JP5823592B2 - Formulation with improved stability - Google Patents

Description

  The present invention relates to improving storage stability by adding an alkaline additive to a pharmaceutical composition of olanzapine that is destabilized by a fluidizing agent.

There are various dosage forms such as liquids, powders, granules, tablets, capsules and the like for oral pharmaceutical preparations. Among them, tablets are most frequently used because of their excellent manufacturability and dosage. In recent years, many orally disintegrating tablets have been developed and marketed for easy administration.
There are various methods for producing orally disintegrating tablets such as freeze-dried mold tablets, wet tablets that dry after forming wet granules, and low-pressure formed tablets that are dried after humidification. There are an increasing number of methods for producing orally disintegrating tablets using a granulator or tableting machine.

  Examples that require orally disintegrating tablets include diseases mainly targeted at the elderly with reduced swallowing ability, such as antihypertensive agents, antidiabetic agents, and dementia agents. The purpose is listed. In addition, it is also useful for a caregiver to quickly administer and swallow a patient who refuses to take a therapeutic agent for psychiatric disorders such as schizophrenia and bipolar disorder (Non-patent Document 1).

  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. Among these, Zydis tablets correspond to the above-mentioned template tablets by freeze-drying. Since Zydis tablets dissolve in the oral cavity within a few seconds, it is excellent as a dosage form for this disease. On the other hand, a special device is required for production, and the preparation is extremely fragile and difficult to handle. Patent Document 1 discloses a method of producing an orally disintegrating tablet of olanzapine by a wet tableting method, but this cannot be produced by a general apparatus, and the average hardness is not sufficient at 3 kp.

  Olanzapine formulation also has stability issues. Patent Document 2 discloses a method of maintaining aesthetics by applying a film coating to tablets because olanzapine fades by contact with certain additives and accelerates under high temperature and high humidity conditions. . In Patent Document 3, the use of an alkaline excipient has a negative effect on the stability of olanzapine. However, if olanzapine is sufficiently mixed with an isolating agent in advance, decomposition is suppressed, and a functional polymer is also disclosed. It is disclosed that coating tablets with can also improve tablet coloration and destabilization by alkaline excipients. However, these are all measures for stabilizing ordinary tablets. Orally disintegrating tablets generally have low tablet hardness and are easily worn away, so the application of a film coating tends to cause chipping of the tablet during operation and damage the appearance, and the presence of a coating also reduces the disintegration property in the oral cavity. Expected to be difficult.

  Therefore, there has been a demand for an oranzapine orally disintegrating tablet that can be produced by a general device that is not special and that is excellent in stability and physical quality.

  Patent Document 4 discloses a rapidly disintegrating preparation containing magnesium carbonate heavy that disintegrates when contacted with moisture, and an oral dispersible tablet containing olanzapine is exemplified, but mentions stability. Not done.

Special table 2008-536922 gazette Japanese National Patent Publication No. 11-502848 Special table 2009-521518 Japanese translation of PCT publication No. 2008-531681

Monthly Pharmaceutical Affairs, 2008.10 (Vol.50 No.11) 25-32

  When an orally disintegrating tablet is produced by a general method for obtaining a normal tablet, in addition to tablet hardness that does not hinder distribution and handling, a problem is how to achieve both rapid disintegration with excellent dosing properties. Among them, as a relatively simple method, it is known that high hardness and quick disintegration can be achieved by blending a fluidizing agent typified by silica (silicic acid). Since sugar alcohols or sugars frequently used as the main excipients for orally disintegrating tablets have poor fluidity, they are also convenient for improving fluidity during granulation. However, fluidizing agents often have the task of promoting drug degradation. Olanzapine is also very stable with the drug substance alone, but when making an orally disintegrating tablet, we investigated a fluidizing agent for the purpose of improving the fluidity of excipients. It was found that related substances increased.

