KR20240079115A - Pharmaceutical composition comprising quetiapine - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing quetiapine, and more specifically, the composition relates to N-nitrosoarylpiperazine (N), a related substance derived from quetiapine, by an acid stabilizer. -Nitroso-Aryl Piperazine (NNAP) production can be suppressed and changes in properties can be minimized and maintained even during storage, thereby improving stability.

Description

Pharmaceutical composition comprising quetiapine {PHARMACEUTICAL COMPOSITION COMPRISING QUETIAPINE}

The present invention relates to a pharmaceutical composition containing quetiapine as an active ingredient, and to a pharmaceutical composition with improved stability by suppressing the production of related substances resulting from the quetiapine.

Quetiapine is a thiazepine whose chemical name is 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine. It is known as an antipsychotic agent belonging to the dibenzothiazepine derivatives, and various salt forms, including fumarate, are known. The mechanism of action of quetiapine or its salt is not well known, but it has an antagonistic effect on dopamine type 2 [Dopamine type 2, (D ₂ )] and serotonin type 2 [serotonin type 2, (5-HT ₂ )] receptors. It is reported to have antipsychotic effects. Side effects related to the use of quetiapine or its salts include drowsiness, sedation, tachycardia, and hypotension, and in rare cases, constipation and weight gain have been reported. It is known that these side effects can be partially avoided by using a sustained-release preparation that can reduce the minimum dose or continuous dose or reduce the number of doses.

However, there has recently been an issue in which N-Nitroso-Aryl Piperazine (NNAP), a related substance, was detected in quetiapine preparations in excess of the allowable daily intake. The temporary allowable daily intake of NNAP was set using the TD ₅₀ of N-nitrosopiperidines, a reference substance with a similar structure, using a read-across approach, and the Ministry of Food and Drug Safety applied this standard. Recall measures have been taken.

In the case of quetiapine, NNAP, a nitrosamine drug substance-related impurities (NDSRI) with a similar structure to the active ingredient known to be a genotoxic substance, tends to increase during use or storage after manufacture. The allowable daily intake of NNAP is 153 ng/day.

Quetiapine is mainly prescribed to treat schizophrenia and bipolar disorder. It is a mechanism that suppresses the excessive activity of neurotransmitters that control mood and behavior in the central nervous system. Recently, as the number of psychiatric patients such as depression has increased, the number of prescriptions for psychiatry-oriented hospitals/clinics has been increasing.

Therefore, there is a need to develop technology for a pharmaceutical composition containing quetiapine that can ensure stability by inhibiting the production of NNAP, a related substance resulting from quetiapine.

Korean Patent Publication No. 10-2011-0027879

The purpose of the present invention is to develop a pharmaceutical containing quetiapine with improved stability by suppressing the production of N-Nitroso-Aryl Piperazine (NNAP), a related substance derived from quetiapine. A composition is provided.

According to the first aspect of the present invention,

The present invention relates to a pharmaceutical composition containing quetiapine or a pharmaceutically acceptable salt thereof, wherein the composition contains an acidic stabilizer as a stabilizer.

In one embodiment of the present invention, the acid stabilizer may include at least one selected from the group consisting of an acidifier and an antioxidant.

In one embodiment of the present invention, the acidifying agent may include one or more selected from the group consisting of ascorbic acid, tartaric acid, malic acid, and maleic acid.

In one embodiment of the present invention, the antioxidant may include one or more selected from the group consisting of synthetic antioxidants and natural sulfur oxidants.

In one embodiment of the present invention, the synthetic antioxidant is propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and sodium pyrosulfite. (sodium pyrosulfite), and the natural antioxidant may include one or more selected from the group consisting of tocopherol, gossypol, and sesamol.

In one embodiment of the present invention, the acid stabilizer may be included in an amount of 0.001 to 8 parts by weight based on 100 parts by weight of quetiapine or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the quetiapine or a pharmaceutically acceptable salt thereof may be included in an amount of 30% by weight to 60% by weight based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the composition may be formulated as an oral preparation.

In one embodiment of the present invention, the oral preparation may be a tablet or capsule.

In one embodiment of the present invention, the tablet may be manufactured by a wet granulation method or a direct compression method.

