JP5563371B2 - Oral tablets containing quetiapine fumarate - Google Patents

Description

  The present invention relates to an oral tablet for quetiapine fumarate and a method for producing the same.

Quetiapine is the chemical name 2- [2- (4-dibenzo [b, f] [1,4] thiazepin-11-yl-1-piperazinyl) ethoxy] -ethanol, which is a dibenzothiazepine-based anti-antigen. Used as a psychiatric drug. Quetiapine antagonizes several neurotransmitter receptors, including dopamine D ₁ and D ₂ receptors, serotonin 5HT _A1 and 5HT ₂ receptors, histamine H ₁ receptors, and adrenergic α ₁ and α ₂ receptors. Acts as a medicine. Quetiapine is considered to exert an effect as an antipsychotic drug mainly through antagonism of dopamine D ₂ receptor and serotonin 5HT ₂ receptor.
Currently, quetiapine and its salts, particularly quetiapine fumarate, are used as therapeutic agents for schizophrenia and bipolar mania.

Quetiapine fumarate is known as a poorly dispersed drug. When an oral solid preparation containing a poorly dispersed drug is introduced into the dissolution test solution, dissolution of the drug substance is inhibited by the change in the properties of the drug substance itself or crystal mutation, and the dissolution occurs due to aggregation and retention at the bottom of the dissolution test beaker. It is known that a defect may occur (Patent Document 1).
As a method for improving the dispersibility of a preparation containing such poorly dispersed drug, conventionally, by adding a large amount of a diluent to the preparation, the drug content with respect to the total amount of the preparation is reduced, resulting in property change or crystal mutation. Methods have been mainly taken to mitigate collapse inhibition.
However, in the method of blending a large amount of diluent, there are problems that the shape of the tablet becomes large and difficult to take, and the dosage is increased in the case of fine granules and granules.

  In Patent Document 1, non-dispersed drug is dispersed by adding a water-insoluble cellulose such as crystalline cellulose, a floatation agent such as sodium alginate, propylene glycol alginate, tragacanth powder or xanthan gum to the poorly dispersed drug. In addition, the elution properties are improved, and the elution properties are fine-tuned by the combined use of surfactants.

JP 2005-508370 A

  An object of the present invention is to improve the dissolution properties of quetiapine fumarate in an oral tablet containing quetiapine fumarate without increasing the amount of diluents such as excipients.

  The present inventors diligently studied the above problems, and in preparing an oral tablet containing quetiapine fumarate, by using both sodium carboxymethyl starch and hydrous silicon dioxide as a disintegrant, It was found that the dissolution property of the tablet was remarkably improved, thereby solving the above-mentioned problems, and the present invention was completed. Furthermore, it was found that the stability of the tablet is improved by using a specific binder in combination.

That is, the present invention
(1)
A quetiapine fumarate-containing oral tablet comprising quetiapine fumarate and both sodium carboxymethyl starch and hydrous silicon dioxide as a disintegrant,
(2)
20-80% by mass of quetiapine fumarate, 5-15% by mass of both sodium carboxymethyl starch and hydrous silicon dioxide as a disintegrant, and the remainder being other pharmaceutical additives based on the total amount of uncoated tablets The quetiapine fumarate-containing oral tablet according to (1) above, wherein the mass ratio of hydrous silicon dioxide to carboxymethyl starch sodium is 100: 3 to 100: 350,
(3)
It contains 20 to 80% by mass of quetiapine fumarate, 1 to 12% by mass of sodium carboxymethyl starch, 0.1 to 10% by mass of hydrous silicon dioxide with respect to the total amount of uncoated tablets, and the remainder is used for other pharmaceuticals. An oral tablet containing quetiapine fumarate according to (1) or (2), which is an additive,
(4)
The quetiapine fumarate-containing oral tablet according to (1) above, which contains hydroxypropylcellulose as a binder as another pharmaceutical additive,
(5)
The quetiapine fumarate oral tablet according to (4) above, containing 1 to 10% by mass of hydroxypropylcellulose as a binder with respect to the total amount of uncoated tablets,

(6)
Other pharmaceutical additives include excipients, and lactose hydrate and calcium hydrogen phosphate hydrate as excipients in a total amount of 20 to 60% by mass based on the total amount of uncoated tablets The oral tablet containing quetiapine fumarate according to any one of (1) to (5) above,
(7)
A quetiapine fumarate comprising a step of mixing and granulating both quetiapine fumarate and sodium carboxymethyl starch as a disintegrant and hydrous silicon dioxide, and a step of tableting the resulting granulated product. A method for producing a salt-containing oral tablet,
(8)
In the mixing and granulating step, hydroxypropylcellulose is used as a binder, and the method for producing an oral tablet containing quetiapine fumarate according to (7) above,
(9)
(7) or (7), wherein before granulation is tableted, the granulation is further mixed with a lubricant and carboxymethyl starch sodium as a disintegrant and then tableted. A method for producing an oral tablet containing quetiapine fumarate according to (8),
About.

