WO1997039752A1

WO1997039752A1 - Sertindole preparation and process for the production thereof

Info

Publication number: WO1997039752A1
Application number: PCT/JP1997/001404
Authority: WO
Inventors: Eizou Wakamiya; Yoshikazu Suzuki; Toshihiro Ogura; Hitoshi Kadota; Toshiro Fujii
Original assignee: Shionogi & Co., Ltd.
Priority date: 1996-04-24
Filing date: 1997-04-23
Publication date: 1997-10-30
Also published as: ZA973433B; AU2405097A; AR006816A1

Abstract

An extremely light-stable sertindole preparation having a coating containing titanium oxide as a light-screening agent, which coating may further contain talc to protect the preparation from discoloration due to titanium oxide. The production of the preparation involves the step of coating a mixed powder, uncoated granules or uncoated tablets containing sertindole and one or more additives with a coating composition comprising titanium oxide and, if necessary, talc.

Description

Description Sertindole-containing preparation and method for producing the same

The present invention relates to a sertindole preparation having high stability to light, and a method for producing the preparation. Background art

Sertindole (Compound name: 5-chloro (4-fluorophenyl) -3- [1- (2-oxoimidazolidin-1-ylethyl) -4-piperidyl] -1H-indole; Described in No. 236 764: International common name (INN): 1- [2- [4- [5-Chloro- (P-fluorophenyl) indole-3-yl] piperidino] ethyl]- 2-imidazolidinone) has both anti-dopamine and anti-serotonin effects and is used as a treatment for schizophrenia. Sertindole is effective in reducing both the positive symptoms of schizophrenia (such as hallucinations and delusions) and the negative symptoms (such as autism, emotions and dementia) even when used in relatively small doses. Have. In addition, sertindole has fewer extrapyramidal side effects such as movement disorders found when using conventional schizophrenia drugs. Japanese Patent Application Laid-Open No. 236 764 describes a sertindole tablet containing lactose and the like. However, the present inventors have found that such conventional sertindole preparations are unstable to light and are hardly practical. Therefore, in order to provide higher quality sertindol preparations, it is necessary to develop a method for stably storing sertindole.

Examples of methods for stably storing a drug that is unstable to light include a method of storing a drug product in a light-shielding bottle, a method of packaging with aluminum foil, and a method of using a packaging material containing an ultraviolet absorber. Is mentioned. However, today ’s drug distribution system and Considering the dispensing work with other drugs in hospitals, these conventional methods are not preferred. Also, considering the stability of the packaged product after the patient has opened it, these conventional methods are not preferable. Disclosure of the invention

An object of the present invention is to provide a sertindole preparation having high stability to light.

The sertindole preparation of the present invention is coated with a skin containing titanium oxide.

In a preferred embodiment, the sertindole preparation of the present invention is a fine granule or a granule.

In another preferred embodiment, the sertindole formulation of the invention is a tablet. In still another preferred embodiment, the sertindole preparation of the present invention is a forcepsell containing the fine granules or granules of the present invention.

In a preferred embodiment, the sertindole formulation of the present invention comprises sertindole

About 2 to about 200 parts by weight of titanium oxide is contained per 100 parts by weight. Preferably, the formulation contains about 0.5 to about 50 parts by weight of titanium oxide per 100 parts by weight of the coating.

In another preferred embodiment, the coating further contains lactose.

In still another preferred embodiment, the coating further contains talc. Preferably, the formulation contains about 20 to about 200 parts by weight per 100 parts by weight of titanium oxide.

In the method for producing a sertindole preparation of the present invention, a step of coating either a mixed powder containing sertindole and an additive, raw granules or uncoated tablets with a coating composition containing titanium oxide Is included.

In a preferred embodiment, the coating composition comprises Sertindole 100 It contains about 2 to about 200 parts by weight of titanium oxide per part by weight.

In another preferred embodiment, the coating composition further comprises lactose.

In yet another preferred embodiment, the coating composition further comprises a bulk.

In another preferred embodiment, in the production method of the present invention, the sertindol preparation is a fine granule, and the production method comprises mixing a mixed powder containing sertindole and lactose with titanium oxide. Coating with the contained coating composition.

