JP6739275B2 - Pharmaceutical composition containing gefitinib as an active ingredient - Google Patents

Description

The present invention relates to a pharmaceutical composition containing gefitinib as an active ingredient, particularly for preparing a pharmaceutical preparation capable of easing the drug insolubilization rate when the pH is changed from 1.5 to 6.5. Regarding things.

ゲフィチニブはＥＧＦＲチロシンキナーゼを選択的に阻害して腫瘍細胞の増殖を抑制する作用を有する。そこで、悪性腫瘍に対する治療剤として開発が進められ、イレッサ（Ｉｒｅｓｓａ（登録商標））の商品名にて抗腫瘍剤として用いられている。特に、野生型のＥＧＦＲよりも変異型ＥＧＦＲに対してよりチロシンキナーゼ阻害活性を有することが判っており、本邦ではＥＧＦＲ遺伝子変異陽性の手術不能又は再発非小細胞肺癌に対する治療剤として提供されている。 Gefitinib has the chemical formula N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine and has the general formula (1) ) Is a compound having a structure represented by

Gefitinib has the effect of selectively inhibiting EGFR tyrosine kinase and suppressing the growth of tumor cells. Therefore, it is being developed as a therapeutic agent for malignant tumors and is used as an antitumor agent under the trade name of Iressa (registered trademark). In particular, it is known to have more tyrosine kinase inhibitory activity against mutant EGFR than wild-type EGFR, and is provided in Japan as a therapeutic agent for EGFR gene mutation-positive inoperable or recurrent non-small cell lung cancer. ..

Gefitinib has a physical property that is hardly soluble in water (>100,000 mL is required to dissolve 1 g. (20°C ± 5°C)), but gefitinib is a weakly basic compound and its solubility in water is large at pH. Dependent. That is, it is soluble at pH 1 (requires 10 to 30 mL of an aqueous solvent to dissolve 1 g), but the solubility is greatly reduced at pH 4 to 6, and the solubility is reduced to about 1 mg/mL at pH 6, and at pH 7. It is practically insoluble.
It is assumed that the pH-dependent water solubility of gefitinib greatly affects the dissolution and absorption of the active ingredient when orally administered. That is, when a medicinal ingredient containing gefitinib as an active ingredient is orally administered, it has good water solubility in the stomach of an acidic environment (pH 1 to 4) and is sufficiently dissolved from the medicinal preparation, and the medicinal ingredient is sufficiently absorbed. It is thought that it is possible to maintain a solution state that can be achieved. However, the small intestine, which is considered to be the highest drug absorption site, has a pH of 4 to 8, and there is a concern that the dissolution of the active ingredient may decrease or that the eluted active ingredient may precipitate from the solution state and become unabsorbed. As a result, there is a problem that the bioavailability of the active ingredient is lowered and the pharmacokinetics are greatly changed. Therefore, it is important that the pharmaceutical preparation containing gefitinib as an active ingredient shows almost no change in drug solubility over pH fluctuation in the digestive tract route of oral administration.

As a pharmaceutical composition in which the pH-dependent water solubility of gefitinib is relaxed, Patent Document 1 discloses a pharmaceutical preparation containing a water-soluble cellulose ether such as hydroxypropylmethylcellulose. This describes an embodiment of a coated tablet in which hydroxypropylmethylcellulose was used as a coating agent containing polyethylene glycol and the like for an inner core tablet containing gefitinib as an active ingredient, and the drug was insolubilized when the pH was changed from 1.5 to 6.5. It states that the speed can be moderated.

Japanese Patent Publication No. 2005-523293

An object of the present invention is to provide a pharmaceutical composition containing gefitinib as an active ingredient, which is for preparing a pharmaceutical preparation having no change in the elution property of the active ingredient from the acidic range to the neutral range. Is an issue. An object of the present invention is to provide a pharmaceutical composition for preparing a pharmaceutical preparation capable of easing the drug insolubilization rate particularly when the pH is changed from pH 1.5 to pH 6.5.

The present inventor uses a polymer containing one or more selected from the group consisting of acrylic acid, acrylic acid alkyl ester, methacrylic acid, and methacrylic acid alkyl ester together with gefitinib as an additive for pharmaceutical preparations, It was found that the rate of drug insolubilization when the pH of a pharmaceutical preparation using is changed from pH 1.5 to pH 6.5 is greatly relaxed, and the present invention has been completed. That is, the gist of the present invention is the following [1] to [6].

