KR102441089B1 - A Pharmaceutical Composition - Google Patents

Abstract

A tablet composition with improved stability is provided.

Description

Pharmaceutical composition {A Pharmaceutical Composition}

The present invention relates to a pharmaceutical composition comprising escitalopram.

Escitalopram is a selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs, the structure of which is shown in Formula 1 below:

[Formula 1]

Unlike other SSRI antidepressants, escitalopram has a wide range of indications, rapid onset of effect, and excellent therapeutic effect and tolerability, so it is used as a primary drug for the treatment of depression and prevention of recurrence. is being marketed.

The United States Pharmacopoeia (USP 42: Escitalopram Tablets) sets the following specifications regarding the content of related substances in escitalopram tablets:

related substances designation Relative Retention Time (RRT) Acceptance criteria (less than (%)) Citalopram Related Compound A 0.33 0.3 Citalopram-related compound B 0.56 0.5 Citalopram-related compound C
(3-oxocitalopram) 0.80 0.5 Escitalopram 1.0 - Citalopram-related compound E
(citalopram N-oxide) 1.4 0.2 Other unspecified impurities - 0.2

In addition, the USP stipulates that the total of all related substances should be 2.0% or less.

Meanwhile, the citalopram-related compounds A, B, C and E are each defined as follows:

Citalopram related compounds A: 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxamide);

Citalopram Related Compounds B: 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile; 3-hydroxycitalopram;

Citalopram related compounds C: 3-(3-dimethylaminopropyl)-3-(4-fluorophenyl)-6-cyano-1( 3H )-isobenzofuranone;

Citalopram related compound E: 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile-N-oxide

The USP stipulates that escitalopram tablets should be stored in a well-closed container, but in reality, most escitalopram tablets are 30 tablets in a plastic container-type tight container. ~200 tablets are stored and distributed.

In the case of storing and distributing tablets in the plastic container as described above, the airtight state is maintained enough to sufficiently block the penetration of moisture and oxygen into the tablet until the plastic container is opened. However, since it cannot sufficiently block the intrusion of moisture and oxygen from the moment it is opened for taking the drug, the decomposition of the drug and the generation of related substances may occur. Therefore, the safety of escitalopram drugs stored and distributed in plastic containers cannot be guaranteed.

These safety issues can occur both when a patient takes medicine while storing it in a plastic container at home, and when a pharmacy divides the tablet stored in a plastic container.

Therefore, in order to solve the stability problem after opening the plastic container, it is preferable to individually package each tablet by PTP (press through package) packaging or the like.

However, when packaging the PTP, since the desiccant and/or antioxidant cannot be put together in each space in which each tablet is packaged, there is a risk that the stability of the PTP is already reduced before opening. That is, PTP packaging may be more disadvantageous than storage in plastic containers in terms of stability of medicines before opening.

U.S. Patent No. 4,943,590

Accordingly, the present inventors have studied to develop a tablet that can sufficiently ensure stability even in PTP packaging as an escitalopram tablet. It was found that a tablet capable of minimizing the generation of related substances could be prepared, and the present invention was completed.

Accordingly, the present invention is to provide an escitalopram tablet with improved stability.

The present invention relates to a pharmaceutical composition containing escitalopram or a pharmaceutically acceptable salt thereof, and specifically, escitalopram containing at least one of light anhydrous silicic acid or hydrogenated oil as a lubricant. It relates to a pharmaceutical composition.

The pharmaceutical composition of the present invention may be in the form of a tablet, preferably coated with a coating layer.

In the present invention, the lubricant may include at least one of light anhydrous silicic acid or hardened oil, and preferably includes both light anhydrous silicic acid and hardened oil as the lubricant.

In the pharmaceutical composition according to the present invention, light anhydrous silicic acid and hydrogenated oil may be included in an amount of 1 to 10%, preferably 1 to 5%, respectively, based on the total weight of the pharmaceutical composition.

The pharmaceutical composition according to the present invention may further include a pharmaceutically acceptable diluent and disintegrant.

For example, as the diluent in the present invention, silicified microcrystalline cellulose, lactose, starch, sucrose, sugar alcohol, inorganic salts such as calcium phosphate, crystalline cellulose, etc. may be used, and silicified microcrystalline cellulose is preferably used.

As the disintegrant in the present invention, crospovidone, starch, carboxymethyl cellulose, crystalline cellulose, etc. may be used, and crospovidone is preferably used.,

The pharmaceutical composition according to the present invention improves stability by inhibiting the production of related substances even during PTP packaging.

According to the present invention, it is possible to provide a tablet with improved stability, which can minimize the decrease in the content of the active ingredient or the generation of related substances even during PTP packaging.