In a preferred embodiment, the powder mixture contains lactose with a particle size of about 10 wm to about 250. BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors have studied the wavelength region of light that affects the degradation of sertindole using a diffraction grating type irradiation spectroscope. As a result, it was found that sertindole was decomposed by light having a wavelength in the ultraviolet region of 350 nm or less, resulting in coloring and a slight decrease in sertindole content.

Based on the above findings, the present inventors attempted to package a sertindole preparation using an ultraviolet ray blocking material. Specifically, Sertindole tablets were packaged in a polyvinyl chloride packaging material containing an ultraviolet absorber such as a salicylic acid derivative, a benzophenone compound, or a benzotriazole compound. However, when a pocket for storing tablets is formed in such a polyvinyl chloride sheet, the stretched portion of the sheet becomes thinner, and the effect of improving the storage stability of tablets by this method is slight. Met. As described above, it was difficult to sufficiently improve the stability of sertindole to light only by packaging the sertindole preparation with the ultraviolet shielding material.

Next, the present inventors studied to impart light-shielding properties to the sertindole preparation itself. Debated. As a result, the present inventors have found that by coating a certindole preparation with a skin containing titanium oxide as a light-shielding agent, sertindole can be stably stored against light, and the present invention has been achieved. It was completed.

The titanium oxide used in the present invention may be any of a crystal type such as a rutile type and an analog type, and the grain size is not particularly limited. Titanium oxide is incorporated into the preparation at a ratio of about 2 to about 200 parts by weight, preferably about 5 to about 100 parts by weight per 100 parts by weight of sertindole.

The sertindole preparation of the present invention can be a fine granule, granule, tablet or capsule. The definition of each dosage form and each excipient used in this specification basically follows the definition of the Japanese Pharmacopoeia, Twelfth Edition. Hereinafter, the present invention will be described in detail for each dosage form. Fine Granules>

Fine granules are preparations that generally pass 10% or less of the total amount through a No. 200 (75 m) sieve. The fine granules of the present invention are usually produced by a fluidized-bed granulation method. Specifically, the mixed powder of sertindole and additives is sieved, and if necessary, granulated with a fluidized bed granulator using lactose nuclei. Clearly, the particles of the mixed powder are coated with particles of the mixed powder using a suspension of titanium oxide (ie, a coating composition) to form a coating on each particle. After the obtained particles are dried and classified, the fine granules of the present invention can be obtained.

Examples of the additives that can be contained in the above-mentioned powder mixture include excipients and binders. As an excipient, lactose, corn starch and the like can be used. As the binder, hydroxybutyl pill cellulose (HPC) is preferably used. Still other commonly used additives may be used.

The above-mentioned coating composition may preferably be an aqueous lactose solution in which titanium oxide is dispersed. A certain amount of light-shielding properties can be obtained even by coating using a heat-dissolved lactose aqueous solution containing no titanium oxide together with a binder. However, according to the present invention, the use of titanium oxide reduces lactose coverage, Light shielding properties can be obtained. In the case of fine granules, the addition amount of titanium oxide is preferably about 10 to about 200 parts by weight, more preferably about 40 to about 100 parts by weight, based on 100 parts by weight of sertindole. . In particular, when about 80 parts by weight or more of titanium oxide is added, the light stability of the obtained fine granules becomes almost perfect. If the coating composition comprises lactose, the lactose content is preferably from about 30 to about 80%, preferably from about 40 to about 70% by weight, based on the total weight of the granule.

The titanium oxide is added for the purpose of preventing photodegradation of sertindole contained in the preparation and accompanying yellowing and reduction of sertindole content. However, as the amount of titanium oxide added increased, the resulting fine granules tended to turn blue-gray due to the dawn. In order to prevent this blue-gray coloring, it is preferable to add talc to the coating composition. The amount of talc is preferably about 20 to about 200 parts by weight, more preferably about 50 to about 100 parts by weight, based on 100 parts by weight of titanium oxide. In particular, by adding about 50 parts by weight or more of talc, discoloration due to titanium oxide in the obtained fine granules can be substantially suppressed. As described above, when the coating composition contains titanium oxide, the light stability of the fine granules can be improved. In addition, the use of titanium oxide can reduce the total amount of coating, thereby reducing the time required for granulation. The granulation time can be further reduced by coarsening the particles of the excipient (eg, lactose) contained in the powder mixture.

The coating composition may further include pharmaceutically acceptable additives such as a plasticizer, a coloring agent, a lubricant, and the like, if necessary.