In an embodiment of the present invention, the oral preparation may be an immediate-release tablet or sustained-release tablet.

According to the pharmaceutical composition of the present invention, the production of N-Nitroso-Aryl Piperazine (NNAP), a related substance resulting from the active ingredient quetiapine, is suppressed by the acid stabilizer, Even during long-term storage, changes in properties are minimized, improving stability.

Figure 1 is a graph showing the stability evaluation results of a pharmaceutical composition containing quetiapine under high temperature and high humidity storage conditions.
Figure 2 is a graph showing the results of stability evaluation of a pharmaceutical composition containing quetiapine under high temperature storage conditions.

Hereinafter, the present invention will be described in more detail.

The pharmaceutical composition according to the present invention contains quetiapine or a pharmaceutically acceptable salt thereof, and the composition contains an acidic stabilizer as a stabilizer.

In the case of NNAP, nitrogen dioxide is generated from Quetiapine EP impurity B(11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine), which is generated during the raw material synthesis process or when the main ingredient is decomposed under high temperature conditions of 80℃ or higher. It is a substance generated by combining (NO ₂ ), and Quetiapine EP impurity B is known to be sensitive to hydrolysis. Although a clear mechanism of action has not been confirmed, the use of the acid stabilizer in the present invention inhibits the production of N-Nitroso-Aryl Piperazine (NNAP), a related substance derived from quetiapine. The role it plays has been confirmed, and the stability of the pharmaceutical composition can be improved.

In one embodiment of the present invention, the acid stabilizer may include one or more selected from the group consisting of acidifiers and antioxidants.

The acid stabilizer may be used alone with the acidifier and antioxidant. However, in order to improve the efficiency of inhibiting the production of NNAP, the acid stabilizer may be used in combination with the acidifier and antioxidant.

In one embodiment of the present invention, the acidifying agent may include one or more selected from the group consisting of ascorbic acid, tartaric acid, malic acid, and maleic acid.

In one embodiment of the present invention, the antioxidant may include one or more selected from the group consisting of synthetic antioxidants and natural sulfur oxidants. The synthetic antioxidant is selected from the group consisting of propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and sodium pyrosulfite. It includes one or more types, and the natural antioxidant may include one or more types selected from the group consisting of tocopherol, gossypol, and sesamol.

In one embodiment of the present invention, the acid stabilizer may be included in an amount of 0.001 parts by weight to 10 parts by weight based on 100 parts by weight of the active ingredient, quetiapine, or a pharmaceutically acceptable salt thereof. . Specifically, the content of the acid stabilizer is 0.001 parts by weight or more, 0.002 parts by weight or more, 0.003 parts by weight or more, 0.004 parts by weight or more, 0.0043 parts by weight or more, 0.01 parts by weight or more, 0.1 parts by weight or more, 1 part by weight or more, or 3 parts by weight. It may be more than 6 parts by weight, 6 parts by weight or less, 7 parts by weight or less, or 8 parts by weight or less. If the content of the stabilizer is less than 0.001 parts by weight, N-Nitroso-Aryl Piperazine (NNAP), a related substance, may be produced in excess of the allowable daily intake, and if it exceeds 8 parts by weight, it may cause damage. As the degree increases, poor properties may occur after the tablet coating process.

In one embodiment of the present invention, quetiapine or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition, may be included in an amount of 30% to 60% by weight based on the total weight of the pharmaceutical composition. . Specifically, the content of quetiapine or a pharmaceutically acceptable salt thereof may be 30% by weight or more, 35% by weight or more, or 40% by weight or less, and may be 50% by weight or less, 55% by weight or less, or 60% by weight or less. If the content is less than 30% by weight, the efficacy of the active ingredient, for example, the efficacy of antipsychotic action by suppressing excessive activity of neurotransmitters that regulate mood and behavior in the central nervous system, may be reduced. 60% by weight If it exceeds %, the production of flexible substances may be promoted during the period of use after manufacturing.

In one embodiment of the present invention, the pharmaceutical composition may be formulated as a tablet or capsule, but is not limited thereto as long as it is a solid preparation that can be ingested orally.

In one embodiment of the present invention, the tablet may be manufactured by a wet granulation method or a direct compression process.

