CN115212177A - Oral solid scored tablet containing Bruton's tyrosine kinase inhibitor and preparation method thereof - Google Patents
Oral solid scored tablet containing Bruton's tyrosine kinase inhibitor and preparation method thereof Download PDFInfo
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- CN115212177A CN115212177A CN202111157352.4A CN202111157352A CN115212177A CN 115212177 A CN115212177 A CN 115212177A CN 202111157352 A CN202111157352 A CN 202111157352A CN 115212177 A CN115212177 A CN 115212177A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides an oral solid scored tablet containing (S) -7- [4- (1-acryloyl piperidine) ] -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-formamide and a preparation method thereof. The oral solid scored tablet has good breaking-off characteristics, is convenient for free combination of drug dosage and has good drug release characteristics.
Description
The technical field is as follows:
the invention belongs to the field of pharmaceutical preparations, and describes an oral solid scored tablet containing Bruton' S Tyrosine Kinase (BTK) inhibitor, in particular (S) -7- [4- (1-acryloyl piperidine) ] -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-formamide and a preparation method thereof.
Background art:
international application WO2014173289A discloses a novel Bruton' S Tyrosine Kinase (BTK), more specifically (S) -7- [4- (1-acryloylpiperidine) ] -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide (generic name Z zebratinib, anubrutinib), having the following chemical structure:
zertinib belongs to a second generation BTK inhibitor that irreversibly inactivates the enzyme by covalently binding to tyrosine kinase. It can be used for treating B lymphocyte tumor (including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle Cell Lymphoma (MCL), waldenstrom Macroglobulinemia (WM), follicular Lymphoma (FL), non-germinal center subtype diffuse large B cell lymphoma (non-GCB DLBCL), etc.) alone or in combination with other drugs.
The anti-tumor severing slice can enhance the clinical administration compliance of dysphagia patients or meet the treatment requirements of patients with incomplete tablet amount. However, achieving dose precision in breaking-off tablets and dose flexibility in clinical use are technical challenges faced by all breakable oral solid tablets: the FDA guidelines require testing after breaking by hand and instrument, respectively, the mass loss after breaking is less than 3.0%, the friability of the divided segment is not more than 1.0%, the divided segment CU meets the USP <905> requirements, the dissolution rate of the divided segment is similar to that of the complete tablet (tablets with upper and lower hardness limits are tested respectively), the divided segment needs to be stable in the medical drug storage box/bottle for at least 3 months, and the like.
Disclosure of Invention
Scored tablets are continuous indentations through the surface of the tablet that serve to divide the tablet into smaller sub-units. The problems with the existing forms of scored tablets are well known. These problems include loss of active drug, inaccurate breaking of the tablet, greater friability or less stability of the broken pieces, etc., and thus breaking the tablet is often less than ideal. Moreover, the material properties are different for different drugs, resulting in different breaking-off difficulties.
To this end, the present invention has been accomplished by selecting appropriate excipients, tablet structures and processing techniques. Specifically, the invention provides a zebritinib oral solid scored tablet which is suitable for administration treatment of patients with dysphagia or patients needing half tablet amount, has good breaking uniformity, meets the requirements of weight difference, weight loss after breaking, friability and dissolution rate, and has the characteristic of quality stability. For example, the fully scored tablet and the divided tablet of the present invention have substantially the same dissolution profile. In one aspect of the present invention, there is provided an oral solid scored tablet comprising zetidine, which comprises (1) 20 to 70% (mass percent), preferably 30 to 50% (mass percent); (2) One or more pharmaceutically acceptable excipients, wherein the scored tablet is an ellipsoid tablet or a circular lamp tablet and at least one side of the scored tablet is scored with one or more indentations. In some embodiments, the zebrafenib is uniformly dispersed in the scored tablet.
In some embodiments of the present invention, the zerewitinib may be in any solid form thereof, such as a crystalline form (e.g., form a disclosed in WO 2018033853A), amorphous form, or a mixture of crystalline and amorphous forms. Preferably, the zerewitinoib is form a, amorphous, or a mixture of form a and amorphous. In some embodiments of the invention, the particle size of the zerewitinoib is below 40 μm.
