U.S. patent application number 17/617530 was filed with the patent office on 2022-08-11 for oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor.
The applicant listed for this patent is BEIGENE SWITZERLAND GMBH. Invention is credited to Jialin BIAN, Zhengming DU, Wenyuan FAN, Huiru LV, Gang QIU, Yiwei SHEN, Shuo XU.
Application Number | 20220249491 17/617530 |
Document ID | / |
Family ID | |
Filed Date | 2022-08-11 |
United States Patent
Application |
20220249491 |
Kind Code |
A1 |
QIU; Gang ; et al. |
August 11, 2022 |
ORAL SOLID TABLET COMPRISING BRUTON'S TYROSINE KINASE INHIBITOR AND
PREPARATION METHOD THEREFOR
Abstract
Provided are an oral solid tablet comprising
(S)-7-[4-(1-acryloylpiperidine)]-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropy-
razolo[1,5-a]pyrimidine-3-carboxamide and preparation method
therefor. The oral solid tablet has good drug release
characteristics, features easy administration, quick and
high-efficient release, no particular requirements on equipment,
and a simple formulation preparation process, can ensure
formulation stability and facilitate transportation and storage,
and is suitable for large-scale production.
Inventors: |
QIU; Gang; (Beijing, CN)
; SHEN; Yiwei; (Beijing, CN) ; FAN; Wenyuan;
(Beijing, CN) ; XU; Shuo; (Beijing, CN) ;
LV; Huiru; (Beijing, CN) ; BIAN; Jialin;
(Beijing, CN) ; DU; Zhengming; (Beijing,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BEIGENE SWITZERLAND GMBH |
Basel |
|
CN |
|
|
Appl. No.: |
17/617530 |
Filed: |
June 10, 2020 |
PCT Filed: |
June 10, 2020 |
PCT NO: |
PCT/CN2020/095352 |
371 Date: |
December 8, 2021 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 9/20 20060101 A61K009/20; A61K 9/28 20060101
A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 10, 2019 |
CN |
PCT/CN2019/090541 |
Claims
1. An solid tablet for oral administration containing Zanubrutinib,
comprising: (1) 20% to 70%, preferably 30% to 50% of Zanubrutinib,
all in mass percentages; and (2) one or more pharmaceutically
acceptable excipients.
2. The solid tablet for oral administration according to claim 1,
wherein the Zanubrutinib is of a crystal form A, an amorphous form,
or a mixture of a crystal form A and an amorphous form.
3. The solid tablet for oral administration according to claim 1 or
2, wherein the excipient is selected from a filler, a binder, a
disintegrant, a wetting agent, a glidant, a lubricant, and any
combination thereof.
4. The solid tablet for oral administration according to claim 3,
wherein the filler is selected from starch, sucrose,
microcrystalline cellulose, mannitol, lactose, pregelatinized
starch, glucose, maltodextrin, cyclodextrin, cellulose, silicified
microcrystalline cellulose, and any combination thereof.
5. The solid tablet for oral administration according to claim 4,
wherein the filler is lactose, and the content of the lactose is
20% to 70%, preferably 40% to 60%, all in mass percentages.
6. The solid tablet for oral administration according to claim 4,
wherein the filler is microcrystalline cellulose, and the content
of the microcrystalline cellulose is 10% to 50%, preferably 30% to
50%, all in mass percentages.
7. The solid tablet for oral administration according to claim 4,
wherein the filler is a combination of lactose and microcrystalline
cellulose, and the contents of the lactose and the microcrystalline
cellulose are 0% to 70% and 0% to 50%, preferably 40% to 60% and 4%
to 10%, respectively, all in mass percentages.
8. The solid tablet for oral administration according to claim 3,
wherein the binder is selected from starch, hypromellose,
polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl
cellulose, methyl cellulose, ethyl cellulose, gelatin, sucrose, and
any combination thereof.
9. The solid tablet for oral administration according to claim 8,
wherein the binder is hypromellose, and the content of the
hypromellose is 0% to 10%, preferably 0% to 5%, all in mass
percentages.
10. The solid tablet for oral administration according to claim 3,
wherein the disintegrant is selected from sodium carboxymethyl
starch, low-substituted hydroxypropyl cellulose, crospovidone,
croscarmellose sodium, croscarmellose, methyl cellulose, pre
gelatinized starch, sodium alginate, and any combination
thereof.
