METHOD FOR MANUFACTURING PREPARATION FOR INJECTION

Abstract

A method for manufacturing a preparation for injection, including a first step of performing at least one treatment selected from the group consisting of a treatment of mixing benzyl benzoate with an antioxidant, a treatment of heating benzyl benzoate, and a treatment of purifying benzyl benzoate and a second step of mixing the benzyl benzoate treated by the first step with fulvestrant.

Claims

1. A method for manufacturing a preparation for injection, comprising: a first step of performing at least one treatment selected from the group consisting of a treatment of mixing benzyl benzoate with an antioxidant, a treatment of heating benzyl benzoate, and a treatment of purifying benzyl benzoate; and a second step of mixing the benzyl benzoate treated by the first step with fulvestrant.

2. The method for manufacturing a preparation for injection according to claim 1, wherein the antioxidant in the treatment of mixing benzyl benzoate with an antioxidant is at least one kind of compound selected from the group consisting of ascorbic acid, ascorbic acid palmitate, thiourea, -tocopherol, -tocopherol, -thioglycerin, cysteine hydrochloride, dihydrolipoic acid, dibutylhydroxytoluene, and propyl gallate.

3. The method for manufacturing a preparation for injection according to claim 1, wherein the antioxidant in the treatment of mixing benzyl benzoate with an antioxidant is ascorbic acid.

4. The method for manufacturing a preparation for injection according to claim 1, wherein an amount of the antioxidant in the treatment of mixing benzyl benzoate with an antioxidant is 0.1% by mass to 2% by mass with respect to an amount of benzyl benzoate.

5. The method for manufacturing a preparation for injection according to claim 1, wherein the treatment of mixing benzyl benzoate with an antioxidant is a treatment of mixing benzyl benzoate with an antioxidant and a medically acceptable solvent.

6. The method for manufacturing a preparation for injection according to claim 5, wherein the medically acceptable solvent is an alcohol.

7. The method for manufacturing a preparation for injection according to claim 6, wherein the alcohol is at least one alcohol selected from the group consisting of ethanol, benzyl alcohol, propylene glycol, polyethylene glycol, and glycofurol.

8. The method for manufacturing a preparation for injection according to claim 6, wherein the alcohol is at least one alcohol selected from the group consisting of ethanol, benzyl alcohol, and propylene glycol.

9. The method for manufacturing a preparation for injection according to claim 1, wherein in the treatment of heating benzyl benzoate, benzyl benzoate is heated to 40 C. to 150 C.

10. The method for manufacturing a preparation for injection according to claim 1, wherein the treatment of purifying benzyl benzoate is performed by at least one kind of technique selected from the group consisting of purification using a column, purification by distillation, and purification by extraction.

Description

EXAMPLES

[0175] Hereinafter, the present invention will be more specifically described with reference to examples. However, as long as the gist of the present invention is maintained, the present invention is not limited to the following examples.

[0176] [Manufacturing of Preparation for Injection]

Example A1

[0177] (First Step: Mixing Treatment)

[0178] Benzyl benzoate (15 parts by mass), 0.05 parts by mass of ascorbic acid, 10 parts by mass of 96% by volume ethanol, and 10 parts by mass of benzyl alcohol were put in a clean glass container including a stirring rod, and mixed together by stirring in the air.

[0179] The mixing time was 30 minutes, and the atmospheric temperature at the time of mixing was 25 C.

[0180] As the benzyl benzoate, Benzyl Benzoate from Merck KGaA was used (quantitative value (assay) 100.3%, manufacturing lot No. K46888906 551).

[0181] (Second Step)

[0182] Then, in the air, the benzyl benzoate-containing mixture obtained through the first step (that is, the mixing treatment) was mixed with 5 parts by mass of fulvestrant, thereby obtaining a fulvestrant-containing solution.

[0183] The mixing time was 30 minutes, and the atmospheric temperature at the time of mixing was 25 C.

[0184] (Third Step)

[0185] Subsequently, castor oil was added to the fulvestrant-containing solution such that the total amount thereof was adjusted to 100 parts by mass, and the solution was homogenized by being further stirred, thereby obtaining a preparation for injection of Example A1.