In some embodiments, the form a has an X-ray powder diffraction pattern comprising diffraction peaks having angle values independently selected from the group consisting of: about 14.8 ± 0.2 °, 15.6 ± 0.2 °, 16.4 ± 0.2 ° and 21.4 ± 0.2 °. In some embodiments, the form a has an X-ray powder diffraction pattern comprising diffraction peaks having angle values independently selected from the group consisting of: about 12.2 + -0.2 deg., 12.9 + -0.2 deg., 14.8 + -0.2 deg., 15.6 + -0.2 deg., 16.4 + -0.2 deg., and 21.4 + -0.2 deg.. In some embodiments, the form a has an X-ray powder diffraction pattern comprising diffraction peaks having angle values independently selected from the group consisting of: about 12.2 + -0.2 deg., 12.9 + -0.2 deg., 14.8 + -0.2 deg., 15.6 + -0.2 deg., 16.4 + -0.2 deg., 17.7 + -0.2 deg., 18.5 + -0.2 deg., 20.7 + -0.2 deg., and 21.4 + -0.2 deg.. In some embodiments, the X-ray powder diffraction pattern of form a is substantially in accordance with figure 1.
In some embodiments of the invention, the excipient is optionally selected from the group consisting of fillers, binders, disintegrants, wetting agents, glidants, lubricants, and any combination thereof.
In some embodiments of the invention, the filler is selected from the group consisting of starch, sucrose, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, glucose, maltodextrin, cyclodextrin, cellulose, silicified microcrystalline cellulose, and any combination thereof.
In some embodiments of the invention, the filler is lactose, which is present in an amount of about 20% to 70%, preferably about 40% to 60%, all by weight.
In some embodiments of the invention, the binder is selected from the group consisting of starch, hypromellose, polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, gelatin, sucrose, and any combination thereof.
In some embodiments of the present invention, the binder is hypromellose, and the content of hypromellose is about 0 to 10%, preferably about 0 to 5%, by mass.
In some embodiments of the invention, the disintegrant is selected from the group consisting of sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, sodium alginate, and any combination thereof.
In some embodiments of the invention, the disintegrant is croscarmellose sodium, and the croscarmellose sodium content is between about 0.5% and 5%, all by mass.
In some embodiments of the invention, the wetting agent is Sodium Lauryl Sulfate (SLS), which is present in an amount of about 0% to 5%, preferably 0.5% to 1.0%, all by mass.
In some embodiments of the invention, the glidant is selected from the group consisting of powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, talc, and any combination thereof.
In some embodiments of the invention, the glidant is colloidal silicon dioxide, and the colloidal silicon dioxide is present in an amount of about 0.1 to 20 percent by mass. More preferably, the colloidal silica is present in an amount of about 4% to 10% by mass.
In some embodiments of the invention, the lubricant is selected from the group consisting of zinc stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium stearyl fumarate, and any combination thereof.
In some embodiments of the invention, the lubricant is preferably magnesium stearate, which is present in an amount of about 0.1% to 2%, preferably about 0.3% to 1%, all by mass.
Furthermore, the zerewitinoib oral solid tablet provided by the invention further comprises a coating agent.
In some embodiments of the invention, the coating agent is selected from the group consisting of opadry film coating powder, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, and any combination thereof. Preferably opadry film coating powder.
In one aspect of the present invention, the present invention provides a method for preparing the zerewitinoib oral solid scored tablet, comprising the steps of:
(1) Mixing the zetinib drug substance and excipients (including, but not limited to, fillers, binders, disintegrants, wetting agents, glidants, and lubricants);
(2) Wet granulating the mixture of the zerewitinoib bulk drug and excipients with purified water, or organic agents (including but not limited to ethanol, acetone), or aqueous or organic solutions containing binders, drying and granulating;
(3) Optionally, mixing the whole granulate with additional excipients (including but not limited to fillers, lubricants, glidants) and compressing in a tablet press with a scored part to form a scored plain tablet with one or more indentations;
(4) Optionally, coating the scored tablet,
if the step (3) is not carried out, putting the whole granules obtained in the step (2) into a tablet press with a scored part for pressing so as to form scored plain tablets with one or more scores, and if the coating is not carried out, the scored plain tablets are scored tablets; if coated, the coated tablet is a scored tablet.
In some embodiments of the invention, the organic reagent in step (2) is selected from the group consisting of ethanol, acetone, and combinations thereof.