11. The solid tablet for oral administration according to claim 10,
wherein the disintegrant is croscarmellose sodium, and the content
of the croscarmellose sodium is 0.5% to 5%, preferably 1% to 3%,
all in mass percentages.
12. The solid tablet for oral administration according to claim 3,
wherein the wetting agent is sodium lauryl sulfate, and the content
of the sodium lauryl sulfate is 0% to 5%, preferably 0.5% to 1.0%,
all in mass percentages.
13. The solid tablet for oral administration according to claim 3,
wherein the glidant is selected from powdered cellulose, magnesium
trisilicate, colloidal silica, talc powder, and any combination
thereof.
14. The solid tablet for oral administration according to claim 13,
wherein the glidant is colloidal silica, and the content of the
colloidal silica is 0.1% to 20%, preferably 4% to 8%, all in mass
percentages.
15. The solid tablet for oral administration according to claim 3,
wherein the lubricant is selected from zinc stearate, glyceryl
monostearate, glyceryl palmitate stearate, magnesium stearate,
sodium fumarate stearate, and any combination thereof.
16. The solid tablet for oral administration according to claim 15,
wherein the lubricant is magnesium stearate, and the content of the
magnesium stearate is 0.1% to 2%, preferably 0.3% to 1%, all in
mass percentages.
17. The solid tablet for oral administration according to any one
of claims 1 to 16, wherein the solid tablet for oral administration
further comprises a coating agent selected from an Opadry film
coating powder, polyvinyl alcohol, hydroxypropyl cellulose,
polyethylene glycol, and any combination thereof, preferably an
Opadry film coating powder.
18. A method for preparing the solid tablet for oral administration
according to any one of claims 1 to 17, wherein the granulation
method of the solid tablet for oral administration is selected from
direct powder compression, dry granulation, and wet granulation,
preferably wet granulation.
19. A method for preparing the solid tablet for oral administration
according to any one of claims 1 to 17, comprising the following
steps: (1) mixing the zanubrutinib and one or more excipients; (2)
subjecting the mixture of the zanubrutinib and one or more
excipients to wet granulation with purified water, or an organic
reagent, or an aqueous solution or an organic solution containing a
binder, followed by drying and sizing; (3) optionally, mixing the
sized granules with an additional excipient and compressing them
into plain tablets; (4) optionally, coating the plain tablets,
wherein, if step (3) is not performed, the sized granules obtained
in step (2) are compressed into plain tablets.
20. The method according to claim 19, wherein the organic reagent
in step (2) is selected from ethanol, acetone, and a combination
thereof.
21. The method according to claim 19 or 20, wherein the additional
excipient in step (3) is selected from a filler, a lubricant, a
glidant, and any combination thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to an solid tablet for oral
administration containing a Bruton's Tyrosine Kinase (BTK)
inhibitor, in particular
(S)-7-[4-(1-acryloylpiperidine)]-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropy-
razolo[1,5-a]pyrimidine-3-carboxamide and a preparation method
thereof.
BACKGROUND ART
[0002] International application WO 2014173289 A disclosed a novel
Bruton's Tyrosine Kinase (BTK), more particularly
(S)-7-[4-(1-acryloylpiperidine)]-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropy-
razolo[1,5-a] pyrimidine-3-carboxamide (with a generic name of
Zanubrutinib), which has a chemical structure as follows:
##STR00001##
[0003] Zanubrutinib belongs to the second-generation BTK inhibitor,
which irreversibly inactivates the tyrosine kinase by covalently
binding with the enzyme. It is used as a single agent or in
combination with other drugs for the treatment of B lymphocyte
tumors, including chronic lymphocytic leukemia/small lymphocytic
lymphoma (CLL/SLL), mantle cell lymphoma (MCL), Waldenstrom's
macroglobulinemia (WM), follicular lymphoma (FL), non-germinal
center subtype diffuse large B-cell lymphoma (non-GCB DLBCL),
etc.
