JP2016079120A - Olanzapine formulation in which stability is improved by packaging - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an orally disintegrating olanzapine tablet in which the increase of analogues by oxidative degradation or a degradation mechanism thereof is reduced over the long time.SOLUTION: The invention provides an orally disintegrating olanzapine tablet preserved in a packaging form where a drying agent having a deoxidation function which utilizes the oxidation mechanism of organic substances is enclosed. Preferably, the drying agent has a deoxidation function and is enclosed in an organic deoxidant, and preferably, the drying agent is also used in combination with the drying agent having a deoxidation function. Preferably, the orally disintegrating tablet has a packaging form of a pillow package or a bottle package. The orally disintegrating olanzapine tablet in which excellent stability is imparted reduces the temporal increase of many degradation products (analogue B, analogue C, thiolactam body, lactam body, and the like) derived from olanzapine, by the packaging form.SELECTED DRAWING: None

Description

  The present invention relates to improving the storage stability of an olanzapine orally disintegrating tablet by packaging.

  Olanzapine, a treatment for schizophrenia and bipolar disorder, is available in four dosage forms from Eli Lilly as Zyprexa (registered trademark): film-coated tablets, Zydis (registered trademark) tablets, fine granules and intramuscular injections. Yes. Zydis tablets are manufactured by freeze-drying and are classified as orally disintegrating tablets in the Japanese Pharmacopoeia.

  Examples that require orally disintegrating tablets include those that are mainly used for elderly people with reduced swallowing ability, as well as treatments for psychiatric disorders such as schizophrenia and bipolar disorder such as olanzapine. It is considered useful for an assistant to promptly administer and swallow a patient who refuses (Non-patent Document 1).

  By the way, it is known that formulation of olanzapine has a problem regarding stability. The literature that describes the stability improvement in the formulation of olanzapine is that olanzapine fades by contact with certain additives and accelerates under high temperature and high humidity conditions. Has been disclosed (Patent Document 1). In addition, the use of alkaline excipients has a negative effect on the stability of olanzapine, but if olanzapine is mixed well with the isolator in advance, the decomposition is suppressed and the tablet is coated with a functional polymer. It is disclosed that the coloration of tablets and the destabilization caused by alkaline excipients can also be improved (Patent Document 2). However, these are all stabilization methods for film-coated tablets. Orally disintegrating tablets generally have low tablet hardness and are easily abraded, so the application of film coating tends to damage the appearance due to chipping of the tablets during operation, and the presence of a coating reduces the disintegration property in the oral cavity. Therefore, implementation is expected to be difficult.

  As related substances generated by destabilization of olanzapine preparations, olanzapine lactam, 4-oxo-form (related substance B), olanzapine thiolactam, 4 ′ -N-oxide (related substance C) is specified. From the chemical structure, it is considered that the 4-oxo form is produced by water, the olanzapine thiolactam, and the 4'-N-oxide form, respectively, mainly due to the action of oxygen. That is, in order to keep the olanzapine formulation stable, it is important to eliminate the influence of humidity and oxygen.

  Patent Document 3 discloses that when an olanzapine-containing preparation is stored for a long period of time, the 4′-N-oxide (related substance C) increases due to peroxide contained in the disintegrant crospovidone. It is disclosed that a low-substituted hydroxypropyl cellulose or a crospovidone having a peroxide content of less than 80 ppm can be used to obtain a preparation that suppresses an increase in related substances. However, there is no description of the effect on other related substances generated in addition to the 4'-N-oxide (related substance C).

  As a method for inhibiting the oxidation of a drug, a method has been shown in which atorvastatin which is easily decomposed by oxygen in the air can be stabilized by applying a film coating mainly composed of a polyvinyl alcohol copolymer (Patent Document 4). However, since this is also a coating, application to orally disintegrating tablets is difficult.

