JP2018115130A - Method for producing erlotinib hydrochloride-containing pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a pharmaceutical composition containing A type crystal of erlotinib hydrochloride, wherein the production of B crystal is inhibited.SOLUTION: The present invention provides a method for producing an erlotinib hydrochloride-containing pharmaceutical composition. As erlotinib hydrochloride for granulation, used is A type crystal, and the granulation is made by wet system. The pharmaceutical composition can contain sodium starch glycolate, and/or croscarmellose sodium and sodium lauryl sulfate, and/or sucrose fatty acid ester. The wet granulation is preferably fluid layer granulation. The pharmaceutical composition is typically a tablet.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a pharmaceutical composition containing type A crystals of erlotinib hydrochloride.

Erlotinib hydrochloride is a drug showing a tumor growth inhibitory action by selectively inhibiting epidermal growth factor receptor-tyrosine kinase. Known crystal forms of erlotinib hydrochloride include A-type crystals, B-type crystals, and E-type crystals. Since B-type crystals are stable, a pharmaceutical composition containing erlotinib hydrochloride B-type crystals and not containing A-type crystals has been proposed (Patent Document 1). In addition, as a pharmaceutical preparation containing erlotinib hydrochloride, Tarceva tablets (Chugai Pharmaceutical Co., Ltd.) are known (Non-patent Document 1), but Tarceva tablets have B-type crystals of erlotinib hydrochloride as active ingredients Does not contain A-type crystals.
Here, since erlotinib hydrochloride is sparingly soluble in water, in order to improve bioavailability, it is required to use a crystal form having as high a solubility as possible in water. In this respect, since the A-type crystal has higher solubility in water than the B-type crystal, it is desirable to use the A-type crystal from the viewpoint of improving bioavailability.

Japanese Patent No. 4689916

Tarceva tablets pharmaceutical interview form

  In addition to the background art described above, the present inventors have clarified that the A-type crystals are unstable and thus easily transfer to the B-type crystals at the time of production or storage of the preparation. Therefore, an object of the present invention is to provide a method for producing a pharmaceutical composition containing erlotinib hydrochloride A-type crystals, wherein the production of B-type crystals is suppressed.

The present inventor repeated researches to solve the above-described problems, and obtained the following knowledge.
(i) In a method for producing a pharmaceutical composition such as a tablet, granule or capsule containing erlotinib hydrochloride, by using A-type crystals as raw material erlotinib hydrochloride and performing granulation in a wet process, Compared to the case of granulation, the formation of B-type crystals is significantly suppressed.
(ii) When sodium starch glycolate and / or croscarmellose sodium is added as a disintegrant, the transition from A-type crystals to B-type crystals is more effectively suppressed.
(iii) When sodium lauryl sulfate and / or sucrose fatty acid ester is added as a surfactant, the transition from A-type crystals to B-type crystals is more effectively suppressed.

The present invention has been completed based on the above findings, and provides the following (1) to (6).
(1) A method for producing erlotinib hydrochloride-containing pharmaceutical composition, wherein the A-type crystal is used as erlotinib hydrochloride to be subjected to granulation, and granulation is performed in a wet manner.
(2) The production method according to (1), wherein the pharmaceutical composition contains sodium starch glycolate and / or croscarmellose sodium.
(3) The production method according to (1) or (2), wherein the pharmaceutical composition comprises sodium lauryl sulfate and / or sucrose fatty acid ester.
(4) In the method for producing a pharmaceutical composition containing erlotinib hydrochloride, the method comprises using A-type crystals as erlotinib hydrochloride to be used for granulation and performing granulation in a wet manner, and the pharmaceutical composition is sodium starch glycolate And / or a croscarmellose sodium and a sodium lauryl sulfate and / or a sucrose fatty acid ester.
(5) The production method according to any one of (1) to (4), wherein the wet granulation is fluidized bed granulation.
(6) The production method according to any one of (1) to (5), wherein the pharmaceutical composition is a tablet.
(7) A pharmaceutical composition produced by the method according to any one of (1) to (6).

