing pressure is 500-1000 Bar; the particle size of the pimavanserin nanocrystal suspension is 300-500 nm;

(4) Mixing with other adjuvants, and encapsulating.

3. The method according to claim 1, wherein in the step (1), the ratio of pimavanserin to water by mass/volume is 1g: 30mL-1g is 100 mL; the pimavanserin accounts for less than 25%, and the poloxamer 188 accounts for 75% -86%; the percentages are mass percentages of the pimavanserin nanocrystalline powder.

4. The preparation method according to claim 1, wherein in the step (1), the mass-to-volume ratio of pimavanserin to water is 1g:65 mL; the pimavanserin accounts for 17% -20%; the poloxamer 188 accounts for 80% -83%.

5. The method of claim 1, wherein: in the step (1), the mass ratio of pimavanserin to poloxamer 188 is 1: 4-1: 5.

6. The method according to claim 1, wherein in the step (2), the homogenizing equipment is a high-pressure homogenizer; the homogenization temperature is 35 ℃; the homogenizing pressure is 750 Bar; the particle size of the pimavanserin nanocrystal suspension is 350-450 nm.

7. The method of claim 1, wherein the pimavanserin nanocrystal suspension has a particle size of 400 nm.

8. The method of claim 1, wherein the spray drying is performed using a spray dryer, and the inlet air temperature is 140 ℃ to 160 ℃.

9. The process according to claim 1, wherein in step (4), the other excipients are microcrystalline cellulose, spray-dried lactose, magnesium stearate.