CN116196284A

CN116196284A - Tofacitinib tablet and preparation method thereof

Info

Publication number: CN116196284A
Application number: CN202211614535.9A
Authority: CN
Inventors: 李孝成; 谢吉元
Original assignee: Nanjing Anmei Pharmaceutical Technology Co ltd
Current assignee: Nanjing Anmei Pharmaceutical Technology Co ltd
Priority date: 2022-12-15
Filing date: 2022-12-15
Publication date: 2023-06-02

Abstract

The invention relates to a tofacitinib citrate tablet formula and a preparation method thereof. The invention adopts active ingredient tofacitinib citrate raw material, filler, disintegrating agent and lubricant to be mixed, and the mixture is prepared into powder for tabletting and coating. Preparing into film coated tablet. The preparation method of the tofacitinib citrate tablet provided by the invention relates to a stable process, and the prepared coated tablet has the advantages of consistent disintegration time limit, dissolution curve and bioavailability with RLD, and higher safety and effectiveness.

Description

Tofacitinib tablet and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a preparation method of a tofacitinib citrate tablet film coated tablet, which comprises the steps of mixing tofacitinib citrate with an excipient, directly tabletting to obtain tablets, and coating.

Technical Field

Tofacitinib citrate is a JAK pathway inhibitor with the first mechanism of action and is a novel oral protein tyrosine kinase inhibitor. Is suitable for adult patients with moderate to severe active Rheumatoid Arthritis (RA) with insufficient curative effect or intolerance to the methotrexate, and can be combined with methotrexate or other non-biological disease-modifying antirheumatic drugs (DMARDs). Use restriction: the use of tofacitinib in combination with biological DMARDs or potent immunosuppressives such as azathioprine and cyclosporine is not suggested.

11 in 2012, FDA approved tofacitinib citrate tablet trade name:

specification of: 5mg was first marketed in the United states; 3 months 2013 is approved for market in japan, trade name: />

Specification of: 5mg; the year 03 of 2017 is licensed to the european union under the trade name: />

Specification 5mg. In 2017, 03 months, the original manufacturer's psicosis was marketed in China as tofacitinib citrate tablet with the trade name: />

The specification is 5mg. The original grinding adopts a dry granulation process for production.

According to the invention, a powder direct tabletting process is adopted, the API and the excipient are mixed to prepare intermediate particles, and then the intermediate particles are tableted and coated, so that the disintegration time limit, the dissolution curve and the bioavailability of the prepared coated tablet are consistent with those of RLD, and the safety and the effectiveness are higher.

Disclosure of Invention

It is an object of the present invention to provide a formulation of tofacitinib citrate in the form of a free-flowing cohesive compressed powder of a tablet that can be tableted with a powder formulation.

It is another object of the present invention to provide a direct compression tablet of a tofacitinib citrate formulation in unit dosage form having acceptable disintegration time, dissolution properties and acceptable hardness and being less prone to disintegration.

It is another object of the present invention to provide a method for preparing compressed tablets of tofacitinib citrate formulation in unit dosage form by direct compression.

The present invention provides a free flowing granular tofacitinib citrate formulation that can be directly compressed into a compressed powder form of a tablet having sufficient hardness, rapidly disintegrating and having an acceptable dissolution profile for direct compression.

In addition to the active ingredient, tableting powders contain a number of inert materials known as excipients, which can be classified according to their role in the final tablet. The main components comprise filler, adhesive active diluent, lubricant, disintegrating agent and glidant.

Drawings

FIG. 1 shows the dissolution profile of tofacitinib citrate tablets in a pH1.0 hydrochloric acid medium

FIG. 2 is a graph showing the dissolution profile of tofacitinib citrate in water

FIG. 3 shows the dissolution profile of tofacitinib citrate tablets in phosphate buffer pH6.8

FIG. 4 shows the dissolution profile of tofacitinib citrate tablet in acetate at pH4.5

Detailed Description

The formula of the invention comprises the following components: tofacitinib citrate (active ingredient), microcrystalline cellulose (filler), lactose (filler), croscarmellose sodium (disintegrant) and magnesium stearate (lubricant).

