WO2016140219A1 - ナノ共結晶を含有する懸濁液または組成物およびこれらの製造方法 - Google Patents
ナノ共結晶を含有する懸濁液または組成物およびこれらの製造方法 Download PDFInfo
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- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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Definitions
- the present invention relates to a suspension or composition containing nano-cocrystals and a method for producing them.
- the conventional techniques may not be sufficient for improving the dissolution properties of organic compounds (particularly poorly soluble drugs).
- the present invention has been made paying attention to such circumstances, and an object thereof is to improve the elution of an organic compound as compared with the prior art.
- Consists of an organic compound and a co-crystal former and contains a co-crystal that does not dissociate by wet grinding, a polymer having a weight average molecular weight of 3,000 or more and a surfactant having a weight average molecular weight of less than 3,000.
- the surfactant is at least one selected from the group consisting of sodium dodecyl sulfate, cetyltrimethylammonium bromide, polysorbate 80, and sodium dioctylsulfosuccinate.
- the method according to one. [10] The method according to any one of [1] to [8], wherein the surfactant is sodium dodecyl sulfate.
- any of the above [26] to [29], wherein the polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, methacrylic acid copolymer and Poloxamer 407 The suspension according to any one of the above.
- the surfactant is at least one selected from the group consisting of sodium dodecyl sulfate, cetyltrimethylammonium bromide, polysorbate 80, and sodium dioctylsulfosuccinate.
- a suspension according to one. [35] The suspension according to any one of [26] to [33], wherein the surfactant is sodium dodecyl sulfate.
- amount of the surfactant is 0.5 to 10 parts by weight with respect to 100 parts by weight of the nanococrystal.
- Nano-cocrystal composed of an organic compound and a co-crystal former, having an average particle size of 300 nm or less, a polymer having a weight average molecular weight of 3,000 or more, and a surface activity having a weight average molecular weight of less than 3,000
- composition according to [56], wherein the ratio of the water solubility (mg / mL) of the co-crystal former to the water solubility (mg / mL) of the organic compound is less than 1.0 ⁇ 10 5 .
- the ratio of water solubility (mg / mL) of the co-crystal former / water solubility (mg / mL) of the organic compound is 5.0 ⁇ 10 4 or less.
- composition according to any one of [56] to [65] wherein the amount of the polymer is 1.5 to 250 parts by weight with respect to 100 parts by weight of the nanococrystal.
- amount of the polymer is 5 to 100 parts by weight with respect to 100 parts by weight of the nanococrystal.
- amount of the surfactant is 0.5 to 10 parts by weight with respect to 100 parts by weight of the nanococrystal.
- FIG. 1 is an X-ray diffraction pattern of an organic compound and a co-crystal before wet pulverization, and an X-ray diffraction pattern of a nano-ized organic compound and a nano-co-crystal after wet pulverization obtained by a powder X-ray diffraction method
- FSD-UREA dissociation
- FSD-ACT co-crystal before wet grinding (h) FSD-ACT (dissociation) after wet grinding
- FIG. 2 is an X-ray diffraction pattern of an organic compound and a co-crystal before wet pulverization, and an X-ray diffraction pattern of a nano-ized organic compound and a nano-co-crystal after wet pulverization obtained by a powder X-ray diffraction method ( 2 (A): (a) CBZ before wet grinding, (b) nano-sized CBZ after wet grinding, (c) CBZ-SAC co-crystal before wet grinding, (d) CBZ-SAC nanocrystals after wet grinding FIG.
- A powder X-ray diffraction method
- FIG. 3 is a Raman spectrum of a powder of an organic compound and a co-crystal, and a Raman spectrum of a suspension of a nano-ized organic compound and a nano-co-crystal (FIG.
- FIG. 3 (A): (a) CBZ powder, (b) Suspension of nano CBZ, (c) powder of CBZ-SAC co-crystal, (d) suspension of CBZ-SAC nano co-crystal;
- FIG. 5 shows the first solution of the Japanese Pharmacopoeia dissolution test using a suspension of nano CBZ, a suspension of CBZ-SAC nano
- FIG. 6 is a graph showing CBZ concentration-time in plasma of a diluted suspension (concentration: 5 mg / mL) of nanoized CBZ and CBZ-SAC nanococrystals obtained by wet grinding.
- the meanings of the abbreviations are as described in the examples.
- FIG. 7 is a solid state 13 C NMR spectrum of a suspension of IMC-SAC nanococrystal ((a) IMC powder, (b) SAC powder, (c) IMC-SAC cocrystal before wet milling. Powder, (d) suspension of IMC-SAC nanococrystal after wet grinding, (e) HPMC powder, (f) SDS powder). The meanings of the abbreviations are as described in the examples.
- FIG. 7 is a solid state 13 C NMR spectrum of a suspension of IMC-SAC nanococrystal ((a) IMC powder, (b) SAC powder, (c) IMC-SAC cocrystal before wet milling
- a solution 1 H NMR spectrum such as a suspension of CBZ-SAC nanococrystals ((a) CBZ-SAC nanococrystal suspension (1% (w / v) HPMC and 0. 02% (w / v SDS), (b) suspension of CBZ-SAC nanococrystals (1% (w / v) HPMC and 0.05% (w / v) SDS), (c ) Suspension of CBZ-SAC nanococrystal (1% (w / v) HPMC and 0.12% (w / v) SDS), (d) SAC heavy aqueous solution, (e) 0.5% A heavy aqueous solution containing (w / v) HPMC and 0.02% (w / v) SDS).
- the meanings of the abbreviations are as described in the examples.
- a co-crystal that is not dissociated by wet pulverization is a polymer having a weight average molecular weight of 3,000 or more (hereinafter sometimes simply referred to as “polymer”) and a weight average molecular weight of less than 3,000.
- a suspension containing nano-cocrystals having an average particle size of 300 nm or less is produced by wet grinding in water containing a surfactant (hereinafter sometimes referred to simply as “surfactant”). And a suspension obtained by the method.
- co-crystal refers to a bond or interaction other than an ionic bond (for example, hydrogen bond, van der Waals force, ⁇ - ⁇ bond, etc.) )
- ionic bond for example, hydrogen bond, van der Waals force, ⁇ - ⁇ bond, etc.