The granules of the present invention may be in any shape such as a sphere, a column, and an irregular shape. The particle size can be any commonly used particle size (eg, about 0.4 to about 2.0 mm in diameter). The granules of the present invention are usually prepared by preparing elementary granules containing sertindole and additives, and then preparing a suspension in which titanium oxide is dispersed (ie, a coating composition). It is obtained by coating granules to form a coating.

Raw granules are usually produced by extrusion granulation (using a columnar granule manufacturing device, etc.), crushing granulation, tumbling granulation, fluidized bed granulation, and the like.

Examples of additives that can be contained in the elementary granules include excipients and binders. As the excipient, sucrose, lactose, mannitol and the like can be used. As the binder, hydroxypropylcellulose (HPC), pregelatinized starch and the like can be used. Still other commonly used additives may be used.

The elementary granules prepared as described above are coated with a coating composition containing titanium oxide.

— Forms a skin containing titanium oxide. Coating may be performed by a fluidized bed type coating apparatus. In order to obtain the desired light stability, the coating amount is about 2 to about 20 parts by weight (in a dry state), preferably about 5 to about 10 parts by weight, based on 100 parts by weight of the raw granules. The addition amount of titanium oxide is preferably about 5 to about 50 parts by weight, more preferably about 10 parts by weight, based on 100 parts by weight of sertindole.

About 30 parts by weight.

The coating composition may contain a water-soluble polymer in addition to titanium oxide. Water-soluble polymers can be used for film formation. As the water-soluble polymer, hydroxypropyl methylcellulose (HPMC), hydroxybutyral cellulose (HPC), polyvinylpyrrolidone (PVP) and the like can be used. The addition amount of the water-soluble polymer is about 1 to about 100 parts by weight, preferably about 10 to about 50 parts by weight, based on 10 parts by weight of titanium oxide. The coating composition may preferably further contain talc. As in the case of the fine granules, by adding talc to the coating composition, the discoloration of the granules to blue-grey due to the exposure of the titanium oxide can be suppressed. The amount of talc added is preferably about 50 to about 200 parts by weight, more preferably about 80 to about 150 parts by weight, based on 100 parts by weight of titanium oxide.

The coating composition may further include pharmaceutically acceptable additives such as a plasticizer, a coloring agent, a lubricant, and the like, if necessary. Pills>

The tablet of the present invention can be obtained by preparing an uncoated tablet containing sertindole. Then coating the uncoated tablet with a suspension in which titanium oxide is dispersed to form a coating.

For uncoated tablets containing sertindole, a mixed powder is prepared by adding pharmaceutically acceptable excipients such as excipients, disintegrants, binders, and lubricants to sertindole. After preparing granules from the mixed powder of the lever, the mixed powder or granules are tableted according to a conventional method. When tableting granules prepared from the mixed powder, a lubricant is usually added after preparing the granules. Uncoated tablets can be manufactured by appropriately using conventional equipment such as a commonly used mixer, kneader, granulator, fluidized bed granulator, and tableting machine.

As the excipient, lactose, corn starch and the like can be used. As the disintegrant, calcium carboxymethylcellulose and the like can be used. Hydroxypropylcellulose can be used as the binder. Magnesium stearate can be used as the lubricant.

The uncoated tablet prepared as described above is coated with a coating composition containing titanium oxide to form a coating containing titanium oxide. Coating can be performed by a conventional pan-type coating machine, a ventilation type coating machine or the like. In order to obtain the desired light stability, the coating amount is about 0.5 to about 10 parts by weight (preferably in a dry state), preferably about 1 to about 5 parts by weight per 100 parts by weight of the element. The amount of titanium oxide to be added is preferably about 2 to about 50 parts by weight, more preferably about 10 to about 30 parts by weight, based on 100 parts by weight of sertindole.

The coating composition may contain a water-soluble polymer in addition to titanium oxide. Water-soluble polymers can be used for film formation. As the water-soluble polymer, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC :), polyvinylpyrrolidone (PVP) and the like can be used. The amount of water-soluble polymer It is about 1 to about 100 parts by weight, preferably about 10 to about 50 parts by weight, based on 10 parts by weight of the evening water. The coating composition may preferably further contain talc. By adding talc to the coating composition, discoloration of the tablet to blue-gray due to exposure to titanium oxide can be suppressed. The amount of talc added is, for example, about 20 to about 100 parts by weight, preferably about 50 to about 80 parts by weight, based on 100 parts by weight of titanium oxide.

