JPH0848632A - Solid composition containing etoposide and solid preparation - Google Patents

Abstract

PURPOSE:To obtain the solid preparation having dissolving and eluting properties nearly equal to those of a liquid preparation, small in the size of the produced preparation, because the amount of the used base material is small, a little in the dosage of the preparation, and capable of being easily administered. CONSTITUTION:The solid solution-like solid composition comprises (A) etoposide and (B) a base agent selected from a water-soluble cellulose ether, polyvinyl pyrrolidone and their mixture, the amount of the component B being 2-4 pts.wt., preferably 2-3 pts.wt., per one pt.wt. of the component A. The water-soluble cellulose ether includes hydroxypropyl cellulose, especially the compound wherein the contents of the methyl group and the hydroxypropoxyl group are 19.0-30.0% and 4.0-12.0%, respectively. The polyvinyl pyrrolidone has a mol.wt. of 25000-1200000, especially approximately 40000. The composition is obtained by dissolving both the components in an organic solvent, and subsequently distilling off the organic solvent or spraying the solution on nuclear particles, etc.

Description

Detailed Description of the Invention

[0001]

The present invention relates to etoposide [chemical name:
4'-demethylepipodophyllotoxin-9- (4,6
-O-ethylidene-β-D-glucopyranoside)] and a specific base material in the form of a solid solution and a solid preparation containing the solid composition.

More specifically, a solid solution solid composition comprising (a) etoposide and (b) a water-soluble cellulose ether, polyvinylpyrrolidone and a mixture thereof, and a solid preparation containing the solid composition. Regarding

[0003]

2. Description of the Related Art Etoposide is a poorly water-soluble substance that exhibits antitumor activity and is poor in oral absorbability in ordinary preparations.
The device is designed to improve the solubility.

For example, JP-A-61-189230 and JP-A-3-86830 disclose a liquid composition in which etoposide, a water-soluble cellulose derivative or polyvinylpyrrolidone is dissolved in a base containing liquid polyalkylene glycol as a main component. A capsule filled with this is disclosed. At present, soft capsules filled with a liquid composition in which etoposide is dissolved are sold under the trade name of, for example, lastet or bepside.

[0005] Such a liquid composition has improved water solubility of etoposide and excellent oral absorbability, but its liquid form has a limitation in the formulation form, and for example, it cannot be in the form of fine granules or tablets. Moreover, its formulation is more complicated than that of a solid composition.

Therefore, a solid composition of etoposide with improved solubility is desired.

As a solid etoposide composition having improved solubility of etoposide, a solid solution composition (solid dispersion) comprising etoposide and polyethylene glycol 8000 is prepared by the Drug Development and
Industrial Pharmacy, Volume 19, 8
Issue, pp. 903-914 (1993) and Inter.
national Journal of Pharm
acoustics, 84, pp. 223-232 (199
2 years).

[0008]

However, in the above solid solution composition, in order to obtain sufficient solubility and elution of etoposide, it is necessary to use a large amount of polyethylene glycol 8000 as a base for etoposide. There is [Drug Development and I
ndustrial Pharmacy, Volume 19, 8
No., pp. 903-914 (1993), see later-described test example], an etoposide preparation formulated using this inevitably becomes large in size, and the dose as a preparation is large, so that it is difficult to take. is there.

The object of the present invention is to provide a solid composition having good solubility and elution properties comparable to those of known liquid compositions, and having a small amount of base, and an easy-to-administer etoposide containing the composition. To provide a solid preparation of

[0010]

As a result of intensive studies, the present inventors have found that (i) etoposide and (b) a solid solution comprising a base selected from water-soluble cellulose ethers, polyvinylpyrrolidone and mixtures thereof. The present invention was completed by finding that a solid solid composition and an etoposide preparation produced using the solid composition are suitable for the purpose of the present invention.

The water-soluble cellulose ether used in the present invention is obtained by substituting a part of the alcohol group, which is a glucose residue in cellulose, into a form such as methyl ether, hydroxypropyl ether and / or hydroxyethyl ether, and It is soluble in water.

As the water-soluble cellulose ether,
Examples thereof include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like.

