KR20200113116A - A film-coated tablet comprising deferasirox - Google Patents

Abstract

The present invention relates to a formulation of deferasirox. Specifically, the present invention relates to a film-coated tablet. Conventional film-coated tablets have side effects such as diarrhea when microcrystalline cellulose is used in an excessive amount due to the use of microcrystalline cellulose and a disintegrant, and there are disadvantages of disintegration and delayed dissolution during moisturization due to the use of the disintegrant. However, in the present invention, a satisfactory disintegration time is achieved without changing pharmaceutical additives and the use of the disintegrant, the stability of a drug is ensured, there are no difficulties in a manufacturing process, and also it is possible to prevent side effects such as diarrhea when using an excessive amount of microcrystalline cellulose.

Description

Film coated tablet containing deferasirox {A FILM-COATED TABLET COMPRISING DEFERASIROX}

The present invention relates to a formulation comprising deferasirox. Specifically, the present invention relates to a film-coated tablet of Deferasirox.

[Features of Deferasirox]

Deferasirox is a compound disclosed in Korean Patent Publication No. 568044, and its chemical name is 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid And its chemical structure is as shown in Equation 1 below.

[Equation 1]

Deferasirox, known as an oral active iron chelator, has been disclosed in Korean Patent Publication No. 616378, but is currently a treatment for chronic iron excess (excessive iron in the body) caused by repeated blood transfusions. It is used as an active ingredient in EXJADE ^® .

In patients receiving regular blood transfusions, treatment with THIS DRUG should be performed after the transfusion of about 20 units of concentrated red blood cells (equivalent to 100 mL/kg) or when clinical monitoring shows clinical evidence of chronic iron accumulation (serum ferritin> 1000 ㎍/L). Alternatively, it is recommended to start the liver iron concentration> 2 mg Fe/g dry weight).

The dosage is calculated in mg/kg, and the closest tablets should be used as a whole. This drug was adjusted to a lower content because it has a higher bioavailability compared to the X-Zide diffusion tablet. If a patient who is currently undergoing chelate treatment with X-Zide diffusion tablets is treated with this drug, it is necessary to use the tablet with the closest amount to the amount calculated by 30% less than the X-Zide diffusion information.

When changing from an existing diffusion tablet to THIS DRUG, an error in the dosage may occur, so care must be taken to ensure that the correct dose is administered. The recommended starting dose for THIS DRUG is 14 mg/kg once a day. However, the starting dose of 21 mg/kg/day can be considered in patients who are transfused in excess of 14 mL/kg/month of concentrated red blood cells (more than 4 units per month in adults) and need to reduce iron overload, and 7 mg/kg The starting dose/day can be considered in patients who are receiving less than 7 mL/kg/month of concentrated red blood cells (less than 20 units per month in adults) and need to maintain iron concentrations.

And in patients who already respond well to deferoxamine therapy, the starting dose of THIS DRUG should be considered as one-third the dose of deferoxamine. For example, a patient receiving a deferoxamine 40 mg/kg/day or equivalent dose for 5 days per week may be initiated at a dose of 14 mg/kg/day of THIS DRUG.

As described above, deferasirox can be prescribed in various ways according to the patient's concentrated red blood cell count and weight.

In addition, serum ferritin is monitored every month, and it is recommended to adjust the dose of THIS DRUG every 3-6 months according to fluctuations in serum ferritin if necessary. The dose can be adjusted in steps of 3.5-7 mg/kg. It should be done individually depending on the response and treatment goals (maintaining or reducing the iron load).

In other words, deferasirox is a drug that requires great flexibility in its dosage.

[Features of formulations containing deferasirox that have been proposed]

As seen above, deferasirox is administered daily for the treatment of chronic iron excess due to blood transfusion, which is referred to as transfusion sera by professional medical staff and clinicians in patients 2 years of age or older, and is a film-coated tablet of 90 mg, 180 mg per tablet. , Contains 360 mg of deferasirox.