  As another method, a case of azelnidipine is known as a method for improving the stability by encapsulating an oxygen scavenger or the like in a packaging form of a pharmaceutical preparation (Patent Document 5). However, the degradation mechanism of drugs varies depending on the chemical structure, and in the formulation of olanzapine in which various degradation products other than oxidative degradation products are produced, there are known formulations that suppress the increase in most degradation products over time by devising the packaging form. Absent.

  From the above, olanzapine preparations as orally disintegrating tablets have been required to have a method for suppressing and stabilizing an increase in various related substances.

Japanese National Patent Publication No. 11-502848 Special table 2009-521518 JP 2014-58461 A WO2011 / 077843 Publication WO 2010/107081

Monthly Pharmaceutical Affairs, 2008.10 (Vol.50 No.11) 25-32 United States Pharmacopeia (36), 4562-4565

  The object of the present invention is to provide an orally disintegrating tablet of olanzapine in which an increase in related substances is reduced over a long period of time.

  When the present inventors store a preparation containing olanzapine under conditions of high temperature and high humidity, a hydrolyzate 4-oxo compound (related substance B) and an oxidative decomposition product 4′-N-oxide compound (related substance C) are obtained. It was found that the number of ring-opened lactams and thiolactams increased little. On the other hand, when an oxygen scavenger or desiccant is enclosed in the packaging form of the preparation and stored under the same conditions, the presence of the desiccant has no effect on the suppression of the increase in related substances, and conversely the thiolactam body increases. It turns out that there is also. In addition, while the oxygen scavenger alone suppresses the thiolactam body, there is anxiety about the suppression of the related substance B derived from moisture, and when the synthetic zeolite is used in combination with the oxygen scavenger for the purpose of removing water, the thiolactam body is simply increased. It has been difficult to suppress all related substances merely by combining oxygen scavengers and desiccants alone or in combination, and further measures have been required.

  As a result of intensive studies to solve the above problems, the present inventors have encapsulated a desiccant having a deoxygenation function utilizing an oxidation mechanism of an organic substance in a packaging form of an olanzapine preparation, whereby related substances B and related substances It has been found that an olanzapine orally disintegrating tablet having excellent stability can be obtained by suppressing the increase over time of most degradation products derived from olanzapine such as substance C, thiolactam and lactam.

  The most suitable for stabilizing the olanzapine orally disintegrating tablet is a desiccant with a deoxygenating function in which a desiccant is enclosed in an organic oxygen scavenger. Furthermore, even if a desiccant is used in combination with a desiccant with a deoxygenating function, stabilization equivalent to or higher can be achieved.

  By enclosing a desiccant with a deoxygenating function or a desiccant with a deoxygenating function and a desiccant in the package, not only the related substance B caused by water, the related substance C caused by oxygen, but also the influence of water and oxygen The olanzapine orally disintegrating tablet excellent in stability can be provided, in which the increase in the total amount of related substances including thiolactam bodies and lactam bodies that are received is significantly suppressed.

The time-dependent transition of the related substance total amount in the storage test of Comparative Examples 1-2 is shown. The time-dependent transition of the related substance C amount in the storage test of Comparative Examples 1-2 is shown. The time-dependent transition of the related substance B amount in the storage test of Comparative Examples 1-2 is shown. The time-dependent transition of the amount of olanzapine thiolactam in the preservation | save test of Comparative Examples 1-2 is shown. The time-dependent transition of the related substance total amount in the storage test of Comparative Examples 3-8 is shown. The time-dependent transition of the amount of olanzapine thiolactam and related substance C in the storage test of Comparative Examples 3-8 is shown. The time-dependent transition of the related substance total amount in the storage test of Example 1 and Comparative Examples 9-11 is shown. The time-dependent transition of the amount of each related substance in the preservation | save test of Example 1 and Comparative Examples 9-11 is shown. The time-dependent transition of the related substance total amount in the storage test of Example 2 and Comparative Examples 12-16 is shown. The time-dependent transition of the amount of each related substance in the storage test of Example 3 and Comparative Examples 17-20 is shown. The time-dependent transition of the related substance total amount in the storage test of Examples 4-5 is shown. The time-dependent transition of the related substance total amount in the storage test of Example 6 and Comparative Examples 21-23 is shown. The time-dependent transition of the related substance total amount in the storage test of Example 7 and Comparative Examples 24-26 is shown. The time-dependent transition of the related substance total amount in the storage test of Example 8 and Comparative Examples 27-29 is shown. The time-dependent transition of the related substance total amount in the storage test of Example 9 and Comparative Examples 30-32 is shown.

