JP6945377B2 - Pharmaceutical tablets containing erlotinib as an active ingredient and methods for manufacturing them - Google Patents

Description

The present invention relates to a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, and which contains an amino group-modified polymer additive, and a method for producing the same.

Erlotinib is a compound having a structure represented by the general formula (1), having a chemical name of N-3- (ethynyl-phenyl) -6,7-bis- (2-methoxyethoxy) -4-quinazolineamine. ..

Elrotinib is a quinazoline derivative and is a selective tyrosine kinase inhibitor (TKI) that targets the Epidermal Growth Factor Receptor (EGFR). It is thought that by competitively antagonizing ATP at the ATP binding site of the intracellular tyrosine kinase region of EGFR, it exhibits an antitumor effect based on suppression of cancer cell growth and induction of apoptosis. It is marketed under the trade name of TARCEVA (registered trademark), and in Japan, it is unresectable recurrence / progression, non-small cell lung cancer exacerbated after cancer chemotherapy, and EGFR gene mutation positive unresectable. It has been approved as a therapeutic agent for non-small cell lung cancer that has not been treated with cancer chemotherapy and pancreatic cancer that cannot be cured and resected due to its recurrence and progression.

Pharmaceutical tablets of errotinib have been reported, and Patent Document 1 contains microcrystalline cellulose, lactose-containing water, povidone K30, sodium starch glycolate, and magnesium stearate inside the tablet, and hydroxypropyl in the coating layer outside the tablet. Thin-layer coated tablets containing methyl cellulose, polyethylene glycol 6000, starch, iron oxide (yellow), titanium oxide are described.

Japanese Patent No. 4456079

The elution of the active ingredient in pharmaceutical tablets is important for the active ingredient to fully exert its effect. A pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof, which can suppress the initial elution of the active ingredient and avoid the rapid elution of the active ingredient, is desirable.

An object of the present invention is a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, which can suppress the initial elution of the active ingredient in water and avoid the rapid elution of the active ingredient, and a method for producing the same. Is to provide.

It is common to consider changing various disintegrants as a means for solving the above-mentioned problem of suppressing the initial elution of the active ingredient in water. Disintegrants include swelling-type disintegrants such as sodium starch glycolate and croscarmellose sodium, and water-conducting disintegrants such as crospovidone, which are variously selected in order to obtain the desired elution property. However, in pharmaceutical tablets containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, the initial elution of the active ingredient in water cannot be suppressed by changing the disintegrant, that is, the rapid active ingredient in water. It was not possible to obtain a pharmaceutical tablet capable of avoiding elution.

As a result of diligent research to solve the above problems, the present inventor has obtained a pharmaceutical tablet containing erlotinib as an active ingredient or a pharmaceutically acceptable salt thereof as an active ingredient, and an amino group-modified polymer additive. The present invention has been completed by finding that it is possible to suppress the initial elution of the active ingredient in water by using a pharmaceutical tablet containing the active ingredient. That is, the gist of the present invention is the following [1] to [6].

[1] A pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient and containing an amino group-modified polymer additive.
[2] The pharmaceutical tablet according to [1], wherein the amino group-modified polymer additive is one or more selected from the group consisting of the aminoalkyl methacrylate copolymer E, the polyvinyl acetal diethylaminoacetate, and the ammonioalkyl methacrylate copolymer.
[3] The pharmaceutical tablet according to [1] or [2], wherein the amino group-modified polymer additive is dispersed inside the pharmaceutical tablet.
[4] The pharmaceutical tablet according to any one of [1] to [3], which contains 0.1% by mass or more and 7% by mass or less of an amino group-modified polymer additive.
[5] The pharmaceutical tablet according to any one of [1] to [4], wherein erlotinib or a pharmaceutically acceptable salt thereof is erlotinib hydrochloride.

[6] The method for producing a pharmaceutical tablet according to any one of [1] to [5], wherein (A) erlotinib or a pharmaceutically acceptable salt thereof, an amino group-modified polymer additive and other additives. The method for producing a pharmaceutical tablet according to any one of [1] to [5], which comprises a step of mixing the above and (B) a step of compression-molding the mixture obtained in the step (A) into tablets.

The pharmaceutical tablet containing erlotinib of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can provide a pharmaceutical tablet capable of suppressing the initial elution of the active ingredient in water. More specifically, it is possible to provide a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, which can suppress the initial elution of the active ingredient in water and avoid the rapid elution of the active ingredient. can.