  The quetiapine fumarate-containing oral tablet of the present invention is a tablet having excellent dissolution properties even though it does not contain a floating agent such as crystalline cellulose. Furthermore, the quetiapine tablet of the present invention has little variation in the quetiapine fumarate content in the preparation, the content uniformity is good, the storage stability is excellent, and the tableting property of the tablet is also good. There is little variation, the tablet hardness is satisfied, and the quality is excellent.

The invention is described in more detail below. Unless otherwise specified, “%” represents mass%, “part” represents mass part, and the ratio represents mass ratio.
The oral tablet containing quetiapine fumarate of the present invention (hereinafter also referred to as the quetiapine tablet of the present invention or the tablet of the present invention) includes both quetiapine fumarate and sodium carboxymethyl starch and hydrous silicon dioxide as a disintegrant, It is characterized by containing. The balance is other pharmaceutical additives. In the present specification, the “plain tablet” means a bare tablet before coating.

The active ingredient quetiapine (2- [2- (4-dibenzo [b, f] [1,4] thiazepin-11-yl-1-piperazinyl) ethoxy] -ethanol) in the quetiapine tablet of the present invention is usually medically The quality of quetiapine used is used. In the quetiapine tablet of the present invention, quetiapine fumarate currently used for medical purposes is used as an active ingredient.
The quetiapine fumarate used in the present invention can be produced by the method described in JP-A-63-8378.
The quetiapine tablet of the present invention contains about 20 to 80%, preferably about 25 to 75%, and more preferably about 35 to 75% of quetiapine fumarate with respect to the total amount of uncoated tablets. Usually, it is manufactured as a tablet containing 25 mg, 50 mg, 100 mg or 200 mg of quetiapine equivalent per tablet. The preferable content of quetiapine fumarate with respect to the total amount of uncoated tablets in a preparation containing 25 to 200 mg of quetiapine is about 25 to 50%, more preferably about 35 to 50%.

The sodium carboxymethyl starch and hydrous silicon dioxide used as the disintegrant in the tablet of the present invention are defined in the 15th revision Japanese Pharmacopoeia, and any of those commercially available can be used.
In the tablet of the present invention, other disintegrants may be used in combination with the disintegrant other than sodium carboxymethyl starch and hydrous silicon dioxide. Examples of such disintegrants include starch, crystalline cellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose.
These other disintegrants may be used in combination as long as the effects of the present invention are achieved, but usually other disintegrants may not be used in the tablet of the present invention.

The content ratio of the total amount of sodium carboxymethyl starch and hydrous silicon dioxide as a disintegrant in the tablet of the present invention is about 5 to 50 parts, preferably about 10 to 40 parts, more preferably 100 parts of quetiapine fumarate. Is about 10 to 30 parts, more preferably about 13 to 20 parts. Further, the content ratio of the total amount of sodium carboxymethyl starch and hydrous silicon dioxide as a disintegrant to the total amount of the uncoated tablet of the present invention is usually about 5 to 20%, preferably about 5 to 15%, more preferably 5 -10%.
In the present invention, the ratio of sodium carboxymethyl starch and hydrous silicon dioxide used as a disintegrant is about 3 to 350 parts, preferably about 3 to 50 parts, more preferably about 4 to 50 parts, with respect to 100 parts of sodium carboxymethyl starch. About 20 parts, more preferably about 4-10 parts.

The content of sodium carboxymethyl starch in the tablet of the present invention is usually about 2 to 30 parts, preferably about 6 to 26 parts, and more preferably about 10 to 20 parts with respect to 100 parts of quetiapine fumarate. Moreover, the content rate with respect to the total amount of the carboxymethyl starch sodium uncoated tablet is about 1 to 12% normally, Preferably it is about 3 to 10%, More preferably, it is about 5 to 10%.
The content ratio of hydrous silicon dioxide in the tablet of the present invention is usually about 0.02 to 40 parts, preferably about 0.2 to 5 parts, more preferably 0.5 to 3 with respect to 100 parts of quetiapine fumarate. About a part. The content of hydrous silicon dioxide with respect to the total amount of uncoated tablets is usually about 0.01 to 10%, preferably about 0.1 to 5%, more preferably about 0.2 to 2%, and still more preferably 0.00. 3 to 1%.

