Solid dispersion, and formulation containing solid dispersion

Abstract

To provide, in one embodiment, a solid dispersion of olaparib wherein olaparib is dispersed in an amorphous form, the production of olaparib-related substances is inhibited, and the dissolution properties of olaparib are sufficiently improved, and also to provide, in another embodiment, an olaparib-containing formulation that contains a solid dispersion of olaparib wherein olaparib is dispersed in an amorphous form, the production of olaparib-related substances is inhibited, and the dissolution properties of olaparib are sufficiently improved.SOLUTION: According to an embodiment, a solid dispersion contains olaparib, a copolymer of vinyl acetate and vinyl pyrrolidone, and hypromellose, hydroxypropylcellulose, or polyvinyl alcohol.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] One embodiment of the present invention relates to a solid dispersion and a formulation comprising the solid dispersion.

[0002] Olaparib (4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one) is an oral molecular targeted drug that selectively inhibits poly(ADP-ribose) polymerase (PARP) and is used as a therapeutic agent for cancers such as breast cancer and ovarian cancer. Since olaparib is a poorly soluble drug, in Patent Document 1, a solid dispersion containing olaparib and a copolymer of vinyl acetate and vinylpyrrolidone, which exhibits low hygroscopicity and a high softening temperature, is used to improve the dissolution of olaparib. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Patent No. 5524220 Summary of the Invention [Problem to be solved by the invention]

[0004] According to the description in Patent Document 1, olaparib is a poorly soluble drug, and a solid dispersion of a copolymer of vinyl acetate and vinylpyrrolidone is expected to improve the dissolution property. However, as a result of the studies by the present inventors, the improvement of the dissolution property of olaparib is insufficient in the solid dispersion of olaparib using the copolymer of vinyl acetate and vinylpyrrolidone as a carrier described in Patent Document 1, and there is room for improvement.

[0005] The present invention aims to solve the above problems, and has as its object to disperse olaparib in an amorphous form in a solid dispersion of olaparib, suppress the formation of related substances of olaparib, and sufficiently improve the dissolution property of olaparib. Alternatively, in one embodiment, it has as its object to provide an olaparib-containing formulation including a solid dispersion of olaparib in which olaparib is dispersed in an amorphous form, suppresses the formation of related substances of olaparib, and sufficiently improves the dissolution property of olaparib. [Means for solving the problem]

[0006] According to one embodiment of the present invention, there is provided a solid dispersion comprising olaparib, a copolymer of vinyl acetate and vinylpyrrolidone, and hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol.

[0007] The weight ratio of olaparib:copolymer:hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol may be 1:1.0-1.6:0.2-1.2.

[0008] The weight ratio of olaparib:copolymer:hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol may be 1:1.3-1.5:0.3-1.0.

[0009] The weight ratio of olaparib:copolymer:hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol may be 1:1.4-1.5:0.4-0.9.

[0010] Furthermore, according to one embodiment of the present invention, there is provided an olaparib-containing formulation comprising the solid dispersion and one or more pharma- ceutically acceptable excipients. Effect of the Invention

[0011] According to one embodiment of the present invention, there is provided a solid dispersion of olaparib in which olaparib is dispersed in an amorphous form, the production of related substances of olaparib is suppressed, and the dissolution property of olaparib is sufficiently improved. Alternatively, according to one embodiment of the present invention, there is provided an olaparib-containing formulation comprising a solid dispersion of olaparib in which olaparib is dispersed in an amorphous form, the production of related substances of olaparib is suppressed, and the dissolution property of olaparib is sufficiently improved. [Brief description of the drawings]

[0012] [Figure 1] 1 is a graph showing the results of a dissolution test of an example of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The solid dispersion and olaparib-containing formulation according to the present invention will be described in detail below. However, the solid dispersion and olaparib-containing formulation according to the present invention are not limited to the description of the following embodiments and examples.

[0014] The solid dispersion according to one embodiment of the present invention comprises olaparib, a copolymer of vinyl acetate and vinylpyrrolidone, and hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol. In one embodiment, the solid dispersion is a pharmaceutical composition in which olaparib is dispersed in a carrier comprising a copolymer of vinyl acetate and vinylpyrrolidone, and hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol. The solid dispersion is a solid pharmaceutical composition in which a drug is dispersed in an inactive base, and refers to a solid pharmaceutical composition in which the drug is in an amorphous form. Thus, the solid dispersion according to this embodiment comprises olaparib in an amorphous form.