- the organic compound and the cocrystal forming agent constituting the cocrystal are not salts.
- the organic compound and the co-crystal former can be combined with a bond or interaction other than an ionic bond to form a co-crystal
- the organic compound may be a salt
- the co-crystal former may be a salt.
- Nano co-crystal generally means a co-crystal having an average particle diameter of less than 500 nm.
- One feature of the production method of the present invention is to produce a suspension containing nano-cocrystals having an average particle size of 300 nm or less.
- the average particle size of the nano-cocrystal is preferably 250 nm or less, more preferably 200 nm or less. This average particle diameter is a value measured by a dynamic scattering method.
- the present invention is characterized by wet pulverization of the cocrystal, not the organic compound itself.
- the organic compound When the organic compound itself is wet-ground, the organic compound may be hydrated. In general, hydrates are less water soluble than anhydrides. In this respect, hydration during wet pulverization can be prevented by forming a cocrystal from the organic compound and the cocrystal former and then wet pulverizing the cocrystal. Also, as shown in Table 12 below, rather than simply wet pulverizing the organic compound, the co-crystal is formed from the organic compound and the co-crystal former, and then the co-crystal is wet pulverized to improve the absorbability. Can be made.
- the present invention is characterized in that a polymer and a surfactant are used in combination in wet pulverization of a cocrystal.
- a suspension containing nano-cocrystals with an average particle size of 300 nm or less cannot be produced. .
- the weight average molecular weight of the polymer is preferably 3,000 to 1,000,000, more preferably 3,000 to 200,000. This weight average molecular weight is a value measured by gel permeation chromatography.
- the polymer is preferably a water-soluble polymer.
- the water-soluble polymer include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, methacrylic acid copolymer, Poloxamer 407, and the like.
- the methacrylic acid copolymer include a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and ethyl acrylate, and the like.
- the amount of monomer units other than methacrylic acid in the methacrylic acid copolymer is preferably 0.5 to 4 mol, more preferably 1 to 3 mol, and still more preferably 1 to 2 mol, relative to 1 mol of methacrylic acid units.
- the concentration of the polymer in water is preferably 0.3-2.5% (w / v), more preferably 0.3-2.0% (w / v), More preferably, it is 0.3 to 1.5% (w / v).
- surfactant examples include sodium dodecyl sulfate, cetyltrimethylammonium bromide, polysorbate 80, sodium dioctylsulfosuccinate (also known as dioctylsodiumsulfosuccinate), and the like. Of these, sodium dodecyl sulfate is preferred.
- the concentration of the surfactant in the water is preferably 0.02 to 0.30% (w / v), more preferably 0.03 to 0.20% (w / v). ), More preferably 0.04 to 0.15% (w / v).
- the organic compound constituting the co-crystal may be any of a neutral compound, an acidic compound, a basic compound, and an amphoteric compound.
- the amphoteric compound means a compound having both an acidic functional group and a basic functional group.
- Examples of neutral compounds include carbamazepine, griseofulvin, progesterone, fenofibrate, and paclitaxel.
- Examples of the acidic compound include indomethacin, ibuprofen, naproxen, ketoprofen, mefenamic acid and the like.
- Examples of basic compounds include itraconazole, ketoconazole, omeprazole, cimetidine, diazepam and the like.
- Examples of amphoteric compounds include furosemide, sulfamethoxazole, piroxicam, meloxicam, enoxacin and the like. Of the above organic compounds, furosemide, carbamazepine and indomethacin are preferred.
- co-crystal forming agent constituting the co-crystal
- examples of the co-crystal forming agent constituting the co-crystal include saccharin, caffeine, fumaric acid, maleic acid, tartaric acid, succinic acid, malic acid, oxalic acid, citric acid, lactic acid, glycolic acid, hippuric acid, cinnamic acid, Malonic acid, adipic acid, mandelic acid, sebacic acid, ascorbic acid, glutamic acid, aspartic acid, glutaric acid, lysine, arginine, tryptophan, benzoic acid, nicotinic acid, salicylic acid, gentisic acid, orotic acid, pamoic acid, lauric acid, palmitic acid Acid, stearic acid, urea, piperazine, hydroquinone, tyrosine, glycine, asparagine, glutamine, valine, serine, proline, alanine, methionine
- the co-crystal can be produced from an organic compound and a co-crystal former by a known method (for example, pulverization method, slurry ripening method, etc.) as described in Non-Patent Documents 3 and 4, for example.
- a known method for example, pulverization method, slurry ripening method, etc.
- a co-crystal having a ratio of water solubility of the co-crystal former (mg / mL) / water solubility of the organic compound (mg / mL) of less than 1.0 ⁇ 10 5 . If there is a large difference in the water solubility of the organic compound and the co-crystal former, the co-crystal obtained from these may become unstable and dissociate during wet grinding.
- This ratio is more preferably 5.0 ⁇ 10 4 or less, and further preferably 1.0 ⁇ 10 4 or less.
- the water solubility is a value at 25 ° C. and 1 atm.
- the concentration of the nanococrystal in water is preferably 1 to 1000 mg / mL (ie 0.1 to 100% (w / v)), more preferably 5 to 500 mg / mL. (Ie 0.5 to 50% (w / v)), more preferably 10 to 200 mg / mL (ie 1.0 to 20% (w / v)).
- Examples of equipment used for wet grinding include planetary mills, bead mills, and attritors. Among these, a planetary mill and a bead mill using beads as a grinding medium are preferable, and a planetary mill using beads is more preferable.
- the material of the beads examples include zirconia, alumina, glass, and steel. Of these, zirconia is preferred.
- the diameter of the beads is preferably 0.01 to 5.0 mm, more preferably 0.02 to 1.0 mm.
- the amount of beads used is preferably 1 to 40% by volume, more preferably 4 to 12% by volume, based on the volume of a grinding chamber such as a planetary mill or a bead mill. It is preferable to perform wet grinding while cooling the grinding chamber.
- the temperature in the pulverization chamber during wet pulverization is preferably ⁇ 20 ° C. to 0 ° C., more preferably ⁇ 15 ° C. to ⁇ 5 ° C.