[0004] The active pharmaceutical ingredient of Zanubrutinib is
slightly hygroscopic. DSC results show that the compound has a
distinct endothermic peak when it melts, and has an initial
temperature and a peak temperature of 139.degree. C. and
144.degree. C., respectively. The melting point of the active
pharmaceutical ingredient is 145.degree. C., which is lower than
the ideal melting point of 150.degree. C. for tablet development,
and the material is relatively viscous, which poses a huge
challenge to the development and large-scale industrial production
of Zanubrutinib tablets. In addition, the Zanubrutinib has a
pH-dependent solubility and belongs to class II (low solubility,
and high permeability) drug of the biopharmaceutical classification
system. Therefore, there is an urgent need to develop a
Zanubrutinib tablet in which the active ingredient can dissolve
quickly from the preparation, so as to maintain the rapid release
of the drug in the whole intestine with good bioavailability.
SUMMARY OF THE INVENTION
[0005] In order to overcome the deficiencies in the physicochemical
properties of Zanubrutinib active pharmaceutical ingredient (API),
such as high viscosity, poor fluidity, and poor solubility, etc.,
and to ensure good dissolution of the drug, the present invention
provides an solid tablet for oral administration containing
Bruton's Tyrosine Kinase inhibitor of Zanubrutinib and a
preparation method thereof. The inventors of the present invention
unexpectedly discovered that a certain amount of colloidal silica
as a glidant and other excipients have a significant contribution
to improve the sticking of the drug and ensure a good dissolution
rate of the drug. The solid tablet for oral administration of
Zanubrutinib of the present invention can be released relatively
quickly in a medium containing sodium lauryl sulfate at pH 1.2
(HCl), for example, the dissolution rate can reach more than 80%
within 30 to 60 min at some prescription excipient ratios;
preferably, the dissolution rate of Zanubrutinib can reach more
than 95% within 30 min at some prescription excipient ratios. In
addition, the solid tablet for oral administration of Zanubrutinib
of the present invention has no special requirements for production
equipment, has a simple preparation process, a stable product, and
low production costs.
[0006] In one aspect of the present invention, there is provided an
solid tablet for oral administration containing Zanubrutinib,
comprising: (1) 20% to 70% (mass percentage), preferably 30% to 50%
(mass percentage) of Zanubrutinib; and (2) one or more
pharmaceutically acceptable excipients.
[0007] In some embodiments of the present invention, the
Zanubrutinib may be in any solid form thereof, such as a crystal
form (e.g., crystal form A disclosed in WO 2018033853 A), an
amorphous form, or a mixture of a crystal form and an amorphous
form. Preferably, the solid tablet for oral administration is of a
crystal form A, an amorphous form, or a mixture of a crystal form A
and an amorphous form. In some specific embodiments of the present
invention, the particle size of the Zanubrutinib is no more than 40
.mu.m.
[0008] In some embodiments, the X-ray powder diffraction pattern of
crystal form A includes diffraction peaks having 2.theta. angle
values independently selected from: about 14.8.+-.0.2.degree.,
15.6.+-.0.2.degree., 16.4.+-.0.2.degree. and 21.4.+-.0.2.degree..
In some embodiments, the X-ray powder diffraction pattern of
crystal form A includes diffraction peaks having 2.theta. angle
values independently selected from: about 12.2.+-.0.2.degree.,
12.9.+-.0.2.degree., 14.8.+-.0.2.degree., 15.6.+-.0.2.degree.,
16.4.+-.0.2.degree. and 21.4.+-.0.2.degree.. In some embodiments,
the X-ray powder diffraction pattern of crystal form A includes
diffraction peaks having 2.theta. angle values independently
selected from: about 12.2.+-.0.2.degree., 12.9.+-.0.2.degree.,
14.8.+-.0.2.degree., 15.6.+-.0.2.degree., 16.4.+-.0.2.degree.,
17.7.+-.0.2.degree., 18.5.+-.0.2.degree., 20.7.+-.0.2.degree. and
21.4.+-.0.2.degree.. In some embodiments, the X-ray powder
diffraction pattern of crystal form A is substantially consistent
with FIG. 1.
[0009] In some embodiments of the present invention, the excipient
is optionally selected from a filler, a binder, a disintegrant, a
wetting agent, a glidant, a lubricant, and any combination
thereof.
[0010] In some specific embodiments of the present invention, the
filler is selected from starch, sucrose, microcrystalline
cellulose, mannitol, lactose, pre gelatinized starch, glucose,
maltodextrin, cyclodextrin, cellulose, silicified microcrystalline
cellulose, and any combination thereof.
[0011] In some specific embodiments of the present invention, the
filler is lactose in a content of about 20% to 70%, preferably
about 40% to 60%, all in mass percentages.