The wet granulation method is a method of mixing a granulating liquid that aids granulation with powder ingredients to form wet agglomerates, and forming larger granules from the wet agglomerates. The granulation liquid may refer to a binding liquid.

In addition, the direct compression process refers to a method of directly compressing raw materials that do not need to be made into granules because they are free-flowing and cohesive in a refiner. The direct hitting process method can improve the stability of the active ingredient and reduce manufacturing costs by reducing the process steps.

In one embodiment of the present invention, the pharmaceutical composition may be formulated as an immediate release dosage form or a sustained release dosage form.

In the present invention, the pharmaceutical composition may contain, in addition to the active ingredient quetiapine or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable additives necessary for formulation.

The pharmaceutically acceptable additives may include one or more selected from the group consisting of excipients, binders, disintegrants, lubricants, and sustained-release agents.

The type and content of these additives can be appropriately selected by those skilled in the art according to the type of specific formulation to be manufactured.

For example, the excipients may be added to ensure smooth formation of a formulation that is convenient to take, and to improve tabletting properties during molding. The excipient may be from the group consisting of lactose, starch, mannitol, cellulose excipient, lactose hydrate, dibasic calcium phosphate, and combinations thereof. The cellulose-based excipient may be selected from microcrystalline cellulose, silicified microcrystalline cellulose, and carboxymethyl cellulose. The content of the excipient is not particularly limited, and may be included in an amount of 20% to 45% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

Additionally, the binder may be added to ensure that the formulation containing the active ingredient is well formed. The binder may be selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and combinations thereof. The content of the binder is not particularly limited, and may be included in an amount of 3% to 10% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

Additionally, the disintegrant can improve the dissolution rate. The disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, and combinations thereof. The content of the disintegrant is not particularly limited, and may be included in an amount of 0.1% to 10% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

Additionally, the lubricant may be added to improve the flowability and gloss of the pharmaceutical composition. The lubricant may be selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof. The content of the lubricant is not particularly limited, and may be included in an amount of 0.3% to 2.0% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

Additionally, the binding solution may be a substance that assists in the formulation of the pharmaceutical composition. In particular, it can help with granulation in the wet granulation method. For example, the binding solution may be purified water.

Additionally, the sustained-release agent can be used when formulating a sustained-release tablet. The sustained-release agent includes hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), polyethylene oxide (PEO), carboxy methyl cellulose sodium (CMC), It may include one or more selected from the group consisting of ethyl cellulose (EC) and carbomer (CB). At this time, when each sustained-release agent is prepared as a 1% solution, the viscosity of at least one type of sustained-release agent may be 4,000 cPs (25°C) or more. The content of the sustained-release agent is not particularly limited, and may be included in an amount of 20% to 45% by weight based on the total weight of the pharmaceutical composition to maximize the effect without affecting other ingredients.

The present invention also provides a method for producing a pharmaceutical composition containing quetiapine or a pharmaceutically acceptable salt thereof as an active ingredient and a stabilizer.

The method for producing a pharmaceutical composition according to the present invention may include mixing the quetiapine or a pharmaceutically acceptable salt thereof with a stabilizer.

Additionally, during the mixing, additives as described above may be mixed together.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

In the following examples and comparative examples, a pharmaceutical composition containing quetiapine in tablet form was prepared. The tablets were manufactured as immediate-release or sustained-release tablets. The immediate-release tablets were manufactured through a wet granulation or direct pressing process. The sustained-release tablet was manufactured by a wet granulation process.

The wet granulation and direct compression processes performed when manufacturing immediate-release tablets or sustained-release tablets are as follows, and the compositions of each Example and Comparative Example are shown in Tables 1 to 3 below.

[Tablet manufacturing method]

1. Immediate-release tablet manufacturing method

1-1. Direct hitting process (Example 11 and Comparative Examples 11 to 13)

In the case of the direct pressing process sample, the sieved quetiapine raw materials, excipients, disintegrants, binders, and stabilizers were placed in a bin mixer (Wytec, 5L) and mixed at 24 rpm for 5 minutes, and the lubricant was added. It was added and further mixed for 2 minutes. The mixed granules were tableted by using a single-shot tablet press (Autotab-200TR, Ichihashiseiki) at a compression pressure of 1650kgf (tablet hardness 8kp).