According to the production method of the present invention, a pharmaceutical composition containing erlotinib hydrochloride A-type crystals, which is free or substantially free of B-type crystals, or has a very small ratio of B-type crystals. Can be manufactured. In addition, the pharmaceutical composition produced by the method of the present invention has suppressed crystal transition during storage.
The method of the present invention is very useful in that the crystal transition of erlotinib hydrochloride from the A-type crystal to the B-type crystal can be suppressed by a simple method employing a wet granulation method.

In addition, when sodium starch glycolate or croscarmellose sodium is used as the disintegrant, the transition from the A-type crystal to the B-type crystal is more effectively suppressed.
In addition, when sodium lauryl sulfate or sucrose fatty acid ester is used as the surfactant, the transition from the A-type crystal to the B-type crystal is more effectively suppressed.

Hereinafter, the present invention will be described in detail.
The production method of the present invention is a method of using a type A crystal as erlotinib hydrochloride to be subjected to granulation and performing granulation in a wet manner in the method of producing a pharmaceutical composition containing erlotinib hydrochloride.

Erlotinib hydrochloride Erlotinib hydrochloride is a compound whose chemical name is N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine monohydrochloride. As erlotinib hydrochloride, for example, powder can be used.
As the raw material erlotinib hydrochloride, A-type crystals are used. The A-type crystal has a characteristic peak of 5.6 ° ± 0.2 ° when represented by a reflection angle 2θ in the X-ray powder diffraction pattern. Also generally 5.6 ° ± 0.2 °, 9.8 ° ± 0.2 °, 18.9 ° ± 0.2 °, 22.7 ° ± 0.2 °, and 23.5 ° ± 0. It has a peak at 2 °. More generally, 5.6 ° ± 0.2 °, 9.8 ° ± 0.2 °, 11.3 ° ± 0.2 °, 18.9 ° ± 0.2 °, 22.7 ° ± 0. 2 °, 23.5 ° ± 0.2 °, 24.2 ° ± 0.2 °, 24.6 ° ± 0.2 °, 25.4 ° ± 0.2 °, 26.2 ° ± 0. It has peaks at 2 ° and 29.3 ° ± 0.2 °.
In addition, the B-type crystal of erlotinib hydrochloride has a characteristic peak of 6.2 ° ± 0.2 ° when represented by a reflection angle 2θ in the X-ray powder diffraction pattern. Also generally 6.2 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.1 ° ± 0.2 °, 25.1 ° ± 0.2 °, and 26.9 ° ± 0. It has a peak at 2 °. More generally, 6.2 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.4 ° ± 0.2 °, 17.0 ° ± 0.2 °, 20.2 ° ± 0. 2 °, 21.1 ° ± 0.2 °, 23.0 ° ± 0.2 °, 24.5 ° ± 0.2 °, 25.1 ° ± 0.2 °, and 26.9 ° ± 0 It has a peak at 2 °.
When the pharmaceutical composition is a tablet, erlotinib hydrochloride can be used so that about 1 to 1000 mg is contained in one tablet, and in particular, it is used so that 25 mg, 100 mg, or 150 mg is contained in one tablet. be able to.

In the wet granulation method of the present invention, the formation of B-type crystals is suppressed by adopting the wet granulation method as the granulation method. The type of wet granulation method is not limited, and examples thereof include a fluidized bed granulation method, a stirring granulation method, a rolling granulation method, an extrusion granulation method, and a crushing granulation method. Of these, fluidized bed granulation is preferred.
The granulating liquid used in wet granulation is not particularly limited, and water, ethanol, or the like can be used. In order to promote granulation, adhesive substances such as starch, carboxymethyl cellulose, and gelatin, sodium lauryl sulfate, sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and polyoxypropylene / polyoxyethylene block A polymer, a surfactant such as polyoxyl 35 castor oil, or the like dissolved in a solvent such as water or ethanol can also be used.
The conditions for wet granulation can be those generally used for the production of pharmaceutical granules.