  In the present invention, “stable” means individual olanzapine-related substances and their related substances by storing them in airtight conditions with or without a desiccant compared to open storage conditions that are directly exposed to heat and humidity. Refers to a state in which the increase in the total amount of related substances including is suppressed.

  The “desiccant with a deoxygenating function” in the present invention refers to a product in which a desiccant is enclosed in a deoxygenating agent using a mechanism that adsorbs oxygen when an organic substance is oxidized. Specific examples include PharmaKeep (registered trademark) KD and CD (Mitsubishi Gas Chemical).

  The “packaging form” in the present invention refers to pillow packaging and bottle packaging generally used for pharmaceuticals, and plastic and glass are suitable for the bottle packaging material. Olanzapine orally disintegrating tablets are encapsulated after PTP is applied beforehand in the case of pillow packaging. In the case of bottle packaging, the bottle is filled directly. At this time, the PTP material is not particularly limited.

  The olanzapine orally disintegrating tablet in the present invention may be prepared by a known method for obtaining ordinary tablets using excipients, disintegrants, binders, lubricants and the like as components. Examples of the excipient include sugar alcohols such as D-mannitol, erythritol, and sorbitol, sugars such as lactose and maltose, inorganic salts such as calcium hydrogen phosphate, and celluloses. Examples of the disintegrant include crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, carmellose, sodium starch glycolate, partially pregelatinized starch, and starch. Binders include starch-based binders such as corn starch, potato starch, wheat starch, dextrin, partially pregelatinized starch, pregelatinized starch, and water-soluble synthetic polymers such as hydroxypropylcellulose, hypromellose, povidone, copolyvidone, and polyvinyl alcohol. Illustrated. Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, calcium stearate, talc, and sucrose fatty acid ester. In addition, a fluidizing agent, a sweetening agent, a corrigent, a coloring agent, a coating agent, a fragrance and the like can be blended as necessary.

  The method for producing an orally disintegrating tablet is not particularly limited, but a general granulating apparatus such as a fluidized bed granulator, a stirrer granulator, a dry granulator, etc. containing a drug and an excipient, a disintegrant, etc. An example is a method of granulating using a slag. Among these, a fluidized bed granulation method is preferable. If a lubricant is mixed with granules obtained by granulation and tableting is performed using a tableting machine, an orally disintegrating tablet can be easily obtained in the same manner as ordinary tablets.

  Examples of preferred embodiments of the present invention will be described below, but the present invention is not limited to the exemplified conditions.