  In studying orally disintegrating tablets of olanzapine, stabilization of the fluidizing agent is preferable in order to achieve both the fluidity of excipients during granulation and the hardness and rapid disintegration of the resulting tablets. We examined how to do it. As a result, it has been found that by adding an alkaline additive, an increase in related substances accompanying the addition of a fluidizing agent can be clearly suppressed, and the present invention has been completed. This was contrary to the result that the alkaline excipient had a negative effect on the stability of olanzapine in Patent Document 3, and was an unexpected effect.

  That is, the present invention is a preparation with improved storage stability by blending an alkaline additive into a pharmaceutical composition of olanzapine that is destabilized by a fluidizing agent.

  According to the present invention, by adding an alkaline additive, olanzapine which can suppress an increase in related substances due to a fluidizing agent, can be produced by a general method, and has excellent stability and physical quality. Oranzapine oral preparations, including orally disintegrating tablets, can be provided.

The relationship between the tablet hardness of Comparative Examples 1-3 and disintegration time is shown. The time-dependent transition of the amount of related substances in the storage test of Comparative Examples 1-3 is shown. The relationship of the tablet hardness and disintegration time of the comparative example 4 and Examples 1-2 is shown. The time-dependent transition of the amount of related substances in the storage test of Comparative Example 4 and Examples 1-2 is shown. The time-dependent transition of the amount of related substances in the preservation | save test of the comparative example 4 and Examples 3-4 is shown. The time-dependent transition of the amount of related substances in the storage test of Comparative Example 5 and Example 5 is shown. The time-dependent transition of the amount of related substances in the storage test of the comparative example 4 and Examples 6-7 is shown. The time-dependent transition of the amount of related substances in the preservation | save test of the comparative example 4, Example 2, and Examples 8-11 is shown. The time-dependent transition of the amount of related substances in the storage test of Comparative Example 6 and Example 12 is shown. The time-dependent transition of the amount of related substances in the storage test of Comparative Example 7 and Example 13 is shown. The time-dependent transition of the amount of related substances in the storage test of Comparative Example 8 and Example 14 is shown. The time-dependent transition of the amount of related substances in the storage test of Comparative Example 9 and Example 15 is shown. The time-dependent transition of the amount of related substances in the storage test of Comparative Example 10 and Examples 16 to 17 is shown. The related substance amount in the light stability test of Comparative Example 4 and Examples 8 to 11 is shown.

  Olanzapine orally disintegrating tablet, which is an example of the present invention in which the decrease in stability due to a fluidizing agent is improved by the addition of an alkaline additive, includes excipients, disintegrants, binders, lubricants and the like as other components. It can be produced by a general method for obtaining ordinary tablets.

  Fluidizers include light silicic anhydride, hydrous silicon dioxide, calcium silicate, magnesium metasilicate aluminate, synthetic aluminum silicate, talc and other silica-based fluidizers, crystalline cellulose, crystalline cellulose and carmellose sodium Etc. are exemplified. Among these, a silica-based fluidizing agent is preferable from the viewpoint of fluidity improving effect and disintegration assisting effect, and light anhydrous silicic acid is more preferable. In addition, destabilization or decrease in stability due to a fluidizing agent refers to a state in which related substances derived from the active ingredient increase due to heat, humidity, or light irradiation compared to a prescription that does not contain this, stabilizing or stability "Improving" refers to a state in which similar substances are reduced as compared with a formulation not containing an alkaline additive. (No line breaks) Note that fluidizing agents may be categorized as excipients in the application for drug approval, but the purpose of the present invention is to add a decrease in stability due to the presence of these in the olanzapine formulation. Therefore, an olanzapine preparation containing the above-described fluidizing agent is an object of the present invention, regardless of the purpose of the approval application.

  As the blending amount of the fluidizing agent increases, the tablet hardness and the disintegration assisting effect increase, but since it is a component that lowers the stability of the drug, 0.1 to 10% by weight in the preparation is preferable, and more preferably 0. 5 to 5% by weight, more preferably 1 to 3% by weight.