Pharmaceutical Composition In the present invention, examples of the pharmaceutical composition include tablets, granules, capsules and the like.
The tablet can be produced by drying and granulating the obtained granulated product by a conventional method and then tableting. At this time, only the granulated product can be tableted, or the granulated product and an additive (for example, a lubricant) can be mixed and tableted. The tablets may be orally disintegrating tablets, chewable tablets and the like in addition to ordinary tablets. Further, it may be a sublingual tablet, buccal tablet, troche tablet or the like absorbed in the oral cavity.
Moreover, the obtained granulated material can be used as a granule as it is or after coating as needed.
Moreover, a capsule can be manufactured by filling the obtained granulated material as it is, or mixing with an additive as needed, and filling a capsule (hard capsule).

In addition to the active ingredient erlotinib hydrochloride, the raw material used for additive granulation can contain excipients. Further, it may further contain one or more additives such as a binder, a disintegrant, a sweetener, a corrigent, a fluidizing agent, a lubricant, a surfactant, a fragrance, and a coloring agent.
In addition, in the manufacture of tablets and capsules, additives mixed with the granulated materials are excipients, binders, disintegrants, sweeteners, corrigents, fluidizers, lubricants, surfactants, fragrances. , May include one or more additives such as colorants.
Additives such as an excipient, a binder, a disintegrant, a surfactant, a sweetener, a corrigent, a fluidizing agent, a lubricant, a surfactant, a fragrance, and a coloring agent are each used alone, Alternatively, two or more kinds can be used in combination.

(Excipient)
Examples of excipients include lactose, lactose hydrate, sucrose, maltose, fructose, glucose (dextrose), sugars such as trehalose; sugar alcohols such as mannitol, maltitol, sorbitol, xylitol, erythritol, lactitol; Starches such as starch, pregelatinized starch, partially pregelatinized starch; celluloses such as crystalline cellulose; dextrin; pullulan; gum arabic; light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminate metasilicate And inorganic excipients such as anhydrous calcium hydrogen phosphate, calcium carbonate, and calcium sulfate.

(Binder)
Examples of the binder include celluloses such as methylcellulose, ethylcellulose, carboxymethylcellulose (carmellose), hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose); polyvinylpyrrolidone (povidone); starch; gelatin; tragacanth gum; Etc.

(Disintegrant)
Examples of disintegrants include crospovidone; carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, celluloses such as crystalline cellulose; starch, pregelatinized starch, partially pregelatinized starch , Starches such as sodium carboxymethyl starch, sodium starch glycolate, hydroxypropyl starch; dextrin; calcium silicate and the like.
Of these, sodium starch glycolate and croscarmellose sodium are preferred in that the crystal transition is more effectively suppressed.

Sodium starch glycolate and / or croscarmellose sodium may be blended in the granulated product, may be blended as an additive mixed with the granulated product, or may be blended in both. In terms of effectively suppressing the crystal transition, it is preferable to blend in the granulated product, or blend in both.
The total amount of sodium starch glycolate and / or croscarmellose sodium is the total amount of the pharmaceutical composition (if the pharmaceutical composition is a tablet with a coating, the total amount of the uncoated tablet, the pharmaceutical composition has a coating with a coating) The total amount of granules before coating with a coating, and the total amount of granules filled in a capsule when the pharmaceutical composition is a capsule (provided that the granules with coating are filled with a coating) About 0.5 to 10% by weight with respect to the total amount of granules before)) is preferred, and this effectively suppresses the crystal transition.

(lubricant)
Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, potassium sodium tartrate, and microcrystalline wax.

(Surfactant)
Examples of the surfactant include sodium lauryl sulfate, sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxypropylene / polyoxyethylene block copolymer, polyoxyl 35 castor oil, and the like. Among these, sodium lauryl sulfate and sucrose fatty acid ester are preferable in that the crystal transition is more effectively suppressed.