Comparative Examples 1 and 2: Comparison of crospovidone having different peroxide contents According to Patent Document 3, when crospovidone having a peroxide content of 80 ppm or less is used, a 4'-N-oxide (related substance C) is produced. It is disclosed that it is suppressed. Prior to the comparison of the packaging forms, in order to investigate the influence of the peroxide content in crospovidone, polyplastidone (registered trademark) XL-10 (produced by ISP, with a peroxide content standard of 400 ppm or less) Peroxide content test report value was 89 ppm), and polyplastidone ULTRA10 (same as 16 ppm) whose same standard is 50 ppm or less was compared.
In accordance with the formulation shown in Table 1, 2479 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech, Mannit P), 63.4 g of light anhydrous silicic acid (manufactured by Nippon Aerosil, Aerosil (registered trademark) 200), magnesium carbonate (manufactured by Kyowa Chemical Industry) After mixing 99.0 g of magnesium carbonate, the mixture was pulverized with a pin mill (manufactured by Hosokawa Micron Corporation, Fine Impact Mill 100 UPZ) at 14,000 rotations. 373.5 g of this pulverized product was taken, 31.9 g of low-substituted hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark) LH22), crospovidone (manufactured by ISP, polyplastidone XL-10: Comparative Example 1 Alternatively, ULTRA10: Comparative Example 2) 14.0 g and Olanzapine 14.0 g were mixed and then charged into a fluid bed granulator (manufactured by Paulek, MP-01). To this, 793.1 g of purified water, 24.6 g of corn starch (manufactured by Nippon Star Chemical Co., Ltd., corn starch ST-C), 0.38 g of sucrose fatty acid ester (Daiichi Kogyo Seiyaku Co., Ltd., DK Ester SS) and L-arginine ( 1.9 g (manufactured by Wako Pure Chemical Industries, special grade of reagent) was dispersed and granulated by spraying 242.7 g of a liquid obtained by heating. Magnesium stearate (manufactured by NOF Co., Ltd., magnesium stearate S) was mixed with the obtained granules, and tableted with a rotary tableting machine (manufactured by Kikusui Seisakusho, VIRG0518SS2AZ) to obtain a preparation. The tablet contained 5 mg of olanzapine in one tablet, the mass was 160 mg, and the shape was φ8.0 mm, 9.5R.

After filling 100 tablets of the obtained preparation into a container made of high-density polyethylene (HDPE), it is stored in a thermo-hygrostat at 40 ° C. and 75% RH in an airtight manner (1 g of allophane lid with desiccant) and opened (without lid). Then, it was taken out after a certain period and the total amount of related substances was measured under the following high performance liquid chromatography (HPLC) conditions. As a result, as shown in FIG. 1, the increase in the total amount of the related substances was small in Comparative Example 2 using poliplastidone ULTRA10 having a low peroxide content, and a significant difference was observed under the open conditions. This difference depends on the amount of related substance C shown in FIG. 2, and it was confirmed that the peroxide content in crospovidone affects the increase in the related substance C. On the other hand, as shown in FIGS. 3 and 4, polyplastidone ULTRA10 had no effect of suppressing the related substance B or thiolactam body.
In the subsequent comparative tests, polyplastidone ULTRA10 was used as the crospovidone unless otherwise specified.
(Related substances measurement conditions by HPLC)
Equipment: LC-2010CHT (Shimadzu Corporation)
Detector: UV absorption photometer (220nm)
Column: Octyl diisopropylsilylated silica gel Column temperature: 35 ° C
Mobile phase: 3.3 mL of phosphoric acid is added to a 30 mM sodium dodecyl sulfate aqueous solution, and the pH is adjusted to 2.5 with a 25% (w / v) aqueous sodium hydroxide solution to 1 L (solution A). Mix 520 mL of acetonitrile with 520 mL of A solution to make B solution. Moreover, 700 mL of acetonitrile is mixed with 300 mL of A solution to prepare C solution. Concentration control is performed for the B liquid and the C liquid at the following times.
Time (minutes) Mobile phase B liquid Mobile phase C liquid 0-20 100 → 0 0 → 100
20-25 0 100
25-27 0 → 100 100 → 0
27-35 100 0
Flow rate: About 1.5 mL / min (Adjust olanzapine retention time to about 13 minutes)
Injection volume: 20 μL

Comparative Example 3-8: open, without desiccant bottle packaging airtight, or in the example bottle packaging enclosing the desiccant, the stabilizing effect of various drying agents compared investigation and open conditions.
According to the formulation shown in Table 2, 12470 g of D-mannitol, 321.3 g of light anhydrous silicic acid, and 502 g of magnesium carbonate were mixed, and then crushed with a granulator (Paulec, Quadrocomil 197S). 1200 g of low-substituted hydroxypropylcellulose, 480 g of crospovidone and 500 g of olanzapine were mixed with 13240 g of this pulverized product, and the mixture was put into a fluidized bed granulator (manufactured by Freund Sangyo Co., Ltd., NFLO-15SJ). This was purified from 8307.6 g of purified water, 258 g of corn starch, 21.5 g of L-arginine (Ajinomoto, L-arginine), 4.3 g of sucrose fatty acid ester, and edible yellow No. 4 (manufactured by Saneigen FFI Corporation) , Edible Yellow No. 4) 8.6 g was dispersed and heated to spray 8000 g of the liquid, and granulated. 15376 g of the obtained granulated product is put into a V-type mixer (manufactured by Tsukasa Kogyo Co., Ltd., PM-V-70-S), mixed with 313.6 g of magnesium stearate, and then tableted with a rotary tableting machine to prepare a formulation. Got.