The present invention is characterized in that it is a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient and containing an amino group-modifying additive. The details will be described below.

The present invention uses erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient. The chemical name for erlotinib is N-3- (ethynyl-phenyl) -6,7-bis- (2-methoxyethoxy) -4-quinazolineamine. The compound can be synthesized by the method described in JP-A-2016-104717. Erlotinib is preferably of medicinal quality.

The active ingredient of the present invention also includes a pharmaceutically acceptable salt of erlotinib. Since erlotinib is a weakly basic compound, it may be in the form of an addition salt with an appropriate acid. For example, without particular limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, tartrate acid, fumaric acid, methanesulfonic acid, 4-toluenesulfonic acid and the like can be mentioned. In the present invention, it is preferable to use erlotinib hydrochloride, and it is preferable that the quality is acceptable as a pharmaceutical product. As for the compound, A-type crystals and B-type crystals are disclosed in Japanese Patent No. 4689916, and E-type crystals are disclosed in Japanese Patent No. 4456079. Patent No. 4456079 discloses the solubility of A-type crystals, B-type crystals, and E-type crystals, and A-type crystals have the highest solubility in water among A-type crystals, B-type crystals, and E-type crystals. Is shown. The pharmaceutical tablet of the present invention is a pharmaceutical tablet in which the active ingredient is slowly released in water, and it is considered that the effect of the invention can be exhibited by using erlotinib hydrochloride containing A-type crystals having high solubility. Therefore, in the present invention, the erlotinib hydrochloride used preferably contains A-type crystalline erlotinib hydrochloride.

The pharmaceutical tablet of the present invention is characterized by containing an amino group-modified polymer additive. The present invention can be applied without particular limitation as long as it is an amino group-modified polymer additive. The amino group-modified polymer additive is preferably of a quality that is acceptable as a pharmaceutical product.

Examples of the amino group-modified polymer additive in the present specification include aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, ammonioalkyl methacrylate copolymer and the like, and aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate are preferably used. , Aminoalkyl Methacrylate Copolymer E is more preferred.
As the aminoalkyl methacrylate copolymer E, which is an amino group-modified polymer additive, a commercially available product may be used. For example, aminoalkyl methacrylate copolymers such as trade name Eudragit (registered trademark) E100 and Eudragit (registered trademark) EPO (Higuchi Shokai Co., Ltd.) can be mentioned, and it is preferable to use Eudragit (registered trademark) EPO. Further, as the polyvinyl acetal diethylaminoacetate, a commercially available product may be used. For example, the trade name AEA (Mitsubishi Chemical Foods) can be mentioned.

The present invention is in the form of a pharmaceutical tablet. The shape of the pharmaceutical tablet is not particularly limited as long as it has a normal shape and size suitable for oral administration.

The pharmaceutical tablets of the present invention include erlotinib or a pharmaceutically acceptable salt thereof and an amino group-modified polymer additive, as well as other additives usually used for preparing a pharmaceutical tablet within a range that does not interfere with the effects of the present invention. May include. For example, ordinary pharmaceutical tablet additives for preparing pharmaceutical tablets, such as disintegrants, binders, lubricants, solubilizers, excipients, concealing agents and colorants, may be used.
These additives can be used without particular limitation as long as the purity is acceptable for pharmaceutical pharmaceutical use. Only one of these additives may be used, or a mixture thereof may be used. It is optionally used when preparing the pharmaceutical tablet.

In the present invention, as the disintegrant, sodium carboxymethyl starch (sodium starch glycolate), crospovidone, carmellose, sodium carmellose, carmellose calcium, croscarmellose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, low-substitution Degree carboxymethyl starch sodium and the like can be mentioned.

Examples of the binder in the present invention include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, crystalline cellulose, corn starch, partially pregelatinized starch polyvinyl alcohol, polyvinylpyrrolidone and the like.

Examples of the lubricant in the present invention include stearic acid, magnesium stearate, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, talc, carnauba wax and the like.

In the present invention, a surfactant is used as the solubilizer, and examples thereof include sodium lauryl sulfate, soybean lecithin, purified soybean lecithin, sorbitan fatty acid ester, and lauromacrogol.

In the present invention, the excipients include lactose anhydride, lactose hydrate, maltose, mannitol, sucrose, sorbitol, xylitol, inositol and the like, which do not correspond to the above-mentioned binders, disintegrants, solubilizers and lubricants. Contains the agent.