Sodium lauryl sulfate and / or sucrose fatty acid ester may be blended in the granulated product, may be blended as an additive mixed with the granulated product, or may be blended in both. In terms of effectively suppressing the crystal transition, it is preferable to blend in the granulated product, or blend in both.
The total amount of sodium lauryl sulfate and / or sucrose fatty acid ester is the total amount of tablets obtained (if the pharmaceutical composition is a tablet with a coating, the total amount of uncoated tablets, the pharmaceutical composition is a granule with a coating). In some cases, the total amount of granules before coating with a coating, or in the case where the pharmaceutical composition is a capsule, the total amount of granules filled in the capsule (provided that the granules having a coating are filled with the coating) About 0.5 to 5% by weight is preferred, more preferably about 1 to 3% by weight, based on the total amount of previous granules)). Thereby, crystal transition is suppressed very effectively.

(Sweetener)
Sweeteners include, for example, mannitol, starch sugar, reduced maltose syrup, sorbitol, sugar, fructose, lactose, honey, xylitol, erythritol, sorbitol, saccharin, licorice and extracts thereof, glycyrrhizic acid, sweet tea, aspartame, stevia, thaumatin Acesulfame potassium, sodium citrate, sucralose and the like.

(Flavoring agent)
Examples of the corrigent include citric acid, sodium citrate, tartaric acid, DL-malic acid, glycine, and DL-alanine.

(Fluidizer)
Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, dry aluminum hydroxide gel, kaolin, calcium silicate, magnesium metasilicate aluminate, and talc. .

(Fragrance)
Examples of the fragrances include strawberry, lemon, lemon lime, orange, l-menthol, mint oil and the like.

(Coloring agent)
Examples of the colorant include yellow iron sesquioxide, titanium oxide, iron sesquioxide, edible tar dye, natural dye, and the like.

As described above, the A-type crystal is a crystal having a characteristic peak at 5.6 ° ± 0.2 ° expressed by a reflection angle 2θ in the X-ray powder diffraction pattern, and the B-type crystal is an X-ray It is a crystal having a characteristic peak at 6.2 ° ± 0.2 ° expressed by a reflection angle 2θ in a powder diffraction pattern.
In the present invention, the peak ratio of the B-type crystal to the A-type crystal (B-type / A-type) is a peak at 2θ = 5.6 ° ± 0.2 ° characteristic of the A-type crystal from the X-ray powder diffraction pattern. And the peak intensity ratio (B-type / A-type) calculated from these intensities are measured.

By the production method of the present invention described above, a granulated product containing erlotinib hydrochloride A-type crystals, no B-type crystals, or substantially no B-type crystals is obtained. Further, from this granulated product, tablets, granules, capsules, etc. containing A-type crystals of erlotinib hydrochloride, no B-type crystals, or substantially no B-type crystals, etc. A pharmaceutical composition is obtained.
The ratio of the B-type crystals is extremely small. That is, the peak ratio of the B-type crystals to the A-type crystals immediately after production of the pharmaceutical composition (B-type / A-type) is, for example, 1.5 or less, and preferably 0. 0.8 or less, more preferably 0.2 or less. Alternatively, it is sealed in an aluminum bag, and the peak ratio of the B-type crystal to the A-type crystal after storage for 2 weeks at a temperature of 60 ° C. and a relative humidity of 60% (B type / A type) is, for example, 3 or less, Further, it is preferably 1.5 or less, more preferably 0.3 or less.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.
(1) Examination of granulation method
Example 1 (fluidized bed granulation)
In a fluidized bed granulator MP-01 (manufactured by Paulec Co., Ltd.), A-type crystals of erlotinib hydrochloride 81.96 g, lactose hydrate (200 M, DMV) 81.54 g, crystalline cellulose (101, Asahi Kasei Chemicals Corporation ) After mixing 105.0 g and 21.0 g of sodium starch glycolate (Primogel, DMV), an aqueous solution in which 6.0 g of sodium lauryl sulfate (Sigma) was dissolved in 194 g of purified water was sprayed to perform fluidized bed granulation. It was. The granulated product obtained in the fluidized bed granulation step was dried at 70 ° C. After the dried granulated product is sized with sieve No. 22, 4.5 g of magnesium stearate (vegetable, Taihei Chemical Industrial Co., Ltd.) is added to the sized product and mixed by hand in a plastic bag. A pre-tablet powder containing salt was obtained. Using a tableting machine (vela5, Kikusui Seisakusho Co., Ltd.), the powder before tableting was tableted so as to be 100 mg per tablet, and A-type crystalline erlotinib hydrochloride-containing tablets were obtained.