The above-mentioned methylcellulose preferably has a methoxyl group content of 26.0 to 33.0%, and is preferably used in the 12th revised Japanese Pharmacopoeia (published by Dai-ichi Law Publishing Company, 1991,
The methyl cellulose described on page 1070 of the following abbreviation) is preferably used. This is, for example, Metroses S
The product name M (manufactured by Shin-Etsu Chemical Co., Ltd.) is available. The hydroxypropyl cellulose preferably has a hydroxypropoxyl group content of 53.4 to 77.5%, and the hydroxypropyl cellulose described on page 1023 of the Pharmacopoeia is preferably used. This is, for example, Nisso HPC
The product having the following trade name (manufactured by Nippon Soda Co., Ltd.) can be obtained. Hydroxypropyl methylcellulose has a methoxyl group content and a hydroxypropoxyl group content of 19.
0 to 30.0%, 4.0 to 12.0% are preferable, and hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906 and hydroxypropylmethylcellulose 2910 described on pages 1025 and 1027 of the Pharmacopoeia are preferably used. It These can be obtained, for example, under the trade names of Metroz 90SH, Metroz 65SH and TC-5 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Among the above-mentioned hydroxypropyl methylcellulose, the content of methoxyl group and hydroxyproposyl group is 28.0-3, respectively.
0.0% and 7.0 to 12.0% are particularly preferable,
Hydroxypropyl methylcellulose 2910 described on page 1027 of the Pharmacopoeia is particularly preferably used.

Among the above water-soluble cellulose ethers, hydroxypropylmethyl cellulose is particularly preferable.

Polyvinylpyrrolidone has a molecular weight of about 250.
Those having a molecular weight of about 40,000 can be used, but those having a molecular weight of about 40,000 are preferable, and those having a molecular weight of 1057
Polyvinylpyrrolidone K30 described on page is preferably used.

The solid composition of the present invention uses water-soluble cellulose ether or polyvinylpyrrolidone as a base. Further, these polymer compounds can be appropriately mixed and used as a base.

The solid solution solid composition of the present invention is prepared by dissolving etoposide and the above-mentioned base in an organic solvent (this liquid is referred to as a solid solution solution), and then distilling off the organic solvent, or the solid solution solution will be described later. It can be produced by spraying the core particles or adding a solid solution to the core particles, and then distilling off the solvent.

The amount of the above-mentioned base compounded is usually 2 to 4 parts by weight, preferably 2 to 3 parts by weight, based on 1 part by weight of etoposide.

When the amount of the base compounded is 1 part by weight or less relative to 1 part by weight of etoposide, a solid solution composition cannot be obtained, and when it is 5 parts by weight or more, the volume of the composition becomes large, This is not preferable because the preparation produced using this will be large.

The organic solvent is not particularly limited as long as it is a solvent capable of dissolving both etoposide and the above-mentioned base, and examples thereof include methanol, ethanol, isopropanol, acetone, chloroform and dichloromethane.
One kind or a mixture of two or more kinds can be used. The amount of the organic solvent used in the solid solution solution is appropriately 1.2 to 3 times the amount required to completely dissolve the etoposide and the base at room temperature.

As the core particles, one kind or a mixture of two or more kinds of usual excipients used in medicines (eg starch, sucrose, lactose, glucose, mannitol etc.) can be used. In addition to the above-mentioned excipients, binders (eg hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, gelatin, gum arabic, carmellose etc.), disintegrants (eg crystalline cellulose, starch etc.), lubricants (eg magnesium stearate) , Talc, etc.) and a surfactant (for example, sodium lauryl sulfate, etc.) may be added to form a powdery or granulated product, and these may be used as core particles. The average particle size of these core particles is preferably 100 to 500 μm, but is not particularly limited.

The composition of the present invention produced as described above comprises
The etoposide is a solid solution substance or core particles in which the etoposide is present in a non-crystalline (amorphous) state in the base material and the solid solution substance is adsorbed.

The solid preparation of the present invention includes solid preparations containing the composition of the present invention, such as powders, fine granules, capsules, tablets and dry syrup, which are orally administered.