In some embodiments of the invention, the additional excipient in step (3) is selected from the group consisting of fillers (e.g. microcrystalline cellulose), lubricants (e.g. magnesium stearate), glidants (e.g. colloidal silicon dioxide), and any combination thereof.
In some embodiments of the present invention, the tablet press may include upper and lower punches with a scoring member disposed intermediate the upper or lower punches to form a score on the tablet. The shape and size of the score can be adjusted by adjusting the shape and size of the score part. In some embodiments of the invention, there is a marking component in the upper or lower punch to form a marking, e.g., ZANU, on the tablet. In some embodiments of the invention, the score may have a different depth, for example from about 5% to about 95%, preferably 8% to 50%, more preferably 10% to 30% of the tablet depth (i.e., tablet thickness).
In some embodiments of the invention, the scored tablet comprises one or more scores, for example, one to four scores. The score serves to guide the subdivision of the tablet. Although fig. 2 shows a tablet having one score, it is contemplated that the tablet may contain more than two scores. In a preferred embodiment, the scored tablet has one score that allows the tablet to be bisected. In the above preparation method, specific examples and contents of the filler, the binder, the disintegrant, the wetting agent, the glidant, the lubricant, and the coating are as described above.
In the above production method, "mixing" in the above production step (1) is performed by a commonly used mixing method. "mixing" is carried out using equipment such as hopper mixers, vertical granulators, FLO-5M, V-mixers, tumbler mixers, and the like.
In the above production method, the granulation in the above production step (2) may be performed using a usual granulation method. The granulation is carried out using equipment such as a wet granulator or the like. Compression is carried out using a conventional tablet press, such as ZP 10A. After tableting, if necessary, "drying" may be performed. For drying, any method used for drying the formulation may be generally used, for example, vacuum drying, fluidized bed drying, and the like. The following terms, as may be used herein, are used according to the definitions set forth below.
All ranges cited herein are inclusive, unless expressly stated to the contrary; that is, the range includes the values of the upper and lower limits of the range, as well as all values in between. For example, temperature ranges, percentages, equivalent ranges, and the like, as described herein, include the upper and lower limits of the ranges, and any value for the continuum between them.
The term "mass percentage" as used herein describes the content of the drug substance zetinib and the various excipients, calculated relative to the total mass of the oral solid tablet.
The term "formulation" as used herein refers to a mixture, aggregate, solution or other combination of substances including an Active Pharmaceutical Ingredient (API) that is suitable for a particular route of administration, e.g., a formulation suitable for compression into a tablet designed for oral administration in the treatment, management, prevention, etc. of a disease state or condition in a patient.
As used herein, "coating" is not limited to the case of coating the entire surface of the coated object (a zerewitinoid-containing plain tablet), but may also refer to the case of partially coating the coated object, absorbing or adsorbing enteric coating components in the coated object, or coating the plain tablet of the inner core. The oral solid tablets prepared according to the invention have a hardness of 60N to 220N, preferably 120N to 170N, more preferably 95N to 140N, and a dissolution rate of more than 85% within 30 minutes. By selecting an appropriate hardness, the tablet is also easily broken.
In some embodiments of the invention, the amount of zerewitinoib in the solid oral tablet is generally from about 70mg to about 400mg of zerewitinoib per tablet, preferably about 80, 160or 320mg of zerewitinoib per tablet.
In some embodiments of the present invention, one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents may also be included in the breakable solid oral tablets to provide pharmaceutically elegant and palatable preparations.
In some embodiments of the invention, the breakable solid oral tablets can be made using a variety of possible shapes (ellipsoid, biconvex circular lamp).
Drawings
Figure 1 is an X-ray powder diffraction pattern of crystalline form a of zerewitinoib.
Fig. 2 is a schematic diagram of the structure of the zerewitinoib oral solid scored tablet of example 1.
Fig. 3A-B are graphs showing the cumulative dissolution of the drug (in vitro dissolution) for the divided and intact tablets of the zebrafenib oral solid scored tablet of example 1.
Fig. 4 is a graphical representation of the stability of the split fragments of the zebritinib oral solid scored tablet of example 1.
The specific implementation mode is as follows:
the following examples may assist those skilled in the art in a more complete understanding of the present invention, but are not intended to limit the invention in any way. Hereinafter, unless otherwise specified, the temperature is in ° c. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, alfa Aesar, or TCI, and used without further purification unless otherwise specified.