- the rotation speed of the grinding chamber is preferably 400 to 2000 rpm, more preferably 500 to 2000 rpm, and the revolution speed is 400 to 2000 rpm, more preferably 500 to 2000 rpm.
- the supply amount of the suspension to the grinding chamber of the planetary mill is preferably 1 to 40% by volume, more preferably 4 to 12% by volume with respect to the volume of the grinding chamber.
- the time for one cycle of wet grinding in the planetary mill is preferably 1 to 15 minutes, more preferably 1 to 5 minutes. In the planetary mill, wet pulverization is preferably repeated in 1 to 10 cycles, more preferably in 3 to 5 cycles.
- the rotational speed of the rotating shaft of the bead mill is preferably 500 to 5000 rpm, more preferably 1000 to 4000 rpm.
- the amount of suspension supplied to the grinding chamber of the bead mill is preferably 1 to 120 kg / hour, more preferably 6 to 60 kg / hour.
- the suspension may be repeatedly supplied to the grinding chamber of the bead mill until a nanococrystal having a desired average particle size is obtained.
- nano cocrystals having an average particle diameter of 300 nm or less may be filtered from the suspension obtained by the above production method.
- the suspension obtained by the above production method may be dried to produce a composition containing nano-cocrystal, polymer and surfactant having an average particle size of 300 nm or less.
- the description of the nanococrystal, polymer and surfactant contained in the composition obtained by this method is as described above.
- drying method examples include spray drying, heat drying, and reduced pressure drying. Of these, spray drying is preferred.
- gas used for spray drying include nitrogen and air.
- the temperature of the gas used for spray drying is preferably 25 to 120 ° C, more preferably 50 to 120 ° C.
- the amount of the polymer in the obtained composition is preferably 1.5 to 250 parts by weight, more preferably 5 to 100 parts by weight with respect to 100 parts by weight of the nanococrystal.
- the amount of the surfactant in the obtained composition is preferably 0.1 to 30 parts by weight, more preferably 0.5 to 10 parts by weight with respect to 100 parts by weight of the nano-cocrystal.
- the present invention also provides a medicament containing the suspension or composition obtained as described above.
- the medicine may be a liquid preparation (for example, injection) or a solid preparation (for example, granule, fine granule, capsule).
- the nanococrystal contained in the suspension can pass through a sterile filtration membrane (about 200 nm), for example, the suspension can be dispersed in an injection solution and then sterilized by filtration to produce an injection. it can. Further, for example, a granule can be produced by formulating a carrier sprayed with a suspension.
- a CBZ-SAC co-crystal was produced by a slurry ripening method. Specifically, equimolar CBZ and SAC were dispersed in acetonitrile, and the resulting slurry was allowed to stand overnight at room temperature. The resulting precipitate was collected by vacuum filtration and vacuum dried at room temperature to obtain a CBZ-SAC co-crystal.
- IMC-SAC co-crystal was produced by a slurry ripening method as described in Non-Patent Document 4. Specifically, equimolar IMC and SAC were dispersed in acetonitrile, and the resulting slurry was allowed to stand at room temperature for 3 days. The resulting precipitate was collected by vacuum filtration and vacuum dried at room temperature to obtain IMC-SAC co-crystal.
- FSD-CAF co-crystal 100 mg is included (5 mL, 17% by volume with respect to the volume of the grinding chamber)
- the obtained suspension was poured into a grinding chamber (dispersed in a volume of 30 mL) and containing zirconia beads (diameter 0.1 mm, 10 g, 8% by volume with respect to the volume of the grinding chamber).
- the wet pulverization was carried out by repeating the cycle of rotation and revolution at 2000 rpm for 2 minutes and rotation and revolution at 500 rpm for 2 minutes three times. During the wet grinding, the grinding chamber was maintained at ⁇ 10 ° C.
- Comparative Example 1 A nano-sized FSD suspension was prepared in the same manner as in Example 1 except that FSD was used instead of the FSD-CAF co-crystal.
- Comparative Example 5 A nano-sized CBZ suspension was produced in the same manner as in Example 1 except that CBZ was used instead of the FSD-CAF co-crystal.
- Example 6 A nano-sized IMC suspension was prepared in the same manner as in Example 1 except that IMC was used instead of the FSD-CAF co-crystal.
- a powder sample (about 2 mg) was placed on a silicon sample plate and scanned between 2 and 35 degrees (2 ⁇ ) at a scanning speed of 6 degrees / minute.
- Powder samples such as nano-sized FSD were prepared by centrifuging the suspensions at 19,000 rpm for 10 minutes with a cooling centrifuge Himac CR21G (manufactured by Hitachi Koki Co., Ltd.) and drying.
- the obtained X-ray diffraction patterns are shown in FIGS.
- the crystallinity before and after wet grinding was calculated from the obtained X-ray diffraction pattern according to the Hermans method. The results are shown in Tables 3-5.
- a suspension containing FSD, HPMC and SDS (FSD physical mixture), FSD-CAF, prepared by adjusting the concentration to be the same as the above suspension and mixing each component with a vortex mixer Suspension containing co-crystal, HPMC and SDS (FSD-CAF physical mixture), suspension containing CBZ, HPMC and SDS (CBZ physical mixture), and CBZ-SAC co-crystal, containing HPMC and SDS
- the suspension (CBZ-SAC physical mixture) the elution concentrations of FSD, FSD-CAF cocrystal, CBZ and CBZ-SAC cocrystal were measured in the same manner as described above. The results (average values) are shown in FIG. 4 and FIG.
- the CBZ concentration in the obtained plasma was measured by LC / MS / MS under the following conditions. The results (average value) are shown in FIG. From the obtained concentration curve, the maximum blood concentration (C max ) and the maximum blood concentration arrival time (T max ) of the drug were measured. The mean residence time (MRT) was calculated by moment analysis, and the area under the drug blood concentration-time curve (AUC 0-24h ) from 0 to 24 hours was calculated by the trapezoidal method.
- BA (%) 100 ⁇ (AUC po ⁇ Dose i.v. ) / (AUC i.v. ⁇ Dose p.o. ) (In the formula, AUC p.o indicates AUC by oral administration, AUC iv indicates AUC by intravenous administration, Dose p.o indicates oral dose, and D. i.v. Indicates intravenous dose.)