  Alkaline additives used to improve stability degradation due to fluidizing agents include alkali metal salts such as sodium polyphosphate and sodium metaphosphate, and alkaline earth such as magnesium oxide, calcium carbonate, precipitated calcium carbonate and magnesium carbonate. Examples thereof include basic metal or magnesium salts, or basic amino acids such as L-arginine and ornithine. Among them, preferred are alkaline earth metal or magnesium salts and basic amino acids, and more preferred are magnesium carbonate and L-arginine. Two or more of these may be combined.

  The larger the amount of the alkaline additive is, the more effective for improving the stability. However, depending on the type of additive, it may cause a delay in disintegration. %, More preferably 0.1 to 5% by weight.

  Excipients are not particularly limited, but suitable for producing orally disintegrating tablets include sugar alcohols such as D-mannitol, erythritol and sorbitol, sugars such as lactose and maltose, calcium hydrogen phosphate Examples thereof include inorganic salts such as cellulose and celluloses. Among these, sugar alcohol is preferable, and D-mannitol is more preferable. Two or more of these may be combined.

  The blending amount of the excipient is a weight adjustment after giving priority to the blending amount of other components, but is preferably 50% by weight or more, more preferably 70% by weight or more in the preparation.

  The disintegrant is not particularly limited, and crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, carmellose, sodium starch glycolate, partially pregelatinized starch, starch and the like are exemplified. . Among these, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium starch glycolate, more preferably crospovidone and low-substituted hydroxypropylcellulose are preferable. Two or more of these may be combined.

  The larger the amount of disintegrant added, the faster the tablet can disintegrate, but it also has negative effects such as swelling when stored under high humidity conditions and lowering the tablet hardness. %, More preferably 5 to 15% by weight.

  The binder is not particularly limited, but starch-based binders such as corn starch, potato starch, wheat starch, dextrin, partially pregelatinized starch, pregelatinized starch, hydroxypropylcellulose, hypromellose, povidone, copolyvidone, polyvinyl A water-soluble synthetic polymer such as alcohol is exemplified. Among these, preferably starch-based, and more preferably corn starch.

  The larger the binder content, the higher the tablet hardness, and the lower the amount, the more advantageous for quick disintegration. However, the amount is preferably 1 to 5% by weight, more preferably 1.5 to 2.5% by weight in the preparation. is there.

  The lubricant is not particularly limited, and examples thereof include magnesium stearate, sodium stearyl fumarate, calcium stearate, talc, and sucrose fatty acid ester. Among these, magnesium stearate and sodium stearyl fumarate are preferable.

  The larger the blending amount of the lubricant, the more advantageous for avoiding tableting troubles such as sticking, but on the other hand, it causes disintegration delay based on hydrophobicity, so 0.1 to 5% by weight in the preparation is preferable. More preferably, it is 0.5 to 2% by weight. However, when an external lubrication device is used, the required function can be satisfied even with a very small amount.

  In addition, a sweetener, a corrigent, a coloring agent, a coating agent, a fragrance | flavor, etc. can also be mix | blended as needed.

  The method for producing the orally disintegrating tablet is not particularly limited, but the drug and excipient, fluidizing agent, disintegrating agent, etc. are generally used such as fluidized bed granulator, stirring granulator, dry granulator, etc. An example is a method of granulating using an automatic granulator. Among these, a fluidized bed granulation method is preferable. The alkaline substance may be added as a powder during granulation, or may be added after being dissolved or dispersed in a binding solution. Then, if a lubricant is mixed with the granule obtained by granulation and tableting is performed using a tableting machine, an orally disintegrating tablet can be easily obtained in the same manner as a normal tablet.

  The present invention is not limited to olanzapine orally disintegrating tablets, and can be applied to any oral preparation of olanzapine that is destabilized by a fluidizing agent. Moreover, the kind and compounding quantity of each additive can also be changed according to the formulation quality to request | require, and are not restricted to the range illustrated above.

  An example of an olanzapine orally disintegrating tablet will be described below with respect to a preferred embodiment of the present invention.