1-2. Wet granulation process (Examples 1 to 10 and Comparative Examples 2 to 10)

In the case of wet granulation process samples, the binder solution was prepared at 20 to 30% by weight based on the tablet mass using purified water and binder, and quetiapine fumarate salt, excipients, and The disintegrant and stabilizer were added and mixed homogeneously for 3 minutes, then the binding solution was added for 2 minutes and kneaded, and kneaded for an additional 3 minutes to form granules. The obtained granules were transferred to a fluidized bed dryer (GR, GREP Lab1), dried to 2.2±0.5% (105°C, 20 min) based on LOD (Loss of Dry Weight), and then cored mill combined with a 0.8 mm sieve. It was established using. Afterwards, the obtained sizing powder was placed in a bin mixer (Wytech, 5L), a lubricant was added, and mixed at 24 rpm for 2 minutes. The mixed granules were tableted by using a single-shot tablet press (Autotab-200TR, Ichihashiseiki) at a compression pressure of 650 kgf (tablet hardness: 8 kp).

2. Method of manufacturing sustained-release tablets

2-1. Wet granulation process (Examples 12 to 15 and Comparative Examples 14 to 15)

All raw materials were prepared by sieving through a 30 mesh sieve, and purified water was used as a binder in an amount of 9.5 to 10.5% by weight based on the mass of the tablets during granulation. Add quetiapine fumarate salt, stabilizer (acidifier and/or antioxidant), sustained release agent, and excipients to a high shear granulator (sejong, SM-5C), mix homogeneously for 3 minutes, and combine for 2 minutes. The solution was added and kneaded, and kneaded for an additional 3 minutes to form granules. The obtained granules were transferred to a fluid bed dryer (GR, GREP Lab1), dried to 2.5 ± 0.5% (105°C, 20 min) based on LOD, and then sized using a cored mill equipped with a 0.8 mm sieve. Afterwards, the obtained sizing powder was placed in a bin mixer (Wytech, 5L), a lubricant was added, and mixed at 24 rpm for 2 minutes. The mixed granules were tableted by tableting (tablet hardness 13 kp) at a compression pressure of 850 kgf using a single-shot tablet press (Autotab-200TR, Ichihashiseiki).

Table 1 below shows the composition of the quetiapine-containing immediate-release tablets of Examples 1 to 11. Examples 1 to 10 are the compositions of quetiapine-containing immediate-release tablets manufactured by a wet granulation process, and Example 11 is the composition of quetiapine-containing immediate-release tablets manufactured by a direct pressing process.

Ingredients (unit: mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 active ingredient Quetiapine fumarate 230.26 230.26 230.26 230.26 230.26 230.26 230.26 230.26 230.26 230.26 230.26 excipient Microcrystalline cellulose 137.54 142.54 142.54 147.44 145.04 147.04 147.53 145.54 142.54 147.43 147.53 lactose monohydrate 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 Calcium phosphate 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 binder povidone 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 binder (Purified water) (150.0) (100.0) (100.0) (150.0) (150.0) (150.0) (150.0) (100.0) (150.0) (150.0) - disintegrant Sodium starch glycolate 36.00 36.00 36.00 36.00 36.00 36.00 36.00 36.00 36.00 36.00 36.00 acidifier ascorbic acid 10.00 5.00 - - - - - - - - - maleic acid - - 5.00 - - - - - - - - tartaric acid - - - 0.10 2.50 - - - - 0.10 - antioxidant BHT - - - - - 0.50 - - - - - Propyl gallic acid - - - - - - 0.01 2.00 - 0.01 0.01 Sodium pyrosulphite - - - - - - - - 5.00 - - lubricant magnesium stearate 6.20 6.20 6.20 6.20 6.20 6.20 6.20 6.20 6.20 6.20 6.20 tablet total mass 500.00 500.00 500.00 500.00 500.00 500.00 500.00 500.00 500.00 500.00 500.00 Manufacture process wet granulation direct hitting process Formulation Immediate-release tablets

Table 2 below shows the composition of the quetiapine-containing immediate-release tablets of Comparative Examples 2 to 13. Comparative Examples 2 to 10 are compositions of quetiapine-containing immediate-release tablets manufactured by a wet granulation process, and Comparative Examples 11 to 13 are compositions of quetiapine-containing immediate-release tablets manufactured by a direct pressing process.