Accordingly, in Korean Patent Information No. 1925671, it can be seen that Ex-Zide has adopted the pill coating tablet.

That is, if possible, X-Zide film-coated tablets should be taken at the same time every day, on an empty stomach at least 30 minutes before food intake, or once a day with a light meal.

This medicine should be swallowed whole with water. Patients who have difficulty swallowing tablets should crush this medicine and sprinkle it on soft foods such as yogurt or apple puree to take the whole.

This drug should be taken completely immediately after crushing, and should not be stored for future use.

Korean Registered Patent Publication No. 568044 Korean Registered Patent Publication No. 616378 Korean Patent Information No. 1925671

However, the film-coated tablet of Korean Patent No. 1925671 does not use existing lactose and sodium lauryl sulfate to improve gastrointestinal irritation of Exide ^TM (deferasirox diffusion tablet), but uses microcrystalline cellulose as a filler and crospovidone as a disintegrant. Thus, it was formulated as a film-coated tablet, and if microcrystalline cellulose is used in excess, it may cause diarrhea (Handbook of Pharmaceutical Excipients), and there is a factor that can delay dissolution due to moisture during storage due to the use of crospovidone, a superdisintegrant. do.

Specifically, Korean Patent No. 1925671 discloses that the main component of Deferasirox contains 45% by weight to 60% by weight based on the total weight of the film-coated tablet, and microcrystalline cellulose as a filler is 10% by weight based on the total weight. 40% by weight, crosslinked polyvinylpyrrolidone (crospovidone) as a disintegrant is 1% to 10% by weight based on the total weight, and polyvinylpyrrolidone (PVP) as a binder is 1% by weight based on the total weight To 5% by weight, the surfactant, poloxamer, contains 0.1% to 2% by weight based on the total weight, while maintaining the treatment results equivalent to those of the commercially available XZide ^™ (Deferasirox diffusion tablet) tablets.

The present invention is characterized in that it is a tablet improved by overcoming the limitations of the conventional formulation using an excessive amount of microcrystalline cellulose and the limitations caused by the use of crospovidone, a superdisintegrant.

The present invention has solved the aforementioned problems by the following means.

1.As a film-coated tablet comprising 90 mg, 180 mg or 360 mg of deferasirox or a pharmaceutically acceptable salt thereof based on deferasirox, the total tablet weight of deferasirox or a pharmaceutically acceptable salt thereof 50 to 60 Film-coated tablet, characterized in that it contains in wt%, and contains low-substituted hydroxypropyl cellulose as a filler.

2. In 1 above, a film-coated tablet comprising 30 to 50% by weight of the low-substituted hydroxypropyl cellulose based on the total weight of the film-coated tablet.

3. The film-coated tablet according to 1 or 2 above, further comprising at least one selected from the group consisting of corn starch, mannitol, pregelatinized starch, and silicified microcrystalline cellulose as a filler.

4. In any one of 1 to 3 above, it does not contain a disintegrant, especially corn starch, CMC-Ca, CMC-Na, PVP, alginic acid, sodium alginate, guar gum, sodium starch glycolate, crospovidone, etc. Film-coated tablet, characterized in that it does not contain a disintegrant.

5. The film-coated tablet according to any one of 1 to 4 above, comprising a solubilizing agent, and wherein the solubilizing agent is polysorbate.

6. The film-coated tablet according to any one of 1 to 5 above, comprising a binder, and wherein the binder is hypromellose.

7. In any one of 1 to 6 above,

(i) 30% to 50% by weight of low-substituted hydroxypropylcellulose based on the total weight of the tablet as a filler;

(Ii) 0.05% to 1% by weight of polysorbate 20 based on the total weight of the tablet as solubilizing agent; And

(Iii) A film-coated tablet comprising 1% to 5% by weight of hypromellose as a binder, based on the total weight of the tablet.

8. The film-coated tablet according to any one of the above 1 to 7, further comprising 0.2% to 1% by weight of colloidal silicon dioxide based on the total weight of the tablet.