Examples A2 to A13

[0186] Preparations for injection of Examples A2 to A13 were obtained by performing the same operation as that in Example A1, except that the composition of the antioxidant and the solvent used in the first step was changed to the composition shown in the following Table 1.

Example A14

[0187] A preparation for injection of Example A14 was obtained by performing the same operation as that in Example A1, except that the composition of the antioxidant and the solvent used in the first step was changed to the composition shown in the following Table 1, and the amount of fulvestrant in the second step was changed to 2 parts by mass.

Examples A15 and A16

[0188] Preparations for injection of Examples A15 and A16 were obtained by performing the same operation as that in Example A1, except that the mixing condition in the first step was changed to the condition described in the following Table 1.

Comparative Example A1

[0189] A preparation for injection of Comparative Example A1 was obtained by performing the same operation as that in Example A1, except that the first step and the second step were changed to the following step a, and a third step was performed after the step a.

[0190] (Step a)

[0191] That is, 5 parts by mass of fulvestrant, 15 parts by mass of benzyl benzoate, 0.05 parts by mass of ascorbic acid, 10 parts by mass of 96% by volume ethanol, and 10 parts by mass of benzyl alcohol were put in a clean glass container including a stirring rod, and mixed together by stirring.

[0192] The mixing time was 30 minutes, and the atmospheric temperature at the time of mixing was 25 C.

Comparative Example A2

[0193] A preparation for injection of Comparative Example A2 was obtained by performing the same operation as that in Comparative Example A1, except that ascorbic acid was used in the step a.

[0194] [Evaluation]

[0195] Measurement of Fulvestrant Sulfone

[0196] Each of the preparations for injection of examples and comparative examples obtained as above was weighed (110 L) and put in a glass vial having a volume of 5 mL (manufactured by NICHIDEN-RIKA GLASS CO., LTD., model: SV-5). Furthermore, by using a transfer pipette, methanol for HPLC was added thereto exactly in an amount of 1 mL, and the resulting solution was stirred using a vortex mixer, thereby obtaining a homogeneous solution.

[0197] The obtained solution was filtered using an all plastic syringe and a Millex syringe filter (manufactured by Merck Millipore, pore size: 0.22 m, material: PVDF), thereby obtaining an evaluation sample 1.

[0198] For the preparation for injection of Example A14, the evaluation sample 1 was obtained by the following method.

[0199] That is, the preparation for injection of Example A14 was weighed (275 L) and put in a glass vial having a volume of 5 mL (manufactured by NICHIDEN-RIKA GLASS CO., LTD., model: SV-5). Furthermore, by using a transfer pipette, methanol for HPLC was added thereto exactly in an amount of 1 mL, and the resulting solution was stirred using a vortex mixer, thereby obtaining a homogeneous solution.

[0200] The obtained solution was filtered using an all plastic syringe and a Millex syringe filter (manufactured by Merck Millipore, pore size: 0.22 m, material: PVDF), thereby obtaining an evaluation sample 1.

[0201] The obtained evaluation sample 1 was measured by high performance liquid chromatography (HPLC) under the following condition, and the proportion (% by mass) of fulvestrant sulfone was determined.

[0202] Furthermore, the proportion (% by mass) of fulvestrant sulfone in the bulk drug of fulvestrant used in examples and comparative examples was determined by preparing an evaluation sample 2.

[0203] The evaluation sample 2 was prepared as follows.

[0204] That is, 50 mg of the bulk drug of fulvestrant was weighed and put in a glass volumetric flask having a volume of 10 mL, and the volume was increased using methanol for HPLC.

[0205] The obtained solution was filtered using an all plastic syringe and a Millex syringe filter (manufactured by Merck Millipore, pore size: 0.22 m, material: PVDF), thereby obtaining a measurement sample 2.

[0206] The obtained evaluation sample 2 was measured by high performance liquid chromatography (HPLC) under the following conditions, and the proportion (% by mass) of fulvestrant sulfone was determined.