Examples of main additives other than the disintegrant that can be used in the tablet of the present invention include binders, excipients, and lubricants, and additions that may be added as necessary. Examples of the agent include sweeteners, flavoring agents, fragrances, fluidizing agents, coloring agents and the like. Moreover, when the tablet of this invention is a coated tablet, a coating agent can be mentioned further.
As the binder, any binder usually used as a binder for tablets can be used. Examples thereof include hydroxypropyl cellulose, ethyl cellulose, methacrylic acid copolymer, gum arabic, polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose, carboxymethyl cellulose, gelatin, sucrose, glucose, tragacanth powder and sodium alginate. Preferred examples include polyvinyl pyrrolidone (PVP) and hydroxypropyl methylcellulose, and hydroxypropylmethylcellulose is more preferred.
In the tablet of the present invention, it is preferable to use hydroxypropylcellulose as the binder from the viewpoint of storage stability. In the tablet using hydroxypropyl cellulose, an increase in the impurity content of quetiapine is suppressed in a severe test as compared with a tablet using other binders such as polyvinylpyrrolidone. Hydroxypropyl cellulose used in the tablet of the present invention is defined in the 15th revision Japanese Pharmacopoeia, is water-soluble (preferably soluble in water at 20 ° C, 10% or more), and is usually marketed. Any material can be used.
As a commercial item of hydroxypropyl cellulose, for example, HPC-SSL (trade name: the same applies below) manufactured by Nippon Soda Co., Ltd. (average molecular weight 15,000-30,000), HPC-SL (average molecular weight 30,000-50) , 000) and HPC-L (average molecular weight 55,000-70,000). Of these, HPC-SSL is more preferable because it can be expected to suppress adhesion to the granulator.
In the tablet of the present invention, it is more preferable to use hydroxypropylcellulose alone as the binder.

  The content of the binder in the tablet of the present invention is usually about 2 to 25 parts, preferably about 2 to 18 parts, more preferably about 2 to 14 parts, and still more preferably 2 to 100 parts of quetiapine fumarate. About 8 parts. The same may be applied when the binder is hydroxypropylcellulose, but it is more preferably about 3 to 12 parts, most preferably 4 to 8 parts. Moreover, the content rate with respect to the total amount of the binder of the binder in the tablet of the present invention is about 1 to 10%, preferably about 1 to 7%. The same may be applied when the binder is hydroxypropylcellulose, but it is more preferably about 1 to 4%, and still more preferably about 2 to 3%.

  The tablet of the present invention usually contains excipients in addition to the above-mentioned disintegrants and binders, and is further commonly used in the field of pharmaceutical preparations such as fluidizing agents, lubricants and anti-aggregation agents as desired. An additive may be included.

Examples of the excipient in the tablet of the present invention include lactose, sucrose, glucose, mannitol, calcium sulfate, and calcium hydrogen phosphate. In the tablet of the present invention, it is preferable to use lactose (hydrate) or calcium hydrogen phosphate (hydrate) or both of them as an excipient, and it is more preferable to use both in combination.
The content rate of the excipient | filler in the tablet of this invention is about 20 to 60% normally with respect to the total amount of an uncoated tablet, Preferably it is about 25 to 60%. The content of the preferable excipient | filler in the tablet containing 25-200 mg of quetiapine is about 30-60%, Preferably it is about 35-60%. Moreover, the content rate of the excipient | filler with respect to 100 parts of quetiapine fumarate is about 20-220 parts normally, Preferably it is about 30-220 parts, The content of the preferable excipient | filler in the tablet containing 25-200 mg of quetiapine is 60. About 160 parts, more preferably about 80-130 parts.
When lactose and calcium hydrogen phosphate are used in combination as the excipient in the tablet of the present invention, the total of both may be the content of the excipient. Each content is about 10 to 150 parts, preferably about 20 to 125 parts of lactose per 100 parts of quetiapine fumarate, and the preferred lactose content in a tablet containing 25 to 200 mg of quetiapine is 40 to 125. About 60 parts, more preferably about 60 to 100 parts, calcium hydrogen phosphate hydrate is about 4 to 40 parts, preferably about 8 to 35 parts, and the preferred content in a tablet containing 25 to 200 mg of quetiapine is About 13 to 35 parts, more preferably about 17 to 30 parts. The content ratio of the uncoated tablet to the total amount of lactose is about 10 to 60%, preferably about 15 to 50%, and the preferable content in a tablet containing 25 to 200 mg of quetiapine is about 20 to 50%, more preferably About 30 to 43%, calcium hydrogen phosphate hydrate is about 2 to 16%, preferably about 3 to 14%, more preferably about 4 to 14%, and a preferable content in a tablet containing 25 to 200 mg of quetiapine is It is about 4 to 16%, preferably about 6 to 14%, more preferably about 8 to 12%.
The ratio of calcium hydrogen phosphate hydrate to 100 parts of lactose hydrate is preferably 20 to 40 parts.

  The lubricant in the tablet of the present invention may be appropriately selected from those usually used, such as magnesium stearate or calcium stearate. In the present invention, magnesium stearate is preferably used. When the lubricant is used, the content of the lubricant with respect to the total amount of the uncoated quetiapine tablet of the present invention is about 0.8 to 10%, preferably about 0.8 to 5%, more preferably 0.00. It is about 8 to 3.2%.

