KR101520792B1 - High load imatinib tablet - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising (a) 30 to 80% by weight of Imatinib or a pharmaceutically acceptable salt thereof; (b) 3 to 10% by weight of a disintegrant; (c) 15 to 30% by weight of a sugar alcohol; And (d) 0.1 to 30% by weight of other pharmaceutical additive. The tablets of high load imatinib of the present invention are excellent in compliance with medicines and disintegration rate, and exhibit an action effect without typical tablet damage in deteriorating quality due to humidification.

Description

High load imatinib tablet {

The present invention relates to tablets comprising high load of active ingredient (API) imatinib or a pharmaceutically acceptable salt thereof.

Formal name for imatinib is 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4- pyridin- 3- yl) pyrimidin- Phenyl] -benzamide, which is a basic active ingredient (API) having the structure of the following formula (I) and is used as a therapeutic agent for chronic myelogenous leukemia (CML).

(I)

Basic active ingredients such as imatinib are generally prepared in the form of an acid addition salt, especially a pharmaceutical formulation as a crystalline acid addition salt. In the case of imatinib, the monomethanesulfonate salt (monomesylate salt) is commercially available worldwide under the trade name Gleevec (Glivec or Gleevec).

In addition, the two crystalline forms of the imatinib monomesylate salt, the alpha-crystalline form and the beta-crystalline form, are disclosed in WO99 / 03854, and the beta-crystalline form has solid physical properties such as solid oral dosage forms such as tablets and capsules ≪ / RTI >

On the other hand, imatinib, which is prescribed as a treatment for chronic myelogenous leukemia (CML), has a daily dosage of about 400 to 800 mg on an adult basis, and patients should take oral imatinib in an excessive amount. However, in the case of tablets containing a small amount of imatinib, there is a problem that the number of tablets to be medicated increases and inconveniences the patient.

To solve this problem, Korean Patent No. 0728846 provides an oral dosage form which is convenient for injecting and provides a daily dose of imatinib. Specifically, the patent document discloses that imatinib is contained in an amount of 30 to 80% based on the total weight of the tablets.

In addition, since the pharmaceutical composition contains imatinib which is an active ingredient at a high load, the disintegrant is used in an excessive amount (10 to 35% by weight) in order to rapidly express the pharmaceutical effect. However, when the disintegrant is used in an excessive amount as described above, as shown in FIG. 1, the tablets may swell due to humidification and cracks may occur, thereby causing deterioration in quality.

Therefore, it is necessary to develop tablets which are excellent in disintegration rate and dissolution rate and at the same time, free from cracking due to humidification, while improving imbalance compliance of patients by including imatinib at high load.

The inventors of the present invention have been aware of this problem, and after repeated research, have come to invent a high-load imatinib tablet satisfying all of the above requirements.

WO99 / 03854 Korean Patent No. 10-0728846

It is an object of the present invention to provide a high load imatinib tablets which are excellent in adherence compliance and disintegration speed and free from cracking due to humidification.

According to one embodiment of the present invention there is provided a pharmaceutical composition comprising (a) 30-80% by weight of imatinib or a pharmaceutically acceptable salt thereof; (b) 3 to 10% by weight of a disintegrant; (c) 15 to 30% by weight of a sugar alcohol; And (d) 0.1 to 30% by weight of other pharmaceutical additive.

In the tablet of the present invention, the imatinib or a pharmaceutically acceptable salt thereof may be present in an amount of 50 to 80% by weight based on the total weight of the tablet.

In the tablets of the present invention, the pharmaceutically acceptable salt may be a monomesylate salt.

In the tablets of the present invention, the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, L-hydroxypropylcellulose, cereal starch, alginic acid, sodium alginate, guar gum and mixtures thereof Among them, it is most preferable to use crospovidone.

In the tablet of the present invention, the sugar alcohol may be selected from the group consisting of mannitol, sorbitol, xylitol, maltitol, isomalt and a mixture thereof, and among them, mannitol is preferably used. The mannitol may also be spray-dried mannitol.

In the tablet of the present invention, the other pharmaceutical additive may be a binder, a lubricant, a lubricant or a mixture thereof.