[0207] HPLC Condition

[0208] Column: XBridge C8 (product name, particle size: 3.5 m, column size: 4.6 mm150 mm, WATERS)

[0209] Mobile phase A: water/acetonitrile/methanol=41/32/27

[0210] Mobile phase B: water/acetonitrile/methanol=10/49/41

[0211] Gradient condition (proportion of mobile phase B): 0% (start).fwdarw.0% (25 min).fwdarw.100% (55 min).fwdarw.100% (65 min).fwdarw.0% (66 min).fwdarw.0% (70 min, stop)

[0212] Detection wavelength: 225 nm

[0213] Flow rate: 2.0 mL/min

[0214] Column temperature: 40 C.

[0215] From a proportion X (% by mass) of fulvestrant sulfone in the evaluation sample 1 and a proportion Y (% by mass) of fulvestrant sulfone in the evaluation sample 2, the rate of increase in fulvestrant sulfone was calculated by the following equation.

[0216] Rate of increase in fulvestrant sulfone (%)=[proportion X (% by mass)proportion Y (% by mass)]/proportion Y (% by mass)100

[0217] Then, from the calculated rate of increase in fulvestrant sulfone, the increase in fulvestrant sulfone at the time of formulating the preparation was evaluated based on the following evaluation standard.

[0218] Evaluation Standard

[0219] A: The rate of increase in fulvestrant sulfone is equal to or lower than 100%.

[0220] B: The rate of increase in fulvestrant sulfone is higher than 100% and equal to or lower than 150%.

[0221] C: The rate of increase in fulvestrant sulfone is higher than 150% and equal to or lower than 200%.

[0222] D: The rate of increase in fulvestrant sulfone is higher than 200%.

TABLE-US-00001 TABLE 1 Antioxidant Solvent Mixing condition Amount Amount Amount Mixing Atmospheric [part by [part by [part by time temperature Rate of increase in Type mass] Type mass] Type mass] [min] [ C.] fulvestrant sulfone [%] Evaluation Example A1 Ascorbic acid 0.05 EtOH 10 BnOH 10 30 25 89 A Example A2 Ascorbic acid 0.05 EtOH 10 BnOH 10 30 25 95 A palmitate Example A3 -Tocopherol 0.05 EtOH 10 BnOH 10 30 25 176 C Example A4 -Tocopherol 0.05 EtOH 10 BnOH 10 30 25 190 C Example A5 Thiourea 0.05 EtOH 10 BnOH 10 30 25 7 A Example A6 -Thioglycerin 0.05 EtOH 10 BnOH 10 30 25 52 A Example A7 Cysteine 0.05 EtOH 10 BnOH 10 30 25 66 A hydrochloride Example A8 Dihydrolipoic acid 0.05 EtOH 10 BnOH 10 30 25 50 A Example A9 Dibutylhydroxytoluene 0.05 EtOH 10 BnOH 10 30 25 157 C Example A10 Propyl gallate 0.05 EtOH 10 BnOH 10 30 25 177 C Example A11 Ascorbic acid 0.02 EtOH 10 BnOH 10 30 25 80 A Example A12 Ascorbic acid 0.10 EtOH 10 BnOH 10 30 25 82 A Example A13 Ascorbic acid 0.05 PG 10 BnOH 10 30 25 120 B Example A14 Ascorbic acid 0.05 PEG400 10 BnOH 10 30 25 117 B Example A15 Ascorbic acid 0.05 EtOH 10 BnOH 10 60 25 166 C Example A16 Ascorbic acid 0.05 EtOH 10 BnOH 10 60 40 85 A Comparative Ascorbic acid 0.05 EtOH 10 BnOH 10 30 25 246 D Example A1 Comparative EtOH 10 BnOH 10 30 25 236 D Example A2

[0223] In Table 1, Ethanol is described as EtOH, Propylene glycol is described as PG, polyethylene glycol (Wako Pure Chemical Industries, Ltd., polyethylene glycol 400) is described as PEG400, and benzyl alcohol is described as BnOH.

[0224] In Table 1, the mixing condition described for Examples A1 to A16 is the mixing condition in the first step, and the mixing condition described for Comparative Examples A1 and A2 is the mixing condition in the step a.

[0225] As is evident from Table 1, in the preparations for injection of Examples A1 to A16, the rate of increase in fulvestrant sulfone is reduced further than in the preparations for injection of Comparative Examples A1 and A2, and the increase in fulvestrant sulfone at the time of formulating the preparations for injection of Examples A1 to A16 is suppressed.