[1] Heavy containing at least one selected from the group consisting of gefitinib or a pharmacologically acceptable salt thereof, drug (A), acrylic acid, acrylic acid alkyl ester, methacrylic acid, and methacrylic acid alkyl ester. A pharmaceutical composition containing the combination (B).
[2] The weight ratio of the drug (A) to the polymer (B) containing one or more selected from the group consisting of acrylic acid, acrylic acid alkyl ester, methacrylic acid, and methacrylic acid alkyl ester is 0.01 to 0. The pharmaceutical composition according to [1], which is 1:1 (w/w).
[3] The polymer (B) containing at least one selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid and alkyl methacrylate is an ethyl acrylate/methyl methacrylate copolymer [1] ~ The pharmaceutical composition according to any one of [2].
[4] The pharmaceutical composition according to any one of [1] to [3], which further contains a binder as an additive.
[5] The pharmaceutical composition according to [4], wherein the binder is polyvinylpyrrolidone.
[6] The pharmaceutical composition according to [5], wherein the content of the binder in the whole pharmaceutical tablet is 5% by mass or more and 30% by mass or less.

The pharmaceutical composition of the present invention containing gefitinib as an active ingredient can be used to prepare a pharmaceutical preparation in which the rate of insolubilization of the active ingredient is moderated when the pH of the acidic range is changed to the neutral range. In particular, it is possible to prepare a pharmaceutical preparation exhibiting the same solubility as in the acidic range even at the neutral pH of the small intestine.

The present invention is a pharmaceutical composition comprising an active ingredient, drug (A), which is a drug which is gefitinib or a pharmaceutically acceptable salt thereof, and which comprises acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester. The polymer (B) containing one or more selected from the group is used as an additive for pharmaceutical preparations. The details will be described below.

The present invention uses a drug (A) which is a drug which is gefitinib or a pharmaceutically acceptable salt thereof as an active ingredient. Gefitinib has the chemical name N-[(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-yl)propoxy]quinazolin-4-amine. The compound is disclosed in JP-A-11-504033 and can be synthesized by the method described therein.
Since gefitinib is a weakly basic compound, it may be in the form of an addition salt with an appropriate acid. For example, a mono- or di-acid addition salt with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, methanesulfonic acid or 4-toluenesulfonic acid is used. May be.
It is desirable to use gefitinib at a quality level that can be used as an active ingredient of a drug. In the present invention, it is preferable to use gefitinib in the free base form as the drug (A) instead of the acid addition salt.

The present invention uses a polymer (B) containing at least one selected from the group consisting of acrylic acid, alkyl acrylates, methacrylic acid, and alkyl methacrylates as an additive for pharmaceutical preparations.
When water-soluble cellulose is used as an additive by using the polymer (B) containing at least one selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester in the present invention It is characterized in that the ability to relax the insolubilization rate of the drug (A), which is a drug which is gefitinib or a pharmaceutically acceptable salt thereof, in the neutral range is improved as compared with

The group consisting of acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester in the present invention includes a carboxylic acid body and an ester body. Examples of the carboxylic acid body include acrylic acid and methacrylic acid. Examples of the ester body include ester bodies of acrylic acid or methacrylic acid and an alkyl alcohol having a carbon number (C1 to C6), such as methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol, pentanol and hexanol. Is mentioned. Preferred are ester forms with methanol, ethanol, propanol, isopropanol, n-butanol and t-butanol, and particularly preferred are ester forms with methanol and ethanol.

The polymer (B) containing at least one selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester in the present invention is acrylic acid, acrylic acid alkyl ester, methacrylic acid, methacrylic acid. A structure other than an alkyl ester may be included.

Examples of the polymer (B) containing at least one selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester in the present invention include methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid. Acid copolymer S, ethyl acrylate/methyl methacrylate copolymer, dry methacrylic acid copolymer LD, methyl acrylate/methacrylic acid/methyl methacrylate copolymer, 2-methyl-5-vinylpyridine methyl acrylate/methacrylic acid copolymer and the like can be mentioned. ..
As the polymer (B) containing at least one selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester in the present invention, ethyl acrylate/methyl methacrylate copolymer is used. Are particularly preferred.

The ethyl acrylate/methyl methacrylate copolymer is a polymer of ethyl acrylate and methyl methacrylate. This polymer may be a diblock copolymer composed of an ethyl acrylate segment and a methyl methacrylate segment, or a copolymer in which ethyl acrylate and methyl methacrylate are randomly bonded. It is more preferable to use a copolymer in which ethyl acrylate and methyl methacrylate are randomly bonded.