For Comparative Example 1, commercially available quetiapine-containing tablets (Seroquel 200mg tablets (Lot No. 60041863, expiration date: 2024.06.30), Alvogen Korea) were purchased and prepared.

Ingredients (unit: mg) Comparative example 2 Comparative example 3 Comparative example 4 Comparative Example 5 Comparative Example 6 Comparative example 7 Comparative example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Comparative Example 13 active ingredient Quetiapine fumarate 230.26 230.26 230.26 230.26 230.26 230.26 230.26 230.26 230.26 230.26 230.26 230.26 excipient Microcrystalline cellulose 147.54 142.54 142.54 142.54 117.54 97.54 142.54 142.54 112.54 147.54 127.54 117.54 lactose monohydrate 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 Calcium phosphate 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 binder povidone 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 binder (Purified water) (150.0) (150.0) (150.0) (150.0) (150.0) (150.0) (150.0) (150.0) (150.0) - - - disintegrant Sodium starch glycolate 36.00 36.00 36.00 36.00 36.00 36.00 36.00 36.00 36.00 36.00 36.00 36.00 alkaline agent L-arginine - 5.00 - - - - - - - - - - Meglumine - - 5.00 - - - - - 5.00 - - - Magnesium Oxide - - - 5.00 30.0 50.0 - - 30.00 - - - sodium bicarbonate - - - - - - 5.00 - - - - - calcium carbonate - - - - - - - 5.00 - - - - acidifier ascorbic acid - - - - - - - - - - 20.00 - maleic acid - - - - - - - - - - - 30.00 lubricant magnesium stearate 6.20 6.20 6.20 6.20 6.20 6.20 6.20 6.20 6.20 6.20 6.20 6.20 tablet total mass 500.00 500.00 500.00 500.00 500.00 500.00 500.00 500.00 500.00 500.00 500.00 500.00 Manufacture process wet granulation direct hitting process Formulation Immediate-release tablets

Table 3 below shows the compositions of Examples 12 to 15 and Comparative Examples 14 to 15 of quetiapine-containing sustained-release tablets manufactured by a wet granulation process.

Ingredients (unit: mg) Example
12 Example
13 Example
14 Example
15 Comparative example
14 Comparative example
15 active ingredient Quetiapine
fumarate 230.26 230.26 230.26 230.26 230.26 230.26 Sustained release agent HPMC K4M - 50 50 50 - 50 HPMC K15M 100 - - - 100 - HPMC K100M 50 100 100 100 50 100 excipient Microcrystalline cellulose 100 100 100 100 100 100 lactose monohydrate 50 50 50 50 50 50 binder (Purified water) (54) (54) (54) (54) (54) (54) acidifier tartaric acid 2.5 - - - - - antioxidant Propyl gallic acid - 0.01 1.0 - - - Sodium pyrosulphite - - - 5.0 - - lubricant magnesium
stearate 10 10 10 10 10 10 tablet total mass 542.76 540.27 541.26 545.26 540.26 540.26 Manufacture process wet granulation Formulation Seobu tablets

The process conditions of the high shear granulator in Examples 1 to 10 and Comparative Examples 2 to 10 are shown in Table 4 below.

Mixed process values federated fair value Agitator rpm 175 rpm 175 rpm Chopper rpm - 3,000 rpm mixing time 3 minutes - union time Binder injection - 2 minutes additional union - 3 minutes

Experimental Example 1: Stability Test

A stability test was conducted on 30 samples prepared in Examples 1 to 15 and Comparative Examples 1 to 15 under the following two conditions:

First condition: exposure conditions in which each sample was packaged in a petrish dish, and

Second condition: Sealed condition in which each sample was packaged in a 50 cc HDPE (High Density Polyethylene) bottle with 1.5 g of silica gel.

Table 5 below summarizes each experimental condition.