In the present invention, the concealing agent and the colorant include titanium oxide, yellow iron oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, zinc oxide, brown iron oxide, talc, edible chlorophyll, and edible blue pigment. Examples include edible red pigments.

The amino group-modified polymer additives described herein are additives that can usually be used as coating bases. In the pharmaceutical tablet of the present invention, it is preferable that the amino group-modified polymer additive is dispersed "inside the pharmaceutical tablet".

As used herein, the term "inside a pharmaceutical tablet" refers to an uncoated tablet portion. The amino group-modified polymer additive is preferably contained in a dispersed state in the portion of the uncoated tablet.

The pharmaceutical tablet of the present invention may be film-coated. In the case of film coating, an amino group-modified polymer additive may be contained in the film-coated portion corresponding to the outside of the pharmaceutical tablet as long as the effect of the present invention is not impaired.

In the present specification, "the amino group-modified polymer additive is dispersed inside the pharmaceutical tablet" means, for example, addition of an active ingredient or other addition other than the amino group-modified polymer additive contained in the uncoated tablet. It is a state in which it is mixed with an agent. It suffices to be mixed as a constituent component of the uncoated tablet, and even if the granulated product containing the active ingredient and other additives contains the amino group-modified polymer additive as a coating layer containing the amino group-modified polymer additive. good.

In the present invention, it is preferable that the above-mentioned amino group-modified polymer additive is contained inside the pharmaceutical tablet. The content of the amino group-modified polymer additive contained in the tablet is preferably 0.1% by mass or more and 7% by mass or less, more preferably 0.1% by mass or more and 5% by mass or less, and 0. . More preferably, it is 1% by mass or more and 2% by mass or less.

Further, the film-coated portion may contain any additive used as a coating agent for pharmaceutical preparations such as a coating base, a concealing agent, a coloring agent, and a dispersant. The concealing agent, coloring agent, and dispersant used for the coating agent have the same meanings as described above.

Examples of the film coating base in the present invention include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol / polyethylene glycol / graft copolymer and the like.

The pharmaceutical tablet in the present invention has 30 to 90 parts by mass of errotinib or a pharmaceutically acceptable salt thereof, 0.1 to 7 parts by mass of an amino group-modified polymer additive, 1 to 50 parts by mass of a binder, and disintegration. A pharmaceutical composition according to a formulation containing 1 to 20 parts by mass of an agent, 0.1 to 5 parts by mass of a lubricant, 0.1 to 30 parts by mass of a solubilizer, and 5 to 50 parts by mass of an excipient. Granules are prepared by mixing and granulating, and organic solvents such as water, ethanol, and methanol and a mixed solvent thereof may or may not be added at the time of granulation, and the pharmaceutical tablets are formed by compression molding. Can be prepared. The pharmaceutical tablet may then be film coated. Preferably, 30 to 70 parts by mass of errotinib or a pharmaceutically acceptable salt thereof, 0.1 to 5 parts by mass of an amino group-modified polymer additive, 1 to 40 parts by mass of a binder, and 1 to 1 to 40 parts by mass of a disintegrant. It is a pharmaceutical tablet containing 10 parts by mass of a lubricant, 1 to 15 parts by mass of a solubilizer, and 5 to 30 parts by mass of an excipient.

The pharmaceutical tablet in the present invention is preferably a pharmaceutical tablet containing 0.1 to 2 parts by mass of an amino group-modified polymer additive, 25 to 35 parts by mass of a binder, and 5 to 10 parts by mass of a disintegrant.

The present invention includes a method for producing a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient.

The method for producing a pharmaceutical tablet of the present invention includes (A) mixing erlotinib or a pharmaceutically acceptable salt thereof, an amino group-modified polymer additive and other additives.

In the method for producing a pharmaceutical tablet of the present invention, it is preferable that the amino group-modified polymer additive is dispersed inside the pharmaceutical tablet. (A) By going through the step of mixing errotinib or a pharmaceutically acceptable salt thereof, an amino group-modified polymer additive and other additives, the amino group-modified polymer additive can be dispersed inside the pharmaceutical tablet. It will be possible. Therefore, this step is important in the present invention.