In the tablet of the present invention, it is also possible to use tablets containing povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan gum, Can be selected.

Also, in the tablet of the present invention, the lubricant and the lubricant may be selected from the group consisting of colloidal silica, magnesium trisilicate, starch, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, stearic acid, Fumarate, sodium lauryl sulfate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, microcrystalline cellulose or mixtures thereof.

According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising (a) 30 to 80% by weight of imatinib or a pharmaceutically acceptable salt thereof; (b) 3 to 10% by weight of a disintegrant; (b) 15 to 30% by weight of alcohol per sugar; (d1) 0.1 to 25% by weight binder; (d2) 0.5 to 3% by weight of a lubricant; And (d3) 0.5 to 2% by weight of a lubricant.

The tablets of the present invention may be coated.

The tablet of the present invention preferably has a disintegration time of 10 minutes or less, and it is preferable that the above-mentioned imatinib or a pharmaceutically acceptable salt thereof is eluted by 80% or more in 15 minutes.

The high-load imidinib tablets of the present invention exhibit an action effect that retains the fastness to breakage while containing a small amount of disintegrant and does not cause cracking due to humidification, as compared with the prior art.

FIG. 1 compares the appearance of tablets prepared in Comparative Example 6 after 4 weeks at 40 DEG C and 75% relative humidity, and shows that damage to the high load imidinib tablets resulting from excessive use of the disintegrant in the prior art It is a photograph showing.
FIG. 2 is a photograph showing the appearance of tablets manufactured in Example 1 of the present invention and after 4 weeks at 40.degree. C. and 75% relative humidity. FIG.

The present invention provides tablets comprising high load of active ingredient (API) imatinib or a pharmaceutically acceptable salt thereof.

The components constituting the imatinib tablets of the present invention may comprise (a) Imatinib or a pharmaceutically acceptable salt thereof, (b) a disintegrant, (c) a sugar alcohol and (d) other pharmaceutical additives.

Hereinafter, each component required for purification of the present invention will be described in detail.

(a) active ingredient: Imatinib  Or a pharmaceutically acceptable salt thereof.

In the tablet of the present invention, the active ingredient is imatinib having the structure of the following formula (I).

(I)

Pharmaceutically acceptable salts of imatinib include, but are not limited to, pharmaceutically acceptable acid addition salts. Examples include inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or suitable organic carboxylic or sulfonic acids, such as aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid (For example, benzoic acid, 2-phenoxy-benzoic acid, 2-phenoxy-benzoic acid, 2-phenoxy-benzoic acid, and the like), carboxylic acid Aliphatic carboxylic acid (e.g., mandelic acid or cinnamic acid), heteroaromatic carboxylic acid (e.g., nicotinic acid or isonicotinic acid), aliphatic sulfonic acid (e.g., Methane-, ethane- or 2-hydroxyethane-sulfonic acid), or an aromatic sulfonic acid (such as benzene-, p-toluene- or naphthalene-2-sulfonic acid). Other examples of acid addition salts include tartrate salts such as (D) (-) tartrate salt or (L) (+) tartrate salt, hydrochloride, citrate salt, , Fumarate salts, succinate salts, benzoate salts, benzenesulfonate salts, pamoate salts, formate salts, malonate salts, 1,5-naphthalene disulfonate salts, salicylate salts, cyclohexane sulfamate salts (R) (-) mandelate salts), glutarate salts, adipate salts, squalate salts, vanillate salts, oxalate salts (especially the (S) -lactate salts) Salcoacetate salts, ascorbate salts (especially (L) -accharide salts and sulfate salts). The pharmaceutically acceptable salt of imatinib is most preferably a monomesylate salt prepared by adding methanesulfonic acid. The imatinib monomesilate salt has a water solubility of 1,300 mg / ml at a pH of less than 5.5.

In addition, in the tablets of the present invention, imatinib or a pharmaceutically acceptable salt thereof is preferably contained at a high load for the purpose of providing a large daily dosage. Specifically, imatinib or a pharmaceutically acceptable salt thereof may be contained in an amount of 30 to 80% by weight, preferably 50 to 80% by weight, based on the total weight of the tablet.