[0012] In some specific embodiments of the present invention, the
filler is microcrystalline cellulose, the microcrystalline
cellulose is internal filler, and the content of the
microcrystalline cellulose filler is about 10% to 50%, preferably
about 30% to 50%, all in mass percentages.
[0013] In some specific embodiments of the present invention, the
filler is a combination of lactose and microcrystalline cellulose,
and the contents of the lactose and the microcrystalline cellulose
are about 0% to 70% and about 0% to 50%, preferably about 40% to
60% and about 4% to 10%, respectively, all in mass percentages.
[0014] In some embodiments of the present invention, the binder is
selected from starch, hypromellose, polyvinylpyrrolidone, sodium
carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose,
ethyl cellulose, gelatin, sucrose, and any combination thereof.
[0015] In some specific embodiments of the present invention, the
binder is hypromellose, and the content of the hypromellose is
about 0% to 10%, preferably about 0% to 5%, all in mass
percentages.
[0016] In some specific embodiments of the present invention, the
binder is croscarmellose sodium in a content of about 0% to 10%,
preferably about 0% to 5%, all in mass percentages.
[0017] In some embodiments of the present invention, the
disintegrant is selected from sodium carboxymethyl starch,
low-substituted hydroxypropyl cellulose, crospovidone,
croscarmellose sodium, croscarmellose, methyl cellulose,
pregelatinized starch, sodium alginate, and any combination
thereof.
[0018] In some specific embodiments of the present invention, the
disintegrant is croscarmellose sodium, and the content of the
croscarmellose sodium is about 0.5% to 5%, preferably about 1% to
3%, all in mass percentages.
[0019] In some embodiments of the present invention, the wetting
agent is sodium lauryl sulfate (SLS), and the content of the sodium
lauryl sulfate is about 0% to 5%, preferably about 0.5% to 1.0%,
all in mass percentages.
[0020] In some embodiments of the present invention, the glidant is
selected from powdered cellulose, magnesium trisilicate, colloidal
silica, talc powder, and any combination thereof.
[0021] In some specific embodiments of the present invention, the
glidant is colloidal silica, and the content of the colloidal
silica is about 0.1% to 20%, which is mass percentage. When the
content of the colloidal silica is less than 0.1% (mass
percentage), colloidal silica cannot effectively disperse the API,
as a result, the rapid disintegration of the tablets and the
dissolution of the API cannot be guaranteed; When the content of
the colloidal silica is greater than 20% (mass percentage), it is
unfavourable for commercialized production due to its huge volume.
More preferably, the content of the colloidal silica is about 4% to
8%, in mass percentage.
[0022] In some embodiments of the present invention, the lubricant
is selected from zinc stearate, glyceryl monostearate, glyceryl
palmitate stearate, magnesium stearate, sodium fumarate stearate,
and any combination thereof.
[0023] In some specific embodiments of the present invention, the
lubricant is magnesium stearate in a content of about 0.1% to 2%,
preferably about 0.3% to 1%, all in mass percentages.
[0024] Still further, the Zanubrutinib solid tablet for oral
administration provided by the present invention further comprises
a coating agent.
[0025] In some embodiments of the present invention, the coating
agent is selected from an Opadry film coating powder, polyvinyl
alcohol, hydroxypropyl cellulose, polyethylene glycol, and any
combination thereof. The Opadry film coating powder is
preferred.
[0026] In one aspect of the present invention, the present
invention provides a method for preparing the Zanubrutinib oral
solid preparation, and the granulation process of which is selected
from direct powder compression, dry granulation, and wet
granulation, preferably wet granulation.
[0027] In one aspect of the present invention, the present
invention provides a method for preparing the Zanubrutinib solid
tablet for oral administration, which comprises the following
steps:
[0028] (1) mixing a Zanubrutinib active pharmaceutical ingredient
and excipients (including but not limited to, a filler, a binder, a
disintegrant, a wetting agent, a glidant, and a lubricant);
[0029] (2) subjecting the mixture of the zanubrutinib active
pharmaceutical ingredient and excipients to wet granulation with
purified water, or an organic reagent (including but not limited to
ethanol, acetone), or an aqueous solution or an organic solution
containing a binder, followed by drying and sizing;
[0030] (3) optionally, mixing the sized granules with an additional
excipient (including but not limited to a filler, a lubricant, a
glidant) and compressing them into plain tablets;
[0031] (4) optionally, coating the plain tablets, wherein if step
(3) is not performed, the sized granules obtained in step (2) are
compressed into plain tablets.