[0226] In Examples A1 to A16, the mixing treatment in the first step was performed in the air. However, in a case where the mixing treatment was performed in a nitrogen atmosphere, the rate of increase in fulvestrant sulfone tended to be further reduced.

Example B1

[0227] (First Step: Heating Treatment)

[0228] Benzyl benzoate was dispensed into a vial under a nitrogen atmosphere, and the vial was stopped with an aluminum seal and heated to 121 C. in an autoclave for 20 minutes.

[0229] As the benzyl benzoate, Benzyl Benzoate from Merck KGaA was used (quantitative value (assay) 100.3%, manufacturing lot No. K46888906 551).

[0230] (Second Step)

[0231] The benzyl benzoate (15 parts by mass) obtained through the first step (that is, heating treatment), 10 parts by mass of 96% by volume ethanol, 10 parts by mass of benzyl alcohol, and 5 parts by mass of fulvestrant were put in a clean glass container including a stirring rod, and mixed together by stirring, thereby obtaining a fulvestrant-containing solution.

[0232] The mixing time was 30 minutes, and the atmospheric temperature at the time of mixing was 25 C.

[0233] (Third Step)

[0234] Subsequently, castor oil was added to the fulvestrant-containing solution such that the total amount thereof was adjusted to 100 parts by mass, and the solution was homogenized by being further stirred, thereby obtaining a preparation for injection of Example B 1.

[0235] For the obtained preparation for injection of Example B1, the rate of increase in fulvestrant sulfone was measured and evaluated by the same method as that described above.

[0236] As a result, it has been found that in the preparation for injection of Example B1, the rate of increase in fulvestrant sulfone was 147% which is lower than the rate of increase in fulvestrant sulfone in the preparation for injection of Comparative Example A2, and the increase in fulvestrant sulfone at the time of formulating the preparation for injection of Example B1 is suppressed.

Example C1

[0237] (First Step: Purification Treatment)

[0238] Benzyl benzoate was purified by passing through a solid phase column (InertSep AL-N, GL Sciences Inc.).

[0239] As the benzyl benzoate, Benzyl Benzoate from Merck KGaA was used (quantitative value (assay) 100.3%, manufacturing lot No. K46888906 551).

[0240] (Second Step)

[0241] The benzyl benzoate (15 parts by mass) obtained through the first step (that is, purification treatment), 10 parts by mass of 96% by volume ethanol, 10 parts by mass of benzyl alcohol, and 5 parts by mass of fulvestrant were put in a clean glass container including a stirring rod, and mixed together by stiffing, thereby obtaining a fulvestrant-containing solution.

[0242] The mixing time was 30 minutes, and the atmospheric temperature at the time of mixing was 25 C.

[0243] (Third Step)

[0244] Subsequently, castor oil was added to the fulvestrant-containing solution such that the total amount thereof was adjusted to 100 parts by mass, and the solution was homogenized by being further stirred, thereby obtaining a preparation for injection of Example C1.

[0245] For the obtained preparation for injection of Example C1, the rate of increase in fulvestrant sulfone was measured and evaluated by the same method as that described above.

[0246] As a result, it has been found that in the preparation for injection of Example C1, the rate of increase in fulvestrant sulfone was 4% which is lower than the rate of increase in fulvestrant sulfone in the preparation for injection of Comparative Example A2, and the increase in fulvestrant sulfone at the time of formulating the preparation for injection of Example C1 is suppressed.

[0247] As described above, it has been found that in a case where a preparation for injection is manufactured by performing at least one treatment selected from the group consisting of a treatment of mixing benzyl benzoate with an antioxidant, a treatment of heating benzyl benzoate, and a treatment of purifying benzyl benzoate and then mixing the treated benzyl benzoate with fulvestrant, the increase in fulvestrant sulfone at the time of formulating the preparation is suppressed.

[0248] The entire disclosure of Japanese Patent Application No. 2018-015311 filed on Jan. 31, 2018 is incorporated into the present specification by reference.

[0249] All documents, patent applications, and technical standards described in the present specification are incorporated into the present specification by reference, as if each of the documents, the patent applications, and the technical standards is specifically and individually described.