After filling the obtained formulation into 100 HDPE containers, Comparative Example 3: Open (without lid), Airtight with lid closed, Comparative Example 4: No desiccant, Comparative Example 5: Silica gel with activated carbon (Dryane ( (Registered Trademark) DO) 0.75 g, Comparative Example 6: Allophane 1 g, Comparative Example 7: Synthetic Zeolite 2.5 g, Comparative Example 8: IDI (registered trademark) PK (incorporated with a lid) one each, enclosed at 25 ° C. 60 And stored in a constant temperature and humidity chamber at 40 ° C. and 75% RH. These were taken out after a certain period and the related substances were measured.
As a result of the measurement, as shown in FIG. 5, the presence or absence of each desiccant hardly affected the stability at 25 ° C. and 60% RH, and Comparative Example 7 (synthetic zeolite) rather increased the total amount of related substances. As shown in FIG. 6, the synthetic zeolite had a large increase in related substances C and thiolactam bodies, and the total amount increased accordingly. In addition, it was found that the thiolactam body does not increase under humidity exposure as shown in FIG. 4, but rather decreases, whereas it maintains or increases when the desiccant is enclosed. Synthetic zeolite has a strong ability to remove water, so it was thought that the secondary decomposition of thiolactam by water was inhibited and accumulated.
On the other hand, at 40 ° C. and 75% RH, no significant difference was found between the opening and each desiccant. In the open state, the amount of each related substance was greatly increased due to the influence of moisture, but the increase was suppressed only by airtightness. Even if a desiccant was used, a further inhibitory effect was observed. There wasn't. Regarding the related substance C, the increase was not suppressed by the desiccant.
From these results, it was found that, in an airtight state, which is a general packaging form of pharmaceuticals, it is not possible to expect an increase in the related substances even if a desiccant is used.

Example 1, Comparative Example 9-11 In the example bottles packaged using deoxygenated function desiccant bottle packaging, to compare the stabilizing effect of the desiccant and oxygen function desiccant.
In accordance with the formulation shown in Table 3, 12470 g of D-mannitol, 301.2 g of light anhydrous silicic acid, and 502 g of magnesium carbonate were mixed and then pulverized with a granulator. 1200 g of low-substituted hydroxypropylcellulose, 480 g of crospovidone and 500 g of olanzapine were mixed with 13220 g of this pulverized product and put into a fluidized bed granulator. In this, 258 g of corn starch, 43 g of L-arginine, 4.3 g of sucrose fatty acid ester, and 8.6 g of edible yellow No. 4 were dispersed in 8286 g of purified water, and 8000 g of the liquid obtained by heating was sprayed and granulated. . 15542 g of the resulting granulated product was put into a V-type mixer, mixed with 316.9 g of magnesium stearate, and then tableted with a rotary tableting machine to obtain a preparation.