One, two, three or more diluents may be selected. Examples of fillers and diluents include, but are not limited to, sugars, compressible sugars, dextrates, dextrins, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, and talc. The filler live diluent may be present, for example, in an amount of about 15% to 40% by weight of the composition. Preferred microcrystalline cellulose, suitable microcrystalline cellulose has an average particle size of about 20nm to 200 nm. Microcrystalline cellulose may be manufactured by a variety of suppliers, and suitable microcrystalline cellulose includes pH101, pH102, pH103, pH105, and pH200 manufactured by FMC, with pH102 being particularly preferred in embodiments of the present invention. With minimal surface area and pore structure. Microcrystalline cellulose is preferably present in an amount of 25% to 70% by weight of the tablet formulation. Another preferred range of the material is 30-70% by weight; another preferred range is 30-32%.

Another diluent is lactose, which is preferably milled to an average particle size of about 50-500 μm prior to formulation, and is present in the tablet formulation in an amount of about 5% to 50% by weight, and may be about 20% to 40% by weight, and most preferably 30% to 35% by weight.

One, two, three or more disintegrants may be selected. Disintegrants include, but are not limited to, starch, viscosity, cellulose; alginate, gums, cross-linked polymers such as cross-linked polyvinylpyrrolidone, cross-linked calcium carboxymethylcellulose, and cross-linked sodium carboxymethylcellulose; soy polysaccharides and guar gum. The disintegrant may be present, for example, in an amount of 2-20%, such as about 5% -10%, such as about 7% by weight of the composition. Disintegrants are also optional but useful components of tablet formulations. Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. For this formulation, croscarmellose sodium is the preferred disintegrant, which is used in tablet formulations in an amount of about 0 to about 10% by weight, may be about 1 to about 4% by weight, and most preferably may be as little as 2.5 to about 3.5% by weight.

One, two, three or more lubricants, pharmaceutically acceptable lubricants and pharmaceutically acceptable flow inhibitors of colloidal silica, magnesium trisilicate, starch, talc, calcium orthophosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered microcrystalline cellulose and microcrystalline cellulose may be selected. The lubricant may be present, for example, in an amount of about 0.1 to 5% by weight of the composition, while the glidant may be present in an amount of about 0.1% to 10% by weight. Lubricants are typically added to prevent sticking of the tableting material, minimize friction during tableting and allow the compressed tablet to exit the die, such lubricants typically being present in the final tablet mixture at less than 1% by weight. The lubricant component may be classified as hydrophilic and hydrophobic. Examples of such lubricants include stearic acid, talc and magnesium stearate. Magnesium stearate reduces friction between the die wall and the tablet mixture during tabletting and pushing. Wherein it helps to prevent sticking of the tablet. Magnesium stearate also aids in powder flow in the hopper and into the die. The granularity is 450-550 μm, and the density is 1.0-1.80g/ml. Which is stable and does not polymerize in the tableting mixture. The lubricant magnesium stearate is preferably used in the formulation. The lubricant is preferably present in the tablet formulation in an amount of 0.1% to 2% by weight.

Thus, in a first embodiment, the present invention relates to an introduction pharmaceutical composition comprising:

A. tofacitinib citrate;

B. a pharmaceutically acceptable diluent;

the ratio of the weight of tofacitinib citrate on a dry weight basis to the weight of the diluent of the tablet is 1-5, preferably 1-2. The above composition, wherein at least one diluent is microcrystalline cellulose, and the weight ratio of tofacitinib citrate on a dry weight basis to microcrystalline cellulose of the tablet is 1-1.5.

The composition comprises 5-30mg, preferably 8-16mg, of tofacitinib citrate.

The above composition wherein the diluent is selected from microcrystalline cellulose and lactose, preferably microcrystalline cellulose and lactose in the composition.

The above composition, further comprising;

A. 0-20% by weight, on a dry weight basis, of a disintegrant;

B. 0.1 to 10% by weight, based on dry weight, of a lubricant.

Preferably, the above composition further comprises:

C. 1-6% by weight, on a dry weight basis, of a disintegrant

D. 0.25-6% by weight, on a dry weight basis, of a lubricant;

the above ratios are obtained on a dry weight basis of tofacitinib citrate and diluent.