In the quetiapine tablet of the present invention, carboxymethyl starch sodium and hydrous silicon dioxide are preferably used in combination as a disintegrant, and hydroxypropylcellulose is preferably used in combination as a binder.
Therefore, the tablet composition of the present invention is exemplified as follows, including preferable cases. All are ratios with respect to the total amount of uncoated tablets.
Quetiapine fumarate: about 20 to 80%, preferably about 25 to 75%, more preferably about 35 to 75%. When 25 to 200 mg of quetiapine is contained per tablet, it is preferably about 25 to 50%, more preferably about 35 to 50%.
Sodium carboxymethyl starch: about 1 to 12%, preferably about 3 to 10%, more preferably about 5 to 10%.
Hydrous silicon dioxide: about 0.01 to 10%, preferably about 0.1 to 5%, more preferably about 0.2 to 2%, still more preferably 0.3 to 1%.
Total of both sodium carboxymethyl starch and hydrous silicon dioxide: about 5 to 20%, preferably about 5 to 15%, more preferably 5 to 10%.
Binder (preferably hydroxypropylcellulose): about 1 to 10%, preferably about 1 to 7%, more preferably about 1 to 4%, still more preferably about 2 to 3%.
Excipient: Usually about 20 to 60%, preferably about 25 to 60%. When containing 25 to 200 mg of quetiapine per tablet, it is usually about 30 to 60%, preferably about 35 to 60%.
Optional component: about 0 to 10%, preferably about 0.8 to 10%, more preferably about 0.8 to 5%, and still more preferably about 0.8 to 3.2%.
The optional component is a component other than the above-mentioned quetiapine fumarate, sodium carboxymethyl starch, hydrous silicon dioxide, binder (preferably hydroxypropylcellulose) and excipient, fluidizing agent, lubricant and agglomeration Such as an inhibitor.

The quetiapine tablet of the present invention may be used as an uncoated tablet or, if necessary, as a coated tablet (for example, a film-coated tablet) by a method such as coating an appropriate film layer on the tablet surface. You can also. Usually, the quetiapine tablet of the present invention is preferably a film-coated tablet. The coating can protect the tablet from discoloration caused by light, heat, humidity, etc., and decomposition of the drug substance, or can conceal the taste of the drug.
The coating is preferably a film coating. The film-forming component for film coating is not particularly limited as long as a film can be formed, but it is preferably composed of a composition containing a water-soluble polymer compound capable of forming a film.

  Examples of the water-soluble polymer compound include polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, hydroxyethyl cellulose, and hypromellose, among which hypromellose is preferable. The content ratio of the film forming component to the total coating component (solid component) is preferably in the range of 65 to 75%.

In film coating, in addition to the above film-forming components, for the purpose of imparting flexibility to the film, shading or coloring to prevent discoloration due to light, decomposition of the drug substance, etc., as necessary, Components such as a plasticizer, an opacifying agent and a colorant may be added to the film coating agent. In the present invention, it is preferable to include these components. Such components include polyethylene glycol (eg, polyethylene glycol 6000), plasticizers such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin and dibutyl phthalate; opacifiers such as titanium oxide; and iron sesquioxide, yellow And coloring agents such as iron sesquioxide and tar pigments. Any of them may be used in a range that achieves the purpose according to the purpose. The composition ratio of the plasticizer, the opacifying agent, and the colorant to the total amount of the coating component is not particularly limited. The agent is preferably in the range of 1 to 2%.
The usage-amount of the coating component (solid component) in the coating agent of the quetiapine tablet of this invention is the range of 1-10% with respect to the total amount of an uncoated tablet, Preferably it is the range of 2-8%.

The production method of the quetiapine tablet of the present invention will be specifically described below.
The uncoated tablet of the quetiapine tablet of the present invention is prepared by crushing the quetiapine drug substance and disintegrating agents, binders and other pharmaceutical additives (for example, excipients) in the presence or absence of an appropriate solvent. Etc.) and mixing by conventional granulation methods such as stirring granulation method, extrusion granulation method, rolling granulation method, fluidized bed granulation method, dry compression granulation method, spray drying granulation method, etc. Granules obtained by granulation, drying, and sizing as necessary are mixed with a disintegrant and a lubricant as necessary to form a tableting powder, which is then compressed using a tableting machine. Can be obtained. Then, if necessary, the coated tablet of the quetiapine tablet of the present invention can be obtained by coating the uncoated tablet.

For example, quetiapine fumarate, sodium carboxymethyl starch as a disintegrant and hydrous silicon dioxide, and other additives (excluding lubricants) are mixed evenly if necessary, and then dissolved in purified water A granulated product can be obtained by granulating with an agent (preferably hydroxypropyl cellulose) using a granulator or the like and drying.
The granulation method in the tablet production method of the present invention may be any of the above-mentioned conventional granulation methods, but in terms of tableting property, fluidity and compression moldability, fluidized bed granulation method. In addition, the stirring granulation method is preferable from the viewpoints of scale-up, ease of setting conditions, and fewer work steps.
Further, carboxymethyl starch sodium and hydrous silicon dioxide as disintegrants may be blended in this granulation step, but in the present invention, at least a part of carboxymethyl starch sodium is granulated before tableting. Tableting is preferred after mixing with the product.
Carboxymethyl starch sodium is about 40 to 70% (mass ratio: the same below), preferably about 4.5 to 60% of the total amount of carboxymethyl starch sodium contained in the uncoated tablet. It is preferable from the standpoint of elution that it is blended with the above and the rest is mixed with the granulated product before tableting.
Drying after granulation may be either drying with a granulator or drying with a shelf-type dryer, etc., and the drying time varies depending on conditions such as the drying temperature. About 20 hours. As an indication of completion of drying, it is preferable to dry until the water content of the granulated product obtained by granulation becomes 1 to 5%.