[0015] As a result of the study by the present inventors, as will be described in the Examples below, in a solid dispersion using a copolymer of vinyl acetate and vinylpyrrolidone as a carrier, sufficient dissolution of olaparib cannot be obtained. Therefore, as a result of studying other carriers that can be used in solid dispersions, it was found that in solid dispersions using hypromellose or hydroxypropyl cellulose as a carrier, when each is used alone, olaparib is crystallized. From this result, it is expected that a solid dispersion in which olaparib is dispersed in hypromellose or hydroxypropyl cellulose cannot naturally obtain good dissolution of olaparib.

[0016] In one embodiment, surprisingly, in the solid dispersion according to this embodiment, olaparib is dispersed in a carrier comprising a combination of a copolymer of vinyl acetate and vinylpyrrolidone and hypromellose or hydroxypropyl cellulose in a specific ratio, thereby maintaining the amorphous form of olaparib, inhibiting the production of related substances of olaparib, and achieving high dissolution properties.

[0017] Furthermore, the inventors have thoroughly investigated carriers to be combined with a copolymer of vinyl acetate and vinylpyrrolidone, and as a result, have found that by dispersing olaparib in a carrier combining a copolymer of vinyl acetate and vinylpyrrolidone with polyvinyl alcohol in a specific ratio, it is possible to maintain the amorphous form of olaparib, inhibit the production of substances related to olaparib, and obtain high dissolution properties.

[0018] Generally, polymers such as polyethylene glycol, polyvinylpyrrolidone, vinyl acetate copolymer, methacrylic acid copolymer, and cellulose derivatives are used as carriers for solid dispersions containing olaparib. However, as is clear from the fact that olaparib crystallizes in solid dispersions using hypromellose or hydroxypropylcellulose alone as a carrier, whether or not olaparib can maintain its amorphous form varies greatly depending on the polymer used as a carrier for solid dispersions containing olaparib. For this reason, it is not easy to select a carrier or combination thereof that can maintain the amorphous form of olaparib. In addition, it is not easy to predict whether sufficient improvement in dissolution can be achieved by combining carriers.

[0019] Furthermore, as shown in the comparative examples described later, whether or not the formation of related substances of olaparib in the solid dispersion can be suppressed greatly varies depending on the polymer used as a carrier for the solid dispersion containing olaparib. Therefore, it is not easy to select a combination of carriers that can suppress the formation of related substances of olaparib in the solid dispersion while achieving an amorphous form of olaparib and sufficiently improving the dissolution property of olaparib.

[0020] Therefore, it is generally difficult to find a combination of additives that maintains the amorphous state, improves dissolution property, and suppresses related substances, and furthermore, it is extremely difficult to optimize the combination to a specific ratio.

[0021] In one embodiment, the solid dispersion according to the present invention comprises olaparib, a copolymer of vinyl acetate and vinylpyrrolidone, and hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol. By combining olaparib with a copolymer of vinyl acetate and vinylpyrrolidone, and hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol, it is possible to maintain the amorphous form of olaparib, suppress the formation of related substances, and obtain sufficient dissolution properties.

[0022] The copolymer of vinyl acetate and vinylpyrrolidone contained in the solid dispersion according to this embodiment is a copolymer of 1-vinyl-2-pyrrolidone (VP) and vinyl acetate (VA), and the mass ratio of vinyl acetate to vinylpyrrolidone is 3: 2. When quantitatively determined, the copolymer of vinyl acetate and vinylpyrrolidone contains 35.3 to 42.0% vinyl acetate (C4H6O2: 86.09) and 7.0 to 8.0% nitrogen (N: 14.01) based on the calculated dry matter.

[0023] In one embodiment, the weight ratio of olaparib:copolymer of vinyl acetate and vinylpyrrolidone:hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol is preferably 1:1.0-1.6:0.2-1.2, more preferably 1:1.3-1.5:0.3-1.0, and even more preferably 1:1.4-1.5:0.4-0.9. When the weight ratio of olaparib:copolymer of vinyl acetate and vinylpyrrolidone:hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol is within this range, the amorphous form of olaparib can be maintained, the generation of related substances can be suppressed, and higher dissolution can be obtained. When the weight ratio of olaparib:copolymer of vinyl acetate and vinylpyrrolidone:hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol is not within the above range, it may be difficult to maintain the amorphous form of olaparib, suppress the generation of related substances, and obtain higher dissolution.