Hereinafter, to help the understanding of the present invention, examples will be described in detail. However, the following examples only illustrate the content of the present invention, and the scope of the present invention is not limited by the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

Experimental Example 1: Preparation of each tablet with a different lubricant

According to the composition of Table 2 below, each tablet was prepared by changing the lubricant.

Specifically, after the components were weighed and mixed according to the content of each composition, a core tablet was prepared from the mixture by a direct tableting method, and the prepared core tablet was coated with a coating layer to prepare a tablet.

Composition of each tablet (content unit mg/1 tablet) ingredient Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 core Escitalopram
oxalic acid chief ingredient 12.77 12.77 12.77 12.77 12.77 12.77 silicification undecided
cellulose excipient 92.23 102.23 102.23 102.23 102.23 102.23 cross povidone disintegrant 7 7 7 7 7 7 talc lubricant 13 - - - - - magnesium stearate lubricant - 3 - - - - light anhydrous silicic acid lubricant - - 3 - - - hydrogenated oil lubricant - - - 3 - - glyceryl behenate lubricant - - - - 3 - stearic acid lubricant - - - - - 3 coating layer Opadry White coating agent 3 3 3 3 3 3 gross weight 128 128 128 128 128 128

Experimental Example 2: Analysis of Related Substances by Accelerated Experiment

Each of the tablets manufactured according to Comparative Examples 1 to 6 were packaged with PTP, and each tablet was packaged with PTP, and accelerated test conditions (ie, temperature 40 Related substances produced at ±2°C, relative humidity 75±5%) were analyzed (the number of test tablets in each test n=3).

The analysis results are shown in Tables 3 to 8 below:

Item Related Substances Acceptance Criteria Early accelerated test
2 weeks accelerated test
4 weeks Comparative Example 1 IMP A ≤0.3% 0.01 0.01 0.01 RRT=0.43 ≤0.2% 0.01 0.01 0.01 IMP B ≤0.5% 0.01 0.02 0.03 IMP C ≤0.5% 0.08 0.14 0.20 RRT=1.34 ≤0.2% ND 0.12 0.06 IMP E ≤0.2% 0.07 0.06 ND total ≤2.0% 0.18 0.36 0.31

Item Related Substances Acceptance Criteria Early accelerated test
2 weeks accelerated test
4 weeks Comparative Example 2 IMP A ≤0.3% 0.01 0.02 0.01 RRT=0.43 ≤0.2% 0.01 0.01 0.01 IMP B ≤0.5% 0.01 0.1 0.07 IMP C ≤0.5% 0.07 0.37 0.41 RRT=1.34 ≤0.2% ND 0.14 0.04 IMP E ≤0.2% 0.08 0.05 0.03 total ≤2.0% 0.18 0.69 0.57

Item Related Substances Acceptance Criteria Early accelerated test
2 weeks accelerated test
4 weeks Comparative Example 3 IMP A ≤0.3% 0.01 0.01 0.00 RRT=0.43 ≤0.2% 0.01 0.01 0.01 IMP B ≤0.5% 0.01 0.01 0.01 IMP C ≤0.5% 0.07 0.07 0.08 RRT=1.34 ≤0.2% ND 0.12 0.08 IMP E ≤0.2% 0.04 ND ND total ≤2.0% 0.14 0.22 0.18

Item Related Substances Acceptance Criteria Early accelerated test
2 weeks accelerated test
4 weeks Comparative Example 4 IMP A ≤0.3% 0.01 0.01 0.00 RRT=0.43 ≤0.2% 0.01 0.01 0.01 IMP B ≤0.5% 0.01 0.01 0.01 IMP C ≤0.5% 0.08 0.07 0.08 RRT=1.34 ≤0.2% ND 0.11 0.08 IMP E ≤0.2% 0.06 ND ND total ≤2.0% 0.17 0.21 0.18

Item Related Substances Acceptance Criteria Early accelerated test
2 weeks Comparative Example 5 IMP A ≤0.3% 0.00 0.00 RRT=0.43 ≤0.2% 0.04 0.04 IMP B ≤0.5% 0.01 0.02 RRT=0.67 ≤0.2% 0.01 0.01 IMP C ≤0.5% 0.06 0.10 IMP E ≤0.2% N.D. N.D. total ≤2.0% 0.12 0.17

Item Related Substances Acceptance Criteria Early accelerated test
2 weeks Comparative Example 6 IMP A ≤0.3% 0.01 0.00 RRT=0.43 ≤0.2% 0.04 0.04 IMP B ≤0.5% 0.01 0.02 RRT=0.67 ≤0.2% 0.01 0.01 IMP C ≤0.2% 0.06 0.10 IMP E ≤0.2% N.D. N.D. total ≤2.0% 0.13 0.17

*) In Tables 3 to 8, RRT = 0.43, RRT = 1.34 and RRT = 0.67 are the compounds eluted through chromatography at the time points where the relative retention times for the escitalopram compound are 0.43, 1.34, and 0.67, respectively. it means.