The coating composition may further contain pharmaceutically acceptable additives such as a plasticizer, a coloring agent, a lubricant and the like, if necessary.

Capsules>

Capsules containing the sertindole fine granules or granules of the present invention obtained as described above in a capsule are also within the scope of the present invention. Also, a capsule in which the capsule of the capsule itself containing titanium oxide is filled with sertindole and an additive is within the scope of the present invention.

Since the fine granules, granules, tablets, and capsules of the present invention are all provided with a light-shielding property, the preparations themselves are used as they are, or in ordinary transparent glass bottle or plastic bottle packaging. Can be stored stably. Fine granules or granules can also be applied to a strip package (SP package) made of polyethylene-mixed fan mix. Tablets or capsules can also be packaged in blister overnight in vinyl chloride packaging.

Thus, according to the present invention, it is possible to impart light-shielding properties to the sertindole preparation itself, and as a result, high storage stability of sertindole can be obtained. In particular, it has been conventionally difficult to form a light-shielding coating in the production of fine granules, but the present invention has made it possible to easily form a coating with high light-shielding properties. . Example

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

<Preparation of fine granules> (Example 1)

A mixture of 5 g of sertindole, 266 g of lactose powder, 15 g of corn starch, and 5 g of hydroxypropylcellulose is charged into a small fluidized bed granulator (UNIGRAD), and 2D0 g of lactose, titanium oxide (T i 0 ₂ ) Spray coating granulation was performed using a 45% by weight aqueous solution containing 4 g and 4 g of talc as a coating composition to obtain a white fine granule. To the obtained fine granules, 2% by weight of light caustic anhydride (Carplex 67, Shionogi) was mixed as an antistatic agent. Table 1 shows the composition of the obtained fine granules.

(Example 2)

A white fine granule was produced in the same manner as in Example 1 except that talc was removed from the coating composition used in Example 1.

(Example 3)

Small flow of 5 g of sertindole, 133 g of DMV lactose 100 with a large particle size as lactose nucleus (average particle size 150 / zm) 133 g, lactose powder 133 g, 15 g of corn starch, and 5 g of hydroxypropyl cellulose A 45% by weight aqueous solution containing 200 g of lactose, 4 g of titanium oxide, and 4 g of talc was coated as a coating composition by spray coating granulation into a layer granulator (Unigrad), and white fine granules were obtained. Obtained. To the obtained fine granules, 0.2% by weight of light gay anhydride (Carbex 67, Shionogi) was mixed as an antistatic agent.

(Comparative Example 1)

A white fine granule was produced in the same manner as in Example 1 except that titanium oxide and talc were removed from the coating composition used in Example 1.

(Comparative Example 2)

Without coating granulation, white fine granules were produced by the extrusion granulation method with the composition shown in Table 1. The equipment and conditions used in each step at this time are shown below.

Mouth size:; iQO g X 3

Sieve of mixed powder: 60 mesh Mixed to kneaded brabender

Granulation Laboratory cylindrical granulator (Cylinder diameter: 0.45mm)

Drying Ventilation dryer

Granulated 30 mesh sieve

Classification Low tap shaker

table 1

(Unit: parts by weight)

The fine granules obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were exposed to light (cumulative irradiation amount was 120 × 10 ⁴ lux 'hours), the residual ratio of sertindole (%), and the exposure The color difference (ΔΕ) of the fine particles due to 'was measured, and the change in the appearance of the fine particles was also visually observed. Table 2

As is evident from Table 2, it was found that the formation of the skin containing titanium oxide almost inhibited the photodegradation of sertindole and provided a high content retention rate (%). The addition of talc suppressed discoloration.

Preparation of mush granules>

(Example 4)

Sugar spherical granules (Non-barrel 101, Freund Sangyo) Charge 2 kg into a tumbling fluidized bed, and spray a mixed powder of 300 g of sertindole and 600 g of mannitol, and apply a 10% by weight aqueous solution of hydroxypropyl cellulose. Rolling granulation was performed by spraying 1 kg. Next, the obtained granules were dried to obtain spherical elementary granules containing 10% by weight of sertindole.