[0024] The inventors have discovered that by using a carrier containing a copolymer of vinyl acetate and vinylpyrrolidone together with hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol in a specific ratio, olaparib can be dispersed in an amorphous state, the production of related substances of olaparib can be suppressed, and the dissolution property of olaparib can be sufficiently improved. This is a new discovery that has not been reported previously, and is not easily conceivable from the prior art.

[0025] [Olaparib-containing formulation] The olaparib-containing formulation of the present invention contains, in addition to the solid dispersion described above, one or more pharma- ceutically acceptable excipients.

[0026] Pharmaceutically acceptable additives contained in the olaparib-containing formulation include excipients, binders, disintegrants, lubricants, etc. One or more of these additives can be selected to form the olaparib-containing formulation. In addition, the formulation may contain an additive that is a combination of two or more of these additives mixed in advance.

[0027] Examples of excipients include, but are not limited to, lactose, sucrose, starch, partially pregelatinized starch, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., crystalline cellulose, cellulose), calcium sulfate, xylitol, lactitol, etc. These excipients can be used alone or in combination of two or more.

[0028] The binder may be selected from, for example, lactose, starch, partially pregelatinized starch, sugars, gum arabic, gum tragacanth, guar gum, pectin, wax binders such as carnauba wax and paraffin, crystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose, copolyvidone, gelatin, polyvinylpyrrolidone (PVP), sodium alginate, and polyvinyl alcohol (PVA), but is not limited thereto.

[0029] The disintegrant can be selected from, for example, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), and the like, but is not limited thereto.

[0030] The lubricant may be selected from, for example, magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, talc, and the like, but is not limited thereto.

[0031] In one embodiment, the olaparib-containing formulation may be a tablet, containing, but not limited to, 100 mg or 150 mg of olaparib per tablet, and the content of olaparib may be varied within a range that provides a therapeutic effect.

[0032] [Method of manufacturing solid dispersion] The solid dispersion according to the present embodiment can be produced by a thermal melting method. For example, olaparib is mixed with the copolymer of vinyl acetate and vinylpyrrolidone described above, and hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol, and the resulting mixture is heated through a thermal melter at a temperature at which the mixture melts and olaparib does not decompose, and then cooled. The cooled mixture is sized to obtain a solid dispersion. In the method for producing the solid dispersion according to the present embodiment, olaparib may be used in either crystalline or amorphous form.

[0033] [Manufacturing method of olaparib-containing formulation] The olaparib-containing formulation according to the present embodiment can be produced by mixing the solid dispersion according to the present embodiment, which contains olaparib, a copolymer of vinyl acetate and vinylpyrrolidone, hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol, and one or more of the above-mentioned pharma- ceutical acceptable additives, and compressing the resulting mixture into tablets. In addition, an additive obtained by combining two or more types of additives and mixing them in advance may be used.

[0034] [Evaluation of the crystallographic form of olaparib] The crystallographic form of olaparib can be evaluated by powder X-ray diffraction measurement. In this specification, "amorphous" means that a broad halo pattern is observed relative to the baseline in a diffraction pattern obtained by powder X-ray diffraction measurement, and no significant peaks derived from crystalline components are observed.

[0035] [Purity evaluation] In the present specification, the purity of olaparib in the solid dispersion is evaluated by quantifying the individual most related substances of olaparib using liquid chromatography. By the area percentage method, the sum of the peak areas of each component of olaparib and related substances derived from olaparib obtained on a chromatogram is set to 100, and the amount (%) of each related substance derived from olaparib is calculated from the ratio of the peak areas.

[0036] [Evaluation of dissolution] In the present specification, the dissolution property of olaparib in a solid dispersion is evaluated by the paddle method of the dissolution test using the second dissolution medium defined in the Japanese Pharmacopoeia, 18th Edition. EXAMPLES

[0037] [Study on carriers for solid dispersions] The carriers used for the solid dispersion were examined.