In the method for producing a pharmaceutical tablet of the present invention, the amino group-modified polymer additive may be mixed as a powder with errotinib or a pharmaceutically acceptable salt thereof and other additives, and the amino group-modified polymer additive may be mixed. It may be dissolved in an organic solvent such as water, ethanol or methanol and an aqueous medium such as a mixed solvent thereof and mixed with errotinib or a pharmaceutically acceptable salt thereof and other additives. Further, after mixing erlotinib or a pharmaceutically acceptable salt thereof and other additives, the amino group-modified polymer additive may be dissolved in the above aqueous medium and sprayed or the like to form a mixture.

The method for producing a pharmaceutical tablet of the present invention includes (B) a step of compression-molding the mixture obtained in step (A) into tablets. The present invention is a pharmaceutical tablet. This compression molding process for obtaining pharmaceutical tablets is important.

In the method for producing a pharmaceutical tablet of the present invention, it is preferable to perform a granulation operation to prepare a granulated product before compression molding the pharmaceutical tablet. The granulated product is a granule having a constant particle size formed by adhering a mixture containing an active ingredient and various additives to each other, and is prepared in order to improve the compression molding ability in a later step. It is a granular material. The granulation operation for preparing the granulated material may be dry granulation or wet granulation. Dry granulation is a granulation method in which water is not added at the time of granulation, and wet granulation is an appropriate amount of an organic solvent such as water, ethanol, methanol or the like and an aqueous medium such as a mixed solvent thereof added to the mixture. Then, a mechanical pressure such as a mixing operation is applied to attach the mixtures to each other, and the mixture is granulated as a granular material. Examples of the granulation operation include a rolling granulation method, a fluidized bed granulation method, a stirring granulation method, and a compression granulation method. As the granulation operation according to the present invention, the granulated product can be prepared by appropriately selecting from these operation methods.
By molding this granulated product into a tablet shape by tableting or the like, an uncoated tablet inside a pharmaceutical tablet can be prepared.

In the method for producing a pharmaceutical tablet of the present invention, a step of film-coating an uncoated tablet may be performed after compression molding. When film coating is performed, the film-coated portion outside the pharmaceutical tablet is prepared by dissolving any additive used in the coating agent in water or a water-soluble solvent containing an organic solvent that can be mixed with water at an arbitrary ratio. Film coating can be performed by injecting or spraying into a coating pan containing an uncoated tablet inside the tablet, blowing hot air onto the tablet surface to remove the solvent from the tablet surface, and drying the tablet. The drying step is preferably performed at room temperature to about 80 ° C. The aqueous solvent may be volatilized and dried by carrying out under reduced pressure.

The pharmaceutical tablet of the present invention is a pharmaceutical tablet in which the initial elution of the active ingredient in water is suppressed. In the present specification, the dissolution test for evaluating the dissolution property is the dissolution test by the second method (paddle method) of the Japanese Pharmacopoeia dissolution test.

The active ingredient errotinib or a pharmaceutically acceptable salt thereof is eluted from the pharmaceutical tablet of the present invention into the test solution by the dissolution test method according to the second method (paddle method) of the Japanese Pharmacopoeia dissolution test, and an ultraviolet visible absorptiometer is used. Alternatively, by evaluating the elution rate of erlotinib into the test solution using liquid chromatography, the pharmaceutical tablet of the present invention can suppress the initial elution of the active ingredient in water and avoid the rapid elution of the active ingredient. It can be confirmed that it is a pharmaceutical tablet having characteristics.

The pharmaceutical tablet of the present invention is a pharmaceutical tablet in which the initial elution of the active ingredient in water is suppressed. More specifically, in the dissolution test by the second method (paddle method) of the Japanese Pharmacopoeia dissolution test, when the test solution is 900 mL of water, the dissolution rate is 70% or less within 15 minutes from the start of the test, which is more preferable. Has an elution rate of 35% or less in 5 minutes and 60% or less in 15 minutes.

Further, the pharmaceutical tablet of the present invention has an dissolution rate of 60% or more within 15 minutes from the start of the test when the dissolution test is performed with a 0.1 M hydrochloric acid aqueous solution test solution containing 1% SLS (sodium lauryl sulfate). More preferably, the elution rate is 70% or more and 90% or less.