9. The film-coated tablet according to any one of the above 1 to 8, further comprising 0.5% to 2.5% by weight of magnesium stearate based on the total weight of the tablet.

The present invention solves the possibility of causing diarrhea (Handbook of Pharmaceutical Excipients) due to an excessive amount of microcrystalline cellulose by not using microcrystalline cellulose as a filler, and using low-substituted hydroxypropyl cellulose, and because no disintegrant is used. Accordingly, the disadvantage of delaying the disintegration and dissolution of the substance due to hydrophilicity, which is a characteristic of the disintegrant, was compensated, and the stability of the drug was also guaranteed.

Furthermore, despite the removal of the disintegrant, which is a pharmaceutical additive, there is no difficulty in manufacturing.

The present invention relates to a film-coated tablet containing deferasirox or a salt thereof, and is a film-coated tablet containing 90 mg, 180 mg or 360 mg of the main component based on deferasirox.

In the present specification, the term deferasirox includes deferasirox or a salt thereof. In other words, it refers to all main ingredients that can exhibit the pharmacological activity of deferasirox without limitation. Hereinafter, deferasirox will be referred to as a drug.

For pharmaceutical additives other than the ingredients in the present specification, any of the ingredients disclosed in Handbook of Pharmaceutical Excipients, etc. may be appropriately adopted.

In the present specification, a filler, a binder, a (super) disintegrant, a lubricant, and a solubilizing agent refer to a component having a function generally referred to in the field of pharmaceuticals. For each component, it is known which one can be used as a filler, binder, disintegrant, lubricant, solubilizing agent, and any of the ingredients disclosed in Handbook of Pharmaceutical Excipients and the like can be appropriately adopted unless otherwise specified.

In the present specification, the disintegration time refers to a time required to disintegrate under a predetermined condition using a general measuring device.

Surprisingly, the present inventors did not use a disintegrant and used a low-substituted hydroxypropyl cellulose, a new filler that was not recognized in the prior invention, so that a delay in disintegration time or difficulty in manufacturing did not appear even without using a disintegrant.

The present invention uses a low-substituted hydroxypropyl cellulose as a filler, and does not use a disintegrant, thus exhibiting the same medicinal effect as the previously invented formulation, and did not show a problem of delaying disintegration and dissolution due to the use of a disintegrant. .

The present invention may include a filler, a binder, a solubilizing agent, and a lubricant, and does not include a disintegrant.

At this time, it is characterized in that a low-substituted hydroxypropyl cellulose is essentially blended as a filler of the present invention. As other fillers, at least one selected from the group consisting of silicified microcrystalline cellulose, corn starch, mannitol, and pregelatinized starch may be further blended. Low-substituted hydroxypropyl cellulose is a multifunctional filler and has excellent flowability and tabletting effect, and is preferably blended in an amount of 30 to 50% by weight based on the total weight of the tablet.

The binder is a combination of at least one selected from the group consisting of starch, such as potato, wheat or corn starch, hydroxyethylcellulose, hydroxymethylcellulose, ethylcellulose, polyvinylpyrrolidone, povidone, and hypromellose. can do. The binder has the effect of imparting constant adsorption, solidification, and consistency to the mixture, and is preferably mixed with hypromellose in an amount of 1 to 5% by weight based on the total weight of the tablet.

Solubilizing agents include, but are not limited to: At least one selected from the group consisting of sodium lauryl sulfate, betaine, quaternary ammonium salt, sorbitan ester, poloxamer and polysorbate is used, and preferably polysorbate 20 is 0.05 to 1% by weight based on the total weight of the tablet. It is desirable to blend.

The lubricant may contain at least one selected from the group consisting of talc, sodium benzoate, glyceryl monostearate, polyoxyethylene glycol, sodium stearyl fumarate, colloidal silicon dioxide and magnesium stearate. The lubricant is die-filled reproducibly by increasing the fluidity of the particles, and in terms of the effect of uniformity of the weight of the tablet during tableting, it is preferable to blend 0.2 to 1.0% by weight of colloidal silicon dioxide based on the total weight of the tablet, and stearic acid It is preferable to blend 0.5 to 2.5% by weight of magnesium.