[0032] In some embodiments of the present invention, the organic
reagent in step (2) is selected from ethanol, acetone, and a
combination thereof.
[0033] In some embodiments of the present invention, the additional
excipient described in step (3) is selected from a filler (e.g.,
microcrystalline cellulose), a lubricant (e.g., magnesium
stearate), a glidant (e.g., colloidal silica), and any combination
thereof.
[0034] In the above-mentioned preparation method, the specific
examples and contents of a filler, a binder, a disintegrant, a
wetting agent, a glidant, a lubricant and a coating are as
described above.
[0035] In the above-mentioned preparation method, the "mixing" in
the above-mentioned preparation step (1) is carried out by a
commonly used mixing method. An apparatus, for example, a hopper
mixer, a vertical granulator, FLO-5M, V-type mixer, a tumbler
mixer, etc., is used for "mixing".
[0036] In the above-mentioned preparation method, the granulation
in the above-mentioned preparation step (2) can be carried out by a
common granulation method. The granulation is carried out by an
apparatus, such as a wet granulator, etc. The compression is
carried out by a conventional tablet press, such as ZP10A. After
the tablet is made, it can be "dried", if necessary. For drying,
any method used to dry the preparation can generally be used, for
example, vacuum drying, fluidized bed drying, etc. The following
terms that can be used herein are used according to the following
definitions.
[0037] Unless it is clearly indicated to the contrary, all ranges
referred herein are inclusive; that is, the range includes the
values of the upper and lower limits of the range and all values
therebetween. For example, the temperature range, percentage,
equivalent range, etc., described herein include the upper and
lower limits of the range and any value in the continuous interval
therebetween.
[0038] As used herein, the term "mass percentage" describes the
contents of the Zanubrutinib active pharmaceutical ingredient and
various excipients, which is calculated with respect to the total
mass of the solid tablet for oral administration.
[0039] The term "preparation" as used herein refers to a mixture,
an aggregate, a solution or other combinations of substances
including the active pharmaceutical ingredients (APIs); the
preparation is suitable for a particular route of administration,
for example, is suitable for compression into a preparation of a
tablet that is designed for oral administration in the treatment,
management, and prevention, etc., of the patient's disease states
or disorders.
[0040] The "coating" as used herein is not limited to the case of
coating the entire surface of the coated object (a plain tablet
containing Zanubrutinib), but can also refers to the partial
coating of the coated object, absorbing or adsorbing the
enteric-coating components onto the coated object, or plain tablets
with an inner core coated. The solid tablet for oral
administrations prepared according to the present invention have a
hardness of 60 N to 220 N, and the dissolution rate exceeds 85%
within 30 minutes.
[0041] In some embodiments of the present invention, the content of
Zanubrutinib in the solid oral tablet is usually about 70 mg to
about 400 mg of Zanubrutinib per tablet, preferably about 80 mg,
160 mg or 320 mg of Zanubrutinib.
[0042] In some embodiments of the present invention, the solid oral
tablet may also contain one or more agents selected from a
sweetening agent, a corrective, a colouring agent and a
preservative to provide a pharmaceutically aesthetic and palatable
preparation.
[0043] In some embodiments of the present invention, the solid oral
tablet can be prepared in a variety of possible shapes (ellipsoid,
capsule, double-sided convex round lamp).
BRIEF DESCRIPTION OF THE DRAWINGS
[0044] FIG. 1 is an X-ray powder diffraction pattern of the crystal
form A of Zanubrutinib.
[0045] FIG. 2 is a schematic diagram of the cumulative drug
dissolution (in vitro dissolution) of the solid tablet for oral
administrations of Zanubrutinib in Example 1.
[0046] FIG. 3 is a schematic diagram of the cumulative drug
dissolution (in vitro dissolution) of the solid tablet for oral
administrations of Zanubrutinib in Example 8 and Example 9. It can
be seen therefrom that the drug dissolution rate of Example 8 is
significantly better than that of Example 9.