- the FSD and FSD-CAF co-crystals showed no significant change in the diffraction pattern before and after wet grinding (FIGS. 1 (a) to (d)).
- Pure FSD diffraction patterns were observed in the diffraction patterns of the powders obtained after wet milling of the crystals, FSD-ACT cocrystal and FSD-NIC cocrystal ((f), (h) and (J))). From these results, it can be seen that the FSD-UREA cocrystal, the FSD-ACT cocrystal, and the FSD-NIC cocrystal are dissociated by wet grinding.
- FSD-CAF having an average particle diameter of less than 200 nm and a small PDI is obtained by wet pulverization of FSD-CAF co-crystal using a polymer (HPMC) and a surfactant (SDS) in combination. A suspension of nanococrystals can be obtained.
- CBZ-SAC having an average particle size of less than 300 nm and a small PDI by wet grinding of a CBZ-SAC co-crystal using a polymer (HPMC) and a surfactant (SDS) in combination.
- HPMC polymer
- SDS surfactant
- the average particle size is less than 200 nm and the PDI is Small IMC-SAC nanococrystal suspensions can be obtained.
- the average particle size of the FSD-CAF nanococrystal, CBZ-SAC nanococrystal and IMC-SAC nanococrystal in suspension is sufficient after storage for 1 month. Was kept small. In industrial implementation, it is considered that the suspension is not stored for a long period exceeding one month.
- FSD-CAF co-crystal obtained by co-crystallization and nano-ized FSD obtained by wet-grinding are first co-crystallized and then wet-ground.
- the FSD-CAF nanococrystal obtained in this manner was excellent in the dissolution property in the first solution of the Japanese Pharmacopoeia dissolution test.
- CBZ-SAC co-crystal CBZ-SAC physical mixture obtained by co-crystallization and nano-ized CBZ obtained by wet pulverization are first co-crystallized and then wet-treated.
- the CBZ-SAC nanococrystal obtained by pulverization was excellent in the dissolution property in the first solution of the Japanese Pharmacopoeia dissolution test.
- the elution of the organic compound can be further improved by combining not only mere cocrystallization or wet pulverization but also cocrystallization and wet pulverization.
- the CBZ-SAC nanococrystal showed 1.2 times AUC 0-24h than nanonized CBZ.
- the bioavailability (BA) of nano CBZ was 78.7%, whereas the bioavailability of CBZ-SAC nanococrystal was 96.0%.
- the CBZ-SAC nanococrystal obtained by first co-crystallizing CBZ and then wet-pulverizing was superior in absorbency compared to nano-ized CBZ obtained simply by wet-grinding.
- Example 7 (1% (w / v) HPMC and 0.02% (w / v) described later, except that heavy water (D 2 O) was used instead of distilled water. ) SDS), Example 8 (1% (w / v) HPMC and 0.05% (w / v) SDS) and Example 10 (1% (w / v) HPMC and 0.12%) (W / v) SDS) 1 H NMR measurement of a suspension of CBZ-SAC nanococrystal produced by wet grinding was conducted using an NMR apparatus JNM-ECX500II (11.7T) manufactured by JEOL RESONANCE. ).