As a result of the above analysis, it was found that when light anhydrous silicic acid or hydrogenated oil was used as a lubricant, the production amount of related substances, particularly Compound C, was the lowest. On the other hand, when magnesium stearate was used as a lubricant, the content of Compound C was 0.41% after 4 weeks of the accelerated test, which was close to the acceptable standard.

Therefore, it can be seen that selecting magnesium stearate as a lubricant is not preferable in terms of stability in the case of PTP packaging of escitalopram tablets.

Experimental Example 3: Preparation of tablets

According to the composition of Table 9 below, a tablet (Example) prepared according to the present invention and a tablet to be used as a control (Comparative Example) were respectively prepared.

Specifically, after the components were weighed and mixed according to the content of each composition, a core tablet was prepared from the mixture by a direct tableting method, and the prepared core tablet was coated with a coating layer to prepare a tablet.

Composition of the tablet of each example (content unit mg/1 tablet) ingredient Example 1 Example 2 Example 3 core Escitalopram
oxalic acid chief ingredient 12.77 12.77 12.77 silicification undecided
cellulose excipient 102.63 92.23 85.23 cross povidone disintegrant 7 7 7
light anhydrous silicic acid lubricant 1.3 6.5 10 hydrogenated oil
(hydrogenated oil) lubricant 1.3 6.5 10 coating layer Opadry White coating agent 3 3 3 gross weight 128 128 128

Composition of the tablet of each comparative example (content unit mg/1 tablet) ingredient Comparative Example 7 Comparative Example 8 Comparative Example 9 core Escitalopram
oxalic acid chief ingredient 12.77 12.77 12.77 silicification undecided
cellulose excipient 90.43 97.73 91.48 cross povidone disintegrant 7 7 7 talc lubricant 12.8 magnesium stearate lubricant 2 glyceryl behenate lubricant 3.75 3.75 stearic acid lubricant 3.75 10 coating layer Opadry White coating agent 3 3 3 gross weight 128 128 128

Experimental Example 4: Tabletability problem

In Comparative Example 8, in which glyceryl behenate and stearic acid were used as lubricants during the manufacturing process of the core tablet, the lubrication power was insufficient, so the sticking phenomenon occurred in which the powder was attached to the lower punch during tableting. Therefore, it was confirmed that the composition of Comparative Example 8 was not suitable in terms of tabletting properties.

Experimental Example 5: Analysis of Related Substances by Severe Test

Each of the tablets prepared according to Examples 1 and 2 and Comparative Examples 7 to 9 were packaged with PTP, and each tablet was packaged with PTP, and the Ministry of Food and Drug Safety announced "Stability test standards for pharmaceuticals, etc." and ICH guidelines According to the harsh test conditions (ie, temperature 60±2℃, relative humidity 80±5%), related substances were analyzed (the number of test tablets in each test n=3).

The analysis results are shown in Tables 11 to 15 below:

Item Related Substances Acceptance Criteria Early Severe test 2 weeks Example 1 IMP A ≤0.3% 0.01 0.03 RRT=0.43 ≤0.2% 0.01 0.01 IMP B ≤0.5% 0.01 0.04 IMP C ≤0.5% 0.08 0.21 IMP E ≤0.2% ND 0.02 total ≤2.0% 0.11 0.31

Item Related Substances Acceptance Criteria Early Severe test 2 weeks Example 2 IMP A ≤0.3% 0.01 0.01 RRT=0.43 ≤0.2% 0.01 0.01 IMP B ≤0.5% 0.00 0.01 IMP C ≤0.5% 0.06 0.09 IMP E ≤0.2% ND 0.01 total ≤2.0% 0.08 0.13

Item Related Substances Acceptance Criteria Early Severe test 2 weeks Comparative Example 7 IMP A ≤0.3% 0.01 0.06 RRT=0.43 ≤0.2% 0.01 0.01 IMP B ≤0.5% 0.01 0.18 IMP C ≤0.5% 0.08 0.48 IMP E ≤0.2% ND 0.16 total ≤2.0% 0.19 0.89

Item Related Substances Acceptance Criteria Early Severe test 2 weeks Comparative Example 8 IMP A ≤0.3% 0.01 0.03 RRT=0.43 ≤0.2% 0.02 0.02 IMP B ≤0.5% ND 0.05 IMP C ≤0.5% 0.05 0.24 IMP E ≤0.2% ND 0.05 total ≤2.0% 0.08 0.39

Item Related Substances Acceptance Criteria Early Severe test 2 weeks Comparative Example 9 IMP A ≤0.3% 0.01 0.03 RRT=0.43 ≤0.2% 0.02 0.02 IMP B ≤0.5% ND 0.09 IMP C ≤0.5% 0.05 0.45 IMP E ≤0.2% ND 0.08 total ≤2.0% 0.08 0.67

**) In Tables 11 to 15, RRT=0.43 means a compound eluted through chromatography when the relative retention time for the escitalopram compound is 0.43.