In another embodiment, the invention relates to a pharmaceutical composition comprising;

A. 1-10% by weight, on a dry weight basis, of tofacitinib citrate;

B. 40-98% by weight of a diluent on a dry weight basis;

C. 0-20 weight of a disintegrant on a dry weight basis;

D. 0.1-10% by weight, based on dry weight, of a lubricant.

Preferably the present invention relates to a pharmaceutical composition comprising:

A. 2-8% by weight, on a dry weight basis, of tofacitinib citrate;

B. 40-95% by weight of a diluent on a dry weight basis;

C. 0.25-6 weight based on dry weight of disintegrant;

D. 0.25-5% by weight, based on dry weight, of a lubricant.

Most preferably, the present invention relates to a composition comprising:

A. 2-6% by weight, on a dry weight basis, of tofacitinib citrate;

B. 40-95% by weight of a diluent on a dry weight basis;

C. 0-10% by weight, on a dry weight basis, of a disintegrant;

D. 0.25-5% by weight, based on dry weight, of a lubricant.

Most preferably, the present invention relates to a composition comprising:

A. 3-6% by weight, on a dry weight basis, of tofacitinib citrate;

B. 50-95% by weight of a diluent on a dry weight basis;

C. 0.25-6 weight based on dry weight of disintegrant;

D. 0.25-5% by weight, based on dry weight, of a lubricant.

Most preferably, the present invention relates to a composition comprising:

A. 3-6% by weight, on a dry weight basis, of tofacitinib citrate;

B. 60-95% by weight of a diluent on a dry weight basis;

C. 0.25-4 weight based on dry weight of disintegrant;

D. 0.25-4% by weight, based on dry weight, of a lubricant.

In the present application, reference to a pharmaceutically acceptable diluent includes at least one diluent as well as a mixture of diluents such as a mixture of 2 or 3 diluents.

Preferably, the above composition comprises:

one or two diluents selected from microcrystalline cellulose and lactose;

microcrystalline cellulose and lactose as two diluents;

30-70%, preferably 50-70% by weight microcrystalline cellulose on a dry weight basis;

30-70% by weight, preferably 50-70% by weight, of microcrystalline cellulose and 10-40% by weight, preferably 25-35% by weight, of lactose, based on dry weight.

Most preferably, the above composition comprises one or two diluents selected from microcrystalline cellulose PH102 and lactose.

Most preferred pharmaceutical compositions comprise lubricant D.

In the present application, reference to a disintegrant refers to at least one disintegrant, including mixtures of disintegrants such as the ones in 2 or 3.

In the present application, reference to a lubricant refers to at least one lubricant, and also includes mixtures of lubricants such as those in 2 or 3.

Tofacitinib citrate, preferably the diluent is microcrystalline cellulose and lactose, preferably a combination of microcrystalline cellulose and lactose, preferably sodium carboxymethyl cellulose crosslinked with a disintegrant, preferably the lubricant is magnesium stearate.

The specific components in the preferred compositions are the following:

A. 3-6% by weight, on a dry weight basis, of tofacitinib citrate;

B. 40-70% by weight, on a dry weight basis, of microcrystalline cellulose;

C. 20-40% by weight lactose on a dry weight basis;

D. 0-10% by weight, on a dry weight basis, of croscarmellose sodium;

E. 0.25-5% by weight, based on dry weight, of magnesium stearate.

The specific components in the preferred compositions are the following:

A. 3.5-6% by weight, on a dry weight basis, of tofacitinib citrate;

B. 40-70% by weight, on a dry weight basis, of microcrystalline cellulose;

C. 20-40% by weight lactose on a dry weight basis;

D. 0-10% by weight, on a dry weight basis, of croscarmellose sodium;

E. on a dry weight basis. 0.25-5% by weight of magnesium stearate.

The specific components in the preferred compositions are the following:

A. 4-5% by weight, on a dry weight basis, of tofacitinib citrate;

B. 50-65% by weight, on a dry weight basis, of microcrystalline cellulose;

C. 20-40% by weight lactose on a dry weight basis;

D. 0-10% by weight, on a dry weight basis, of croscarmellose sodium;

E. on a dry weight basis. 0.25-5% by weight of magnesium stearate.

The specific components in the preferred compositions are the following:

A. 4-5% by weight, on a dry weight basis, of tofacitinib citrate;

B. 50-65% by weight, on a dry weight basis, of microcrystalline cellulose;

C. 25-35% by weight lactose on a dry weight basis;

D. 2-3% by weight, on a dry weight basis, of croscarmellose sodium;

E. on a dry weight basis. 0.5-2% by weight of magnesium stearate.

The specific components in the preferred compositions are the following:

A. 4-4.5% by weight, on a dry weight basis, of tofacitinib citrate;

B. 55-65% by weight, on a dry weight basis, of microcrystalline cellulose;

C. 28-35% by weight lactose on a dry weight basis;

D. 2.5-3% by weight, on a dry weight basis, of croscarmellose sodium;

E. on a dry weight basis. 0.5-1.5% by weight of magnesium stearate.

In another embodiment, the present invention relates to any of the above compositions, wherein lubricant D is only optionally included in the formulation, but lubricant D is preferably included in the composition weight.