Comparative Examples 1 to 3: Example in which a fluidizing agent is blended and no alkaline additive is blended D-mannitol (manufactured by Mitsubishi Corporation Foodtech, Mannit P), light anhydrous silicic acid (manufactured by Nippon Aerosil, Aerosil (registered trademark) 200) ) And aspartame (manufactured by Ajinomoto Co., Inc., Ajinomoto KK Aspartame) were mixed and then pulverized at 14,000 revolutions with a pin mill (manufactured by Hosokawa Micron, Fine Impact Mill 100UPZ). Low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark) LH22), crospovidone (ISP, polyplastidone (registered trademark) XL-10) and olanzapine were mixed with this, and corn starch ( Using a paste obtained by heating an aqueous dispersion of corn starch ST-C (manufactured by Nippon Star Chemical Co., Ltd.), granulation was performed on a 2800 tablet scale using a fluidized bed granulator (manufactured by Paulek, MP-01). Magnesium stearate (manufactured by NOF Corporation, magnesium stearate S) was mixed with the obtained granules, and then tableted with a rotary tableting machine (manufactured by Kikusui Seisakusho, VIRG0518SS2AZ) to obtain a preparation having the composition shown in Table 1. . The tablet contained 5 mg of olanzapine in one tablet, the mass was 160 mg, and the shape was φ8.0 mm, 9.5R.

  For each formulation obtained with tableting pressures of 650, 750, 800, 850, and 950 kgf / kg, tablet hardness of 10 tablets (hardness meter: Schleunigel 8M) and disintegration time of 6 tablets (disintegration tester: manufactured by Toyama Sangyo Co., Ltd.) NT-60H, test conditions: water, 37 ° C.) As a result, the disintegration time at a constant tablet hardness was shortened as the amount of light anhydrous silicic acid was increased as shown in FIG.

Since the preparations of Comparative Examples 1 to 3 had no problem as physical properties as orally disintegrating tablets, the stability was investigated. After filling 100 tablets in a high density polyethylene (HDPE) container, store it in a thermostatic oven at 40 ° C and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time I took it out. As a result of measuring the total amount of related substances under the following high performance liquid chromatography (HPLC) conditions, as shown in FIG. 2, the amount of related substances tends to increase as the amount of light anhydrous silicic acid increases. It was not acceptable quality.
(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 4, Example 1, Example 2: Example in which magnesium carbonate was used in combination with light anhydrous silicic acid In Comparative Example 4, 470.9 g of D-mannitol and 11.5 g of light anhydrous silicic acid were mixed and then pulverized with a pin mill. Thereafter, 375.2 g was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose, and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. In this, 18.0 g of corn starch and 0.28 g of sucrose fatty acid ester (Daiichi Kogyo Seiyaku Co., Ltd., DK Ester (registered trademark) SS) were dispersed in 581.7 g of purified water, and the paste solution 242. 7g was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 1, 452.9 g of D-mannitol and 11.5 g of light anhydrous silicic acid were mixed and then pulverized by a pin mill, and 361.2 g was weighed, to which 14.0 g of olanzapine, low substituted hydroxypropylcellulose 31. 9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this solution, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 23.1 g of magnesium carbonate (magnesium carbonate, manufactured by Kyowa Chemical Industry Co., Ltd.) were dispersed in 364.7 g of purified water, and the paste solution 242. 7g was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 2, 452.9 g of D-mannitol, 11.5 g of light anhydrous silicic acid, and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 375.2 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. This was sprayed and granulated with 242.7 g of the paste prepared in Comparative Example 4. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.

  FIG. 3 shows the relationship between the tablet hardness of 10 tablets and the disintegration time of 6 tablets for each formulation obtained at tableting pressures of 650, 750, 800, 850, and 950 kgf / kg. Magnesium carbonate is the tablet hardness. And had little effect on disintegration.

  Since the preparations of Comparative Example 4 and Examples 1 and 2 had no problem with the physical properties as an orally disintegrating tablet, the stability was investigated. After filling 100 tablets into a container made of HDPE, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with a desiccant) and open (no lid), and remove it after a certain period of time to remove related substances. It was measured. As a result, as shown in FIG. 4, in the preparation of Comparative Example 4, the number of related substances tends to increase, whereas in Examples 1 and 2 containing magnesium carbonate, the increase in related substances was clearly suppressed. In particular, the effect of improving the stability under high humidity conditions was great. Further, the effect of improving the stability was the same whether magnesium carbonate was added as a powder during granulation or dispersed in a binder solution.