[0038] [Example 1] As the carrier, a copolymer of vinyl acetate and vinylpyrrolidone (PVPVA) and hydroxypropyl cellulose (HPC) were used. 15 g of olaparib crystals were mixed with 21 g of PPVVA (VA64 (registered trademark), BASF Japan Ltd.), 13.5 g of HPC (HPC-SSL, Nippon Soda Co., Ltd.), and 1.1 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation). The resulting mixture was passed through a thermal melter and cooled. The cooled mixture was pulverized in a pulverizer to obtain the solid dispersion of Example 1.

[0039] [Example 2] A copolymer of vinyl acetate and vinylpyrrolidone (PVPVA) and hypromellose (HPMC) were used as carriers. 15 g of olaparib crystals were mixed with 21 g of PPVVA (VA64 (registered trademark), BASF Japan Co., Ltd.), 13.5 g of HPMC (TC-5 (registered trademark), E, ​​Shin-Etsu Chemical Co., Ltd.), and 1.1 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation). The resulting mixture was passed through a thermal melter and cooled. The cooled mixture was pulverized in a pulverizer to obtain the solid dispersion of Example 2.

[0040] [Example 3] As a carrier, a copolymer of vinyl acetate and vinylpyrrolidone (PVPVA) and polyvinyl alcohol (PVA) were used. 15 g of olaparib crystals were mixed with 22.35 g of PPVVA (VA64 (registered trademark), BASF Japan Co., Ltd.), 7.5 g of PVA (Parteck (registered trademark) MXP, Merck Millipore Co., Ltd.), and 1.1 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation). The resulting mixture was passed through a thermal melter and cooled. The cooled mixture was pulverized in a pulverizer to obtain the solid dispersion of Example 3.

[0041] [Comparative Example 1] A copolymer of vinyl acetate and vinylpyrrolidone (PVPVA) was used as a carrier. 15 g of olaparib crystals were mixed with 34.5 g of PPVVA (VA64 (registered trademark), BASF Japan Ltd.), and 1.1 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation). The resulting mixture was passed through a thermal melter and cooled. The cooled mixture was pulverized in a pulverizer to obtain a solid dispersion of Comparative Example 1.

[0042] [Comparative Example 2] Hydroxypropyl cellulose (HPC) was used as a carrier. 10 g of olaparib crystals were mixed with 23 g of HPC (HPC-SSL, Nippon Soda Co., Ltd.) and 0.73 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation). The resulting mixture was passed through a thermal melter and cooled. The cooled mixture was pulverized in a pulverizer to obtain a solid dispersion of Comparative Example 2.

[0043] [Comparative Example 3] Hypromellose (HPMC) was used as a carrier. 10 g of olaparib crystals were mixed with 23 g of HPMC (TC-5 (registered trademark), R, Shin-Etsu Chemical Co., Ltd.) and 0.73 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation). The resulting mixture was passed through a thermal melter and cooled. The cooled mixture was pulverized in a pulverizer to obtain a solid dispersion of Comparative Example 3.

[0044] [Comparative Example 4] Polyvinylpyrrolidone (PVP) was used as a carrier. 10 g of olaparib crystals were mixed with 23 g of PVP (K30, Daiichi Kogyo Seiyaku Co., Ltd.) and 0.73 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation). The resulting mixture was passed through a thermal melter and cooled. The cooled mixture was pulverized in a pulverizer to obtain a solid dispersion of Comparative Example 4.

[0045] [Comparative Example 5] As a carrier, a copolymer of vinyl acetate and vinylpyrrolidone (PVPVA) and polyvinylpyrrolidone (PVP) were used. 15 g of olaparib crystals were mixed with 21 g of PPVVA (VA64 (registered trademark), BASF Japan Co., Ltd.), 13.5 g of PVP (K25, Daiichi Kogyo Seiyaku Co., Ltd.), and 1.1 g of light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation). The resulting mixture was passed through a thermal melter and cooled. The cooled mixture was pulverized in a pulverizer to obtain a solid dispersion of Comparative Example 5.

[0046] [Evaluation of amorphous materials] The amorphous form of olaparib in the solid dispersions of Examples 1, 2, and 3, and Comparative Examples 1 to 5 was confirmed by powder X-ray diffraction measurement. The measurement was performed using a Bruker D8 ADVANCE powder X-ray diffractometer under the conditions of Cu-Ka radiation, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 10.0 to 25.0°, scan speed: 1 sec / step, and step size: 0.015°.