- 1 H NMR measurement was performed on a heavy aqueous solution of SAC and a heavy aqueous solution containing 0.5% (w / v) HPMC and 0.02% (w / v) SDS. Specifically, 1 H NMR measurement of the sample was performed with a 5 mm AT / FG probe at a temperature of 25 ° C., a sample rotation speed of 15 Hz, and a chemical shift standard of 4.67 ppm of HDO in heavy water as a measurement solvent. The obtained 1 H NMR spectrum is shown in FIG.
- a nanococrystal suspension having a mean particle size of 300 nm or less, a polymer, and a surfactant-containing composition are obtained by drying the nanococrystal suspension by a spray drying method or the like. I was able to.
- the present invention is useful for improving the dissolution of organic compounds, particularly for improving the dissolution of poorly soluble drugs for drug development.
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Abstract
Description
難溶性薬物の溶出性を向上させることは、医薬品開発のために重要である。難溶性薬物の溶出性を向上させる技術としては、沈殿法または湿式粉砕等による難溶性薬物の微細化、或いは難溶性薬物の塩または共結晶の形成が知られている(特許文献1~4および非特許文献1~4)。ここで「共結晶」とは、一般に、該共結晶を構成する多成分がイオン結合以外の結合または相互作用で結びついている結晶を意味する。
[3] 共結晶形成剤の水溶解度(mg/mL)/有機化合物の水溶解度(mg/mL)の比が、5.0×104以下である前記[1]に記載の方法。
[4] 共結晶形成剤の水溶解度(mg/mL)/有機化合物の水溶解度(mg/mL)の比が、1.0×104以下である前記[1]に記載の方法。
[6] ポリマーが、ヒドロキシプロピルメチルセルロースである前記[1]~[4]のいずれか一つに記載の方法。
[8] ポリマーの重量平均分子量が、3,000~200,000である前記[1]~[6]のいずれか一つに記載の方法。
[10] 界面活性剤が、ドデシル硫酸ナトリウムである前記[1]~[8]のいずれか一つに記載の方法。
[12] 水中のポリマーの濃度が0.3~2.0%(w/v)である前記[1]~[10]のいずれか一つに記載の方法。
[13] 水中のポリマーの濃度が0.3~1.5%(w/v)である前記[1]~[10]のいずれか一つに記載の方法。
[15] 水中の界面活性剤の濃度が0.03~0.20%(w/v)である前記[1]~[13]のいずれか一つに記載の方法。
[16] 水中の界面活性剤の濃度が0.04~0.15%(w/v)である前記[1]~[13]のいずれか一つに記載の方法。
[18] 水中のポリマーの濃度が0.3~2.0%(w/v)であり、界面活性剤の濃度が0.03~0.20%(w/v)である前記[1]~[10]のいずれか一つに記載の方法。
[19] 水中のポリマーの濃度が0.3~1.5%(w/v)であり、界面活性剤の濃度が0.04~0.15%(w/v)である前記[1]~[10]のいずれか一つに記載の方法。
[21] 水中のナノ共結晶の濃度が0.5~50%(w/v)である前記[1]~[19]のいずれか一つに記載の方法。
[22] 水中のナノ共結晶の濃度が1.0~20%(w/v)である前記[1]~[19]のいずれか一つに記載の方法。
[28] 共結晶形成剤の水溶解度(mg/mL)/有機化合物の水溶解度(mg/mL)の比が、5.0×104以下である前記[26]に記載の懸濁液。
[29] 共結晶形成剤の水溶解度(mg/mL)/有機化合物の水溶解度(mg/mL)の比が、1.0×104以下である前記[26]に記載の懸濁液。
[31] ポリマーが、ヒドロキシプロピルメチルセルロースである前記[26]~[29]のいずれか一つに記載の懸濁液。
[33] ポリマーの重量平均分子量が、3,000~200,000である前記[26]~[31]のいずれか一つに記載の懸濁液。
[35] 界面活性剤が、ドデシル硫酸ナトリウムである前記[26]~[33]のいずれか一つに記載の懸濁液。
[37] ポリマーの濃度が0.3~2.0%(w/v)である前記[26]~[35]のいずれか一つに記載の懸濁液。
[38] ポリマーの濃度が0.3~1.5%(w/v)である前記[26]~[35]のいずれか一つに記載の懸濁液。
[40] 界面活性剤の濃度が0.03~0.20%(w/v)である前記[26]~[38]のいずれか一つに記載の懸濁液。
[41] 界面活性剤の濃度が0.04~0.15%(w/v)である前記[26]~[38]のいずれか一つに記載の懸濁液。
[43] ポリマーの濃度が0.3~2.0%(w/v)であり、界面活性剤の濃度が0.03~0.20%(w/v)である前記[26]~[35]のいずれか一つに記載の懸濁液。
[44] ポリマーの濃度が0.3~1.5%(w/v)であり、界面活性剤の濃度が0.04~0.15%(w/v)である前記[26]~[35]のいずれか一つに記載の懸濁液。
[46] ナノ共結晶の濃度が0.5~50%(w/v)である前記[26]~[44]のいずれか一つに記載の懸濁液。
[47] ナノ共結晶の濃度が1.0~20%(w/v)である前記[26]~[44]のいずれか一つに記載の懸濁液。
[53] ポリマーの量が、ナノ共結晶100重量部に対して5~100重量部である前記[51]に記載の組成物。
[55] 界面活性剤の量が、ナノ共結晶100重量部に対して0.5~10重量部である前記[51]~[53]のいずれか一つに記載の組成物。
[58] 共結晶形成剤の水溶解度(mg/mL)/有機化合物の水溶解度(mg/mL)の比が、5.0×104以下である前記[56]に記載の組成物。
[59] 共結晶形成剤の水溶解度(mg/mL)/有機化合物の水溶解度(mg/mL)の比が、1.0×104以下である前記[56]に記載の組成物。