Example 2 (wet kneading)
In a mortar, 27.32 g of erlotinib hydrochloride in the form of A, 27.18 g of lactose hydrate (200M, DMV), 35.0 g of crystalline cellulose (101, Asahi Kasei Chemicals Corporation), sodium starch cricholate (primogel) Then, 7.0 g of DMV) was mixed, and then an aqueous solution in which 2.0 g of sodium lauryl sulfate (Sigma) was dissolved in 14 g of purified water was added dropwise, followed by stirring and granulating with a pestle. The obtained granulated product was dried at 70 ° C. After the dried granulated product is sized with sieve No. 22, 1.5 g of magnesium stearate (vegetable, Taihei Chemical Industrial Co., Ltd.) is added to the sized product and mixed by hand in a plastic bag. A pre-tablet powder containing salt was obtained. Thereafter, A-type crystalline erlotinib hydrochloride-containing tablets were obtained by the same production method as in Example 1.

Comparative Example 1 (dry granulation)
In a plastic bag, 27.32 g of erlotinib hydrochloride in the form of A, 27.18 g of lactose hydrate (200 M, DMV), 35.0 g of crystalline cellulose (101, Asahi Kasei Chemicals Corporation), sodium starch cricholate (primo Gel, DMV) 7.0 g, sodium lauryl sulfate (Sigma) 2.0 g, and magnesium stearate (vegetable, Taihei Chemical Industrial Co., Ltd.) 0.75 g were mixed. The mixed powder was put into a roller compactor (TF-MINI, Freund Sangyo Co., Ltd.), compression molded, and then pulverized with a power mill (P-04S, Dalton Co.). To the obtained powder, 0.75 g of magnesium stearate (vegetable, Taihei Chemical Industrial Co., Ltd.) was added and manually mixed in a plastic bag to obtain a pre-tablet powder containing erlotinib hydrochloride of A-type crystals. Thereafter, A-type crystalline erlotinib hydrochloride-containing tablets were obtained by the same production method as in Example 1.

(Measurement of crystal transition rate)
Each tablet obtained in Examples 1 and 2 and Comparative Example 1 was sealed in an aluminum bag and allowed to stand at a temperature of 60 ° C. and a relative humidity of 60% for 2 weeks. Thereafter, the crystal form of erlotinib hydrochloride in the tablet was measured by a powder X-ray diffractometer (D8 ADVANCE, Bruker AEX Co., Ltd.) using CuKα. The measurement sample was lightly pulverized in an agate mortar, packed in a sample cup, and set in the apparatus. The tube voltage and tube current were set to 40 kV and 40 mV, respectively, and scanning was performed in the range of 2 ° to 40 ° of the scanning axis 2θ. From the obtained X-ray powder diffraction pattern, the intensity of the peak of 2θ = 5.6 ° ± 0.2 characteristic of the A type crystal and 2θ = 6.2 ° ± 0.2 characteristic of the B type crystal are obtained. The peak intensity was measured, and the peak intensity ratio (B type / A type) was calculated.
The results are shown in Table 1.