For tabletting, especially direct tabletting, the above composition comprises 4-4.5% by weight of tofacitinib citrate on a dry weight basis.

Additional conventional excipients, such as the conventional solid fillers described above, may optionally be added to the formulations described herein.

The above formulations are particularly useful for the preparation of pharmaceutical tablets, such as tabletting or preferably direct tabletting, and can provide the necessary physical properties, dissolution and drug release characteristics required by one of ordinary skill in the art. Thus, in another embodiment, the invention relates to the use of any of the above formulations for the preparation of a pharmaceutical tablet, in particular for granulation, direct compression and dry granulation.

The above formulations are also particularly useful for the preparation of tablets, especially tabletting and very preferably direct tabletting.

In particular, the tablets obtained with the above formulation have very low friability problems, very good crushing strength, improved production firmness, optimal tablet thickness to tablet weight ratio, less water in the formulation, in particular in direct compression, and better friability.

Direct compression of the present invention includes mixing and compression. The excipient grade is selected with a view to maintaining the particle size within a range that provides uniformity of powder mixing and uniformity of tofacitinib citrate content, which prevents segregation of the powder in the hopper during direct compression. The use of these excipients has the advantage that they impart compressibility, cohesiveness and flowability to the powder mixture. In addition, direct compression provides competitive unit production costs, shelf life, eliminates heat and moisture, disperses the primary particles, provides physical stability, and ensures particle size uniformity.

In the development of the pharmaceutical compositions described herein, the applicant has found that

1. The tofacitinib citrate particles have a particle size distribution of less than 100 microns, preferably 10-80 microns,

the present invention relates to tabletting, preferably direct tabletting, wherein the dispersion contains tofacitinib citrate and wherein the particle size distribution of the tablet is at least 90% < 10-80 microns.

The combination of the first and second embodiments described above provides tablets, preferably direct compression tablets, with good compactibility.

The invention thus also relates to tabletting, preferably direct tabletting, wherein the dispersion comprises tofacitinib citrate, and wherein at least 60%, preferably 80%, and most preferably 90% of the particle size distribution in the 1, tablet is less than 100 microns, more preferably 10-80 microns.

In a third embodiment, the invention relates to compressed tablets, preferably direct compressed tablets, wherein the dispersion comprises tofacitinib citrate particles, and wherein the particle size distribution in the tablet is at least 60%, preferably 80% most preferably 90% less than 100 microns, most preferably 10-80 microns.

Example 1

For the preparation of tablets of size 4mg (direct compression) a 5kg batch was prepared in an amount equivalent to when the unit 4mg of peroxygefitinib citrate was combined with 61mg of microcrystalline cellulose, 30.7mg of lactose, 3mg of croscarmellose sodium. The ingredients were premixed in a convection mixer and then sieved through a 850 μm sieve, the mixture was mixed in a box mixer and then mixed with magnesium stearate so that each 4mg tablet had a single tablet weight of 100mg and a tablet weight of 200mg containing 8mg of the active ingredient, and the mixture had excellent compactibility and was compactable into a powder of the desired tablet size.