Examples 3 and 4: Examples in which the amount of magnesium carbonate was varied In order to investigate the effect of the amount of magnesium carbonate on stability improvement, each of Examples 3 and 4 was 1 mg / tablet and 10 mg / tablet, respectively. A formulation was prepared.
In Example 3, 467.3 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 3.6 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 375.2 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. To this, 18.0 g of corn starch and 0.27 g of sucrose fatty acid ester were dispersed in 581.7 g of purified water, and 242.7 g of paste liquid obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 4, 434.9 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 36.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 375.2 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. This was sprayed and granulated with 242.7 g of the paste prepared in Example 3. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.

  After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 5, as compared with Comparative Example 4, even when the compounding amount of magnesium carbonate was 1 mg / tablet (Example 3), an increase in related substances was suppressed. In particular, the effect of improving the stability under high humidity conditions was great.

Comparative Example 5, Example 5: Example in which L-arginine was used in combination with calcium silicate The stability was compared using calcium silicate as the fluidizing agent and L-arginine as the alkaline additive.
Comparative Example 5 was prepared by mixing 473.8 g of D-mannitol and 8.6 g of calcium silicate (made by Tomita Pharmaceutical Co., Ltd., FLORITE (registered trademark) RE), pulverizing with a pin mill, and weighing 375.2 g. 14.0 g, 31.9 g of low-substituted hydroxypropyl cellulose, and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. To this, 33.0 g of corn starch and 0.51 g of sucrose fatty acid ester were dispersed in 1066.5 g of purified water, and 242.7 g of paste solution obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 5, 1253.3 g of D-mannitol, 23.8 g of calcium silicate, and 49.5 g of crospovidone were mixed and then ground by a pin mill, and 412.7 g was weighed. This was put into a fluidized bed granulator, and 385.0 g of an aqueous solution obtained by dissolving 18.0 g of L-arginine (manufactured by Wako Pure Chemical Industries, Ltd., reagent grade) in 432.0 g of purified water was sprayed. Olanzapine 14.0 g and low-substituted hydroxypropylcellulose 31.9 g were mixed with 389.2 g of the obtained powder and charged into a fluidized bed granulator. To this, 25.5 g of corn starch and 0.39 g of sucrose fatty acid ester were dispersed in 824.1 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.

  After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 6, compared to Comparative Example 5, Example 5 containing L-arginine inhibited the increase in related substances. In particular, the effect of improving stability under airtight conditions was great.

Examples 6 to 7: Examples in which L-arginine was used in combination with light anhydrous silicic acid, light anhydrous silicic acid was used as a fluidizing agent, and L-arginine in an amount smaller than that in Example 5 was used as an alkaline additive, and the stability was compared. .
In Example 6, after mixing D-mannitol (859.3 g) and light anhydrous silicic acid (21.1 g) and pulverizing with a pin mill, 373.5 g was weighed, to which olanzapine (14.0 g), low-substituted hydroxypropylcellulose 31. 9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this solution, 9.6 g of corn starch, 0.15 g of sucrose fatty acid ester and 0.7 g of L-arginine were dispersed in 310.0 g of purified water, and granulated by spraying 242.7 g of paste obtained by heating. . 6.0 g of magnesium stearate was mixed with 394.0 g of the obtained granulated product, and then tableted with a rotary tableting machine.
In Example 7, 373.0 g of the pulverized product of D-mannitol and light anhydrous silicic acid obtained in Example 6 was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropyl cellulose, and crospovidone 14. 0 g was mixed and charged into a fluidized bed granulator. In this, 9.6 g of corn starch, 0.15 g of sucrose fatty acid ester and 1.5 g of L-arginine are dispersed in 309.0 g of purified water, and 242.7 g of paste obtained by heating is sprayed and granulated. . 6.0 g of magnesium stearate was mixed with 394.0 g of the obtained granulated product, and then tableted with a rotary tableting machine.