  After filling the obtained formulation with 100 tablets in a container made of HDPE, as Example 1, a desiccant with a deoxygenating function (manufactured by Mitsubishi Gas Chemical, Pharmakeep KD-10S), as Comparative Example 9, 1 g of allophane as a desiccant, As Comparative Example 10, 2 g of allophane was enclosed and the lid was tightened. In addition, as a comparative example 11, an opening without a lid was prepared and stored in a constant temperature and humidity chamber at 25 ° C. and 60% RH and 40 ° C. and 75% RH (comparative example 11 is only 40 ° C.) and then taken out after a certain period of time. The substance was measured. As a result, in Example 1 using the desiccant with a deoxygenating function, an increase in the total amount of related substances was clearly suppressed under any conditions as shown in FIG. FIG. 8 shows the transition of individual related substances. The thiolactam body showed an increasing tendency in Comparative Examples 9 and 10 in which the desiccant was enclosed, and increased in Comparative Example 10 having a larger amount of desiccant, whereas it hardly increased in Example 1. The lactam body also increased in Comparative Examples 9 and 10, whereas Example 1 remained almost unchanged as in the case of opening. Furthermore, the increase in the related substance C was clearly suppressed in Example 1 as compared with Comparative Examples 9 and 10, and the related substance B was suppressed to the same extent as the desiccant.

Example 2, Comparative Examples 12 to 16: Examples using PTP desiccant with deoxygenation function In PTP packaging, the stabilizing effects of desiccant and desiccant with deoxygenation function were compared.
After packaging the preparations shown in Table 3 in polypropylene PTP, PTP alone (no aluminum pillow) was used as Comparative Example 12; thereafter, there was no desiccant as Comparative Example 13, 2.5 g of silica gel as Comparative Example 14, and Comparative Example 15 1 g of synthetic zeolite, aluminum pillow package with ID sheet (30 × 70 mm) as comparative example 16, and aluminum pillow package with desiccant with deoxidation function (manufactured by Mitsubishi Gas Chemical, Pharmakeep KD-20) as example 2. The prepared material was prepared and stored in a constant temperature and humidity chamber at 25 ° C. and 60% RH and 40 ° C. and 75% RH, taken out after a certain period of time, and related substances were measured. As a result, as shown in FIG. 9, the increase in related substances was suppressed by applying aluminum pillow packaging as compared with PTP alone, but Comparative Examples 14 to 16 enclosing various desiccants did not enclose the desiccant. The values were almost the same as those of Comparative Example 13. That is, in the case of PTP aluminum pillow packaging as well as bottle packaging, the desiccant did not have the effect of suppressing the increase of related substances. On the other hand, only in Example 2, the increase in related substances was clearly suppressed as compared with each Comparative Example, and a remarkable stabilizing effect was recognized in the desiccant with a deoxygenating function.

Example 3, Comparative Example 17 to 20: In combination with Example bottle wrapped with deoxidant drying agent, in addition to the oxygen function desiccant, in addition to a combination of oxygen scavenger and drying agent as a comparative, oxygen scavenger and Each desiccant was used alone.
After filling the HDPE container with 100 tablets of the formulation shown in Table 3, Example 3 as a desiccant with deoxygenating function (manufactured by Mitsubishi Gas Chemical, Pharmakeep CD-1G), as Comparative Example 17 1 g of synthetic zeolite, As Example 18, one oxygen scavenger (Mitsubishi Gas Chemical Co., Ltd., T-10N: using iron oxidation mechanism) was put in each, and as Comparative Example 19, one oxygen scavenger and one synthetic zeolite were used together, and the lid Tightened to make it airtight. As Comparative Example 20, an opening without a lid was prepared. These were stored in a constant temperature and humidity chamber at 40 ° C. and 75% RH, taken out after a certain period of time, and related substances were measured.
The total amount of individual and related substances is shown in FIG. The synthetic zeolite of Comparative Example 17 markedly suppressed the related substance B, but there were many increases in related substance C and thiolactam bodies, and the total amount of related substances was the second largest after the opening of Comparative Example 20. In contrast to Comparative Example 17, the oxygen scavenger of Comparative Example 18 was effective in suppressing related substance C and thiolactam, but related substance B due to moisture tended to increase. The behavior of the related substance of Comparative Example 19 in which the oxygen scavenger and the synthetic zeolite were used in combination was close to that of the synthetic zeolite, and the related substance C and the thiolactam body increased compared to the oxygen scavenger. On the other hand, Example 3 using the desiccant with a deoxygenating function suppressed the whole related substance C and the thiolactam body as a whole, and as a result, suppressed the related substance total amount most.