As a result of the above analysis, it was found that the amount of production of related substances, particularly Compound C, was the lowest in the purification of Examples 1 and 2 using light anhydrous silicic acid and hydrogenated oil as lubricants.

On the other hand, the purification of Comparative Example 7 using talc and magnesium stearate as lubricants produced as much as 0.48% of impurity C, which was close to the acceptable standard. Therefore, according to the harsh test, Comparative Example 7 is highly likely to exceed the allowable standard value of impurity C in the stability test.

In addition, Comparative Example 8 using glyceryl behenate and stearic acid as lubricants More impurity C was produced than 1 or 2, and the tabletting property was poor as mentioned above. In addition, in the tablet of Comparative Example 9, as much as 0.45% of impurity C was generated, it was almost close to the acceptable standard, and the tablet became soft during the stability test, causing a problem of stability in properties.

Therefore, it can be confirmed that the escitalopram tablets of Examples 1 and 2 using anhydrous light silicic acid and magnesium stearate as lubricants according to the present invention have the best stability and minimize the generation of related substances even during PTP packaging. there was. In addition, there was no problem in terms of flowability and tabletting properties of the powder even in the tableting process, so it was excellent in terms of the manufacturing process.

Experimental Example 6: Analysis of impurity C in related substances by harsh test

Four types of products (control drugs A to D in Table 16 below) were selected among the existing escitalopram 10mg commercial products packaged in a plastic bottle, and some tablets were taken immediately after opening the plastic bottle and immediately PTP packaging , PTP is subjected to a severe test on each tablet while packaged (temperature 60±2℃, relative humidity 80±5%), and the amount of impurity C produced is analyzed, and the result is compared with the test result of Example 1 above. (number of test tablets in each test n=3).

The analysis results are shown in Table 16 below:

Drug type Early 1 week of harsh test Severe test 2 weeks Control drug A 0.09 0.52 1.55 Control drug B 0.10 0.17 0.37 Control drug C 0.14 0.40 1.20 Control drug D 0.16 0.34 0.63 Example 1 0.08 0.12 0.21

***) The lubricants used in each reference drug are as follows:

Control drug A: light anhydrous silicic acid and magnesium stearate;

Control drug B: talc and magnesium stearate

Control drug C: magnesium stearate

Control drug D: magnesium stearate

As a result of the above analysis, it was found that the production amount of Compound C was the lowest in the purification of Example 1 using light anhydrous silicic acid and hydrogenated oil as lubricants.

On the other hand, in most of the commercially available products, the amount of compound C produced during PTP packaging exceeded the acceptable standard, and even in products that did not exceed the production amount of compound C, the amount of compound C was much higher than in Example 1.

Therefore, it was confirmed that the escitalopram tablet of Example 1 according to the present invention had better stability than the existing commercially available products, thereby minimizing the generation of related substances even during PTP packaging.

The present invention provides an escitalopram tablet with improved stability.

Claims (8)

A pharmaceutical composition containing escitalopram or a pharmaceutically acceptable salt thereof, comprising:
As a lubricant, it contains at least one of light anhydrous silicic acid or hydrogenated oil,
The content of the lubricant is 1 to 10% (w/w) based on the total weight of the pharmaceutical composition. The pharmaceutical composition according to claim 1, comprising light silicic anhydride and hydrogenated oil as lubricants. The pharmaceutical composition according to claim 1 or 2, which is a tablet formulation. The pharmaceutical composition according to claim 3, further comprising a diluent and a disintegrant. The pharmaceutical composition according to claim 4, wherein the diluent is at least one selected from the group consisting of silicified microcrystalline cellulose, lactose, starch, sucrose, sugar alcohol, calcium phosphate, and crystalline cellulose. 5. The pharmaceutical composition according to claim 4, comprising crospovidone as a disintegrant. The pharmaceutical composition according to claim 3, wherein the tablet formulation is coated with a coating layer. 5. The pharmaceutical composition of claim 4 comprising silicified microcrystalline cellulose as a diluent.