JP2017206488A - Gefitinib tablet and method for producing gefitinib tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tablet that has a high content of gefitinib and is reduced in size, and a method of producing the same.SOLUTION: A gefitinib tablet has the content of gefitinib of 60 mass% or more. Preferably, the mass ratio of an excipient to a disintegrator [excipient/disintegrator] is 10.0 or less, and more preferably, the mass ratio of the excipient to the disintegrator [excipient/disintegrator] is 6.0 or less.SELECTED DRAWING: None

Description

  The present invention relates to a gefitinib tablet containing gefitinib as an active ingredient and a method for producing the same.

  Gefitinib, i.e. N- (3-chloro-4-fluorophenyl) -7-methoxy-6- [3- (morpholine-4-yl) propoxy] quinazolin-4-amine, is inoperable or recurrent non-small It is known as a therapeutic agent for cell lung cancer (see Patent Document 1). As gefitinib tablets, tablets containing 250 mg of gefitinib in one tablet are marketed.

Japanese Patent No. 4544863

  However, the above-mentioned tablet on the market is a tablet having a total weight of about 500 mg containing 250 mg of gefitinib and approximately the same amount of additives in one tablet, and has a diameter of about 11 mm and a thickness of about 5.4 mm. I must. Such large tablets are difficult to swallow, and are particularly difficult to administer to the elderly and others with poor swallowing ability.

  The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a tablet having a large content of gefitinib and reduced in size and a method for producing the tablet.

The present invention has the following configuration.
[1] A gefitinib tablet having a gefitinib content of 60% by mass or more.
[2] The gefitinib tablet according to [1], wherein the mass ratio of the excipient to the disintegrant [excipient / disintegrant] is 10.0 or less.
[3] The gefitinib tablet according to [2], wherein the mass ratio of the excipient to the disintegrant [excipient / disintegrant] is 6.0 or less.
[4] The gefitinib tablet according to any one of [1] to [3], wherein the disintegrant content is 2.0% by mass or more.
[5] The gefitinib tablet according to any one of [1] to [4], wherein the content of the excipient is 30% by mass or less.
[6] The gefitinib tablet according to any one of [1] to [5], which does not contain stearic acid, sodium stearyl fumarate, glycerin fatty acid ester, sucrose fatty acid ester, talc, or calcium stearate.
[7] A method for producing a gefitinib tablet having a gefitinib content of 60% by mass or more, a granulation step of granulating a granulating powder containing gefitinib, and a granulated product obtained by the granulation step A method for producing a gefitinib preparation comprising a compression step of compressing a powder for compression comprising:
[8] The method for producing gefitinib tablets according to [7], wherein the gefitinib tablet contains a disintegrant and the disintegrant is added to the granulating powder.

  ADVANTAGE OF THE INVENTION According to this invention, the content of gefitinib is large and can provide the tablet reduced in size and its manufacturing method.

Hereinafter, the present invention will be described in detail.
[Gefitinib tablets]
The gefitinib tablet of the present invention (hereinafter also simply referred to as “tablet”) contains 60% by mass or more of gefitinib as an active ingredient in 100% by mass of the tablet.
The content of gefitinib in the tablet is preferably 70% by mass or more, and more preferably 80% by mass or more. When the content of gefitinib in the tablet is not less than the above lower limit, the tablet can be miniaturized. Further, since gefitinib has binding properties, the content in the tablet is increased as in the above range, and even if the content of additives such as excipients is relatively small, sufficient moldability is ensured, Can be tableted without problems.

  The content of gefitinib in 100% by mass of the tablet is preferably 95% by mass or less, more preferably 90% by mass or less, and further preferably 85% by mass or less. When the content of gefitinib in the tablet is not more than the above upper limit value, an additive can be contained in the tablet, and the characteristics of the contained additive can be imparted to the tablet.

The tablet of the present invention may contain one or more additives. Examples of additives include disintegrants, excipients, binders, surfactants, lubricants, colorants, fluidizing agents, etc. Any additive that can be used in the pharmaceutical field is used. it can.
The tablet of the present invention preferably contains a disintegrant among the additives, and the content of the disintegrant is preferably 2.0% by mass or more, more preferably 5.0% by mass or more in 100% by mass of the tablet. Preferably, 5.8% by mass or more is more preferable, and 6.3% by mass or more is particularly preferable. When the content of the disintegrant in the tablet is not less than the above lower limit, even if the tablet is miniaturized by increasing the content of gefitinib in the tablet, the dissolution property can be maintained well. On the other hand, the disintegrant content in 100% by mass of the tablet may be 15% by mass or less because the dissolution improvement effect tends to saturate even if the addition amount of the disintegrant is increased by a certain amount or more. 10 mass% or less is more preferable.

  Examples of disintegrants include cellulosic disintegrants (croscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropylcellulose, etc.), crospovidone, starch disintegrants (corn starch, sodium starch glycolate, partial Alpha-modified starch, hydroxypropyl starch, etc.) can be used, and one or more of these can be used, but from the viewpoint of disintegration and dissolution, cellulosic disintegrants are preferred, and croscarmellose sodium is particularly preferred. It is preferable to use it.