DETAILED DESCRIPTION OF EMBODIMENTS
[0047] The following examples can help those skilled in the art to
understand the present invention more comprehensively, but do not
limit the present invention in any way. In the following, unless
otherwise specified, the temperature is in .degree. C. Reagents are
purchased from commercial providers such as Sigma-Aldrich, Alfa
Aesar or TCI, and can be used without further purification unless
otherwise specified.
Example 1
[0048] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 160 mg
[0049] Prescription (Per 100 g Plain Tablets):
TABLE-US-00001 Zanubrutinib (Crystal form A) 34.8 g Lactose 53.2 g
Croscarmellose sodium 2 g Colloidal silica 4.5 g Sodium lauryl
sulfate 1 g Microcrystalline cellulose 4 g Magnesium stearate 0.5 g
Opadry 2.4 g
[0050] Preparation Process: 53.2 g of lactose, 2 g of
croscarmellose sodium, 1 g of sodium lauryl sulfate and 34.8 g of
Zanubrutinib are added into a high-shear granulator (MYCROMIX,
manufactured by BOSCH) and mixed for 5 minutes, an appropriate
amount of purified water is added for granulation, followed by
dying and then sizing, 4.5 g of colloidal silica, 4 g of
microcrystalline cellulose and 0.5 g of magnesium stearate are
further added and mixed. After mixing, the above ingredients are
pressed into tablets to obtain plain tablets. The above-mentioned
plain tablets are coated with 2.4 g of Opadry to obtain solid
tablet for oral administrations containing Zanubrutinib.
[0051] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The
in vitro dissolution experiment is determined by an automatic
sampling dissolution tester (Model: 708+850DS, purchased from
AGILENT), according to USP<711>, the "dissolution" is
determined using the basket method, the automatic sampling
dissolution tester is set at a water bath temperature of
37.+-.0.5.degree. C., at a rotating speed of 100 rpm, with a pH 1.2
(HCl)+0.5% SLS dissolution medium of a volume of 900 mL. Samples
are taken at 10 min, 15 min, 30 min, 45 min, and 60 min, and all
samples are passed through a 0.45 .mu.m filter membrane, and the
samples are determined and analyzed according to the sample
dissolution test method. As shown in FIG. 2, when the Zanubrutinib
solid tablet for oral administration of the present invention is in
a pH 1.2 (HCl)+0.5% SLS medium, more than 90% of Zanubrutinib is
dissolved at 30 minutes, which can meet the requirements of rapid
release.
[0052] In the following Examples 2-12, the drug cumulative
dissolution (in vitro dissolution) are all measured according to
the method of Example 1.
Example 2
[0053] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 160 mg
[0054] Prescription (Per 100 g Plain Tablets):
TABLE-US-00002 Zanubrutinib (Crystal form A) 36.2 g Lactose 55.6 g
Croscarmellose sodium 2.2 g Colloidal silica 4.3 g Sodium lauryl
sulfate 1.1 g Magnesium stearate 0.5 g
[0055] Preparation Process: 55.6 g of lactose, 2.2 g of
croscarmellose sodium, 1.1 g of sodium lauryl sulfate, 4.3 g of
colloidal silica and 36.2 g of Zanubrutinib are added into a
high-shear granulator and mixed for 5 minutes, an appropriate
amount of purified water is added for granulation, followed by
dying and then sizing, and 0.5 g of magnesium stearate is further
added and mixed. After mixing, the above ingredients are pressed
into tablets to obtain plain tablets, that is, an solid tablet for
oral administration containing Zanubrutinib.
[0056] Drug Cumulative Dissolution (In Vitro Dissolution) Test:
About 90% of Zanubrutinib is dissolved at 30 minutes.
Example 3
[0057] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 160 mg
[0058] Prescription (Per 100 g Plain Tablets):
TABLE-US-00003 Zanubrutinib (Crystal form A) 33.3 g Lactose 49.2 g
Hypromellose 2 g Croscarmellose sodium 2 g Colloidal silica 4 g
Sodium lauryl sulfate 1 g Microcrystalline cellulose 8 g Magnesium
stearate 0.5 g
[0059] Preparation Process: 49.2 g of lactose, 2 g of
croscarmellose sodium, 1 g of sodium lauryl sulfate and 33.3 g of
Zanubrutinib are added into a high-shear granulator and mixed for 5
minutes, 2 g of hypromellose aqueous solution is added for
granulation, followed by dying and then sizing, 4 g of colloidal
silica, 8 g of microcrystalline cellulose and 0.5 g of magnesium
stearate are further added and mixed. After mixing, the above
ingredients are pressed into tablets to obtain plain tablets, that
is, an solid tablet for oral administration containing
Zanubrutinib.