The granulated product obtained by the granulation is usually preferably sized. The sized particles are preferably sized so that the longest diameter of the sized granules is 1 mm or less, preferably 0.8 mm or less, more preferably 0.6 mm or less, and even more preferably 0.5 mm or less.
A granulated product obtained by the granulation, or a granule obtained by sizing the granulated product, a lubricant can be added and mixed uniformly to obtain a tableting powder. It is preferable to prepare a tableting powder by adding sodium carboxymethyl starch as a disintegrant and a lubricant (preferably magnesium stearate) and mixing uniformly. The addition amount of carboxymethyl starch sodium as a disintegrant in this step is 30 to 60%, preferably 4 to 5.5%, based on the total amount of carboxymethyl starch sodium as a disintegrant contained in the uncoated tablet. Degree.

  The quetiapine tablet (plain tablet) of the present invention is produced by tableting the tableting powder by a conventional method. The tableting conditions in the tableting process are not particularly limited as long as the target tablets can be obtained. Usually, the tableting pressure of the uncoated tablet is about 4 to 15 kN.

The tablet (plain tablet) of the present invention obtained above can be used as the tablet of the present invention by appropriately coating the tablet (for example, film coating) as necessary.
The film coating can be performed by a conventional method. For example, the coating component (water-soluble polymer, and, if necessary, an opacifying agent, a plasticizer, a colorant, and the like) mixed with a solvent for a coating solution composed of water and / or an organic solvent is used as a coating solution. The film-coated tablet of the present invention can be obtained by coating the quetiapine uncoated tablet of the present invention using an appropriate coating apparatus and then drying. Examples of the organic solvent include alcohols (such as methyl alcohol, ethyl alcohol, and isopropyl alcohol), ketones (such as acetone and ethyl methyl ketone), and chlorinated hydrocarbons (such as methylene chloride and dichloroethane). As the solvent for the coating solution, water or a mixed solution of water and C2-C4 alcohol such as ethyl alcohol is preferable, and a mixed solution of water and ethyl alcohol is more preferable.
As the coating apparatus, a coating pan that is usually used for coating tablets can be used. Specifically, a high coater (trade name, manufactured by Freund Sangyo Co., Ltd.), a doria coater (trade name, manufactured by Paul Wrec Co., Ltd.). And so on. Moreover, drying of the coated tablet at this time can be performed by a conventional method.
The obtained coated tablet may be polished (glazed) if desired. Polishing may be performed by a conventional method, and polishing wax such as carnauba wax may be added to polish the film-coated tablet.
Through the above steps, a coated quetiapine tablet of the present invention can be obtained.

Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.
Regarding the tablets obtained in the examples of the present invention, the hardness of the uncoated tablets is in the range of 3.0 to 7.0 kgf for tablets containing quetiapine equivalent to 25 mg per tablet, and equivalent to 100 mg per tablet. For tablets containing quetiapine, the range was 6.0-14.0 kgf. The hardness of the coated tablet is in the range of 4.0 to 8.0 kgf for tablets containing 25 mg equivalent amount of quetiapine per tablet, and 7.0 for tablets containing 100 mg equivalent amount of quetiapine per tablet. The range was 15.0 kgf. Both the uncoated tablet and the coated tablet of the present invention have preferable hardness.

Example 1
A 25 mg quetiapine tablet (plain tablet) of the present invention was produced according to the formulation and production method shown in Table 1 below.
After uniformly mixing 28.8 parts of quetiapine fumarate, 42.2 parts of lactose (200), 10.00 parts of calcium hydrogenphosphate hydrate and 10.0 parts of hydrous silicon dioxide, polyvinylpyrrolidone (PVP, average (Molecular weight 58,000, trade name: Plasdon K-29 / 32, manufactured by IS Japan Co., Ltd.) 5.0 parts of water was appropriately added and kneaded, and granulated in a mortar. After granulation, drying was performed at 60 ° C. with a shelf-type dryer, followed by sieving with a 30 mesh sieve and sizing. The 30 mesh-on product was pulverized in a mortar and then mixed with the 30 mesh pass product. To 96.00 parts of the resulting granulated product, 3.00 parts of sodium carboxymethyl starch (ROQUETTE, trade name GLYCOLYS ^RTM ) and 1.00 parts of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) were added and mixed. By doing so, a powder for tableting was obtained.
This tableting powder was tableted with a single tableting machine (multi-functional tablet machine, manufactured by Kimura Machine Seiko Co., Ltd.) under the conditions of a heel diameter of 6.0 mm and a tablet hardness of 4.0 to 6.0 kgf, and 25 mg of quetiapine. The containing tablet (plain tablet) was manufactured.