1st condition 2nd condition storage status exposure
(Petrician dish) sealed
(HDPE bottle) Storage conditions high temperature and humidity
(60℃/90%RH) High temperature
(80℃) Storage period 2 weeks 3 days

As shown in Table 5, each sample in the exposed condition packaged in the Petri dish was stored in a 60°C/90%RH condition chamber (MMM, Climacell) for 2 weeks, and each sample in the sealed condition packaged in the HDPE bottle After being stored in an 80℃ chamber (Labfine, FLT-600S) for 3 days, a test was conducted to measure the amount of N-Nitroso-Aryl Piperazine (NNAP) produced, a nitroso related substance. did. A test was conducted to measure the amount of nitrocarbon related substances (NNAP) produced. It was determined that the smaller the amount of NNAP produced, the better the stability.

Using an appropriate dilution solution capable of extracting NNAP, for example, an aqueous methanol solution (25 to 50 v/v %) mixed with methanol and purified water in an appropriate ratio, the final concentration of NNAP was adjusted to 33 μg/mL, and the solution was used as the test solution. This was performed using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), and the degree of production of Nitroso related substances was analyzed.

-Analysis conditions-

(1) Device used: Waters Xevo TQ-XS

(2) Column: Phenomenex Kinetex F5 (3.0 x 100 mm, 2.6 μm) column

(3) Column temperature: 40℃

(4) Apply gradient analysis conditions using mobile phase: 0.1% Fumaric acid in purified water, 0.1% Fumaric acid in methanol.

(5) Flow rate: 0.3 ml/min

(6) Injection volume: 20 ml

Mass spectrometer conditions are as listed in Table 6 below.

Ionization Mode APCI (+) Capillary (kV) N/A Desolvation Temp. N/A Probe Temp. 550℃ Desolvation gas flow (L/hr) N/A Cone gas flow (L/hr) N/A Corona (μA) 20.2 Source Temp. 150℃ Acquisition Time 8.0 ~ 13.0 min (MS introduction time) Scan mode MRM Analyze m/z
(mass-to-charge ratio) Cone (V) Collision (eV) NNAP 325.1 → 227 20 15

According to the analysis conditions described above, the degree of formation of Nitroso related substances was analyzed. Under LC conditions, 8 to 10 minutes, including the retention time of NNAP, were introduced into MS, and NNAP was ionized using the APCI(+) method. At this time, among the various ions that can be generated from NNAP (m/z 325.1), a molecule (daughter ion) with a molecular weight of 227 was quantified to confirm the more accurate amount of NNAP generated, and the results are shown in Tables 7 and 8.

Table 7 and Figure 1 below show the results of analyzing the degree of production of Nitroso related substances for samples stored under the first conditions (exposure, high temperature/high humidity, and 2 weeks) as described in Table 4 above. In Comparative Examples 12 and 13, the stabilizer was contained in excessive amounts and the friability standard was exceeded, so NNAP evaluation was not performed.

Unit: ng/day initial value 2 weeks Unit: ng/day initial value 2 weeks Example 1 < 3 35 Comparative Example 1 84 243 Example 2 < 3 45 Comparative Example 2 < 3 157 Example 3 < 3 57 Comparative Example 3 < 3 344 Example 4 < 3 96 Comparative Example 4 < 3 220 Example 5 < 3 24 Comparative Example 5 < 3 167 Example 6 < 3 41 Comparative Example 6 < 3 142 Example 7 < 3 31 Comparative Example 7 < 3 135 Example 8 < 3 < 3 Comparative Example 8 < 3 192 Example 9 < 3 60 Comparative Example 9 < 3 295 Example 10 < 3 11 Comparative Example 10 < 3 188 Example 11 < 3 24 Comparative Example 11 < 3 147 Example 12 < 3 27 Comparative Example 14 < 3 183 Example 13 < 3 35 Comparative Example 15 < 3 187 Example 14 < 3 < 3 - - - Example 15 < 3 67 - - -

Referring to Table 7 and Figure 1, it can be seen that Examples 1 to 15 all contain acidifiers and/or antioxidants as stabilizers, so the NNAP production amount is less than 150 ng/day, which is the temporary allowable daily intake. On the other hand, Comparative Example 1 is a commercially available quetiapine-containing tablet (Seroquel 200mg tablet (Lot No. 60041863, expiration date: 2024.06.30), Alvogen Korea), in which NNAP was produced in excess of the temporary allowable daily intake of NNAP. Confirmed. In addition, it was confirmed that Comparative Examples 2 to 11 did not contain a stabilizer or contained an alkalinizing agent as a stabilizer, producing NNAP that was close to or exceeded the temporary allowable daily intake of NNAP.