  The tablet of the present invention may contain an excipient for the purpose of further improving tablet moldability and the like. However, as described above, the gefitinib tablet of the present invention does not necessarily contain an excipient because it is excellent in tablet moldability. It does not have to be contained. In the case of containing an excipient, the additive amount of the excipient is preferably 30% by mass or less in 100% by mass of the tablet, 25% by mass or less, 1 to 20% by mass, or 1 to 10% by mass. There may be. When an excipient is contained, the lower limit of the excipient content in 100% by mass of the tablet is not particularly limited, and is, for example, about 0.01% by mass.

  Examples of the excipient include crystalline cellulose, lactose hydrate, anhydrous lactose, purified white sugar, D-mannitol, potato starch, pregelatinized starch, etc., and one or more of these can be used. It is preferable to use at least one of cellulose and lactose hydrate.

In the gefitinib tablet of the present invention, the mass ratio of the excipient to the disintegrant [excipient / disintegrant] is preferably 10.0 or less, more preferably 6.0 or less, and further preferably 4.0 or less. 1.0 or less is particularly preferable. Thereby, even if the gefitinib content in the tablet is increased and the tablet is reduced in size, the dissolution property can be maintained well and the tablet moldability is also excellent.
In addition, content here is content on a mass basis.
The mass ratio of the excipient to the disintegrant [excipient / disintegrant] is preferably 0.5 or more from the viewpoint that both the disintegration and dissolution properties of the tablet and the tablet moldability are excellent.

Examples of the binder include povidone (polyvinylpyrrolidone), hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), polyvinyl alcohol, stearyl alcohol, ammonio methacrylate copolymer, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, dextrin, water candy One or more of these can be used, and povidone is particularly preferred.
Examples of the surfactant include sodium lauryl sulfate and polyoxyethylene sorbitan monolaurate. One or more of these can be used, and sodium lauryl sulfate is particularly preferable.
Examples of the colorant include yellow ferric oxide, ferric oxide, edible yellow No. 4, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, etc., one of these The above can be used.
Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, heavy anhydrous silicic acid, and synthetic aluminum silicate, and one or more of these can be used.
Examples of other additives include polymers having a vinyl alcohol unit (for example, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer, etc.), titanium oxide, etc. Among them, polyvinyl alcohol is preferable in terms of stability.

As the lubricant, known ones can be used, but magnesium stearate is preferably used, and neither stearic acid, sodium stearyl fumarate, glycerin fatty acid ester, sucrose fatty acid ester, talc or calcium stearate is used. It is preferable. When using at least one of stearic acid, sodium stearyl fumarate, glycerin fatty acid ester, sucrose fatty acid ester, talc and calcium stearate as a lubricant, the mixture (powder for compression) used for tableting adheres to wrinkles, etc. For example, the tablet formability may be inferior. On the other hand, by using magnesium stearate, even if the content of gefitinib in the tablet is large, the tablet moldability is more excellent.
When the tablet contains stearic acid, sodium stearyl fumarate, glycerin fatty acid ester, sucrose fatty acid ester, talc and calcium stearate, the total content thereof may be 0.5% by mass or less in 100% by mass of the tablet. preferable.

Examples of the tablet of the present invention include ordinary tablets and intraoral quick disintegrating tablets that disintegrate with saliva or a small amount of water. The ordinary tablet may be composed of only a plain tablet, or may be a film-coated tablet (FC tablet) comprising a plain tablet and a coating covering the plain tablet.
In the case of an FC tablet, the coating preferably contains a polymer having a vinyl alcohol unit exemplified as an additive (for example, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer). Among these, polyvinyl alcohol is preferable in terms of stability. On the other hand, the polyvinyl alcohol / polyethylene glycol / graft copolymer may precipitate from the coating.

[Method for producing tablets]
The tablet production method of the present invention is a method for producing a gefitinib tablet containing gefitinib in an amount of 60% by mass or more, and is obtained by granulating a granulating powder containing gefitinib, and obtained by the granulation step. A compression step of compressing the powder for compression including the granulated product. When the tablet of the present invention is an FC tablet, it may further have a coating step for coating the uncoated tablet obtained in the compression step.

When producing a tablet containing a disintegrant, (1) a method of adding the total amount of the disintegrant used to the granulating powder, (2) a method of adding the total amount of the disintegrant used to the powder for compression, (3) Although there is a method of adding a part of the disintegrant to be used to the granulating powder and adding the remaining amount to the compressing powder, etc., in terms of obtaining tablets that are more excellent in disintegration and dissolution properties, the above It is preferable to employ the method (1).
The present inventor considers this point as follows.
That is, by adding the total amount of the disintegrant to the granulating powder, excessive aggregation of gefitinib particles after the tablet disintegrates is suppressed, and as a result, the disintegration and dissolution properties of the tablet are considered to be excellent.
The granulation step, the compression step, and the coating step can be performed by known methods.