(b) Disintegration

Korean Patent No. 0728846 discloses that the disintegrant is contained in an amount of 10 to 35% by weight in order to quickly elute a high load imatinib of 30 to 80% by weight.

However, as mentioned in the background art, when the disintegrant is used in an excessive amount in the above range, there is a problem that the tablets swell due to humidification and cracks occur.

In order to solve such problems, the present invention preferably includes 3 to 10% by weight of a disintegrant based on the total weight of tablets, more preferably 5 to 10% by weight. That is, the present invention can solve the problem of humping with excessive use of the disintegrant by using a small amount of disintegrant than the prior art.

On the other hand, the lowering of the disintegration rate and the dissolution rate with a small amount of the disintegrant can be solved by using sugar alcohol as an excipient.

In the present invention, the disintegrant may be selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, L-hydroxypropylcellulose, cereal starch, alginic acid, sodium alginate, guar gum, Among them, crospovidone is most preferably used, but not limited thereto.

(c) Excipient: Sugar alcohol

In the preparation of a tablet in general, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, silicic anhydride, calcium phosphate, dextrin, dextrose, dextrates, maltose, sucrose, mannitol, sorbitol, xylitol, Isomalt, and the like can be used.

However, it is most preferable to use sugar alcohol as an excipient for providing high load imidinib tablets which are excellent in compliance with medicines and disintegration speeds and are free from cracks due to humidification.

In the present invention, even when the disintegrant is not used in excess of 10% by weight or less, excellent disintegration and dissolution rates can be achieved by using sugar alcohol as an excipient. In particular, the tablets of the present invention may exhibit a disintegration rate within 10 minutes and a dissolution rate of elution of greater than 80% within 15 minutes.

In order to achieve the above object, in the present invention, the sugar alcohol is preferably contained in an amount of 15 to 30% by weight, and exhibits excellent disintegration rate and dissolution rate in the above range.

In the present invention, the sugar alcohol may be selected from the group consisting of mannitol, sorbitol, xylitol, maltitol, isomalt, erythritol, arabitol, ribitol, galactitol, lactitol, Other product names of other commercially available manufacturers may also be used. For example, PEARLITOL SD 200, the same product as mannitol, Roquette Freres, France) can also be used.

In order to achieve the above object, in the present invention, the sugar alcohol is preferably mannitol, sorbitol, xylitol, maltitol, isomalt.

(d) Other pharmaceutical additives

The tablets of the present invention may further contain excipients (sugar alcohols) and other pharmaceutical additives in addition to the disintegrant.

The additive may include, but is not limited to, a binder, a lubricant, and a lubricant.

In the tablet of the present invention, the binding agent is selected from the group consisting of povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, , But is not limited thereto.

Further, in the tablet of the present invention, the binder may be contained in an amount of 0.1 to 25% by weight based on the total weight of the tablets.

In the tablet of the present invention, the lubricant and lubricant may be selected from the group consisting of colloidal silica, magnesium trisilicate, starch, talc, calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, stearic acid, But are not limited to, sodium lauryl sulfate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, microcrystalline cellulose or mixtures thereof.

In the tablet of the present invention, the lubricant may be contained in an amount of 0.5 to 3% by weight based on the total weight of the tablet, and the lubricant may be contained in an amount of 0.5 to 2% by weight based on the total weight of the tablet.

High load Imatinib  refine

According to one embodiment of the present invention there is provided a pharmaceutical composition comprising (a) 30-80% by weight of imatinib or a pharmaceutically acceptable salt thereof; (b) 3 to 10% by weight of a disintegrant; (c) 15 to 30% by weight of a sugar alcohol; And (d) 0.1 to 30% by weight of other pharmaceutical additive.

According to another embodiment of the present invention, the imatinib or a pharmaceutically acceptable salt thereof may be present in an amount of 50 to 80% by weight based on the total weight of the tablet.