The use of the pharmaceutical product using the pharmaceutical tablet of the present invention is not particularly limited as long as it is a disease for which erlotinib has a therapeutic effect. For example, it can be applied to the treatment of malignant tumors. More specifically, non-small cell lung cancer, pancreatic cancer, glioma, colorectal cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, renal cancer, head and neck cancer, myelodysplastic syndrome, and esophageal cancer can be mentioned. Although not limited to these diseases, it can be mentioned as a preferable disease to be applied.

The dose of the drug using the pharmaceutical preparation of the present invention can be naturally changed depending on the gender, age, physiological condition, pathological condition, etc. of the patient, but for example, a drug in the range of 10 mg to 1 g as erlotinib is administered per day for an adult. .. Although not limited to this dose, it can be mentioned as a preferred dose to be applied.

Hereinafter, the present invention will be further described with reference to Examples. However, the present invention is not limited to these examples.

[Example 1] Preparation of EPO-added tablet of Eudragit (registered trademark) errotinib hydrochloride (A-type crystal) 365 g, lactose hydrate (manufactured by Freund Sangyo Co., Ltd.) 230 g, crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.) 290 g, Eudragit (manufactured by Asahi Kasei Chemicals Co., Ltd.) After mixing 5 g of EPO (manufactured by Ebonic), 80 g of sodium starch glycolate (manufactured by JRS Pharma), and 10 g of sodium lauryl sulfate (manufactured by Domestic Chemical Co., Ltd.), granulation was performed by a compression granulation method. 20 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was mixed with the granulated granules to obtain a powder for tableting.
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 1 summarizes the formulation of the tablet preparation of Example 1.

[Example 2] Preparation of EPO-added tablet of Eudragit (registered trademark) errotinib hydrochloride (A-type crystal) 365 g, lactose hydrate (manufactured by Freund Sangyo Co., Ltd.) 230 g, crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.) 288 g, Eudragit (manufactured by Asahi Kasei Chemicals Co., Ltd.) After mixing 7 g of EPO (manufactured by Ebonic), 80 g of sodium starch glycolate (manufactured by JRS Pharma), and 10 g of sodium lauryl sulfate (manufactured by Domestic Chemical Co., Ltd.), granulation was performed by a compression granulation method. 20 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was mixed with the granulated granules to obtain a powder for tableting.
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 2 summarizes the formulation of the tablet preparation of Example 2.

[Example 3] Preparation of EPO-added tablet of Eudragit (registered trademark) errotinib hydrochloride (A-type crystal) 365 g, lactose hydrate (manufactured by Freund Sangyo Co., Ltd.) 230 g, crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.) 279 g, Eudragit (manufactured by Asahi Kasei Chemicals Co., Ltd.) After mixing 16 g of EPO (manufactured by Ebonic), 80 g of sodium starch glycolate (manufactured by JRS Pharma), and 10 g of sodium lauryl sulfate (manufactured by Domestic Chemical Co., Ltd.), granulation was performed by a compression granulation method. 20 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was mixed with the granulated granules to obtain a powder for tableting.
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 3 summarizes the formulation of the tablet preparation of Example 3.

[Comparative Example 1] Preparation of Eudragit (registered trademark) EPO-free tablets 365 g of errotinib hydrochloride (A-type crystal), 230 g of lactose hydrate (manufactured by Freund Sangyo Co., Ltd.), 295 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.), starch After mixing 80 g of sodium glycolate (manufactured by JRS Pharma Co., Ltd.) and 10 g of sodium lauryl sulfate (manufactured by Domestic Chemical Co., Ltd.), granulation was performed by a compression granulation method. 20 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was mixed with the granulated granules to obtain a powder for tableting.
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 4 summarizes the formulations for preparing tablets of Comparative Example 1.

[Comparative Example 2] Preparation of Eudragit (registered trademark) EPO-free tablets 365 g of errotinib hydrochloride (A-type crystal), 230 g of lactose hydrate (manufactured by Freund Sangyo Co., Ltd.), 295 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.), cloth After mixing 80 g of carmellose sodium (manufactured by Fushimi Pharmaceutical Co., Ltd.) and 10 g of sodium lauryl sulfate (manufactured by Domestic Chemical Co., Ltd.), granulation was performed by a compression granulation method. 20 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was mixed with the granulated granules to obtain a powder for tableting.
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 5 summarizes the formulations for preparing tablets of Comparative Example 2.