  After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 7, as compared with Comparative Example 4, Examples 6 to 7 in which a small amount of L-arginine was blended suppressed the increase in related substances.

Examples 8 to 11: Examples in which magnesium carbonate and L-arginine were used in combination with light anhydrous silicic acid, light anhydrous silicic acid was used in combination with a fluidizing agent, and magnesium carbonate and L-arginine were used in combination in an alkaline additive, and the stability was compared.
In Example 8, 452.2 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and then 374.6 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this solution, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 0.92 g of L-arginine were dispersed in 386.9 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. . The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 9, 451.4 g of D-mannitol, 11.5 g of light anhydrous silicic acid, and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 374.1 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this solution, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 1.8 g of L-arginine were dispersed in 386.0 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. . The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 10, 45.7 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 373.5 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 2.8 g of L-arginine were dispersed in 385.0 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. . The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 11, 449.3 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and then 372.4 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. To this, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 4.6 g of L-arginine were dispersed in 383.2 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. . The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.

  After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 8, in Examples 8 to 11 in which L-arginine was used in combination with Example 2 in which only magnesium carbonate was added, an increase in related substances was suppressed as the amount of L-arginine was increased. It was.

Comparative Example 6, Example 12: Example in which L-arginine is used in combination with crystalline cellulose Stability was compared using crystalline cellulose as the fluidizing agent and L-arginine as the alkaline additive.
Comparative Example 6 was prepared by mixing 693.8 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech, Mannit C) and 94.1 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corp., Theolas (registered trademark) UF711), and sieving with a JP 30 sieve. Thereafter, 372.4 g was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose, and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. 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. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 12, the same powder component as in Comparative Example 6 was put into a fluidized bed granulator, and 16.8 g of corn starch and 6.5 g of L-arginine (Ajinomoto Co.) were dispersed in 536.7 g of purified water and heated. Then, 242.7 g of the paste liquid obtained was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.

  After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 9, compared to Comparative Example 6, Example 12 containing L-arginine suppressed the increase in related substances.

Comparative Example 7 and Example 13: Crystalline cellulose / carmellose sodium combined with L-arginine Crystalline cellulose / carmellose sodium was used as the fluidizing agent, and L-arginine was used as the alkaline additive, and the stability was compared.
Comparative Example 7 and Example 13 have the same formulation and manufacturing method as in Table 8, except that the crystalline cellulose was replaced with crystalline cellulose / carmellose sodium (produced by Asahi Kasei Chemicals, Theolas RC-A591NF) as compared with Comparative Example 6 and Example 12. A formulation was obtained.

  After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 10, compared to Comparative Example 7, Example 13 containing L-arginine suppressed the increase in related substances.

Comparative Example 8, Example 14: Example in which L-arginine was used in combination with aluminum silicate Aluminum silicate was used as the fluidizing agent and L-arginine was used as the alkaline additive, and the stability was compared.
In Comparative Example 8, 769.1 g of D-mannitol (Mannit C) and 18.8 g of aluminum silicate (manufactured by Wako Pure Chemical Industries, Ltd., reagent) were mixed, and after sieving with JP30 sieve, 375.2 g was weighed. To this, 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose, and 14.0 g of crospovidone were mixed and put into a fluidized bed granulator. 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. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 14, the same powder component as in Comparative Example 8 was charged into a fluidized bed granulator, and 16.8 g of corn starch and 6.5 g of L-arginine (manufactured by Ajinomoto) were dispersed in 536.7 g of purified water and heated. Then, 242.7 g of the paste liquid obtained was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.

  After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 11, compared to Comparative Example 8, in Example 14 in which L-arginine was blended, the increase in related substances was significantly suppressed.

Comparative Example 9, Example 15: Example in which L-arginine was used in combination with talc Stability was compared using talc as the fluidizing agent and L-arginine as the alkaline additive.
Comparative Example 9 and Example 15 were the same as those in Comparative Example 8 and Example 14 except that aluminum silicate was replaced with talc (manufactured by Matsumura Sangyo, High Filler (registered trademark) # 17) as shown in Table 10. The preparation was obtained by the manufacturing method.