[61] ポリマーが、ヒドロキシプロピルメチルセルロースである前記[56]~[59]のいずれか一つに記載の組成物。
[63] ポリマーの重量平均分子量が、3,000~200,000である前記[56]~[61]のいずれか一つに記載の組成物。
[65] 界面活性剤が、ドデシル硫酸ナトリウムである前記[56]~[63]のいずれか一つに記載の組成物。
[67] ポリマーの量が、ナノ共結晶100重量部に対して5~100重量部である前記[56]~[65]のいずれか一つに記載の組成物。
[69] 界面活性剤の量が、ナノ共結晶100重量部に対して0.5~10重量部である前記[56]~[67]のいずれか一つに記載の組成物。
本発明は、湿式粉砕により解離しない共結晶を、重量平均分子量が3,000以上であるポリマー(以下、単に「ポリマー」と記載することがある。)および重量平均分子量が3,000未満である界面活性剤(以下、単に「界面活性剤」と記載することがある。)を含有する水中で湿式粉砕することによって、平均粒子径が300nm以下であるナノ共結晶を含有する懸濁液を製造する方法および該方法によって得られる懸濁液を提供する。
以下の実施例等で使用する略号の意味は以下の通りである。
(1)有機化合物
FSD:フロセミド
CBZ:カルバマゼピン
IMC:インドメタシン
(2)共結晶形成剤
SAC:サッカリン
CAF:カフェイン
UREA:尿素
ACT:アセトアミド
NIC:ニコチンアミド
(3)ポリマーおよび界面活性剤
HPMC:ヒドロキシプロピルメチルセルロース
SDS:ドデシル硫酸ナトリウム
(4)その他
FSD物理混合物:FSD、HPMCおよびSDSを含有する懸濁液
FSD-CAF物理混合物:FSD-CAF共結晶、HPMCおよびSDSを含有する懸濁液
CBZ物理混合物:CBZ、HPMCおよびSDSを含有する懸濁液
CBZ-SAC物理混合物:CBZ-SAC共結晶、HPMCおよびSDSを含有する懸濁液
有機化合物として使用したフロセミド(両性化合物、分子量=330.74g/mol、純度≧99.0%、水溶解度=0.006mg/mL)は東京化成工業株式会社から購入し、無水カルバマゼピン(中性化合物、分子量=236.27g/mol、純度≧97.0%、水溶解度=0.22mg/mL)およびインドメタシン(酸性化合物、分子量=357.79g/mol、純度≧98.0%、水溶解度=0.0095mg/mL)は和光純薬工業株式会社から購入した。
共結晶形成剤として使用したサッカリン(水溶解度=3.4mg/mL)、カフェイン(水溶解度=22mg/mL)、尿素(水溶解度=1,000mg/mL)、アセトアミド(水溶解度=2,000mg/mL)およびニコチンアミド(水溶解度=1,000mg/mL)は和光純薬工業株式会社から購入した。
ポリマーとして使用したヒドロキシプロピルメチルセルロース(TC-5Eグレード、重量平均分子量=16,000)は、信越化学工業株式会社から購入した。
界面活性剤として使用したドデシル硫酸ナトリウムは和光純薬工業株式会社から購入した。
共結晶の製造に使用した全ての有機溶媒は和光純薬工業株式会社から購入した。
(1)FSDを含む共結晶の製造
FSD-CAF共結晶、FSD-UREA共結晶、FSD-ACT共結晶およびFSD-NIC共結晶を、非特許文献3の記載に従い、数滴の有機溶媒を使用する粉砕法によって製造した。詳しくは、乳鉢に等モルのFSDおよび共結晶形成剤を秤り取り、5~6滴の有機溶媒(FSD-CAFおよびFSD-ACTにはアセトニトリルを、FSD-NICはアセトンを使用)を加えて、これらを乳棒で20分間粉砕した粉末を回収し、室温で真空乾燥させて、共結晶を得た。
CBZ-SAC共結晶をスラリー熟成法により製造した。詳しくは、等モルのCBZおよびSACをアセトニトリル中に分散させ、得られたスラリーを室温で一晩放置した。得られた沈殿物を真空ろ過で回収し、室温で真空乾燥させて、CBZ-SAC共結晶を得た。
IMC-SAC共結晶を、非特許文献4の記載に従いスラリー熟成法により製造した。詳しくは、等モルのIMCおよびSACをアセトニトリル中に分散させ、得られたスラリーを室温で3日間放置した。得られた沈殿物を真空ろ過で回収し、室温で真空乾燥させて、IMC-SAC共結晶を得た。
実施例1
0.5%(w/v)のHPMCおよび0.02%(w/v)のSDSを含有する蒸留水(以下「配合溶液」と記載する)中に、FSD-CAF共結晶(CAFの水溶解度/FSDの水溶解度=3.7×103)を分散させた後、ジルコニアビーズを用いた自転・公転ナノ粉砕機NP-100(株式会社シンキー製、遊星型ミル)によって湿式粉砕して、FSD-CAFナノ共結晶を含有する懸濁液を製造した。詳しくは、ボルテックスミキサーVTX-3000L(株式会社エル・エム・エス製)を使用して、FSD-CAF共結晶(100mg)を配合溶液(5mL、粉砕室の容積に対して17容積%)を含む粉砕室(容積30mL)中に分散させ、ジルコニアビーズ(直径0.1mm、10g、粉砕室の容積に対して8容積%)を含む粉砕室に、得られた懸濁液を注いだ。自転および公転の回転数2000rpmで2分間、および自転および公転の回転数500rpmで2分間のサイクルを3回繰り返して、湿式粉砕を行った。湿式粉砕中、粉砕室を-10℃に維持した。湿式粉砕後に得られたジルコニアビーズおよび懸濁液の混合物を、遠心フィルター/メッシュ室に移し、400rpmで1分間回転させて、ジルコニアビーズを分離し、懸濁液を回収した(水中のFSD-CAFナノ共結晶の濃度=20mg/mL=2%(w/v))。
FSD-CAF共結晶の代わりにCBZ-SAC共結晶(SACの水溶解度/CBZの水溶解度=1.5×10)を用いたこと以外は実施例1と同様にして、CBZ-SACナノ共結晶の懸濁液を製造した。
FSD-CAF共結晶の代わりにIMC-SAC共結晶(SACの水溶解度/IMCの水溶解度=3.6×102)を用いたこと以外は実施例1と同様にして、IMC-SACナノ共結晶の懸濁液を製造した。
FSD-CAF共結晶の代わりにFSDを用いたこと以外は実施例1と同様にして、ナノ化FSDの懸濁液を製造した。
FSD-CAF共結晶の代わりにFSD-UREA共結晶(UREAの水溶解度/FSDの水溶解度=1.7×105)を用いたこと以外は実施例1と同様にして、懸濁液を製造した。
FSD-CAF共結晶の代わりにFSD-ACT共結晶(ACTの水溶解度/FSDの水溶解度=3.3×105)を用いたこと以外は実施例1と同様にして、懸濁液を製造した。
FSD-CAF共結晶の代わりにFSD-NIC共結晶(NICの水溶解度/FSDの水溶解度=1.7×105)を用いたこと以外は実施例1と同様にして、懸濁液を製造した。
FSD-CAF共結晶の代わりにCBZを用いたこと以外は実施例1と同様にして、ナノ化CBZの懸濁液を製造した。
FSD-CAF共結晶の代わりにIMCを用いたこと以外は実施例1と同様にして、ナノ化IMCの懸濁液を製造した。
(1)粉末X線回折法