Example 1
And (3) preparing the zerewitinoside oral solid scored tablet, wherein the specification is 160mg. The prescription is as follows (per 100g of plain tablets):
the preparation process comprises the following steps: 53.2g of lactose, 2g of croscarmellose sodium, 1g of sodium lauryl sulfate and 34.8g of zebertinib were added to a high shear granulator (MYCROMIX, manufactured by BOSCH) and mixed for 5 minutes, an appropriate amount of purified water was added to granulate, dried and granulated, and 4.5g of colloidal silicon dioxide, 4g of microcrystalline cellulose and 0.5g of magnesium stearate were added and mixed. Mixing, tabletting with tablet press (national medicine Longli ZP10A type tablet press) equipped with elliptical die to obtain scored plain tablet, wherein the upper punch of the tablet press is equipped with an equilateral triangular (width x height, 0.70mm x 0.35 mm) scoring component, and the lower punch is equipped with an equilateral triangular ZANU (width x height, 0.38mm x 0.15 mm) marking protuberance. The plain tablets were coated with 2.4g of opadry to give oral solid scored tablets containing zebritinib. The structure of the prepared oral solid scored tablet is shown in fig. 2. As shown in fig. 2, the oval scored tablet has a length of 14mm, a width of 6.5mm, and a thickness of 5.7mm, wherein the length, width, and thickness are the maximum length, width, and thickness of the tablet, the score is located at the midpoint of the length, the indicia ZANU is located on the surface opposite the score, the radius R1 of the arc between the length and width is 3.25mm, and the radius R2 of the arc between the length and thickness is 5.06mm.
A scale-up test was performed according to the proportions given in example 1 to prepare 3000 scored tablets for the following test.
1) Test items for oral solid scored tabletsThe weight difference is as follows:randomly taking 30 complete scored tablets, respectively adopting a manual segmentation mode and a slicer segmentation mode, taking one segmentation segment in each complete tablet to weigh, and not calculating the average weight of other parts. Gradually weigh 30 fragments.
The weight of the divided segments is not more than one, and the divided segments exceed 85-115% of the average weight, and if more than one divided segment exceeds 85-115% of the average weight, or the weight of the divided segment is more than 75-125% of the average weight, the divided segment is judged to be unqualified.
Weight loss in cutting: taking 15 complete tablets, respectively detecting the upper limit and the lower limit of the hardness range of 95N-140N of the complete tablets, and comparing the total weight of the divided fragments (30 half tablets in total) with the total weight of the 15 complete tablets, controlling the weight loss within 3.0 percent of the total weight of the 15 complete tablets, and preventing the tablet fragments in the tablet breaking process from participating in calculating the weight loss.
Friability: the upper limit and the lower limit of the hardness range of the whole tablet are respectively taken to carry out friability inspection, and the result meets the requirements of a 0923 tablet friability inspection method in the fourth part of 2020 edition of Chinese pharmacopoeia. And (3) testing results: the weight difference between the manual cutting and the slicing device, the weight loss after the hand cutting and the slicing device are broken and the friability meet the standard requirements within the hardness range of 95N-140N. The results are shown in Table 1.
Table 1:
2) Cumulative dissolution of drug (in vitro dissolution) test for oral solid scored tablets:
in vitro dissolution test is carried out by using an automatic sampling dissolution instrument, wherein the dissolution rate of Chinese pharmacopoeia 0931 is determined by using a basket method, the water bath temperature of the automatic sampling dissolution instrument is set to be 37 +/-0.5 ℃, the rotating speed is 75rpm, 0.1N hydrochloric acid containing 0.2% of sodium dodecyl sulfate is used as a dissolution medium, and the volume is 900mL. Sampling at 5min, 10min, 15min, 30min, 45min and 60min respectively, filtering all samples with 0.45 μm filter membrane, and determining and analyzing according to the dissolution rate determination method. The zebrafenib oral solid scored whole tablets and divided tablets of example 1 had a dissolution (%) greater than 85% in the above dissolution medium at 30min, meeting the rapid release requirements, and the results are shown in table 2. From the dissolution profile plot (FIG. 3A), it can be seen that the dissolution was similar in the intact and segmented pieces.