According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising (a) 30 to 80% by weight of imatinib or a pharmaceutically acceptable salt thereof; (b) 3 to 10% by weight of a disintegrant; (b) 15 to 30% by weight of alcohol per sugar; (d1) 0.1 to 25% by weight binder; (d2) 0.5 to 3% by weight of a lubricant; And (d3) 0.5 to 2% by weight of a lubricant.

Tablets of the present invention may be coated. The coating may be a sugar, film coating, enteric coating, sustained-release coating, preferably film-coated. As the film coating agent, conventionally used cellulose derivatives which dissolve or disperse HPC, HPMC, CMC and the like in water can be used. As the coating method, a usual method can be used, and examples thereof include a pan coating method, a fluidized bed coating method and a compression coating method.

The tablets of the present invention do not use excessive amounts of the disintegrant, so there is no cracking caused by the humidification. In addition, even when a small amount of disintegrant is used, disintegration speed and dissolution rate are excellent by using mannitol as an excipient. Specifically, the tablet of the present invention preferably has a disintegration time of 10 minutes or less, and it is preferable that the active ingredient imatinib or a pharmaceutically acceptable salt thereof is eluted by 80% or more in 15 minutes.

The tablet of the present invention can be used as a therapeutic agent for chronic myelogenous leukemia, and the active ingredient imatinib or a pharmaceutically acceptable salt thereof can be contained at 100 to 800 mg per tablet, preferably 400 to 800 mg per tablet have. This content of imatinib tablets is suitable for administration once or twice daily for the treatment of chronic myelogenous leukemia in adult patients. The adult patient is defined as a patient whose age is about 16 years old and whose body weight is about 50 kg or more.

Hereinafter, preferred embodiments and experimental examples are provided to facilitate understanding of the present invention. However, the following examples and experimental examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples and experimental examples.

Example  1 to 7

In order to prepare the imatinib tablets of the present invention, the ingredients and contents of the following Table 1 were included and were manufactured by the following production method.

≪ Preparation of granules &

The imatinib monomesilate salt and sugar alcohol are mixed with each other. The binding agent, hydroxypropylcellulose, is dissolved in ethanol to form a binding solution. The resulting mixture is granulated using a high share mixer (SM-5C (Sejong PharmaTech)) and dried in a dryer.

<After mixing>

After the dried granules are formulated, add crospovidone, sugar alcohol, magnesium stearate, talc, and mix using a double cone mixer.

<Punjab>

Use a KORSCH-Single Press to calibrate.

Tablets: shape (round), thickness (3.3 to 3.4 mm), inner diameter (9.1 mm)

<Coating>

Prepare the coating solution by adding Opadry 03B66936 to 80% ethanol solution and coat it with O'Hara LAB COAT SYSTEM.

[Table 1]

(Unit: mg)

Comparative Example  1 to 12

The imatinib tablets were prepared by the ingredients and the contents shown in Tables 2 to 4 below. The preparation method and dimensions of the tablets are the same as in Examples 1 to 7. [

[Table 2]

(Unit: mg)

[Table 3]

(Unit: mg)

[Table 4]

(Unit: mg)

Experimental Example  1 to 3

Experimental Example  1: Disintegration  Changes in physical properties of tablets according to their contents

The physical properties of the tablets were varied according to the disintegrant content through the tablets prepared in Comparative Example 1-6.

As shown in Table 5 below, when the disintegrant was added at about 15% or more, it was confirmed that cracks were generated on the surface of the coated film as the tablets swelled in the film-coated tablets due to the disintegration.

On the other hand, when the content of the disintegrant was less than 10%, there was no problem in the stability of the property, but it was confirmed that the disintegration time was long and the elution speed was slow due to the small amount of the disintegrant.

[Table 5]

Experimental Example  2: Physical properties of tablet according to excipient type

The tablets prepared in Examples 2 and 4-7 and Comparative Examples 7-9 were compared and the physical properties of tablets were examined according to the type of excipient.

In Examples 2, 4-7 and Comparative Example 7-9, only the kinds of excipients were different, and their contents were the same as 20 wt% based on the total weight of the tablets.