Examples 4 to 5: Examples of using desiccant in combination with desiccant with deoxygenation function in bottle packaging After filling 100 tablets of HDPE containers with the same formulation and production method as in Table 3, removal as Example 4 Desiccant with oxygen function (Pharmakeep (registered trademark) CD-1G), as Example 5, 1 g of desiccant with deoxygenation function and 1 g of allophane desiccant were used together, the lid was closed, and constant temperature and humidity at 25 ° C. and 60% RH Stored in a container. These were taken out after a certain period and the related substances were measured.
The total amount of related substances is shown in FIG. The desiccant with a deoxygenating function of Example 4 suppressed the increase of related substances as compared with the comparative examples so far, but Example 5 combined with allophane further did not increase the related substances very much. High stabilization effect was shown.

Comparative Examples 21 to 23, Example 6: Example in which stability was compared with crystalline cellulose compounded formulation In order to investigate the stability in a formulation containing components different from Tables 1 to 3, a formulation formulated with crystalline cellulose was used, The stabilization effect by the desiccant was compared.
The formulations of Comparative Examples 21 to 23 and Example 6 shown in Table 4 were prepared by mixing 693.8 g of D-mannitol and 94.1 g of crystalline cellulose (Asahi Kasei Chemicals, Theolas (registered trademark) UF711). After sieving, 372.4 g was weighed and mixed with 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose and 14.0 g of crospovidone (Polyplastidone XL-10), and fluidized bed granulation. I put it in the machine. To this, 16.8 g of corn starch was dispersed in 543.2 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. This granulated product (395.0 g) was mixed with 5.0 g of magnesium stearate and then tableted with a rotary tableting machine.

After filling 100 tablets of the obtained preparation into a container made of HDPE, Comparative Example 21: Open (without lid), Airtight with the lid closed, Comparative Example 22: No desiccant, 1 g of desiccant allophane as Comparative Example 23 As Example 6, one pharmakeep CD-1G, a desiccant with a deoxygenating function, was added. These were stored in a constant temperature and humidity chamber at 40 ° C. and 75% RH, taken out after a certain period of time, and related substances were measured.
The total amount of related substances is shown in FIG. The increase in the related substances was larger than the prescriptions shown in Tables 1 to 3 under the open conditions of Comparative Example 21, but was suppressed to the same extent in Comparative Example 22 without desiccant and Comparative Example 23 with allophane enclosed, and deoxygenated. Example 6 using a desiccant with a function had a higher inhibitory effect.

Comparative Examples 24-26, Example 7: Comparative Example of Stability Comparison with Crystalline Cellulose / Carmellose Sodium Formulation Formulation In order to investigate the effect of the formulation, a formulation containing crystalline cellulose / carmellose sodium was used, and stability with a desiccant was used. We compared the effects.
Comparative Examples 24-26 and Example 7 were as shown in Table 5, except that the crystalline cellulose was replaced with crystalline cellulose / carmellose sodium (Theoras RC-A591NF, manufactured by Asahi Kasei Chemicals) as compared with Comparative Examples 21-23 and Example 6. Obtained a preparation with the same formulation and manufacturing method.

After filling 100 tablets of the obtained preparation into a container made of HDPE, Comparative Example 24: Open (no lid), Airtight with the lid closed, Comparative Example 25: No desiccant, 1 g of desiccant allophane as Comparative Example 26 As Example 7, one pharmakeep CD-1G, a desiccant with a deoxygenating function, was added. These were stored in a constant temperature and humidity chamber at 40 ° C. and 75% RH, taken out after a certain period of time, and related substances were measured.
The total amount of related substances is shown in FIG. The increase in the related substances was larger than the prescriptions shown in Tables 1 to 3 under the open conditions of Comparative Example 24, but Comparative Example 25 without desiccant and Comparative Example 26 with allophane were suppressed to the same extent, and deoxygenation. Example 7 using a desiccant with a function had a higher inhibitory effect.