乾式造粒した場合（比較例１）、Ａ型結晶のピーク強度に対して約３倍のピーク強度を有するＢ型結晶が検出され、Ｂ型結晶への相転移が進行していることが確認されたが、湿式造粒した場合は（実施例１、２）、Ｂ型結晶の生成が顕著に抑制された。

In the case of dry granulation (Comparative Example 1), a B-type crystal having a peak intensity about three times the peak intensity of the A-type crystal is detected, and it is confirmed that the phase transition to the B-type crystal is in progress. However, when wet granulation was performed (Examples 1 and 2), the formation of B-type crystals was significantly suppressed.

(2) Examination of the type of disintegrant
Example 2 (sodium starch glycolate)
Example 2 above uses sodium starch glycolate as a disintegrant.

Example 3 (croscarmellose sodium)
Except for using 7.0 g of sodium croscarmellose (Ac-Di-Sol, DSP Gokyo Food & Chemical Co., Ltd.) instead of 7.0 g of sodium starch chollate (Primogel, DMV) of Example 2. Obtained a type A crystalline erlotinib hydrochloride-containing tablet by the same production method as in Example 2.

Example 4 (low-substituted hydroxypropylcellulose)
Implementation was performed except that 7.0 g of low-substituted hydroxypropylcellulose (L-HPC21, Shin-Etsu Chemical Co., Ltd.) was used instead of 7.0 g of sodium starch glycolate (Primogel, DMV) of Example 2. In the same manner as in Example 2, type A crystalline erlotinib hydrochloride-containing tablets were obtained.

Example 5 (Crospovidone)
A production method similar to that of Example 2 except that 7.0 g of crospovidone (Collidon CL-F, BASF) was used instead of 7.0 g of sodium starch glycolate (Primogel, DMV) of Example 2. Thereby obtaining A-type crystalline erlotinib hydrochloride-containing tablets.

Example 6 (carmellose)
According to the same production method as in Example 2, except that 7.0 g of carmellose (NS-300, Nichirin Kagaku) was used instead of 7.0 g of sodium starch glycolate (Primogel, DMV) in Example 2. A-type crystalline erlotinib hydrochloride-containing tablets were obtained.

Example 7 (Partially pregelatinized starch)
Production similar to Example 2 except that 7.0 g of partially pregelatinized starch (PC-10, Asahi Kasei) was used in place of 7.0 g of sodium starch glycolate (Primogel, DMV) of Example 2. According to the method, A-type crystalline erlotinib hydrochloride-containing tablets were obtained.

(Measurement of crystal transition rate)
Each tablet obtained in Examples 2 to 7 was sealed in an aluminum bag and allowed to stand at a temperature of 60 ° C. and a relative humidity of 60% for 2 weeks. Immediately after tablet production and after standing for 2 weeks, X-ray powder diffraction was performed under the same measurement conditions as in paragraph 0032. From the X-ray powder diffraction pattern, 2θ = 5.6 ° ± 0. The intensity of the peak 2 and the intensity of the peak 2θ = 6.2 ° ± 0.2 characteristic of the B-type crystal were measured, and the peak intensity ratio (B-type / A-type) was calculated. In Examples 5 to 7, X-ray powder diffraction was performed only immediately after production.
The results are shown in Table 2.

何れの崩壊剤を使用した場合も、Ｂ型への結晶転移が抑制された。中でも、デンプングリコール酸ナトリウム、又はクロスカルメロースナトリウムを使用した場合は、結晶転移が特に効果的に抑制されており、製造直後には、Ｂ型結晶への転移は実質的に認められなかった。

When any disintegrant was used, the crystal transition to B type was suppressed. Among them, when sodium starch glycolate or croscarmellose sodium was used, the crystal transition was particularly effectively suppressed, and substantially no transition to B-type crystals was observed immediately after production.

(3) Examination of the type of surfactant
Example 2 (sodium lauryl sulfate)
In Example 2 described above, sodium lauryl sulfate is used as the surfactant.