As can be seen from the following Table 6, in both of Examples 2 and 4-7 and Comparative Examples 7-9, a small amount of the disintegrant was used, and the stability test was judged to be satisfactory without occurrence of cracks. However, in Comparative Example 7-9 in which sugar alcohol was not used and other excipients were used, the disintegration time was more than 10 minutes and the disintegration rate was lowered. In the dissolution test, 80% or more of the excipient was not eluted within 15 minutes.

[Table 6]

Experimental Example  3: Sugar alcohol  Changes in physical properties of tablets according to their contents

The tablets prepared in Examples 1-3 and Comparative Examples 10-12 were compared and the physical properties of the tablets were examined according to the content of sugar alcohol (mannitol).

Specifically, the amount of crospovidone, which is a disintegrant, was fixed, and the disintegration time, the elution test, and the qualitative test were carried out by using mannitol as an excipient in proportions of the additive.

As can be seen in Table 7 below, it was found that the disintegration rate and the dissolution rate were superior when mannitol was used as an excipient at 15 to 30% by weight based on the total weight of the tablet.

[Table 7]

How to measure

1) Disintegration time: The disintegration time of the test solution in the disintegration test method of the General Test Methods of the Korean Pharmacopoeia was determined by using 3 solutions.

2) Dissolution Test: Dissolution Tester 1000 mL of the eluate was added to each container, and 1 tablet of the prepared tablets was added. The tablets were tested according to the dissolution test method 2 in General Test Methods of the Korean Pharmacopoeia according to the following dissolution conditions. The standard of eligibility is the same as the standard and the test method, and the dissolution rate for 15 minutes is 80% or more.

&Lt; Dissolution condition >

- Number of revolutions: 50 rpm

- Elution time: 15 minutes

- Test temperature: 37 ± 0.5 ℃

- Elution test solution: 0.1 M hydrochloric acid solution 1000 mL

3) Stability test: Changes in film coating properties were observed at 40 ℃ and 75% relative humidity for 4 weeks.

Claims (13)

Based on the total weight of the tablet,
(a) 50 to 80% by weight of imatinib or a pharmaceutically acceptable salt thereof;
(b) 3 to 10% by weight of a disintegrant; And
(c) 15 to 30% by weight of a sugar alcohol;
(d) 0.1 to 30% by weight of other pharmaceutical additives;
Lt; / RTI &gt; tablets. delete 2. The high boehmite inhibitor of claim 1, wherein said pharmaceutically acceptable salt is a monomesylate salt. The disintegrant of claim 1, wherein the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, L-hydroxypropylcellulose, cereal starch, alginic acid, sodium alginate, guar gum, High load imatinib tablets. 5. The tablet of claim 4, wherein the disintegrant is crospovidone. The high load imidinib tablet according to claim 1, wherein the sugar alcohol is selected from mannitol, sorbitol, xylitol, maltitol, isomalt or a mixture thereof. The tablet of claim 1 wherein said other pharmaceutical additive is a binder, lubricant, lubricant, or mixture thereof. The composition of claim 7, wherein the binder is selected from the group consisting of povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan gum, Lt; / RTI &gt; tablets. 8. The composition of claim 7, wherein the lubricant and lubricant are selected from the group consisting of colloidal silica, magnesium trisilicate, starch, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, stearic acid, sodium stearyl fumarate, Wherein the tablet is selected from the group consisting of sodium lauryl sulfate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered celluloses, microcrystalline cellulose, and mixtures thereof. 8. The method of claim 7,
(a) 50 to 80% by weight of imatinib or a pharmaceutically acceptable salt thereof;
(b) 3 to 10% by weight of a disintegrant;
(c) 15 to 30% by weight of a sugar alcohol;
(d1) 0.1 to 25% by weight binder;
(d2) 0.5 to 3% by weight of a lubricant; And
(d3) 0.5 to 2% by weight of a lubricant;
Lt; RTI ID = 0.0 &gt; Imatinib &lt; / RTI &gt; The tablet of claim 1, wherein the tablet is coated. The tablet of claim 1, wherein the disintegration time is within 10 minutes. 3. The tablet of claim 1, wherein the imatinib or a pharmaceutically acceptable salt thereof elutes at least 80% within 15 minutes.

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