[Comparative Example 3] Preparation of Eudragit (registered trademark) EPO-free tablets 365 g of errotinib hydrochloride (A-type crystal), 230 g of lactose hydrate (manufactured by Freund Sangyo Co., Ltd.), 295 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.), cloth After mixing 80 g of povidone (manufactured by BASF) and 10 g of sodium lauryl sulfate (manufactured by Domestic Chemical Co., Ltd.), granulation was performed by a compression granulation method. 20 g of magnesium stearate (Japanese Pharmacopoeia magnesium stearate) was mixed with the granulated granules to obtain a powder for tableting.
This tableting powder was used in a tableting machine to produce tablets of erlotinib hydrochloride having a tablet diameter of 10.5 mm, a tablet curvature of 12.0 mm, a thickness of about 5.10 mm, a mass of about 450 mg, and a hardness of 60 N or more.
Table 6 summarizes the formulations for preparing tablets of Comparative Example 3.

[Test Example 1] Dissolution test The tablets obtained in Examples 1 to 3 and Comparative Examples 1 to 3 were prepared by the method described in the Japanese Pharmacopoeia using a water test solution prepared by the Japanese Pharmacopoeia. The dissolution rate was evaluated by the second method (paddle method) of the method dissolution test.
The details of the dissolution test conditions were set as follows.
・ Dissolution tester: NTR-6200A, manufactured by Toyama Sangyo Co., Ltd. ・ Test solution volume: 900 mL
・ Test solution temperature: 37 ± 0.5 ° C
・ Paddle rotation speed: 100 rpm
・ Analytical equipment: Ultraviolet-visible spectrometer (UV-1700, manufactured by Shimadzu Corporation)
-Measurement wavelength: 250 nm
As a standard solution sample for quantitative analysis, an errotinib hydrochloride solution was prepared at an arbitrary concentration using water as a test solution, and the absorbance at a wavelength of 250 nm was measured, and this was used as a standard value in the test solution. In the dissolution test, the absorbance of the solution at each time point was measured to calculate the concentration of erlotinib hydrochloride in the solution at each time point and the elution rate was calculated. The results obtained are shown in Table 5.

From the results in Table 5, it was found that in the aqueous test solution, the tablets of Examples 1 to 3 had a significantly different dissolution rate of erlotinib hydrochloride 30 minutes after the start of the dissolution test as compared with the tablets of Comparative Example 1. .. The tablets of Examples 1 to 3 can suppress the initial elution in water and elute the active ingredient erlotinib hydrochloride. On the other hand, in the tablet of Comparative Example 1, the active ingredient elutes rapidly immediately after the start of the elution test, and it is not possible to suppress the initial elution in water. Therefore, it was confirmed that the addition of Eudragit® EPO into tablets can bring about significant suppression of initial elution in water.
Further, Comparative Example 1 using sodium starch glycolate, Comparative Example 2 using croscarmellose sodium, and Comparative Example 3 using crospovidone were compared, and no difference was observed in the tendency of elution. Therefore, even if the type of swelling disintegrant is changed or the swelling disintegrant is changed to a water-conducting disintegrant, it is not possible to suppress the initial elution into tablets under the condition that Eudragit EPO is not added. It was suggested.

Claims (4)

A pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, which contains an amino group-modified polymer additive and contains an amino group-modified polymer additive.
The amino group-modified polymer additive is one or more selected from the group consisting of the aminoalkyl methacrylate copolymer E, the polyvinyl acetal diethyl aminoacetate, and the ammonioalkyl methacrylate copolymer.
The amino group-modified polymer additive is dispersed inside the pharmaceutical tablet.
Pharmaceutical tablets. The pharmaceutical tablet according to claim 1, wherein the amino group-modified polymer additive is contained in an amount of 0.1% by mass or more and 7% by mass or less. The pharmaceutical tablet according to claim 1 or 2 , wherein erlotinib or a pharmaceutically acceptable salt thereof is erlotinib hydrochloride. A method for producing a pharmaceutical tablet containing erlotinib or a pharmaceutically acceptable salt thereof as an active ingredient, in which (A) erlotinib or a pharmaceutically acceptable salt thereof, an amino group-modified polymer additive and other additives are mixed. Including the step of compression molding the mixture obtained in the step (B) and the step (A) into tablets.
The amino group-modified polymer additive is one or more selected from the group consisting of the aminoalkyl methacrylate copolymer E, the polyvinyl acetal diethyl aminoacetate, and the ammonioalkyl methacrylate copolymer.
Method for manufacturing pharmaceutical tablets.