Example 4
[0060] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 320 mg
[0061] Prescription (Per 100 g Plain Tablets):
TABLE-US-00004 Zanubrutinib (Crystal form A) 50 g Croscarmellose
sodium 4 g Colloidal silica 12.0 g Sodium lauryl sulfate 1 g
Microcrystalline cellulose 32.5 g Magnesium stearate 0.5 g Opadry
1.5 g
[0062] Preparation Process: 50 g of Zanubrutinib, 4 g of
croscarmellose sodium, 12.0 g of colloidal silica, 1 g of sodium
lauryl sulfate, 32.5 g of microcrystalline cellulose are sieved and
then mixed in a high-shear granulator, then 0.5 g of magnesium
stearate is added and mixed uniformly. The mixed powder is pressed
directly to obtain plain tablets. The above-mentioned plain tablets
are coated with a coating liquid containing 2.4 g of Opadry to
obtain solid tablet for oral administrations containing
Zanubrutinib.
[0063] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The
dissolution rate (%) of the drug at 30 minutes is about 80%.
Example 5
[0064] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 80 mg
[0065] Prescription (Per 100 g Plain Tablets):
TABLE-US-00005 Zanubrutinib (Crystal form A) 26.7 g Lactose 23.8 g
Croscarmellose sodium 2 g Colloidal silica 4 g Sodium lauryl
sulfate 1 g Microcrystalline cellulose 40 g Hypromellose 2 g
Magnesium stearate 0.5 g Opadry 1.5 g
[0066] Preparation Process: 23.8 g of lactose, 40 g of
microcrystalline cellulose, 2 g of croscarmellose sodium, 1 g of
sodium lauryl sulfate, 4 g of colloidal silica, and 26.7 g of
Zanubrutinib are added to a fluidized bed, then 2 g of a
hypromellose aqueous solution is sprayed for granulation, followed
by drying and then magnesium stearate is added and mixed. After
mixing, the above ingredients are pressed into tablets to obtain
plain tablets. The above-mentioned plain tablets are coated with a
coating liquid containing 1.5 g of Opadry to obtain solid tablet
for oral administrations containing Zanubrutinib.
Example 6
[0067] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 80 mg
[0068] Prescription (Per 100 g Plain Tablets):
TABLE-US-00006 Zanubrutinib (Crystal form A) 26.7 g Lactose 35.8 g
Croscarmellose sodium 2 g Colloidal silica 4 g Sodium lauryl
sulfate 1 g Silicified microcrystalline cellulose 30 g Magnesium
stearate 0.5 g
[0069] Preparation Process: 26.7 g of Zanubrutinib, 2 g of
croscarmellose sodium, 4 g of colloidal silica, 1 g of sodium
lauryl sulfate, 35.8 g of lactose and 30 g of silicified
microcrystalline cellulose are sieved and then mixed in a
high-shear granulator, then 0.5 g of magnesium stearate is added
and mixed uniformly. The powder is pressed into tablets directly,
coated with an Opadry coating liquid to obtain solid tablet for
oral administrations containing Zanubrutinib.
Example 7
[0070] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 320 mg
[0071] Prescription (Per 100 g Plain Tablets):
TABLE-US-00007 Zanubrutinib (Crystal form A) 50.0 g Lactose 36.5 g
Croscarmellose sodium 4 g Colloidal silica 8 g Sodium lauryl
sulfate 1 g Magnesium stearate 0.5 g
[0072] Preparation Process: 50.0 g of Zanubrutinib, 4 g of
croscarmellose sodium, 8 g of colloidal silica, 1 g of sodium
lauryl sulfate, 36.5 g of lactose are sieved and then mixed in a
high-shear granulator, then 0.5 g of magnesium stearate is added
and mixed uniformly. The powder is pressed directly into tablets to
obtain plain tablets, that is, an solid tablet for oral
administration containing Zanubrutinib.
[0073] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The
dissolution rate (%) of the drug at 30 minutes is about 40%.