TABLE 2
In addition, two batches of 3000 scored tablets were prepared according to the formulation of example 1, wherein the first batch had a scored tablet size of 80mg and a hardness of 75N and the second batch had a scored tablet size of 160mg and a hardness of 120N. 30 tablets were randomly taken from the second batch of scored tablets and manually divided. The 60 first scored tablets, 30 second scored tablets, and 30 second scored whole tablets were then subjected to a dissolution rate (in vitro dissolution) test, the results of which are shown in fig. 3B.
2) Stability testing of the split fragments of oral solid scored tablets:
the post-split fractions were examined for stability for 90 days under 30 ℃/75% RH conditions, and the main test items were appearance, content/related substances, moisture and dissolution (see FIG. 4). The results are shown in Table 3.
TABLE 3
Note 1. The calculation method for a single impurity is an external standard method.
2. The total impurities are calculated as the sum of the individual impurities, greater than 0.05%.
The following examples 2-12 were all prepared and tested according to the method of example 1.
Example 2
Preparation of Zebritinib oral solid tablet with specification of 160mg
The prescription is (per 100g of plain tablets):
the preparation process comprises the following steps: 55.6g of lactose, 2.2g of croscarmellose sodium, 1.1g of sodium lauryl sulfate, 4.3g of colloidal silicon dioxide and 36.2g of zebu tinib were added to a high shear granulator and mixed for 5 minutes, an appropriate amount of purified water was added to granulate, after drying, the granules were sized, and 0.5g of magnesium stearate was added and mixed. Mixing and tabletting to obtain plain tablets, namely the oral solid scored tablet containing the zebrinib.
Drug cumulative dissolution (in vitro dissolution) test: at 30min about 90% of the zetinib was dissolved out.
Example 3
Preparation of Zebritinib oral solid tablet with specification of 160mg
The prescription is (per 100g of the tablet):
the preparation process comprises the following steps: 49.2g of lactose, 2g of croscarmellose sodium, 1g of sodium lauryl sulfate and 33.3g of zebritinib were added to a high shear granulator and mixed for 5 minutes, 2g of hypromellose aqueous solution was added to granulate, and after drying, granules were granulated, and 4g of colloidal silicon dioxide, 8g of microcrystalline cellulose and 0.5g of magnesium stearate were added and mixed. Mixing and tabletting to obtain plain tablets, namely the oral solid scored tablets containing the zebrinib.
Example 4
Preparation of Zebritinib oral solid tablet with specification of 320mg
The prescription is (per 100g of plain tablets):
the preparation process comprises the following steps: 50g of zeblitinib, 4g of croscarmellose sodium, 12.0g of colloidal silicon dioxide, 1g of sodium lauryl sulfate and 32.5g of microcrystalline cellulose were sieved, mixed in a high shear granulator, and then 0.5g of magnesium stearate was added and mixed uniformly. And directly tabletting the mixed powder to obtain the plain tablets. The plain tablets were coated with a coating solution containing 2.4g of opadry to obtain oral solid scored tablets containing zebritinib.
Drug cumulative dissolution (in vitro dissolution) test: the dissolution (%) of the drug at 30min was about 80%.
Example 5
Preparation of Zebritinib oral solid tablet with specification of 80mg
The prescription is (per 100g of the tablet):
the preparation process comprises the following steps: lactose 23.8g, microcrystalline cellulose 40g, croscarmellose sodium 2g, sodium lauryl sulfate 1g, colloidal silicon dioxide 4g and zebrafenib 26.7g were added to the fluidised bed, an aqueous solution containing hydroxypropyl methylcellulose 2g was sprayed on to granulate, the magnesium stearate added after drying and mixing. Mixing, and tabletting to obtain plain tablet. The plain tablets were coated with a coating solution containing 1.5g of opadry to obtain oral solid scored tablets containing zebritinib.
Example 6
Preparation of Zebritinib oral solid tablet with specification of 80mg
The prescription is (per 100g of the tablet):
the preparation process comprises the following steps: 26.7g of zebertinib, 2g of croscarmellose sodium, 4g of colloidal silicon dioxide, 1g of sodium lauryl sulfate, 35.8g of lactose and 30g of silicified microcrystalline cellulose are sieved and mixed in a high shear granulator, 0.5g of magnesium stearate is added and mixed well. Directly tabletting the powder and coating the powder with an Opadry coating solution to obtain the oral solid scored tablet containing the zetinib.