A 5% by weight aqueous coating solution containing 240 g of hydroxymethyl propyl methylcellulose, 24 g of Macrogol 6000, 80 g of titanium oxide (Freund Corporation, rutile type), and 100 g of talc was applied to a Worth Yuichi type fluidized bed. 100 parts by weight of the above granules were coated in a dry state with 8 parts by weight using a mixing machine.Table 3 below shows the compositions of the components used.

Table 3

(Unit: parts by weight)

The obtained granules were packed in SP and irradiated with a fluorescent lamp (cumulative irradiation amount: 336 × 10 lex-hours). As a result, no decrease in the content of sertindole and no change in appearance of the packed granules were observed.

Preparation of pill tablets>

(Example 5)

To 0.5 kg of sertindole, 8.0 kg of lactose, 6.0 kg of corn starch, and 5 kg of low-substituted 'hydroxypropylcellulose (L-HPC) O.5 kg as disintegrant were added to prepare a powder, to which polyvinylpyrrolidone was added. 3.5 kg of a 15% aqueous solution of (PVP) was sprayed to perform fluidized bed granulation. After drying, 1 part by weight of magnesium stearate (lubricant) was mixed with 100 parts by weight of the obtained granules, and the mixture was compressed into tablets to obtain uncoated tablets (φ7.0 mardal, 157 mg 锭). Contains 5 sertindole per tablet).

A 10% aqueous coating solution containing 240 g of hydroxypropyl methylcellulose, 24 g of Macrogol 6000, 80 g of titanium oxide (Freund Corporation, Lutheran type), and 0.01 g of red No. 3 aluminum lake pigment was applied to Hiko Co., Ltd. The above uncoated tablets were coated with 4 mgZ tablets in a dry state using I (Future Int Industry). Table 4

(Unit: parts by weight)

The obtained tablets were irradiated with a fluorescent lamp (cumulative irradiation amount: 336 lux 'hours) in an unpackaged state in the same manner as in Example 4. As a result, no decrease in the content of sertindole and no change in appearance of the tablet were observed.

(Comparative Example 3)

The uncoated tablets prepared in Example 5 were coated with an ultraviolet absorber (benzotriazo B) in blister-type packaging. The tablets of Example 5 (after coating) and the blister-packed uncoated tablets were irradiated with a fluorescent lamp (cumulative irradiation amount of 336 × 10 lex's) in the same manner as in Example 4. As a result, in the packaged product, the content of certindole was reduced and the appearance change of the tablet was slightly improved. On the other hand, the preparation of the present invention showed remarkable photostability even in an unpackaged state. Industrial applicability

According to the present invention, a sertindole preparation having high storage stability against light is provided. The sertindole preparation of the present invention has a small decrease in the content during storage and little discoloration due to exposure to light.

Claims

The scope of the claims

1. Sertindole preparation coated with a skin containing titanium oxide.

2. The sertindole preparation according to claim 1, which is a fine granule or a granule.

3. The sertindole preparation according to claim 1, which is a tablet.

4. A sertindole preparation which is a capsule containing the fine granules or granules according to claim 2.

5. The sertindole preparation according to claim 1, wherein the titanium oxide is contained in a ratio of about 2 to about 200 parts by weight based on 100 parts by weight of sertindole.

6. The sertindole preparation according to claim 1, wherein the titanium oxide is contained in a ratio of about 0.5 to about 50 parts by weight based on 100 parts by weight of the skin.

7. The sertindole preparation according to claim 1, wherein the skin further contains lactose.

8. The sertindole preparation according to claim 1, wherein the skin further contains talc.

9. The sertindole preparation according to claim 8, wherein the talc is contained in a ratio of about 20 to about 200 parts by weight based on 100 parts by weight of titanium oxide.

10. A method for producing a sertindole preparation, which comprises a step of coating any of mixed powder, elementary granules, or uncoated tablets containing sertindole and additives with a coating composition containing titanium oxide. .

11. The method according to claim 10, wherein the titanium oxide is contained in the coating composition in a ratio of about 2 to about 200 parts by weight per 100 parts by weight of sertindole.

12. The method of claim 10, wherein said coating composition further comprises lactose.

13. The method of claim 10, wherein the coating composition further comprises talc. Manufacturing method.

14. The sertindole formulation is a 'fine granule' and comprises the step of coating a mixed powder containing sertindole and lactose with a coating composition containing titanium oxide. The production method described in 1.

15. The production method according to claim 14, wherein the particle size of lactose contained in the mixed powder is about 10 m to about 250 Aim.