Example 8 (sucrose fatty acid ester)
In the same manner as in Example 2, except that 2.0 g of sucrose fatty acid ester (Mitsubishi Chemical Foods Co., Ltd.) was used instead of 2.0 g of sodium lauryl sulfate (Sigma) in Example 2, type A Crystalline erlotinib hydrochloride-containing tablets were obtained.

Example 9 (polysorbate 80)
A-type crystalline erlotinib hydrochloride contained in the same production method as in Example 2, except that 2.0 g of polysorbate 80 (Kanto Chemical) was used instead of 2.0 g of sodium lauryl sulfate (Sigma) in Example 2. I got a tablet.

Example 10 (polyoxyethylene (196) polyoxypropylene (67) glycol)
Example 2 except that 2.0 g of polyoxyethylene (196) polyoxypropylene (67) glycol (Collifor P407, BASF) was used instead of 2.0 g of sodium lauryl sulfate (Sigma) of Example 2. A-type crystalline erlotinib hydrochloride-containing tablets were obtained by the same production method.

Example 11 (Polyoxyl 35 castor oil)
In the same manner as in Example 2, except that 2.0 g of polyoxyl 35 castor oil (Collifor EL) was used instead of 2.0 g of sodium lauryl sulfate (Sigma) in Example 2, type A crystalline erlotinib A hydrochloride-containing tablet was obtained.

(Measurement of crystal transition rate)
Each tablet obtained in Examples 2 and 8 to 11 was sealed in an aluminum bag and allowed to stand at a temperature of 60 ° C. and a relative humidity of 60% for 2 weeks. Immediately after tablet production and after standing, X-ray powder diffraction was performed under the same measurement conditions as in paragraph 0032. From the X-ray powder diffraction pattern, 2θ = 5.6 ° ± 0.2, which is characteristic of A-type crystals, The intensity of the peak and the intensity of the peak at 2θ = 6.2 ° ± 0.2 characteristic of the B-type crystal were measured, and the peak intensity ratio (B-type / A-type) was calculated. In Examples 9 to 11, X-ray powder diffraction was performed only immediately after production.
The results are shown in Table 3 below.

何れの界面活性剤を使用した場合も、Ｂ型への結晶転移が抑制された。中でも、ラウリル硫酸ナトリウム、ショ糖脂肪酸エステルを使用した場合は、結晶転移が特に効果的に抑制されていた。

When any surfactant was used, the crystal transition to B type was suppressed. Among them, when sodium lauryl sulfate and sucrose fatty acid ester were used, the crystal transition was particularly effectively suppressed.

  According to the production method of the present invention, a tablet containing type A crystals of erlotinib hydrochloride can be efficiently produced by a simple method of wet granulation. Erlotinib hydrochloride is a poorly water-soluble drug, but since the A-type crystals have a relatively high water solubility, the method of the present invention is very useful.

Claims (6)

  In the manufacturing method of the erlotinib hydrochloride containing pharmaceutical composition, the manufacturing method which uses A type crystal | crystallization as erlotinib hydrochloride to use for granulation, and performs granulation wet.   The manufacturing method of Claim 1 in which the said pharmaceutical composition contains sodium starch glycolate and / or croscarmellose sodium.   The manufacturing method of Claim 1 in which the said pharmaceutical composition contains a sodium lauryl sulfate and / or a sucrose fatty acid ester.   In the method for producing a pharmaceutical composition containing erlotinib hydrochloride, the method is a production method in which A-type crystals are used as erlotinib hydrochloride to be subjected to granulation, and granulation is performed in a wet manner, and this pharmaceutical composition comprises sodium starch glycolate, and / or Or the manufacturing method containing croscarmellose sodium and containing sodium lauryl sulfate and / or a sucrose fatty acid ester.   The manufacturing method in any one of Claims 1-4 whose wet granulation is fluidized-bed granulation. The manufacturing method in any one of Claims 1-5 whose said pharmaceutical composition is a tablet.