加速電圧40kV、管電流50mAおよびCu Kα線(λ=0.154nm)の条件でX線回折装置 Ultima IV(株式会社リガク製)を用いる粉末X線回折法により、湿式粉砕前のFSD、FSD-CAF共結晶、FSD-UREA共結晶、FSD-ACT共結晶、FSD-NIC共結晶、CBZ、CBZ-SAC共結晶、IMCおよびIMC-SAC共結晶のX線回折パターン、並びに実施例1~3および比較例1~6の湿式粉砕で得られたナノ化FSD、FSD-CAFナノ共結晶、FSD-UREA(解離)、FSD-ACT(解離)、FSD-NIC(解離)、ナノ化CBZ、CBZ-SACナノ共結晶、ナノ化IMCおよびIMC-SACナノ共結晶のX線回折パターンを測定した。詳しくは、粉末試料(約2mg)をシリコン試料プレートに置き、2および35度(2θ)間をスキャン速度6度/分でスキャンした。ナノ化FSD等の粉末試料は、それらの懸濁液を冷却遠心機 Himac CR21G(日立工機株式会社製)により19,000rpmで10分間遠心分離し、乾燥して、調製した。得られたX線回折パターンを図1および図2に示す。また、得られたX線回折パターンから、Hermans 法に従い、湿式粉砕前後における結晶化度を計算した。結果を表3~表5に示す。
励起源としての発光ダイオードレーザー(785nm、400mW)および空冷CCD検出器を備えた RXN systems(Kaiser Optical Systems 製)を使用して、CBZ、CBZ-SAC共結晶、IMCおよびIMC-SAC共結晶の粉末のラマンスペクトル、並びに実施例2および3および比較例5および6の湿式粉砕で得られたナノ化CBZ、CBZ-SACナノ共結晶、ナノ化IMCおよびIMC-SACナノ共結晶の懸濁液のラマンスペクトルを測定した。なお、粉末はガラスプレート上に置いて測定し、懸濁液は2mL石英セルに入れて測定した。スペクトルを集めるために、プローブシステムを備えた1倍対物レンズを使用した。スペクトルは、4cm-1のスペクトル幅および10秒の露光で取得した。得られたラマンスペクトルを図3に示す。
Malvern zetasizer nano ZS(Malvern Instruments Ltd. 製)を使用して、実施例1~3および比較例1、5および6の湿式粉砕で得られた懸濁液の粒子(ナノ化FSD、FSD-CAFナノ共結晶、ナノ化CBZ、CBZ-SACナノ共結晶、ナノ化IMCおよびIMC-SACナノ共結晶)の平均粒子径およびゼータ電位を測定した。平均粒子径およびゼータ電位の測定では、懸濁液をそれぞれ、蒸留水で100倍および15倍に希釈した。また、懸濁液の粒子の粒度分布を評価するため、多分散指数(PDI)も測定した。結果を表3~表5に示す。
実施例1~3および比較例1、5および6の湿式粉砕で得られたナノ化FSD、FSD-CAFナノ共結晶、ナノ化CBZ、CBZ-SACナノ共結晶、ナノ化IMCおよびIMC-SACナノ共結晶の懸濁液の物理的安定性を評価するため、これらの保存開始時、5℃または25℃で1ヶ月または3ヶ月保存後に、上記と同様にして平均粒子径およびゼータ電位を測定した。また保存3ヶ月後に、上記と同様にしてラマンスペクトルを測定した。また、保存開始時および5℃または25℃で3ヶ月保存後に、ナノ化FSD等の純度を下記条件のHPLCで測定した。なお、HPLC分析では、アセトニトリルおよび水(体積混合比3:2)の混合溶媒に懸濁液を溶解させて、100倍に希釈した試料溶液を使用した。結果を表6~表11に示す。
機器:Prominence UFLC(島津製作所製)
検出:230nm
カラム:YMC-Pack Pro C18、4.6mm i.d.×150mm、5μm
カラム温度:40℃
流量:1.0mL/分
注入量:10μL
実行時間:30分
移動相A:酢酸アンモニウム水溶液(濃度:50mM)
移動相B:アセトニトリル
グラジエントプログラム:表1
日本薬局方のパドル法において、37℃で、それぞれ250mLの日本薬局方溶出試験第1液(pH=1.2)を使用し、溶出試験装置NTR 6100A(富山産業株式会社製)のパドル回転速度を50rpmに設定して、上記懸濁液を用いて溶出試験を行った。溶出した試料を所定の時点で回収し、0.02μmのポリエチレン製メンブレンフィルター(Entegris Inc. 製)でろ過し、ろ液を上記(4)と同じ条件でHPLC測定し、実施例1および2並びに比較例1および5の湿式粉砕で得られたナノ化FSD、FSD-CAFナノ共結晶、ナノ化CBZおよびCBZ-SACナノ共結晶の溶出濃度を測定した。溶出試験は3回行った。
また、濃度が上記懸濁液と同じになるように調整し、各成分をボルテックスミキサーで混合することによって製造した、FSD、HPMCおよびSDSを含有する懸濁液(FSD物理混合物)、FSD-CAF共結晶、HPMCおよびSDSを含有する懸濁液(FSD-CAF物理混合物)、CBZ、HPMCおよびSDSを含有する懸濁液(CBZ物理混合物)、並びにCBZ-SAC共結晶、HPMCおよびSDSを含有する懸濁液(CBZ-SAC物理混合物)を用いて、それぞれ、FSD、FSD-CAF共結晶、CBZおよびCBZ-SAC共結晶の溶出濃度を上記と同様にして測定した。
結果(平均値)を図4および図5に示す。
実施例2の湿式粉砕で得られたCBZ-SACナノ共結晶の懸濁液および比較例5の湿式粉砕で得られたナノ化CBZの懸濁液の濃度を蒸留水で5mg/mLに希釈した。得られた各懸濁液を、絶食状態のCrl:CD(SD)IGSラット(8週齢、雄、日本チャールス・リバー株式会社)に経口投与した。投与用量をフリーのCBZとして25mg/5mL/kgに設定し、各懸濁液で投与を3回行った。投与後15および30分、並びに1、2、4、8および24時間に、血液サンプルを採取し、遠心分離して、血漿を得た。得られた血漿中のCBZ濃度を、下記条件のLC/MS/MSで測定した。結果(平均値)を図6に示す。得られた濃度曲線より、薬物の最高血中濃度(Cmax)および最高血中濃度到達時間(Tmax)を実測した。また、モーメント解析により平均滞留時間(MRT)を、トラペゾイダル法により、0~24時間の薬物血中濃度-時間曲線下面積(AUC0-24h)を計算した。
機器:Prominence UFLC(島津製作所製)
検出:API4000-3(株式会社エービーサイエックス製)
イオン化モード:ターボイオンスプレー
イオンポラリティモード:ポジティブ
ターボプローブ温度:550℃
カラム:CAPCELL CORE C18(2.1mm×50mm、2.7μm)
カラム温度:50℃
流量:0.5mL/分
注入量:1μL
実行時間:7分
移動相A:ギ酸アンモニウム(10mmol/L)およびギ酸(0.2体積%)の水溶液
移動相B:ギ酸(0.2体積%)のアセトニトリル溶液
グラジエントプログラム:表2
BA(%)
=100×(AUCp.o.×Dosei.v.)/(AUCi.v.×Dosep.o.)