The above powders and fine granules can be prepared, for example, by sizing the composition of the present invention and, if necessary, mixing it with an excipient, a lubricant and the like. Granules are prepared by mixing the composition of the present invention with an excipient, a disintegrating agent, etc., and subjecting it to a wet granulation method (extrusion granulation method, tumbling granulation method, fluidized bed granulation method, spray granulation method, etc. )
It can be prepared by granulating by a dry granulation method (crushing granulation method, etc.). Capsules and tablets are prepared by adding the above-mentioned powders, fine granules or granules, and if necessary, the above-mentioned excipients, disintegrating agents, lubricants, surfactants and fluidizing agents (eg light anhydrous silicic acid). After the addition, it can be prepared by filling capsules or compression molding them. The dry syrup is obtained by sizing the composition of the present invention, if necessary, and adding a corrigent (eg sucrose), an emulsifier (eg polysorbate 80 etc.), a suspending agent (eg carmelose sodium etc.) and the like. Can be prepared.

[0025]

In the composition and preparation of the present invention, etoposide exists in an amorphous state in a base material selected from water-soluble cellulose ether, polyvinylpyrrolidone and a mixture thereof (see Test Example 2 described later). In addition, despite having a solid composition or a solid preparation, it has solubility and dissolution properties comparable to those of the liquid preparation (see Test Examples 1 and 3 described below). Moreover, in the composition of the present invention, since the amount of the base used is small, the preparation produced from the composition is small and the dose as the preparation is small. Further, the composition of the present invention and the solid preparation of the present invention have good storage stability (see Test Example 4 described below). Therefore, the solid preparation of the present invention has good absorbability and is useful as a solid preparation that can be easily taken.

The effects of the present invention will be described in detail below with reference to test examples. Incidentally, the etoposide content in the test example, using para-bromophenol as an internal standard substance,
High performance liquid chromatography under the following conditions (hereinafter referred to as HPLC)
Method).

Conditions of HPLC method: Column: Wakosil-II 5C18 [150 m
m × 4.6 mm, manufactured by Wako Pure Chemical Industries, Ltd.]-Eluent: mixed solution of 6 volumes of water and 4 volumes of methanol-Column temperature: 40 ° C-Flow rate: 1.3 ml / min-Detection method: Absorbance at UV285 nm Measurement

[Test Example] Test Example 1 (Solubility Test) 1) Sample (a) Composition of Example 1 [etoposide: hydroxypropylmethylcellulose = 1: 3 (weight ratio)] (b) Composition of Comparative Example 1 Product [etoposide: polyethylene glycol 8000 = 1: 5 (weight ratio)] (c) Composition of Comparative Example 2 [etoposide: polyethylene glycol 8000 = 1: 40 (weight ratio)] (d) Etoposide bulk powder 2) Test method Add a sample equivalent to 3 mg of etoposide to 3 ml of water.
The mixture was stirred at ℃ for 72 hours and then filtered, and the etoposide content in the filtrate was quantified by the HPLC method. 3) Test Results Table 1 shows the amount of etoposide dissolved and the amount of bulk etoposide dissolved in the composition of Example 1, the composition of Comparative Example 1 and the composition of Comparative Example 2.

[0029]

[Table 1] As described above, the composition of the present invention exhibits excellent solubility as compared with the composition of Comparative Example and bulk etoposide powder even if the amount of the base used is small.

Test Example 2 (Powder X-ray Diffraction Test) 1) Sample (a) Composition of Example 1 [etoposide: hydroxypropylmethylcellulose = 1: 3 (weight ratio)] (b) Composition of Example 2 [ Etoposide: Polyvinylpyrrolidone = 1: 3 (weight ratio)] (C) Composition of Example 4 [Etoposide: Hydroxypropylmethylcellulose = 1: 2 (weight ratio)] 2) Test method By powder X-ray diffraction method under the following conditions: The presence or absence of a unique peak of the etoposide crystal was examined.