  After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 12, compared to Comparative Example 9, Example 15 containing L-arginine suppressed the increase in related substances.

Comparative Example 10 and Examples 16 to 17: Examples of using light anhydrous silicic acid in combination with magnesium oxide or sodium polyphosphate Light anhydrous silicic acid as a fluidizing agent, magnesium oxide (Example 16) or sodium polyphosphate as an alkaline additive ( Example 17) was used to compare the stability.
In Comparative Example 10, 384.6 g of D-mannitol (Mannit C) and 9.4 g of light anhydrous silicic acid were mixed, and after sieving with JP 30 sieve, 375.2 g was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. To this, 24.0 g of corn starch was dispersed in 776.0 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 16, 369.9 g of D-mannitol (Mannit C), 9.4 g of light anhydrous silicic acid, and 14.7 g of magnesium oxide (made by Wako Pure Chemical Industries, Ltd., reagent grade) were mixed, and then sieved with a JP 30 sieve. Thereafter, 375.2 g was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose, and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. This was sprayed and granulated with 242.7 g of the paste prepared in Comparative Example 10. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
Example 17 was prepared by mixing 369.9 g of D-mannitol (Mannit C) and 9.4 g of light anhydrous silicic acid, and then sieving it with a JP 30 sieve, and weighing 361.2 g, to which 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. To this, 299.6 g of purified water is sprayed with 242.7 g of paste obtained by dispersing 9.6 g of corn starch and 18.5 g of sodium polyphosphate (manufactured by Wako Pure Chemical Industries, Ltd., food additive) and heating. Grained. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.

  After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 13, as compared with Comparative Example 10, the increase in the related substances was suppressed in both Example 16 in which magnesium oxide was blended and Example 17 in which sodium polyphosphate was blended. In particular, the effect of improving the stability under high humidity conditions was great.

  Since olanzapine increases the number of related substances even when irradiated with light due to the coexistence of a fluidizing agent, the photostability test (tester: manufactured by Nagano Science Co., Ltd., LTL-200AS-14WC) was conducted on the preparations of Comparative Example 4 and Examples 8-11. went. The preparation was stored in an open petri dish and irradiated at 25 ° C. with a white lamp until 5000 lux / hour and a total illumination of 1.2 million lux · hr. The results of measuring related substances after irradiation are shown in FIG. As in Examples 8 to 11, the amount of related substances was suppressed as the combined amount of L-arginine was increased as compared with Comparative Example 4.

  According to the present invention, by adding an alkaline additive to the olanzapine pharmaceutical composition that is destabilized by a fluidizing agent, an increase in related substances due to heat, humidity, and light irradiation can be suppressed. It is possible to provide an oral preparation of olanzapine including an orally disintegrating tablet which can be produced by the method and is excellent in stability and physical quality.

Claims (6)

An oral formulation of olanzapine containing a fluidizing agent and an alkaline substance , and the increase in the olanzapine related substances over time caused by the destabilization of olanzapine accompanying the blending of the fluidizing agent is suppressed by the addition of the alkaline substance. And an oral preparation containing at least L-arginine as an alkaline substance . The oral preparation according to claim 1, further comprising magnesium carbonate as an alkaline substance. The oral preparation according to claim 1 or 2 , wherein the fluidizing agent is a silica-based fluidizing agent or a fluidizing agent containing crystalline cellulose. Fluidizing agent light anhydrous silicic acid silica, hydrous silicon dioxide, calcium silicate, magnesium aluminometasilicate, is at least one selected from synthetic aluminum silicate and talc, oral formulation of claim 3, wherein. The oral preparation according to claim 3 , wherein the fluidizing agent containing crystalline cellulose is at least one selected from crystalline cellulose and crystalline cellulose / carmellose sodium. The oral preparation according to any one of claims 1 to 5 , wherein the oral preparation is an orally disintegrating tablet.