Example 8
[0074] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 320 mg
[0075] Prescription (Per 100 g Plain Tablets):
TABLE-US-00008 Zanubrutinib (Crystal form A) 50.0 g Croscarmellose
sodium 4 g Colloidal silica 8 g Sodium lauryl sulfate 1 g
Microcrystalline cellulose 36.5 g Magnesium stearate 0.5 g
[0076] Preparation Process: 50.0 g of Zanubrutinib, 36.5 g of
microcrystalline cellulose, 4 g of croscarmellose sodium, 8 g of
colloidal silica, 1 g of sodium lauryl sulfate are sieved and then
mixed in a high-shear granulator, then 0.5 g of magnesium stearate
is added and mixed uniformly. The powder is pressed directly into
tablets to obtain plain tablets, that is, an solid tablet for oral
administration containing Zanubrutinib.
[0077] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The
dissolution curve of the drug is shown in FIG. 3. It can be seen
that the dissolution is greater than 80% at 30 minutes.
Example 9
[0078] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 320 mg
[0079] Prescription (Per 100 g Plain Tablets):
TABLE-US-00009 Zanubrutinib (Crystal form A) 60.0 g Croscarmellose
sodium 4 g Colloidal silica 0.8 g Sodium lauryl sulfate 1 g
Microcrystalline cellulose 33.7 g Magnesium stearate 0.5 g
[0080] Preparation Process: 60 g of Zanubrutinib, 33.7 g of
microcrystalline cellulose, 4 g of croscarmellose sodium, 0.8 g of
colloidal silica, 1 g of sodium lauryl sulfate are sieved and then
mixed in a high-shear granulator, then 0.5 g of magnesium stearate
is added and mixed uniformly. The powder is pressed directly into
tablets to obtain plain tablets, that is, an solid tablet for oral
administration containing Zanubrutinib.
[0081] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The
dissolution curve of the drug is shown in FIG. 3. It can be seen
that the dissolution is less than 60% at 30 minutes.
Example 10
[0082] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 320 mg
[0083] Prescription (Per 100 g Plain Tablets):
TABLE-US-00010 Zanubrutinib (Crystal form A) 46.69 g Croscarmellose
sodium 4.38 g Colloidal silica 0.88 g Sodium lauryl sulfate 0.88 g
Microcrystalline cellulose 46.69 g Magnesium stearate 0.50 g
[0084] Preparation Process: 53.2 g of lactose, 2 g of
croscarmellose sodium, 1 g of sodium lauryl sulfate and 34.8 g of
Zanubrutinib are added into a high-shear granulator (MYCROMIX,
manufactured by BOSCH) and mixed for 5 minutes, an appropriate
amount of purified water is added for granulation, followed by
dying and then sizing, 4.5 g of colloidal silica, 4 g of
microcrystalline cellulose and 0.5 g of magnesium stearate are
further added and mixed. After mixing, the above ingredients are
pressed into tablets to obtain plain tablets, that is, an solid
tablet for oral administration containing Zanubrutinib.
[0085] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The
dissolution rate (%) of the drug at 60 minutes is about 80%.
Example 11
[0086] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 320 mg
[0087] Prescription (Per 100 g Plain Tablets):
TABLE-US-00011 Zanubrutinib (Crystal form A) 46.69 g Lactose 46.69
g Croscarmellose sodium 4.38 g Colloidal silica 0.88 g Sodium
lauryl sulfate 0.88 g Magnesium stearate 0.50 g
[0088] Preparation Process: According to a method similar to
Example 10, the solid tablet for oral administrations containing
Zanubrutinib can be prepared.
[0089] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The
dissolution rate (%) of the drug at 60 minutes is less than
80%.
Example 12
[0090] Preparation of Solid Tablet for Oral Administrations of
Zanubrutinib, Specification: 320 mg
[0091] Prescription (Per 100 g Plain Tablets):
TABLE-US-00012 Zanubrutinib (Crystal form A) 22.21 g Croscarmellose
sodium 3.00 g Colloidal silica 0.50 g Sodium lauryl sulfate 0.50 g
Microcrystalline cellulose 73.29 g Magnesium stearate 0.50 g
[0092] Preparation Process: According to a method similar to
Example 10, the solid tablet for oral administrations containing
Zanubrutinib can be prepared.
[0093] Although the foregoing description teaches the principles of
the present invention and provides examples for the purpose of
illustration, the practice of the present invention includes all
common changes, adaptations and/or modifications within the scope
of the following claims. The references involved in this disclosure
are incorporated herein by reference.
* * * * *