Powder X-ray Diffraction Measurement Conditions-Using RINT1000 manufactured by Rigaku Denki Co., Ltd., Ni filter, CuKα ray (40 kV, 20 mA), scanning speed 3
Measured in ° / min. 3) Test Results No specific peak of etoposide crystals was observed in any of the compositions of the present invention, and it was confirmed that etoposide was present in an amorphous state in the base material.

Test Example 3 (Dissolution test) 1) Sample (a) Composition of Example 1 [etoposide: hydroxypropylmethylcellulose = 1: 3 (weight ratio)] (b) Composition of Example 2 [etoposide: polyvinyl Pyrrolidone = 1: 3 (weight ratio)] (C) Preparation of Example 3 [Preparation in which core particles adsorb etoposide: hydroxypropylmethylcellulose = 1: 3 (weight ratio)] (2) Composition of Comparative Example 1 [Etoposide: polyethylene glycol 8000 = 1: 5 (weight ratio)] (e) Composition of Comparative Example 2 [etoposide: polyethylene glycol 8000 = 1: 40 (weight ratio)] (f) Soft capsule (commercially available product) 2 ) Test method In a 200 ml Erlenmeyer flask, 100 m of water was used as a test solution.
1), keep the temperature at 37 ° C in a constant temperature layer, add a sample of 100 mg of etoposide to the test solution while stirring, and elute the etoposide at certain time intervals (after 5, 15, 30 and 60 minutes). The dissolution rate was determined by the HPLC method. 3) Test results Figure 1 shows the change in elution rate of etoposide from each sample over time.
Shown in

The compositions and preparations of the present invention all showed very good dissolution properties, which were equivalent to or higher than those of the commercially available soft capsules filled with the liquid preparation.
On the other hand, in the composition of Comparative Example 1, the elution amount was inferior even if the amount of the base material (polyethylene glycol 8000) used was larger than that in the case of the present invention. When a large amount of the base material (polyethylene glycol 8000) was used (composition of Comparative Example 2), the same dissolution rate as that of the composition of the present invention was exhibited for the first time.

Test Example 4 (Storage Stability Test) The sample was stored at 40 ° C. for 6 months under a sealed stopper or at 40 ° C. under a relative humidity of 75% for 1 month, and the etoposide residual ratio in the sample and The etoposide elution rate from the sample was measured to examine the storage stability. 1) Sample (a) The composition of Example 1 [etoposide: hydroxypropylmethylcellulose = 1: 3 (weight ratio)] (b) The preparation of Example 3 [etoposide: hydroxypropylmethylcellulose = 1: 3 (weight ratio)] Preparation adsorbed on core particles] (C) Commercial soft capsule 2) Test method a) Measurement of residual rate of etoposide in sample Quantitated by HPLC method to determine residual rate with respect to content at the start of the storage stability test. b) Measurement of elution rate In a 200 ml Erlenmeyer flask, 100 m of water was used as a test solution.
1, and kept at 37 ° C. in a constant temperature layer, and while stirring with a stirrer, a sample corresponding to 100 mg of etoposide was added to the test solution, and a certain time elapsed (after 5, 15, 30 and 60 minutes).
The elution amount of etoposide from the sample was quantified for each case by the HPLC method to obtain the elution rate. 3) Test results The results are shown in Table 2. The * mark in the table indicates the test result when stored at 40 ° C. and 75% relative humidity.

[0035]

[Table 2] The compositions and preparations of the present invention showed good storage stability without any decrease in etoposide content (residual rate) or dissolution rate after long-term storage.

[0036]

EXAMPLES The present invention will be described below with reference to examples and comparative examples.

Example 1 2.5 g of etoposide and 7.5 g of hydroxypropylmethylcellulose (trade name: TC-5E: manufactured by Shin-Etsu Chemical Co., Ltd., conforming to the pharmacopoeia) were dissolved in 250 ml of a mixed solution of dichloromethane / ethanol (8: 2). The solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure at about 60 ° C. After crushing this,
Sifted through a sieve having an opening of 500 μm to obtain 10 g of the powdery composition of the present invention.