[Examples 1 to 5, Comparative Example 1]
Tablets (uncoated tablets) were produced according to the formulation shown in Table 1 below.
Gefitinib, lactose hydrate, crystalline cellulose, croscarmellose sodium (ND2HS), povidone, sodium lauryl sulfate are mixed to obtain a granulating powder, water is added to the granulating powder, and the mixture is granulated. Drying and sizing were performed. Magnesium stearate was added to the resulting granulated product and mixed to obtain a powder for compression. The powder for compression was subjected to tableting with a single tableting machine to obtain an uncoated tablet. About the obtained uncoated tablet (tablet), tableting property was evaluated as dissolution property and tablet moldability as follows. The results are shown in Table 1.

<Elution properties>
The dissolution test was performed at 50 revolutions per minute by the paddle method using one obtained tablet and 900 mL of the test solution (pH 5.0, diluted Mclvaine buffer).
After a predetermined time from the start of the test (in this example, the results after 15 minutes and 60 minutes are shown as follows), 10 mL or more of the eluate was collected and filtered through a membrane filter having a pore size of 0.45 μm or less. In each filtrate, 5 mL of the filtrate collected first was removed, 1 mL of the next filtrate was accurately weighed, and 9 mL of 0.1 mol / L hydrochloric acid test solution was accurately added. 2 mL of this solution was accurately weighed and 2 mL of 0.1 mol / L hydrochloric acid test solution was added accurately to obtain a sample solution.
Separately, about 28 mg of gefitinib for quantification (separately measuring moisture) was accurately weighed and dissolved in 0.1 mol / L hydrochloric acid test solution to make exactly 100 mL. 5 mL of this solution was accurately weighed and 0.1 mol / L hydrochloric acid test solution was added to make exactly 100 mL to obtain a standard solution.
The sample solution and the standard solution were tested by the UV-visible absorbance measurement method, and the absorbance at a wavelength of 341 nm was measured. The elution rate (%) of each sample solution at a predetermined time was determined based on the absorbance of the standard solution.

<Tabletability>
The state of adhesion of the powder for compression to the punches of the tableting machine after tableting was visually confirmed and evaluated in three stages. The evaluation results are indicated by the following symbols.
○: Almost no adhesion to the soot.
Δ: Slight adhesion to the soot is observed.
X: Adhesion to wrinkles is remarkable.

As shown in Table 1, the tablet of Comparative Example 1 had a mass of 500 mg, whereas the tablets of Examples 1 to 5 had a mass of 300 to 400 mg, and were sufficiently miniaturized.
Moreover, the tablet of Examples 1-5 compared with the tablet of the comparative example 1 in the dissolution test using the test liquid of pH 5.0, and the dissolution rate after 15 minutes and 60 minutes is comparable, Despite being miniaturized, it had good dissolution properties.
Furthermore, the tablets of Examples 1 to 5 were hardly observed to adhere to the wrinkles.

[Example 6]
Uncoated tablets were obtained in the same manner as Example 1. Next, the obtained uncoated tablet contains a coating solution (water and ethanol (the mass ratio of water to ethanol is 1: 1), polyvinyl alcohol, polyethylene glycol, titanium oxide, iron sesquioxide, and yellow iron sesquioxide. Liquid) was coated with a coating machine (Pyreck Co., Doria Coater), dried, and then polished with Carnauba wax to obtain FC tablets having the coating formulations shown in Table 2.
About the obtained FC tablet, dissolution property and tablet moldability were evaluated in the same manner as in Example 1. The results are shown in Table 2.

  As shown in Table 2, the formulation of Example 6 had a mass of about 300 mg, was downsized, and no problem was found in dissolution and tableting properties.

[Examples 7 to 12]
An uncoated tablet (tablet) was obtained in the same manner as in Example 1 except that other lubricants shown in Table 3 were used instead of the magnesium stearate used in Example 1, and tableting property was evaluated. . The results are shown in Table 3.
As shown in Table 3, in Examples 7 to 12 using a lubricant other than magnesium stearate, some adhesion to the ridge was observed during tableting molding.

Claims (8)

  A gefitinib tablet having a gefitinib content of 60% by mass or more.   The gefitinib tablet according to claim 1, wherein the mass ratio of the excipient to the disintegrant [excipient / disintegrant] is 10.0 or less.   The gefitinib tablet according to claim 2, wherein the mass ratio of the excipient to the disintegrant [excipient / disintegrant] is 6.0 or less.   The gefitinib tablet as described in any one of Claims 1-3 whose content of a disintegrating agent is 2.0 mass% or more.   The gefitinib tablet as described in any one of Claims 1-4 whose content of an excipient | filler is 30 mass% or less.   The gefitinib tablet according to any one of claims 1 to 5, which does not contain stearic acid, sodium stearyl fumarate, glycerin fatty acid ester, sucrose fatty acid ester, talc and calcium stearate. A method for producing a gefitinib tablet having a gefitinib content of 60% by mass or more,
A method for producing a gefitinib preparation comprising a granulation step of granulating a granulating powder containing gefitinib, and a compression step of compressing a compression powder containing a granulated product obtained in the granulation step. The gefitinib tablet contains a disintegrant;
The method for producing gefitinib tablets according to claim 7, wherein the disintegrant is added to the granulating powder.