The present invention can be prepared according to any method for producing a wet-coated tablet. For example, the present invention can be prepared by obtaining granules according to the wet granulation method and tableting them. Specifically, according to an embodiment of the present invention, after mixing the drug with a part of the low-substituted hydroxypropyl cellulose as one of the fillers, granulating according to the wet granulation method using a binding liquid containing a binder and a surfactant, After mixing a part of the low-substituted hydroxypropyl cellulose, which is one of the fillers, to, it can be prepared by adding a lubricant to tabletting.

The wet granulation method can adopt a conventional method, for example, it can be obtained by wet granulation while mixing in a high shear mixer and drying in a fluid bed dryer.

When tabletting, the lubricant can be mixed into granules by later mixing and tableted.

The effects of the present invention are illustrated through the following examples. For reference, the examples only represent embodiments of the present invention, and the protection scope of the present invention should not be limited thereto.

[Example]

In order to prepare a film-coated tablet containing deferasirox according to the present invention, it was prepared as follows.

First, the binder and the solubilizer were weighed according to the amount of the raw material, and then a binder solution dissolved in purified water was prepared using a stirrer. Next, deferasirox, a part of the filler, and a disintegrant were added to a high-speed mixer to prepare a mixture that was mixed for 3 to 7 minutes, and then the prepared binding solution was added to a high-speed mixer, followed by kneading, and a wet mixture was prepared. After drying the wet mixture in a drying oven at 50 to 60° C., the dried granules were passed through a #12 to #30 mesh screen to prepare a sized product. A part of the filler is added to the prepared sized product, and mixed in a mixer for 10 to 20 minutes. A lubricant is added to the mixture to the mixer, and the mixed mixture is finally filled for 1 to 5 minutes, and tabletting is performed with a hardness of 15 to 25 kp. After weighing the coating agent according to the amount of the raw material, a film coating solution was prepared using water using a stirrer and then coated on the tablet to prepare a film-coated tablet. The dissolution test results are shown in Table 2 below.

The dissolution test of the Deferasirox film-coated tablet prepared in the above example was evaluated for dissolution rate according to the dissolution test method among general test methods of the Korean Pharmacopoeia. As the elution medium (900 mL), pH6.8 + 0.5% Tween20 maintained at about 37 °C was used, and the rotation speed of the paddle was 50 rpm during the elution test.

The eluate was collected at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, and 120 minutes after the start of the dissolution test, and the filtered solution using a 0.45 um membrane filter was used as the sample solution. The absorbance was measured and analyzed.

The results of Comparative Examples 1 to 3 and Example 1 are disclosed in Table 2.

combination
purpose ingredient Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 chief ingredient Deferasirox 360.00 360.00 360.00 360.00 Filler Microcrystalline cellulose 214.15 259.15 Filler Low-substituted hydroxypropyl cellulose 259.15 259.00 Disintegrant Crospovidone 45.00 Binder Polyvinyl pyrrolidone K-30 15.00 15.00 15.00 Solubilizer Pluronic F68 0.65 0.65 0.65 Binder Hypromellose 2910 15.00 Solubilizer Polysorbate 20 0.80 Lubricant Colloidal silicon dioxide 3.20 3.20 3.20 3.20 Lubricant Magnesium stearate 10.00 10.00 10.00 10.00 Total (mg) 648.00 648.00 648.00 648.00 coating Coating agent Opadry Blue 20.00 20.00 20.00 20.00 Final tablet mass (mg) 668.00 668.00 668.00 668.00

The unit of Table 1 is mg. As shown in Table 2, in the case of Example 1, expected elution even if microcrystalline cellulose as a filler and crospovidone as a disintegrant were not used, and only low-substituted hydroxypropyl cellulose as an excipient was used. The results were confirmed.