From these results, it was confirmed that when quetiapine-containing tablets contain an acidifying agent and/or an antioxidant as a stabilizer, the stability can be improved by inhibiting NNAP production.

In addition, Examples 7, 8, 10, and 11 contain the antioxidant propyl gallate as a stabilizer, and in this case, it can be seen that the effect of inhibiting NNAP production is more than 50 times greater than that of Comparative Example 2, which does not contain a stabilizer. You can. In particular, Example 10 was confirmed to have an effect of inhibiting NNAP production more than 10 times that of Comparative Example 2 by including a combination of tartaric acid, an acidifier, and propyl gallic acid, an antioxidant, as a stabilizer. Examples 4 and 7 are cases where tartaric acid, an acidifier, and propyl gallic acid, an antioxidant, were used as stabilizers, respectively. Example 10 showed an effect of inhibiting NNAP production about 1.5 times and 5 times, respectively, compared to Examples 4 and 7. .

From these results, it was found that when the quetiapine-containing tablet contains a combination of an acidifier and an antioxidant as a stabilizer, the NNAP production inhibitory effect is further improved compared to when the quetiapine-containing tablet contains them alone.

In addition, although there is a difference in the amount of binding solution between Examples 1 and 2, it can be seen that there is no significant difference in the effect of inhibiting NNAP production.

In addition, Examples 7 and 11 relate to tablets manufactured by wet granulation and direct compression processes, respectively, but it can be seen that there is no significant difference in the effect of inhibiting NNAP production.

Table 8 and Figure 2 below show the results of analyzing the degree of production of Nitroso related substances for samples stored under the second condition (exposure, high temperature, and 3 days) as described in Table 4 above.

Unit: ng/day initial value 3 days Unit: ng/day initial value 3 days Example 1 < 3 54 Comparative Example 1 84 586 Example 2 < 3 66 Comparative Example 2 < 3 240 Example 3 < 3 81 Comparative Example 3 < 3 429 Example 4 < 3 134 Comparative Example 4 < 3 254 Example 5 < 3 35 Comparative Example 5 < 3 220 Example 6 < 3 61 Comparative Example 6 < 3 197 Example 7 < 3 39 Comparative Example 7 < 3 183 Example 8 < 3 <3 Comparative Example 8 < 3 211 Example 9 < 3 88 Comparative Example 9 < 3 317 Example 10 < 3 16 Comparative Example 10 < 3 226 Example 11 < 3 33 Comparative Example 11 < 3 446 Example 12 < 3 43 Comparative Example 12 < 3 - Example 13 < 3 51 Comparative Example 13 < 3 - Example 14 < 3 <3 Comparative Example 14 < 3 311 Example 15 < 3 95 Comparative Example 15 < 3 327

Referring to Table 8 and Figure 2, similar to Table 7, when the quetiapine-containing tablet contains an acidifying agent and/or antioxidant as a stabilizer, it acts to inhibit NNAP production and improves stability. , it was found that when quetiapine-containing tablets contained a combination of an acidifier and an antioxidant as stabilizers, the inhibitory effect on NNAP production was further improved compared to when they were contained alone.

In particular, Example 7 is a case where propyl gallate, an antioxidant, is used as a stabilizer. Despite containing a small amount of propyl gallate (0.0043 parts by weight based on 100 parts by weight of quetiapine fumarate), the stabilizer was used as a stabilizer. It was confirmed that the inhibitory effect on NNAP production was significantly improved compared to Comparative Example 2 without it. In addition, it can be seen that Example 8 shows a complete improvement effect by showing a NNAP value below the limit of quantification. Example 8 contains 0.87 parts by weight of propyl gallate based on 100 parts by weight of quetiapine fumarate.

In addition, similar effects to immediate-release tablets were confirmed in extended-release tablets.

Experimental Example 2: Friability test

The friability of the quetiapine-containing tablets prepared in Examples and Comparative Examples was measured using a friability measuring device (TAR 200, ERWEKA, Germany).