Example 2 0.5 g of etoposide and 1.5 g of polyvinylpyrrolidone (molecular weight about 40,000, manufactured by BASF, conforming to pharmacopoeia)
50 ml of a mixture of dichloromethane and ethanol (8: 2)
After dissolving in, the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure at about 60 ° C. After crushing this, it was sieved with a sieve having an opening of 500 μm to obtain 2 g of the powdery composition of the present invention.

Example 3 1) Preparation of core particles D-mannitol 3675 g and lactose 1000 g were fluidized in a fluidized bed granulation dryer, and hydroxypropylmethyl cellulose (TC-5E: manufactured by Shin-Etsu Chemical Co., Ltd., conforming to the pharmacopoeia). The product) was sprayed with an aqueous solution of 100 g dissolved in 3 l of water, granulated, and dried. 25 g of sodium lauryl sulfate was mixed with this granulated product to obtain 4700 g of core particles. 2) Preparation of preparation 1.5 g of etoposide and 4.5 g of hydroxypropylmethyl cellulose (TC-5E: manufactured by Shin-Etsu Chemical Co., Ltd., conforming to the pharmacopoeia) are added to dichloromethane / ethanol (8: 2).
It was dissolved in 75 ml of the mixed solution. While stirring 54 g of the above-mentioned core particles, the above-mentioned solution was added, dried and then sized with a sieve having an opening of 500 μm to obtain 60 g of the fine granules of the present invention.

Example 4 0.5 g of etoposide and 1.0 g of hydroxypropylmethyl cellulose (TC-5E: manufactured by Shin-Etsu Chemical Co., Ltd., conforming to the pharmacopoeia) were added to dichloromethane / ethanol (8: 2).
After dissolving in 100 ml of the mixed solution, the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure at about 60 ° C. After crushing this, open 50
It was passed through a 0 μm sieve to obtain 1.5 g of the powdery composition of the present invention.

Comparative Example 1 0.3 g of etoposide and polyethylene glycol 80
1.5 g of 00 was stirred under heating (about 80 ° C.), allowed to cool at room temperature to solidify, and then pulverized to an opening of 500 μ.
Sifted through a m sieve to obtain 1.8 g of the powdery composition of Comparative Example 1.

Comparative Example 2 0.3 g of etoposide and polyethylene glycol 80
12 g of 00 was dissolved by stirring under heating (about 80 ° C.), and this was left to cool at room temperature to solidify, then pulverized and sieved with a sieve having an opening of 500 μm to give the powder of Comparative Example 2. Substances 12.
3 g were obtained.

[Brief description of drawings]

FIG. 1 Elution of etoposide from the composition of Example 1, the composition of Example 2, the formulation of Example 3, the composition of Comparative Example 1, the composition of Comparative Example 2 and a commercial soft capsule over time. The rate transition is shown.

[Explanation of symbols]

 Elution rate of etoposide from the composition of Example 1 Elution rate of etoposide from the composition of Example 2 Elution rate of etoposide from the preparation of Example 3 * Elution of etoposide from the composition of Comparative Example 1 Rate + Elution rate of etoposide from the composition of Comparative Example 2 □ Elution rate of etoposide from commercial soft capsule

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display area A61K 47/32 GB 47/38 GB BC07H 17/04

Claims (6)

[Claims] 1. A solid solution solid composition comprising (a) etoposide and (b) a base selected from water-soluble cellulose ether, polyvinylpyrrolidone and a mixture thereof. 2. The solid composition in the form of a solid solution according to claim 1, wherein the water-soluble cellulose ether is hydroxypropylmethyl cellulose. 3. The solid solution solid composition according to claim 1, which comprises 1 part by weight of etoposide and 2 to 4 parts by weight of a base. 4. The content of 1 part by weight of etoposide and the contents of methoxyl group and hydroxypropoxyl group are each 19.0.
~ 30.0%, 4.0 to 12.0% hydroxypropyl methylcellulose 2 to 4 parts by weight of a solid composition in the form of a solid solution. 5. One part by weight of etoposide and a molecular weight of about 250.
00 to about 1200000 polyvinylpyrrolidone 2 to 4
A solid composition in the form of a solid solution consisting of 1 part by weight. 6. An etoposide solid preparation containing the solid solution solid composition according to claim 1.