The ethyl acrylate/methyl methacrylate copolymer (B) used in the present invention preferably has a number average molecular weight of 750 kilodaltons or less.

The present invention contains a drug (A), which is a drug that is gefitinib or a pharmaceutically acceptable salt thereof, and one or more selected from the group consisting of acrylic acid, acrylic acid alkyl ester, methacrylic acid, and methacrylic acid alkyl ester. A pharmaceutical composition containing the polymer (B). The weight ratio of the drug (A) to the polymer (B) is not particularly limited as long as the effects of the present invention are exhibited, but the weight ratio of the drug (A) to the polymer (B) is 0. It is preferably 001 to 0.5:1. It is more preferably 0.01 to 0.1:1.

A binding agent is also included as an additive in the pharmaceutical composition of the present invention. As the binder, carboxyvinyl polymer, polyvinylpyrrolidone, vinyl acetate-vinylpyrrolidone copolymer, ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, ammonioalkylmethacrylate copolymer, polyvinyl alcohol- Examples thereof include acrylic acid-methyl methacrylate copolymer, partially neutralized polyacrylic acid, polyvinyl alcohol, and butyl methacrylate-methyl methacrylate copolymer.
As the binder in the present invention, it is preferable to use polyvinylpyrrolidone.

The polyvinylpyrrolidone used as the binder in the present invention preferably has a number average molecular weight of 28000 to 54000.

The pharmaceutical composition of the present invention is selected from the group consisting of drug (A), which is a drug that is gefitinib or a pharmaceutically acceptable salt thereof, acrylic acid, an acrylic acid alkyl ester, methacrylic acid, and a methacrylic acid alkyl ester. In addition to the polymer (B) containing one or more of the following, and a binder, other additives usually used for preparing a pharmaceutical preparation may be contained within a range that does not impair the effects of the present invention. For example, usual additives for pharmaceutical preparations for preparing pharmaceutical preparations such as disintegrants, solubilizers, lubricants, excipients, masking agents and coloring agents may be used.
These additives can be used without particular limitation as long as they have a purity that is acceptable for pharmaceutical formulation applications. These additives may be used alone or as a mixture thereof. It is optionally used in preparing the pharmaceutical composition or pharmaceutical preparation.

Examples of the disintegrant in the present invention include sodium carboxymethyl starch, crospovidone, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, low-substituted carboxymethyl starch sodium and the like.

Examples of the solubilizer in the present invention include sodium lauryl sulfate, soybean lecithin, purified soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol and the like.

In the present invention, examples of the lubricant include stearic acid, magnesium stearate, zinc stearate, aluminum stearate, glyceryl monostearate, sodium stearyl fumarate, calcium stearate, talc and carnauba wax.

In the present invention, the excipients include lactose, maltose, mannitol, sucrose, sorbitol, xylitol, inositol, crystalline cellulose, hydroxypropylmethylcellulose, corn starch, partially pregelatinized starch, and the like, the above binders, disintegrants, solubilizers , Additives that do not correspond to lubricants are included.

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

The present invention includes a pharmaceutical preparation containing gefitinib as an active ingredient, which is prepared by molding the above-mentioned pharmaceutical composition. Since gefitinib is orally administered and provided for the treatment of malignant tumor, it is preferably an oral preparation. Examples of the oral dosage form include tablets, dispersible tablets, hard capsules, soft capsules, granules, powders, pills, orally disintegrating tablets, chewable tablets, effervescent tablets, troches, drops and the like. A pharmaceutical preparation using the pharmaceutical composition of the present invention is preferably used as a tablet.

When the pharmaceutical composition of the present invention is applied to a tablet, one or more selected from the group consisting of gefitinib or a salt thereof, drug (A), acrylic acid, acrylic acid alkyl ester, methacrylic acid, and methacrylic acid alkyl ester. It may be a tablet formed by mixing the polymer (B) contained, the binder, and any pharmaceutical formulation additive to prepare a granule, and then compression-molding the granule. Alternatively, a tablet containing the drug (A), which is gefitinib or a salt thereof, is used as an inner core tablet, which contains one or more selected from the group consisting of acrylic acid, acrylic acid alkyl ester, methacrylic acid, and methacrylic acid alkyl ester. The embodiment may be a tablet coated with a coating film containing the polymer (B).