Comparative Examples 1-1 and 1-2
In the formulation of Table 1 below, in Example 1 above, instead of hydrous silicon dioxide, crospovidone (trade name: crospovidone CL-F, manufactured by BASF) and corn starch (manufactured by Nippon Food Chemical Co., Ltd.) were each used. Except for use, quetiapine tablets (uncoated tablets) of Comparative Examples 1-1 and 1-2 containing 25 mg of quetiapine were obtained by the same production method as in Example 1 above.

Test example 1
Dissolution test Take 1 quetiapine tablet obtained in Example 1 and Comparative Examples 1-1 and 1-2, and use 900 mL of Japanese Pharmacopoeia second solution (pH about 6.9) as a test solution, The dissolution test was performed at 50 revolutions per minute. Ten minutes after the start of the dissolution test, 10 mL of the eluate was taken out for measurement, and immediately supplemented with 10 mL of the test solution heated to 37 ± 0.5 ° C. The collected eluate was filtered through a membrane filter having a pore size of 0.45 μm or less. Exclude 5 mL of the first filtrate, accurately weigh 1 mL of the next filtrate, and accurately add 1 mL of water to make the sample solution.
Separately from the sample solution, the quantitative quetiapine fumarate was dried at 105 ° C. for 2 hours, 32 mg of which was accurately weighed and dissolved in methanol to make exactly 100 mL. 2 mL of this solution was accurately weighed and the above-mentioned Japanese Pharmacopoeia second solution (test solution) was added to make exactly 20 mL. A solution obtained by accurately weighing 1 mL of this solution is used as a standard solution.
A sample solution and a standard solution (10 μL each) were accurately weighed and measured by liquid chromatography under the following conditions. quetiapine n th the collected sample solution and standard solution _{(C 21 H 25 N 3 O} 2 S) the peak area of each the _{A T (n)} and _{A S,} by the following equation, when n-th sample solution taken The dissolution rate (%) of each uncoated tablet was calculated.

Formula 1

W _S : Weighed amount of quetiapine fumarate for quantification (mg)
C: Content of quetiapine (C ₂₁ H ₂₅ N ₃ O ₂ S) in 1 tablet (mg)
In this test example, W _S = 32 and C = 25.

Liquid chromatography test condition detector: UV absorption photometer (measurement wavelength 254 nm)
Column: A stainless steel tube having an inner diameter of 3 mm and a length of 10 cm was filled with octadecylsilylated silica gel for liquid chromatography having an average particle diameter of 3 μm.
Column temperature: Constant temperature around 30 ° C. Mobile phase: 1: 1 mixed solution of ammonium acetate (77 → 10000) and acetonitrile Flow rate: Adjusted so that the retention time of quetiapine was about 4 minutes.

  Table 2 shows the dissolution rate after 10 minutes in the quetiapine tablets obtained in Example 1, Comparative Example 1-1, and Comparative Example 1-2. The dissolution test was performed twice, and the dissolution rate is shown as the average value. When sodium carboxymethylcellulose and hydrous silicon dioxide were used in combination as a disintegrant, a tablet showing an excellent dissolution rate was obtained.

Example 2
A 25 mg quetiapine tablet (plain tablet) of the present invention was produced according to the formulation and production method shown in Table 3 below.
In Example 1, except that 40.0 parts of quetiapine fumarate, 36.5 parts of lactose (200), 0.50 part of hydrous silicon dioxide, and 7.0 parts of sodium carboxymethyl starch were used. Produced a powder for tableting by the same production method as in Example 1. This tableting powder is tableted using a rotary tableting machine (VELA5 manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a diameter of 5.5 mm and a tablet hardness of 3.0 to 7.0 kgf, and quetiapine tablets containing 25 mg of quetiapine. (Uncoated tablet) was obtained.

Comparative Example 2
In the formulation of Table 3 below, quetiapine containing 25 mg of quetiapine in the same manner as in Example 2 except that 37.0 parts of lactose (200) was used and no hydrous silicon dioxide was used. A tablet (uncoated tablet) was obtained.

Test example 2
Dissolution test One quetiapine tablet obtained in Example 2 and Comparative Example 2 was taken, and a dissolution test was conducted in the same manner as in Test Example 1. The test solution was collected 5, 10, 15, 30 and 60 minutes after the start of the dissolution test. From the peak area (A _{T (n)} and A _S ) of quetiapine (C ₂₁ H ₂₅ N ₃ O ₂ S) of the sample solution and the standard solution collected at the nth time at this time, in the same manner as in Test Example 1, The dissolution rate (%) of each uncoated tablet was calculated at the time of n-th sample solution collection.

  The results of the dissolution test of the quetiapine tablets obtained in Example 2 and Comparative Example 2 are shown in Table 2 and FIG. When a combination of sodium carboxymethylcellulose and hydrous silicon dioxide as a disintegrant was used, a tablet showing an excellent dissolution rate was obtained compared to the case where sodium carboxymethylcellulose was used alone.