The measurement targets were quetiapine-containing tablets prepared in Examples 1 and 2 and Comparative Examples 5, 6, 7, 12, and 13, and the friability measurement results showed that the active ingredient, quetiapine, and acid stability were obtained. The purpose was to confirm the correlation between the content ratio of the topic and its friability.

The measurement conditions were to set the sample amount (6.5g, 13 tablets) according to the USP <1216> TABLET FRIABILITY test, then measure at 25 rpm for 4 minutes (total number of rotations: 100), and measure the amount of tablet mass reduction before and after the test. . This was repeated a total of 4 times (total number of rotations: 400) to check the friability of the tablets, and the results are listed in Table 9 below. Friability can be calculated using Equation 1 below:

<Equation 1>

Friability (%) = (Initial mass-Final mass/Initial mass)*100.

Table 9 below shows the friability measurement results of quetiapine-containing tablets prepared in Examples 1 and 2 and Comparative Examples 5, 6, 7, 12, and 13. Friability indicates the physical strength of the tablet, and the smaller the calculated friability value, the better the physical strength of the tablet.

unit: % Example
One Example
2 Comparative example
5 Comparative example
6 Comparative example
7 Comparative example
12 Comparative example
13 100 rotations 0.19 0.11 0.12 0.14 0.15 0.28 0.25 400 rotations 0.56 0.36 0.43 0.51 0.54 0.93 0.85

Referring to Table 9, Comparative Example 12 is a tablet containing 10 parts by weight or more of an acidifying agent as a stabilizer, based on 100 parts by weight of quetiapine, which is an active ingredient. Discoloration occurred during storage, causing a problem in property stability. there was. In addition, Comparative Examples 12 and 13 were confirmed to have a friability measurement result of 0.6 or more. If the friability is high, tablets may be ground during coating, which may cause property problems. In particular, in the case of products with large batch sizes, the stability of tablet properties may be further reduced due to high friability. For example, when applying a batch size of 200,000 T (ton) or more with a tablet mass of 500 mg, it can be predicted that the probability of poor quality after the tablet coating process will increase by about 3-4%.

Although the present invention has been described above with limited examples and drawings, the present invention is not limited thereto, and the technical idea of the present invention and the following description will be provided by those skilled in the art in the technical field to which the present invention pertains. Of course, various modifications and variations are possible within the scope of equivalence of the patent claims.

Claims (11)

A pharmaceutical composition containing quetiapine or a pharmaceutically acceptable salt thereof,
A pharmaceutical composition comprising an acidic stabilizer as a stabilizer. According to paragraph 1,
A pharmaceutical composition wherein the acid stabilizer includes at least one selected from the group consisting of an acidifier and an antioxidant. According to paragraph 2,
A pharmaceutical composition wherein the acidifying agent includes at least one selected from the group consisting of ascorbic acid, tartaric acid, malic acid, and maleic acid. According to paragraph 2,
A pharmaceutical composition wherein the antioxidant includes at least one selected from the group consisting of synthetic antioxidants and natural sulfur oxidizing agents. According to clause 4,
The synthetic antioxidant is selected from the group consisting of propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and sodium pyrosulfite. Contains one or more types,
A pharmaceutical composition wherein the natural antioxidant includes at least one selected from the group consisting of tocopherol, gossypol, and sesamol. According to paragraph 1,
A pharmaceutical composition wherein the acid stabilizer is included in an amount of 0.001 parts by weight to 8 parts by weight based on 100 parts by weight of the quetiapine or a pharmaceutically acceptable salt thereof. According to paragraph 1,
A pharmaceutical composition wherein the quetiapine or a pharmaceutically acceptable salt thereof is contained in an amount of 30% to 60% by weight based on the total weight of the pharmaceutical composition. According to paragraph 1,
A pharmaceutical composition, wherein the composition is formulated as an oral preparation. According to clause 8,
A pharmaceutical composition wherein the oral preparation is a tablet or capsule. According to clause 9,
A pharmaceutical composition wherein the tablet is manufactured by a wet granulation method or a direct compression method. According to clause 8,
A pharmaceutical composition wherein the oral preparation is an immediate-release tablet or sustained-release tablet.