Example 7
Preparation of Zebritinib oral solid tablet with specification of 320mg
The prescription is (per 100g of plain tablets):
the preparation process comprises the following steps: 50.0g of zebertinib, 4g of croscarmellose sodium, 8g of colloidal silicon dioxide, 1g of sodium lauryl sulfate and 36.5g of lactose are sieved and mixed in a high shear granulator, and then 0.5g of magnesium stearate is added and mixed uniformly. Directly tabletting the powder to obtain a plain tablet, namely the oral solid scored tablet containing the zebritinib.
Drug cumulative dissolution (in vitro dissolution) test: the drug content is about 40% in 30 min.
Example 8
Preparation of Zebritinib oral solid tablet with specification of 320mg
The prescription is (per 100g of plain tablets):
the preparation process comprises the following steps: 50.0g of zeblitinib, 36.5g of microcrystalline cellulose, 4g of croscarmellose sodium, 8g of colloidal silicon dioxide and 1g of sodium lauryl sulfate were sieved, mixed in a high shear granulator, and then 0.5g of magnesium stearate was added and mixed uniformly. And directly tabletting the powder to obtain a plain tablet, namely the oral solid scored tablet containing the zebritinib.
Drug cumulative dissolution (in vitro dissolution) test: the dissolution of the medicine is more than 80% in 30 min.
Example 9
Preparation of Zebritinib oral solid tablet with specification of 320mg
The prescription is (per 100g of the tablet):
the preparation process comprises the following steps: 60g of zerewitinoib, 33.7g of microcrystalline cellulose, 4g of croscarmellose sodium, 0.8g of colloidal silicon dioxide and 1g of sodium lauryl sulfate were sieved and mixed in a high shear granulator, and 0.5g of magnesium stearate was added and mixed well. And directly tabletting the powder to obtain a plain tablet, namely the oral solid scored tablet containing the zebritinib.
Drug cumulative dissolution (in vitro dissolution) test: the dissolution rate of the medicine is less than 60% in 30min
Example 10
Preparation of Zebritinib oral solid tablet with specification of 320mg
The prescription is (per 100g of the tablet):
the preparation process comprises the following steps: 53.2g of lactose, 2g of croscarmellose sodium, 1g of sodium lauryl sulfate and 34.8g of zebertinib were added to a high shear granulator (MYCROMIX, manufactured by BOSCH) and mixed for 5 minutes, an appropriate amount of purified water was added to granulate, dried and granulated, and 4.5g of colloidal silicon dioxide, 4g of microcrystalline cellulose and 0.5g of magnesium stearate were added and mixed. Mixing and tabletting to obtain plain tablets, namely oral solid scored tablets containing zebritinib.
Drug cumulative dissolution (in vitro dissolution) test: the dissolution (%) of the drug at 60min was about 80%.
Example 11
Preparation of Zebritinib oral solid tablet with specification of 320mg
The prescription is (per 100g of the tablet):
the preparation process comprises the following steps: oral solid scored tablets containing zebritinib may be prepared according to a similar method to that of example 10.
Drug cumulative dissolution (in vitro dissolution) test: the dissolution rate (%) of the medicine in 60min is less than 80%.
Example 12
Preparation of Zebritinib oral solid tablet with specification of 320mg
The prescription is (per 100g of the tablet):
the preparation process comprises the following steps: oral solid scored tablets containing zebritinib may be prepared according to a similar method to that of example 10.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications within the scope of the following claims. The documents to which this disclosure relates are incorporated herein by reference.
Claims (20)
1. An oral solid scored tablet comprising zebritinib, comprising: (1) 20-70% of zerewitinoib, preferably 30-50%, by mass percent; (2) One or more pharmaceutically acceptable excipients, wherein the zetinib is homogeneously dispersed in the scored tablet, the scored tablet is an ellipsoid tablet or a circular lamp tablet, and at least one side of the scored tablet is scored with one or more indentations.
2. The oral solid scored tablet of claim 1, wherein the zebritinib is form a, amorphous, or a mixture of form a and amorphous.
3. The oral solid scored tablet of claim 1 or 2, wherein said excipients are selected from the group consisting of fillers, binders, disintegrants, wetting agents, glidants, lubricants and any combination thereof.
4. The oral solid scored tablet of claim 3, wherein the filler is selected from the group consisting of starch, sucrose, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, glucose, maltodextrin, cyclodextrin, cellulose, silicified microcrystalline cellulose, and any combination thereof.