Example 3
The 100 mg quetiapine tablet (plain tablet) of the present invention was obtained by the formulation and production method shown in Table 5 below.
Uniform mixing of 46.05 parts quetiapine fumarate, 30.45 parts lactose (200), 10.00 parts calcium hydrogen phosphate hydrate, 4.00 parts sodium carboxymethyl starch and 0.50 parts hydrous silicon dioxide did. Thereafter, water in which 5.00 parts of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., trade name HPC-L) was dissolved was appropriately added and kneaded, and fluidized bed granulator (Multiplex MP-01, Powrec Co., Ltd. Granulated and dried. Next, the mixture was sieved with a 30 mesh sieve and sized. The 30 mesh-on product was pulverized with a speed mill (32 mesh) and then mixed with the 30 mesh pass product. To 96.00 parts of the resulting granulated product, 3.00 parts of sodium carboxymethyl starch (ROQUETTE, trade name GLYCOLYS ^RTM ) and 1.00 parts of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) were added and mixed. By doing so, a powder for tableting was obtained.
The tableting powder was tableted with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a heel diameter of 8.5 mm and a tablet hardness of 6.0 to 14.0 kgf, and a tablet containing 100 mg of quetiapine ( Uncoated tablet).
The tablet showed excellent dissolution properties similar to Example 2.

Test example 3
Severe test The quetiapine tablet (plain tablet) produced in Example 3 was subjected to a severe test, and each quetiapine tablet (plain tablet) after the severe test was subjected to a purity test.
About the tablet manufactured in Example 3, immediately after production (initial), after standing for 4 weeks under constant temperature and humidity conditions of 40 ° C. and 75% RH, and after standing for 4 weeks under constant temperature condition of 60 ° C., The following purity test was performed.
Each quetiapine tablet was made into a powder, an amount corresponding to 10 mg of quetiapine was weighed, and 20 mL of a water / acetonitrile mixture (1: 1) was added and shaken. The supernatant obtained by centrifuging this solution was used as a sample solution.
10 μL of the sample solution was accurately weighed and measured by high performance liquid chromatography under the following conditions. About the sample solution, the peak area derived from the substance of Table 5 containing quetiapine fumarate and the area of the peak derived from each related substance considered to be an impurity other than those were measured by an automatic integration method.

Test condition detector: UV spectrophotometer (measurement wavelength: 254 nm)
Column: A column in which a stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was filled with octadecylsilylated silica gel for chromatography having a diameter of 5 μm was used.
Column temperature: constant temperature around 30 ° C. Mobile phase A: ammonium acetate solution (77 → 100,000)
Mobile phase B: Acetonitrile mobile phase feeding: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.
Time after injection Mobile phase A Mobile phase B
(Minutes) (vol%) (vol%)
0 to 15 80 → 40 20 → 60
15 to 25 40 → 10 60 → 90
25-30 30 90
Flow rate: 1.0 mL per minute
Area measurement range: The range after the solvent peak is approximately twice the retention time of quetiapine. Based on the obtained liquid chromatography peak area value, the total peak area of each related substance relative to the total peak area. The ratio (%) was calculated. The results are shown in Table 6 below.
In the preparation using hydroxypropylcellulose (HPC-L) as a binder, an increase in impurities after a severe test was suppressed even under wet heat conditions (40 ° C., humidity 75%).

Example 4
A 25 mg quetiapine tablet (coated tablet) of the present invention was produced by the following formulation and production method.
(1) Quetiapine fumarate 39.97 parts, lactose (200) 38.03 parts, calcium hydrogen phosphate hydrate 10.00 parts, sodium carboxymethyl starch (trade name GLYCOLYS ^RTM manufactured by ROQUETTE) 3.00 And 0.50 part of hydrous silicon dioxide were mixed uniformly, and then kneaded by adding water appropriately dissolving 2.50 parts of hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) and stirring and granulating. Granulation was performed using a machine (VG-10, manufactured by Paul Wrec Inc.). After granulation, drying was performed at 60 ° C. for 6 hours with a shelf dryer, and then sieved with a 30 mesh sieve to adjust the size. The 30 mesh-on product was pulverized with a speed mill (32 mesh) and then mixed with the 30 mesh pass product. By adding 3.00 parts of sodium carboxymethyl starch and 3.00 parts of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) to 94.00 parts of the obtained granulated product, a powder for tableting is obtained. It was.
This tableting powder was tableted with a rotary tableting machine (VELA5 manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a heel diameter of 5.5 mm and a tablet hardness of 3.0 to 7.0 kgf, and a tablet containing 25 mg of quetiapine (elementary Tablet).

(2) 68.97 parts of hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd.) was dispersed in absolute ethanol, purified water was added, and dissolved by stirring to obtain a 7.17% by mass solution of hypromellose. 14.80 parts of polyethylene glycol 6000 (trade name: Macrogol ^RTM 6000, manufactured by NOF Corporation) was stirred and dissolved in the solution. Further, 14.80 parts of titanium oxide was dispersed, and 0.86 parts of iron sesquioxide and 0.57 parts of yellow iron sesquioxide were dissolved to prepare a film coating solution.
The uncoated tablet obtained in the above (1) was put into a film coating apparatus (manufactured by Freund Sangyo Co., Ltd.) and coated with the above film coating solution. An appropriate amount of carnauba wax was added to the obtained film-coated tablet for polishing to obtain a film-coated tablet containing 25 mg of circular quetiapine having a mass of 75 mg.