[0047] The evaluation results of the amorphous form are shown in Table 1. [Table 1]

[0048] From the results in Table 1, it was confirmed that olaparib was in an amorphous form in the solid dispersions of Examples 1, 2, and 3 in which PVPVA and HPC, HPMC, or PVA were used as carriers. It was also confirmed that Comparative Examples 1, 4, and 5 in which PVPVA or PVP alone, or a combination of PVPVA and PVP were used as carriers, were also in an amorphous form. On the other hand, it was confirmed that olaparib crystallized in the solid dispersions of Comparative Examples 2 and 3 in which HPC or HPMC alone was used as a carrier. From the results in Table 1, it was revealed that when HPC or HPMC alone was used as a carrier, an amorphous form of olaparib could not be achieved.

[0049] [Purity evaluation] The solid dispersions of Example 1, Example 2, Example 3, and Comparative Example 4 were stored in a sealed state at 40°C and a relative humidity of 75% for one month. The purity of the solid dispersions of Example 1, Example 2, and Comparative Example 4 after storage was evaluated by high performance liquid chromatography. For the measurement, a high performance liquid chromatograph manufactured by Shimadzu Corporation was used, a measurement column InertSustain C18 (4.6 mmφ×150 mm, 5 μm) was installed, and the column temperature was 35°C and the flow rate was 1.0 mL / min. The mobile phase was delivered by changing the mixture ratio of mobile phase A (water / phosphoric acid mixture (1000:1)) and mobile phase B (acetonitrile) to control the concentration gradient.

[0050] The purity evaluation results are shown in Table 2.

[0051] [Table 2]

[0052] From the results in Table 2, it was confirmed that the production of related substances of olaparib was suppressed in the solid dispersions of Examples 1, 2, and 3, and the purity of olaparib was high. On the other hand, it was confirmed that the purity of olaparib in the solid dispersion of Comparative Example 4 exceeded 0.2%, which is the threshold value required for confirmation of safety. It was revealed that the solid dispersion of Comparative Example 4 was in an amorphous form, but could not suppress the production of related substances.

[0053] [Evaluation of dissolution] The solid dispersions of Example 1, Example 2, Example 3, Comparative Example 1 and Comparative Example 5 were evaluated for dissolution property using the dissolution test method of the 18th Edition of the Japanese Pharmacopoeia (paddle method, 50 rpm, second dissolution fluid).

[0054] The evaluation results of dissolution are shown in Table 3 and FIG.

[0055] [Table 3]

[0056] From the results of Table 3 and Figure 1, it was confirmed that the dissolution rate of olaparib was high in the solid dispersions of Examples 1, 2, and 3. On the other hand, in the solid dispersions of Comparative Example 1 and Comparative Example 5, the maximum dissolution rate was equivalent to that of the solid dispersions of Examples 1, 2, and 3, but the area under the dissolution rate time curve (AUC) value was low, and it was confirmed that the dissolution rate of olaparib was lower than that of the solid dispersions of Examples 1, 2, and 3. It was revealed that the dissolution rate of olaparib was sufficiently improved by using PVPVA in combination with HPMC, HPC, or PVA as a carrier for the solid dispersion containing olaparib.

Claims

1. Olaparib and A copolymer of vinyl acetate and vinylpyrrolidone; hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol.

2. 2. The solid dispersion of claim 1, wherein the weight ratio of the olaparib:the copolymer:the hypromellose, hydroxypropyl cellulose or polyvinyl alcohol is 1:1.0-1.6:0.2-1.

2.

3. 3. The solid dispersion of claim 2, wherein the weight ratio of the olaparib:the copolymer:the hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol is 1:1.3-1.5:0.3-1.

0.

4. 4. The solid dispersion of claim 3, wherein the weight ratio of the olaparib:the copolymer:the hypromellose, hydroxypropyl cellulose, or polyvinyl alcohol is 1:1.4-1.5:0.4-0.

9.

5. An olaparib-containing formulation comprising the solid dispersion according to any one of claims 1 to 4 and one or more pharma- ceutically acceptable excipients.

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