The polymer (B) containing at least one selected from the group consisting of the drug (A) which is gefitinib or a salt thereof, acrylic acid, alkyl acrylate, methacrylic acid, alkyl methacrylic acid and a binder, Further, a "tablet formed by optionally mixing a pharmaceutical preparation additive and optionally preparing a granule, and then compression-molding" means gefitinib or a salt thereof, acrylic acid, an alkyl acrylate, methacryl which is an active ingredient. Polymer (B) containing at least one selected from the group consisting of acids and methacrylic acid alkyl esters, and additives for pharmaceutical preparations such as binders, disintegrants, solubilizers, lubricants and excipients A tablet prepared by blending the agents and optionally preparing granules and then compression-molding the granules is shown. The binder, binder, disintegrant, solubilizer, lubricant, and excipient used as the pharmaceutical additive have the same meanings as described above.
The tablet contains 30 to 90 parts by mass of gefitinib, and 0.05 to 20 parts by mass of a polymer containing one or more selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester. 0.1 to 25 parts by mass of binder, 1 to 20 parts by mass of disintegrant, 0 to 5 parts by mass of solubilizer, 0.1 to 5 parts by mass of lubricant, and 5 to 50 of excipient. Mixing a pharmaceutical composition according to the formulation contained in parts by mass, optionally adding an organic solvent such as water, ethanol, methanol and the like, and granulating to prepare a granule, which is compression molded Tablets can be prepared with. Preferably, 50 to 85 parts by mass of gefitinib, 1 to 10 parts by mass of a polymer containing one or more polymers selected from the group consisting of acrylic acid, acrylic acid alkyl esters, methacrylic acid, and methacrylic acid alkyl esters, a binder. 1 to 15 parts by mass, a disintegrant to 1 to 10 parts by mass, a solubilizer to 0 to 5 parts by mass, a lubricant to 0.1 to 5 parts by mass, and an excipient to 5 to 40 parts by mass. A pharmaceutical composition according to a prescription.

The present invention relates to a group consisting of (1) an inner core containing the drug (A) which is gefitinib or a pharmaceutically acceptable salt thereof, and (2) an acrylic acid, an acrylic acid alkyl ester, a methacrylic acid, a methacrylic acid alkyl ester. A preferable embodiment includes a pharmaceutical tablet including a coating layer that covers the inner core and contains the polymer (B) containing one or more selected from the above.
The "inner core containing the drug (A) which is gefitinib or a pharmaceutically acceptable salt thereof" means gefitinib or a salt thereof which is an active ingredient, and a binder, a disintegrating agent, a solubilizing agent, a lubricant, an excipient. An uncoated tablet prepared by blending an additive for pharmaceutical preparations such as a shape agent and optionally preparing a granule and then compression-molding the granule is shown. The binder, binder, disintegrant, solubilizer, lubricant and excipient used for the inner core component have the same meanings as described above.
The uncoated tablet serving as an inner core contains 30 to 90 parts by mass of gefitinib, 0.1 to 25 parts by mass of a binder, 1 to 20 parts by mass of a disintegrant, 0 to 5 parts by mass of a solubilizer, and a lubricant. 0.1 to 5 parts by mass and a pharmaceutical composition containing 5 to 50 parts by mass of an excipient are mixed, and an organic solvent such as water, ethanol, methanol, etc., and a mixed solvent thereof are optionally added to prepare the composition. Granules are granulated to prepare granules, and the granules are compression-molded to prepare an uncoated tablet serving as an inner core. Preferably, gefitinib is 50 to 85 parts by mass, the binder is 1 to 15 parts by mass, the disintegrant is 1 to 10 parts by mass, the solubilizer is 0 to 5 parts by mass, and the lubricant is 0.1 to 5 parts by mass. A pharmaceutical composition according to a formulation containing 5 to 40 parts by mass of an excipient.

In addition, it is preferable to perform granulation operation to prepare granules before compression molding of the pharmaceutical composition. The granulation operation may be dry granulation in which an appropriate mechanical pressure is applied to the pharmaceutical composition for granulation, and mechanical pressure such as mixing by adding an appropriate amount of water or an organic solvent is applied. It may be wet granulation in which granulation is performed by adding. In preparing the product of the present invention, it is more preferable to select this wet granulation.
By molding this granulated product into a tablet shape by tableting or the like, an uncoated tablet as an inner core can be prepared.

The uncoated tablet serving as the inner core preferably contains a binder in order to control tablet formability and dissolution rate. In the present invention, the content of gefitinib as an active ingredient is increased to prepare uncoated tablets having a content of preferably more than 50 parts by mass, more preferably 60 parts by mass or more, and further preferably 70 parts by mass or more as gefitinib. Therefore, the content of the binder in the total mass of the uncoated tablet is preferably 5% by mass or more and 30% by mass or less.