(式中、AUCp.o.は経口投与でのAUCを示し、AUCi.v.は静脈内投与でのAUCを示し、Dosep.o.は経口投与用量を示し、Dosei.v.は静脈内投与用量を示す。)
また、図5に示されるように、共結晶化によって得られたCBZ-SAC共結晶(CBZ-SAC物理混合物)および湿式粉砕して得られたナノ化CBZよりも、まず共結晶化し、次いで湿式粉砕して得られたCBZ-SACナノ共結晶が、日本薬局方溶出試験第1液中の溶出性に優れていた。
以上のように、単なる共結晶化または湿式粉砕だけでなく、共結晶化および湿式粉砕を組み合わせることによって、有機化合物の溶出性をさらに向上させることができる。
実施例3と同様にして、0.5%(w/v)のHPMCおよび0.02%(w/v)のSDSを含有した蒸留水中で湿式粉砕することによって製造したIMC-SACナノ共結晶の懸濁液の固体13C NMR測定を、JEOL RESONANCE社製のNMR装置JNM-ECX500II(11.7T)を用いて行った。同様に、IMCの粉末、SACの粉末、湿式粉砕前のIMC-SAC共結晶の粉末、HPMCの粉末およびSDSの粉末の固体13C NMR測定を行った。詳しくは、3.2mmHX MASプローブで室温にて、交差分極マジック角回転(CP/MAS)法を用いて、6KHzの試料回転数、外部標準物質としてヘキサメチルベンゼン(-CH3:17.17ppm)を用いて、前記サンプルの固体13C NMR測定を行った。得られた固体13C NMRスペクトルを図7に示す。
蒸留水の代わりに重水(D2O)を使用したこと以外は、後述する実施例7(1%(w/v)のHPMCおよび0.02%(w/v)のSDS)、実施例8(1%(w/v)のHPMCおよび0.05%(w/v)のSDS)および実施例10(1%(w/v)のHPMCおよび0.12%(w/v)のSDS)と同様にして湿式粉砕することによって製造したCBZ-SACナノ共結晶の懸濁液の1H NMR測定を、JEOL RESONANCE社製のNMR装置JNM-ECX500II(11.7T)を用いて行った。同様に、SACの重水溶液、並びに0.5%(w/v)のHPMCおよび0.02%(w/v)のSDSを含有する重水溶液の1H NMR測定を行った。詳しくは、5mmAT/FGプローブで温度25℃にて、試料回転数15Hz、化学シフト基準は測定溶媒である重水中のHDOのピークを4.67ppmとして、前記サンプルの1H NMR測定を行った。得られた1H NMRスペクトルを図8に示す。
実施例4~14および比較例7~10
水中のポリマー(HPMC)および界面活性剤(SDS)の濃度を表13に示すように変更したこと以外は実施例2と同様に湿式粉砕して、CBZ-SACナノ共結晶の懸濁液を製造した。得られた懸濁液中のCBZ-SACナノ共結晶の平均粒子径およびPDIを、上記と同様にして測定した。結果を表13に示す。
実施例3と同様にして製造したIMC-SACナノ共結晶の懸濁液に、添加剤としてd-マンニトールを2.0%(w/v)添加し、上記と同様にして、得られた懸濁液中のIMC-SACナノ共結晶の平均粒子径およびPDIを測定した。次に、ナノスプレードライヤーB-90(BUCHI製)を用いた噴霧乾燥法(ポンプ速度1、噴霧速度25%、温度120℃、および圧力35mPa、空気気流下)にて、前記懸濁液の噴霧乾燥を行った。乾燥後、得られた乾燥粉末を回収し、蒸留水中に再懸濁させて、得られた懸濁液中のIMC-SACナノ共結晶の平均粒子径およびPDIを、上記と同様にして測定した。これらの結果を表14に示す。
Claims (13)
- 有機化合物および共結晶形成剤から構成され、湿式粉砕により解離しない共結晶を、重量平均分子量が3,000以上であるポリマーおよび重量平均分子量が3,000未満である界面活性剤を含有する水中で湿式粉砕して、平均粒子径が300nm以下であるナノ共結晶、ポリマー、界面活性剤および水を含有する懸濁液を製造する方法。
- 共結晶形成剤の水溶解度(mg/mL)/有機化合物の水溶解度(mg/mL)の比が、1.0×105未満である請求項1に記載の方法。
- ポリマーが、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ポリビニルアルコール、ポリエチレングリコール、メタクリル酸コポリマーおよびPoloxamer 407からなる群から選ばれる少なくとも一つである請求項1または2に記載の方法。
- 界面活性剤が、ドデシル硫酸ナトリウム、臭化セチルトリメチルアンモニウム、ポリソルベート80、およびナトリウム ジオクチルスルホスクシネートからなる群から選ばれる少なくとも一つである請求項1~3のいずれか一項に記載の方法。
- 水中のポリマーの濃度が0.3~2.5%(w/v)であり、界面活性剤の濃度が0.02~0.30%(w/v)である請求項1~4のいずれか一項に記載の方法。
- 請求項1~5のいずれか一項に記載の方法によって得られた懸濁液。
- 有機化合物および共結晶形成剤から構成され、平均粒子径が300nm以下であるナノ共結晶、重量平均分子量が3,000以上であるポリマー、重量平均分子量が3,000未満である界面活性剤および水を含有し、前記共結晶が湿式粉砕により解離しないものである懸濁液。
- 共結晶形成剤の水溶解度(mg/mL)/有機化合物の水溶解度(mg/mL)の比が、1.0×105未満である請求項7に記載の懸濁液。
- 請求項1~5のいずれか一項に記載の方法によって得られた懸濁液を乾燥して、平均粒子径が300nm以下であるナノ共結晶、ポリマーおよび界面活性剤を含有する組成物を製造する方法。
- 請求項9に記載の方法によって得られた組成物。
- 有機化合物および共結晶形成剤から構成され、平均粒子径が300nm以下であるナノ共結晶、重量平均分子量が3,000以上であるポリマーおよび重量平均分子量が3,000未満である界面活性剤を含有し、前記共結晶が湿式粉砕により解離しないものである組成物。
- 共結晶形成剤の水溶解度(mg/mL)/有機化合物の水溶解度(mg/mL)の比が、1.0×105未満である請求項11に記載の組成物。
- 請求項6~8のいずれか一項に記載の懸濁液または請求項10~12のいずれか一項に記載の組成物を含有する医薬。
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EP3266445A4 (en) | 2018-11-14 |
EP3266445B1 (en) | 2022-05-11 |
US20180036244A1 (en) | 2018-02-08 |
JPWO2016140219A1 (ja) | 2017-12-14 |
JP6830058B2 (ja) | 2021-02-17 |
US10226426B2 (en) | 2019-03-12 |
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