Elution time
(min) Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Dissolution rate Standard Deviation Dissolution rate Standard Deviation Dissolution rate Standard Deviation Dissolution rate Standard Deviation 5 42.7 8.8 17.7 9.5 41.1 7.6 35.2 8.7 10 64.2 5.7 37.2 3.2 63.0 4.8 65.3 6.5 15 72.9 5.3 51.5 3.8 75.0 2.2 77.3 4.7 30 80.7 5.0 64.2 3.5 83.6 1.1 85.2 2.1 45 84.3 4.8 70.3 3.2 87.6 1.2 88.9 1.5 60 86.3 2.1 74.2 2.7 88.4 1.3 90.0 1.6 90 87.7 1.7 78.1 2.6 90.3 1.2 91.4 1.1 120 88.4 1.1 80.5 2.8 91.7 1.3 92.5 0.9

The film-coated tablet of Example 1 was further subjected to a dissolution test, a purity test, a long-term test and an accelerated test depending on the content. Each test was carried out immediately after manufacture, at 3 months and 6 months, respectively. Long-term tests were conducted on those stored in the conditions of 25±2℃ and relative humidity of 60±5% (RH), and the accelerated test was conducted under the conditions of 40±2℃ and 75±5% (RH). It was carried out as a target. The results are shown in Tables 3 and 4.

Long-term preservation test Test Items standard first 3 months 6 months Appearance Double-sided convex oval-shaped film-coated tablet with dark blue corners fitness fitness fitness Dissolution test 75%(Q) or more 83.0% 85.0% 82.0% Disintegration time Within 60 minutes 3-4 minutes 3-4 minutes 3-4 minutes Purity test Individually related substances 0.1% or less 0.1% or less 0.1% or less 0.1% or less Total related substances 0.3% or less 0.3% or less 0.3% or less 0.3% or less content 95.0 ∼ 105.0% 99.8% 100.2% 99.6%

Accelerated test Test Items standard first 3 months 6 months Appearance Double-sided convex oval-shaped film-coated tablet with dark blue corners fitness fitness fitness Dissolution test 75%(Q) or more 83.0% 84.0% 83.0% Disintegration time Within 60 minutes 3-4 minutes 3-4 minutes 3-4 minutes Purity test Individually related substances 0.1% or less 0.1% or less 0.1% or less 0.1% or less Total related substances 0.3% or less 0.3% or less 0.3% or less 0.3% or less content 95.0 ∼ 105.0% 99.8% 100.0% 100.4%

As a result of the experiment, a comparison was made of the case of using a new filler, low-substituted hydroxypropyl cellulose, polysorbate 20 as a solubilizer, and hypromellose as a binder, and mixing with the filler used in the conventional patent without using a disintegrant As a result, Example 1 showed the expected dissolution pattern, and there was no problem of cracking the tablet during product production and transportation and storage of the finished product.

Claims (4)

Deferasirox or a pharmaceutically acceptable salt thereof as a film-coated tablet comprising 90 mg, 180 mg or 360 mg of deferasirox, based on the total weight of the tablet, deferasirox or a pharmaceutically acceptable salt thereof. A film-coated tablet comprising 50 to 60% by weight and containing low-substituted hydroxypropyl cellulose as a filler. The method of claim 1,
(I) 30% to 50% by weight of low-substituted hydroxypropylcellulose based on the total weight of the tablet as a filler;
(Ii) 0.05% to 1% by weight of polysorbate 20 based on the total weight of the tablet as solubilizing agent; And
(Iii) A film-coated tablet comprising 1% to 5% by weight of hypromellose as a binder, based on the total weight of the tablet. The film-coated tablet according to claim 1, further comprising 0.2% to 1% by weight of colloidal silicon dioxide based on the total weight of the tablet. The film-coated tablet of claim 1, further comprising 0.5% to 2.5% by weight of magnesium stearate based on the total weight of the tablet.