"Coating layer containing polymer (B) containing at least one selected from the group consisting of acrylic acid, acrylic acid alkyl ester, methacrylic acid and methacrylic acid alkyl ester" for coating the uncoated tablet as the inner core , An acrylic acid, an acrylic acid alkyl ester, a methacrylic acid, a methacrylic acid alkyl ester, and an aqueous solution containing a polymer (B) containing one or more selected from the group consisting of The coating layer can be provided by uniformly adhering it to the surface by an operation such as spraying and drying it.
The aqueous solution containing the polymer (B) containing at least one selected from the group consisting of acrylic acid, acrylic acid alkyl ester, methacrylic acid, and methacrylic acid alkyl ester means acrylic acid, acrylic acid alkyl ester, and methacrylic acid. A solution of a polymer (B) containing at least one selected from the group consisting of an acid and an alkyl methacrylic acid in water or an aqueous solvent containing an organic solvent arbitrarily miscible with water such as ethanol or acetone. This aqueous solution may contain any additive used for a coating agent of a pharmaceutical preparation such as a masking agent, a colorant, a dispersant, a plasticizer and the like. The masking agent, the coloring agent and the like may be dissolved in the aqueous solution and used, or may be used in a suspended state.

The coating layer containing the polymer (B) containing one or more selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester is the acrylic acid, acrylic acid alkyl ester, or methacrylic acid. 60 to 100 parts by mass of a polymer (B) containing one or more selected from the group consisting of acids and methacrylic acid alkyl esters, 0 to 10 parts by mass of a masking agent and/or a colorant, and 0 to a dispersant. It is preferably a composition having a formulation containing 10 parts by mass and a plasticizer in an amount of 0 to 20 parts by mass. Examples of the dispersant include macrogol. Examples of the plasticizer include glycerin, propylene glycol, polyethylene glycol having a molecular weight of 300 to 6000, triglyceride such as castor oil, diethyl phthalate and the like. Preferably, 70 to 99 parts by mass of the polymer (B) containing one or more selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester, titanium oxide, iron sesquioxide, A coating layer composition having a formulation containing 0 to 10 parts by mass of a masking agent and/or a coloring agent, which is one or a combination thereof selected from the group consisting of yellow ferric oxide, silicic acid anhydride, and magnesium oxide. is there.
The coating layer composition is one or more selected from the group consisting of acrylic acid, acrylic acid alkyl ester, methacrylic acid, and methacrylic acid alkyl ester, wherein water or an aqueous solvent containing an organic solvent that can be mixed with water at an arbitrary ratio is used. By preparing an aqueous solution at a concentration at which the polymer (B) containing is sufficiently dissolved, it can be used as a coating agent for forming a coating layer.

As a method for coating an uncoated tablet serving as an inner core with a coating layer containing a polymer (B) containing at least one selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid and alkyl methacrylate, , An aqueous solution containing a polymer (B) containing at least one selected from the group consisting of acrylic acid, alkyl acrylate, methacrylic acid, and methacrylic acid alkyl ester, and an uncoated tablet serving as an inner core. A group consisting of the acrylic acid, acrylic acid alkyl ester, methacrylic acid, and methacrylic acid alkyl ester on the plain tablet surface by pouring or spraying into a coating pan and sending hot air to the tablet surface to remove the solvent from the tablet surface and drying. The coating layer can be provided by uniformly adhering the polymer (B) containing one or more selected from the above and then drying. The drying step is preferably performed at room temperature to about 80°C. By performing under reduced pressure, the aqueous solvent may be volatilized and dried.

The use of the pharmaceutical composition using the pharmaceutical composition of the present invention is not particularly limited as long as it is a disease having a therapeutic effect by the drug (A) which is gefitinib or a pharmaceutically acceptable salt thereof. For example, it can be applied to the treatment of malignant tumors. More specifically, lung cancer, breast cancer, prostate cancer, ovarian cancer, colorectal cancer, gastric cancer, brain tumor, head cancer, cervical cancer, bladder cancer, pharyngeal cancer, renal cancer, skin cancer, cervical cancer, intrauterine Membrane cancer, vaginal cancer, vulvar cancer, uterine cancer, thyroid cancer, leukemia, lymphoid malignant tumor and the like 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 composition of the present invention can be naturally changed according to the sex, age, physiological condition, pathological condition, etc. of the patient, but for example, per adult adult, gefitinib or a pharmaceutically acceptable salt thereof is used. A drug in the range of 0.5 to 15 mg/kg body weight is administered as the drug (A). More preferably, for example, the drug in the range of 1 to 10 mg/kg body weight is administered. It is not limited to this dose, but may be mentioned as a preferable 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]
Gefitinib (250 mg) as powder, polyvinylpyrrolidone (povidone: 35 mg), and sodium lauryl sulfate (2 mg) were mixed in a mortar. Upon carrying out Test Example 1 described later, the mixed powder was dissolved, and a liquid ethyl acrylate/methyl methacrylate copolymer (15 mg) was added to the solution and stirred to form a uniform solution.
Comparative Examples 1 to 5 had the compositions shown in Table 1, and were prepared by mixing the powder components in a mortar and adding the liquid components without mixing when carrying out Test Example 1, as in Example 1.