Example 5
A 100 mg quetiapine tablet (coated tablet) of the present invention was produced by the following formulation and production method.
(1) Quetiapine fumarate 46.05 parts, lactose (200) 30.95 parts, calcium hydrogen phosphate hydrate 10.00 parts, sodium carboxymethyl starch (trade name GLYCOLYS ^RTM manufactured by ROQUETTE) 4.00 And 0.50 part of hydrous silicon dioxide were mixed uniformly, and then kneaded by appropriately adding water in which 2.50 parts of hydroxypropylcellulose (HPC-SSL) was dissolved, and a stirring granulator (manufactured by POWREC Co., Ltd.) , VG-10). After granulation, drying was performed at 60 ° C. for 6 hours with a shelf dryer, and then sieved with a 30 mesh sieve to adjust the size. The 30 mesh-on product was pulverized with a speed mill (32 mesh) and then mixed with the 30 mesh pass product. By adding 3.00 parts of sodium carboxymethyl starch and 3.00 parts of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) to 94.00 parts of the obtained granulated product, a powder for tableting is obtained. It was.
The tableting powder was tableted with a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a heel diameter of 8.5 mm and a tablet hardness of 6.0 to 14.0 kgf, and a tablet containing 100 mg of quetiapine ( Uncoated tablet).

(2) 68.77 parts of hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd.) was dispersed in absolute ethanol, purified water was added and dissolved by stirring to obtain a 7.17% by mass solution of hypromellose. 14.76 parts of polyethylene glycol 6000 (trade name Macrogol ^RTM 6000, manufactured by NOF Corporation) was stirred and dissolved in the solution. Further, 14.76 parts of titanium oxide was dispersed, and 1.72 parts of yellow ferric oxide was dissolved to prepare a film coating solution.
The uncoated tablet obtained in the above (1) was put into a film coating apparatus (manufactured by Freund Sangyo Co., Ltd.) and coated with the above film coating solution. An appropriate amount of carnauba wax was added to the obtained film-coated tablet for polishing to obtain a film-coated tablet containing 100 mg of circular quetiapine having a mass of 257 mg.

  According to the present invention, it is possible to provide an oral tablet containing quetiapine fumarate with improved dissolution. In addition, the uniformity of quetiapine content in the preparation is good, the quetiapine fumarate content is small in variation, the tablet moldability and tablet hardness are satisfied, and the tableting properties of the tablet are also good, It is possible to provide a quetiapine fumarate-containing oral tablet with little variation and excellent quality.

Claims (9)

The quetiapine fumarate-containing oral tablet uncoated tablet has a quetiapine fumarate salt content of 1 to 12% by weight based on the total amount of uncoated tablets and carboxymethyl starch sodium and 0.1 to 10 based on the total amount of uncoated tablets quetiapine fumarate containing tablets for oral use, characterized in that it contains by mass% moisture dioxide silicon. In Quetiapine fumarate content of the tablets for oral use uncoated weight ratio of silicon dioxide hydrate with respect carboxymethyl starch sodium, 100: 3 to 100: Quetiapine fumarate content according to 350 der Ru請 Motomeko 1 Oral tablets. The total amount of the plain tablet Quetiapine fumarate containing tablets for oral use, the content of Quetiapine fumarate is 20 to 80 wt%, for tablets quetiapine fumarate-containing oral described 請 Motomeko 1 or 2 . Quetiapine fumarate content of the tablets for oral use base tablets further hydroxypropylcellulose, lactose or a hydrate thereof and / or calcium hydrogen phosphate or a hydrate thereof of claims 1, characterized in that it comprises containing 3 Oral tablet containing quetiapine fumarate according to any one of the above. The oral tablet containing quetiapine fumarate according to any one of claims 1 to 4, wherein the oral tablet containing quetiapine fumarate is a coated tablet. The quetiapine fumarate-containing oral tablet according to claim 5, wherein the coated tablet is a film-coated tablet. Was added to quetiapine fumarate and carboxymethyl starch sodium and hydrated silicon dioxide, the step of preparing a mixture containing these components, granules a tablet that step, and the resulting granulating the mixture The manufacturing method of the tablet for oral use containing a quetiapine fumarate characterized by including the process to do. Before tableting granules, the granulated product, further Namerasawazai及Beauty carboxymethyl starch sodium, was added and mixed, according to claim 7, characterized in that the tablet A method for producing an oral tablet containing quetiapine fumarate. Adding quetiapine fumarate and hydrous silicon dioxide to produce a mixture containing these components, granulating the mixture, adding lubricant and sodium carboxymethyl starch to the granulated product And a method for producing an oral tablet containing quetiapine fumarate, comprising the step of tableting the obtained granulated product.