5. The oral solid scored tablet according to claim 4, wherein said filler is lactose, said lactose being present in an amount of 20 to 70%, preferably 40 to 60%, all by mass.
6. The oral solid scored tablet according to claim 4, wherein the filler is microcrystalline cellulose and the content of the microcrystalline cellulose is between 10 and 50 percent, preferably between 30 and 50 percent, each by mass.
7. The oral solid scored tablet according to claim 4, wherein said filler is a combination of lactose and microcrystalline cellulose, said lactose and microcrystalline cellulose being present in an amount of 0-70% and 0-50%, respectively, preferably 40-60% and 4-10%, both in mass percent.
8. The oral solid scored tablet of claim 3, wherein the binder is selected from the group consisting of starch, hypromellose, polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, gelatin, sucrose, and any combination thereof.
9. The oral solid scored tablet according to claim 8, wherein the binder is hypromellose, and the content of hypromellose is 0 to 10%, preferably 0 to 5%, by mass.
10. The oral solid scored tablet of claim 3, wherein the disintegrant is selected from the group consisting of sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, sodium alginate, and any combination thereof.
11. The oral solid scored tablet according to claim 10, wherein the disintegrant is croscarmellose sodium, the content of which is 0.5 to 5%, preferably 1 to 3%, by mass.
12. The oral solid scored tablet according to claim 3, wherein said wetting agent is sodium lauryl sulfate, said sodium lauryl sulfate being present in an amount of 0% to 5%, preferably 0.5% to 1.0%, all by mass.
13. The oral solid scored tablet of claim 3, wherein said glidant is selected from the group consisting of powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, talc, and any combination thereof.
14. The oral solid scored tablet according to claim 13, wherein the glidant is colloidal silicon dioxide in an amount of 0.1 to 20%, preferably 4 to 8%, by weight.
15. The oral solid scored tablet of claim 3, wherein the lubricant is selected from the group consisting of zinc stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium fumarate stearate, and any combination thereof.
16. The oral solid scored tablet according to claim 15, wherein the lubricant is magnesium stearate in an amount of 0.1 to 2%, preferably 0.3 to 1% by weight.
17. The oral solid scored tablet according to any one of claims 1 to 16, wherein said oral solid scored tablet further comprises a coating agent selected from the group consisting of opadry film coating powder, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, and any combination thereof, preferably opadry film coating powder.
18. A method of making the oral solid scored tablet of any one of claims 1-17, comprising the steps of:
(1) Mixing the zerewitinib and one or more excipients;
(2) Wet granulating the mixture of the zertinib and one or more excipients with purified water, or an organic agent, or an aqueous or organic solution containing a binder, drying and straightening granules;
(3) Optionally, mixing the sized particles with additional excipients and compressing in a tablet press with a scored section to form a scored tablet having one or more indentations;
(4) Optionally, coating the scored tablet,
wherein, if step (3) is not performed, the whole granulated particles obtained in step (2) are put into a tablet press with a scored part to be pressed to form a scored plain tablet having one or more scores,
wherein the zebrafenib is uniformly dispersed in the scored plain tablet, and the scored plain tablet is an ellipsoid tablet or a round lantern tablet.
19. The method of claim 18, wherein the organic reagent in step (2) is selected from the group consisting of ethanol, acetone, and combinations thereof.
20. The process according to claim 18 or 19, wherein the additional excipients in step (3) are selected from the group consisting of fillers, lubricants, glidants and any combination thereof.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111759817A (en) * | 2020-05-22 | 2020-10-13 | 南京海纳医药科技股份有限公司 | Febuxostat-containing tablet and preparation method thereof |
| CN112057427A (en) * | 2019-06-10 | 2020-12-11 | 百济神州(苏州)生物科技有限公司 | Oral solid tablet containing Bruton's tyrosine kinase inhibitor and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112057427A (en) * | 2019-06-10 | 2020-12-11 | 百济神州(苏州)生物科技有限公司 | Oral solid tablet containing Bruton's tyrosine kinase inhibitor and preparation method thereof |
| CN111759817A (en) * | 2020-05-22 | 2020-10-13 | 南京海纳医药科技股份有限公司 | Febuxostat-containing tablet and preparation method thereof |
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