[Table 1]

[Test Example 1] pH fluctuation test In order to investigate the change in the solubility of gefitinib of Example 1 and Comparative Examples 1 to 5 during pH fluctuation, a test was carried out under the following conditions.
Test solution 1: A solution having a pH of around 1.5 obtained by dissolving 10 g of sodium chloride in 5000 mL of 0.07 mol/mL hydrochloric acid Test solution 2: 33.44 g of water in a 2.5 mol/mL potassium dihydrogen phosphate aqueous solution Solution around pH 12 obtained by dissolving sodium oxide Dissolution tester: NTR-6200A, manufactured by Toyama Sangyo Co., Ltd. Test solution temperature: 37±0.5° C.
Paddle rotation speed: 100 rpm
Analytical instrument: UV-visible spectrophotometer (UV-1700, manufactured by Shimadzu Corporation)
Measurement wavelength: 247nm

Test solution 1 (500 mL) was placed in a vessel and placed in a dissolution tester, and the powder compositions of Example 1 and Comparative Examples 1 to 5 were added thereto, and then liquid components were added and the mixture was clarified with a paddle of 100 rpm. The mixture was stirred until it was dissolved. The absorbance at a wavelength of 247 nm was measured in a dissolved state, and the value was used as a reference value. Then, the test liquid 2 (13.4 mL) was charged while rotating the paddle at 100 rpm. When the pH of the liquid when the test liquid 1 (500 mL) and the test liquid 2 (13.4 mL) were mixed was measured in advance, it was confirmed to be about 6.5. 2 minutes, 5 minutes, 7 minutes, and 10 minutes after the test solution 2 was added, the absorbance at a wavelength of 247 nm was measured and compared with a reference value to determine the residual rate (%) of gefitinib in the solution. It was calculated. The results are shown in Table 2.

The solubility of gefitinib varies greatly depending on the pH. That is, it is known that 250 mg of gefitinib easily dissolves in 500 mL of a liquid having a pH of about 1.5, because the lower the pH, the higher the solubility. On the other hand, it is known that the solubility is extremely lowered in a solution having a pH of more than 5, and it is hardly dissolved particularly when it has a pH of more than 6. In Test Example 1, the pH was rapidly increased from about 1.5 to about 6.5, but in this case, it is considered that gefitinib dissolved in the solution is precipitated. It is known that the precipitation of gefitinib can be suppressed by adding water-soluble celluloses (Japanese Patent Laid-Open No. 2005-523293), but in Test Example 1, by using an ethyl acrylate/methyl methacrylate copolymer, It was confirmed that the suppression effect was far higher than that when water-soluble celluloses were used. Compared with before adjusting the pH to 6.5, when gefitinib alone or hypromellose which is a water-soluble cellulose was used, and when other polymer compounds were used, the residual ratio was 10 minutes after the pH was changed to 6.5. While it decreased to about 5 to 30%, the residual rate of 90% or more was shown when the ethyl acrylate/methyl methacrylate copolymer was used.

Claims (5)

A pharmaceutical composition comprising gefitinib or a drug (A) which is a pharmaceutically acceptable salt thereof, and a polymer (B) containing an ethyl acrylate/methyl methacrylate copolymer . The pharmaceutical composition according to claim 1, wherein the weight ratio of the drug (A) to the polymer (B) is 0.01 to 0.1:1 (w/w). The pharmaceutical composition according to claim 1 or 2 , further comprising a binder as an additive. The pharmaceutical composition according to claim 3 , wherein the binder is polyvinylpyrrolidone. The pharmaceutical composition according to claim 3 or 4 , wherein the content of the binder in the entire pharmaceutical composition is 5% by mass or more and 30% by mass or less.