Example 2

Direct compression of lower speed preferably 8mg tablets can be prepared using the same procedure described in example 1 above

The process comprises the following steps:

A. adding tofacitinib citrate, microcrystalline cellulose, lactose and croscarmellose sodium into a convection mixer for mixing;

B. grinding and sieving the material A;

C. adding the material B into a box-type mixer for mixing;

D. adding magnesium stearate into the material of C for mixing to obtain mixed powder;

E. tabletting the material D to obtain plain tablets;

F. and coating the tablet of E to obtain the tofacitinib citrate tablet film coated tablet.

The comparison with RLD results are as follows:

sheet weight difference:

homemade	RLD
		+0.28，-0.71	+1.21，-1.73

Hardness difference:

homemade	RLD
		Average hardness: 94.6N	Average hardness: 92.5N
Hardness range: 85.6-106.7N	Hardness range: 83.7-125.3N

Disintegration time limit:

homemade	RLD
		2.07min	2.43min

Dissolution curves are shown in fig. 1, 2, 3 and 4:

hydrochloric acid medium with pH1.0

Time	Homemade	RLD
			5	67.42	64.67
10	86.71	83.98
			15	94.02	89.87
20	97.00	93.08
			30	99.31	94.94
45	99.42	95.96
			60	99.89	95.49

Aqueous medium

phosphate buffer at pH6.8

Time	Homemade	RLD
			5	86.65	76.99
10	98.35	93.64
			15	100.66	95.90
20	101.06	96.07
			30	101.55	96.16
45	101.56	96.44
			60	101.96	96.33

Acetate buffer at pH4.5

Time	Homemade	RLD
			5	76.98	73.94
10	92.44	85.96
			15	97.04	93.83
20	98.73	96.90
			30	99.36	97.67
45	99.42	97.50
			60	99.55	98.30

The tablet quality index of the powder direct tabletting process is consistent with that of the RLD dry granulating process, and the in-vitro dissolution is consistent.

Claims

1. A pharmaceutical powder direct compression tablet comprises a dispersion of tofacitinib citrate and has a particle size distribution D90 < 100 μm in the formulation.

2. The pharmaceutical powder direct compression tablet of claim 1, wherein the dispersion comprises tofacitinib citrate and wherein the ratio of tablet thickness to tablet weight is 0.03-0.05mm/mg, the particle size distribution in the tablet is at least 60% 10-100 μm and the ratio of tablet thickness to tablet weight is 0.01-0.03mm/mg.

3. The pharmaceutical powder direct compression tablet according to claim 1, wherein the particle size distribution in the tablet is 10-80 microns and the ratio of the thickness in the tablet to the tablet weight is 0.01-0.03mm/mg.

4. The pharmaceutical powder direct compression tablet according to any one of claims 1-2, wherein at least 80% of the particle size distribution in the tablet is 10-100 microns, wherein at least 20% of the particle size distribution in the tablet is 10-250 microns.

5. A pharmaceutical powder direct compression tablet according to any one of claims 1-2, wherein between 0-10 minutes 85% -99.5% of the active ingredient is released and between 10-15 minutes 90-99.5% of the active ingredient is released.

6. The pharmaceutical powder direct compression tablet according to any one of claims 1-2, wherein the particle size distribution of the tablet pharmaceutical excipient is 5-400 microns, the pharmaceutical powder direct compression tablet being a direct compression tablet.

7. A method of preparing a powder formulation tabletting tablet according to any one of claims 1 to 10 in unit dosage form comprising:

A. the following components are mixed according to the weight percentage based on the weight:

6-60% by weight of tofacitinib citrate and at least one excipient selected from the group consisting of fillers, disintegrants and lubricants, on a weight basis. Forming a powder that can be directly compressed into a tablet from the powder.

B. And C, pressing the formula prepared in the step A into a tofacitinib citrate tablet in a unit dosage form.

8. A method of preparing a powder direct compression tablet according to any one of claims 1-2 in unit dosage form comprising:

A. the following ingredients were mixed in percentages by weight:

tofacitinib citrate, 4-8% by weight based, 40-95% by weight of diluent, 0-10% by weight based, disintegrant, 0.25-6% by weight based, lubricant, 0.5-5% by weight based, coating to form tofacitinib citrate in the form of a tableted powder capable of being directly compressed into tablets by powder.

B. Pressing the formula prepared in the step A into a unit dosage form of tofacitinib citrate tablet;

C. and B, coating the tofacitinib citrate tablet with 0.5-5% of coating layer by weight based on the weight of the tofacitinib citrate tablet pressed in the step B to obtain the tofacitinib citrate tablet film coated tablet.

9. The method of claims 1-2, wherein the mixed formulation comprises;

25-70% by weight of microcrystalline cellulose;

5-40% by weight of lactose;

0-10% by weight, based on the weight, of croscarmellose sodium;

0.25-6% by weight of magnesium stearate;

0.5-5% by weight of a coating powder based on the weight.