Comparative Examples 27-29, Example 8: Examples in which stability was compared with a preparation containing aluminum silicate In order to investigate the influence of the preparation, a preparation containing aluminum silicate was used, and the stabilizing effect of the desiccant was compared.
The preparations of Comparative Examples 27 to 29 and Example 8 shown in Table 6 were mixed with 769.1 g of D-mannitol and 18.8 g of aluminum silicate (manufactured by Wako Pure Chemical Industries, Ltd.), and then sieved with JP 30 sieve. After that, 375.2 g was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose, and 14.0 g of crospovidone (Polyplastidone XL-10) were mixed into the fluidized bed granulator. I put it in. To this, 16.8 g of corn starch was dispersed in 543.2 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. This granulated product (395.0 g) was mixed with 5.0 g of magnesium stearate and then tableted with a rotary tableting machine.

After filling 100 tablets of the obtained preparation into a container made of HDPE, Comparative Example 27: Open (no lid), Airtight with the lid closed, Comparative Example 28: No desiccant, 1 g of desiccant allophane as Comparative Example 29 In Example 8, one pharmakeep CD-1G, a desiccant with a deoxygenating function, was added. These were stored in a constant temperature and humidity chamber at 40 ° C. and 75% RH, taken out after a certain period of time, and related substances were measured.
The total amount of related substances is shown in FIG. The increase in the related substances is extremely large in the open condition of Comparative Example 27 as compared to the formulations shown in Tables 1 to 3, whereas Comparative Example 23 with allophane enclosed and Comparative Example 22 without desiccant are suppressed to the same extent. Example 6 using a desiccant with a deoxygenating function was most suppressed.

Comparative Examples 30 to 32, Example 9: Examples in which stability was compared with a talc formulation In order to investigate the influence of the formulation, a formulation blended with talc was used, and the stabilization effect by the desiccant was compared.
In Comparative Examples 30 to 32 and Example 9, as shown in Table 7, aluminum silicate was replaced with talc (manufactured by Matsumura Sangyo, High Filler (registered trademark) # 17) as compared with Comparative Examples 27 to 29 and Example 8. Except for the above, a preparation was obtained by the same formulation and production method.

After filling 100 tablets of the obtained preparation into a container made of HDPE, Comparative Example 30: Open (no lid), Airtight with the lid closed, Comparative Example 31: No desiccant, 1 g of desiccant allophane as Comparative Example 32 As Example 9, one pharmakeep CD-1G, a desiccant with a deoxygenating function, was added. These were stored in a constant temperature and humidity chamber at 40 ° C. and 75% RH, taken out after a certain period of time, and related substances were measured.
The total amount of related substances is shown in FIG. The degree of increase in related substances is large under the open conditions of Comparative Example 30, whereas Comparative Example 31 without a desiccant and Comparative Example 32 with allophane enclosed are suppressed to the same extent, and an experiment using a desiccant with a deoxygenating function is performed. In Example 9, the effect of further suppressing was high.

  All of the preparations in Tables 4 to 7 had a large increase in related substances compared to the preparations in Tables 1 to 3. In the airtight state, the use of a desiccant did not contribute to stability improvement in most preparations, whereas when a desiccant with a deoxygenating function was used, the increase in related substances was most suppressed in all preparations. It was confirmed that a stable state can be maintained.

  According to the present invention, by using a desiccant with a deoxidizing function in the packaging of olanzapine orally disintegrating tablets, it is possible to suppress an increase in most related substances derived from olanzapine and maintain stable quality over a long period of time. can do.

Claims (3)

  An olanzapine orally disintegrating tablet stored in a packaging form in which a desiccant having a deoxygenating function utilizing an oxidation mechanism of organic substances is enclosed.   The olanzapine orally disintegrating tablet according to claim 1, further comprising a desiccant encapsulated. The olanzapine orally disintegrating tablet according to claim 1 or 2, wherein the packaging form is pillow packaging or bottle packaging.