JP7429013B2 - カンナビジオールの新しい固体形態およびその使用 - Google Patents
カンナビジオールの新しい固体形態およびその使用 Download PDFInfo
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- JP7429013B2 JP7429013B2 JP2020550056A JP2020550056A JP7429013B2 JP 7429013 B2 JP7429013 B2 JP 7429013B2 JP 2020550056 A JP2020550056 A JP 2020550056A JP 2020550056 A JP2020550056 A JP 2020550056A JP 7429013 B2 JP7429013 B2 JP 7429013B2
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
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- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 201000005040 opiate dependence Diseases 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 150000002913 oxalic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- GZXOHHPYODFEGO-UHFFFAOYSA-N triglycine sulfate Chemical class NCC(O)=O.NCC(O)=O.NCC(O)=O.OS(O)(=O)=O GZXOHHPYODFEGO-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本特許出願は、2017年12月11日に出願された米国特許出願第62/597,307号への優先権の利益を主張する。
1.おおよその溶解度
秤量された試料を、室温で溶媒または溶媒混合物のアリコートで処理した。混合物は、溶解を促進するために添加の間に超音波処理した。試験物質の完全な溶解は、目視検査によって判定した。溶解度は、完全な溶解を提供するために使用される全溶媒に基づいて推定した。実際の溶解度は、大きすぎる溶媒のアリコートを使用したため、または溶解速度が遅いため、計算された値よりも大きくなる場合がある。溶解度は、溶解が実験中に発生しなかった場合、「未満」として表される。アリコートを1回だけ添加した結果完全に溶解した場合、溶解度は、「より大きい」と表される。
1.インデックス化
インデックス化は、回折パターンのピーク位置を仮定して、結晶学的単位格子のサイズおよび形状を判定するプロセスである。この用語は、Millerインデックスラベルを個々のピークに割り当てることからその名を得た。XRPDインデックス化は、いくつかの目的を果たす。パターン内のすべてのピークが単一の単位格子によってインデックス化される場合、これは、試料が単一の結晶相を含有することの強力な証拠である。インデックス化溶液を仮定して、単位格子体積を、直接計算することができ、それらの溶媒和状態を判定するのに有用であり得る。インデックス化は、結晶形態の堅牢な説明でもあり、特定の熱力学的状態ポイントでのその相のすべての利用可能なピーク位置の簡潔な要約を提供する。XRPDパターンのインデックス化は、TRIADS(商標)ソフトウェアを使用して行った(米国特許第8,576,985号を参照)。割り当てられた消滅記号、単位格子パラメーター、および導出された数量と一致する空間群は、それぞれの図に表形式で表示され、各形態のためのインデックス化溶液を提供する。
試料は、0.8x~10xの対物レンズで交差した偏光子を備えた1次赤補償器を備えた実体顕微鏡下で観察した。
溶液NMRスペクトルは、399.82MHzの1Hラーモア周波数でAgilent DD2-400分光計を使用して取得した。試料を重水素化クロロホルムに溶解させた。スペクトルは、6.6μsの1Hパルス幅、スキャン間の2.5秒の遅延、64102データポイントを有する6410.3のスペクトル幅、および40の共同追加スキャンで取得した。信号対雑音比を改善するために、262144ポイントおよび0.2Hzの指数線広がり係数を有するVarian VNMR6.1Cソフトウェアを使用して、自由誘導減衰を処理した。
a.PANalytical X’PERT Pro MPD回折計-透過
XRPDパターンは、Optixの長い細焦点光源を使用して生成されたCu放射線の入射ビームを使用して、PANalytical X’Pert PRO MPD回折計で収集した。楕円傾斜多層ミラーを使用して、Cu Kα X線を、試験片を通して検出器に集束させた。分析の前に、シリコン試験片(NIST SRM640e)を分析して、Si 111ピークの観測された位置がNIST認定位置と一致していることを確認した。試料の試験片を3μmの厚さのフィルムで挟み、透過形状で分析した。ビームストップ、短い散乱防止エクステンション、散乱防止ナイフエッジを使用して、空気によって生成される背景を最小限に抑えた。入射ビームと回折ビームのためのソーラースリットを使用して、軸発散からの広がりを最小限に抑えた。回折パターンは、試験片から240mmのところに位置する走査型位置検出器(X’Celerator)およびData Collectorソフトウェアv.2.2bを使用して収集した。各パターンのデータ収集パラメーターは、ミラーの前の発散スリット(DS)を含めて、本報告書のデータセクションの画像の上に表示される。
DSC分析は、TA Instruments 2920示差走査熱量計を使用して行った。温度較正は、NISTトレース可能インジウム金属を使用して行った。試料をアルミDSC皿に入れ、蓋をし、重量を正確に記録した。試料皿として構成された秤量されたアルミニウム皿を、セルの基準側に置いた。各サーモグラムのデータ取得パラメーターおよび皿構成は、本報告書のデータセクションの画像に表示される。サーモグラムに関する法コードは、開始温度および終了温度、ならびに加熱速度の略語であり、例えば、-30-250-10は、「-30℃~250℃、10℃/分」を意味する。
FT-IRデータは、Ever-Glo中/遠IR光源、臭化カリウムビームスプリッター、および重水素化硫酸トリグリシン検出器を備えたNicolet FTIR6700フーリエ変換赤外分光光度計(Thermo Nicolet)で取得した。波長検証は、NIST SRM1921b(ポリスチレン)を使用して行った。ゲルマニウム(Ge)結晶を備えた減衰全反射アクセサリ(Thunderdome(商標)、Thermo Spectra-Tech)をデータ収集に使用した。各スペクトルは、4cm-1のスペクトル分解能で収集された256の共同追加スキャンを表す。きれいなGe結晶で背景データセットを取得した。Log1/R(R=反射率)スペクトルは、相互に対するこれらの2つのデータセットの比率を取ることによって得た。
TG分析は、IR炉を備えたTA Instruments Discovery熱重量分析計を使用して行った。温度較正は、ニッケルおよびAlumel(商標)を使用して行った。各試料をアルミニウム皿に置いた。試料を密閉し、蓋に穴を開け、その後、TG炉に挿入した。炉を窒素下で加熱した。各サーモグラムのデータ取得パラメーターは、本報告書のデータセクションの画像に表示される。取得スキャン速度は、サーモグラムヘッダーに記録されるが、加熱範囲は、個々のプロットから判定され得る。
カンナビジオールは、X線粉末回折(XRPD)および1H NMR分光法で分析した。
カンナビジオールの共結晶スクリーニングは、主に薬学的に許容されるコフォーマーを使用して行った。カンナビジオールの共結晶を対象とする68の実験は、34のコフォーマーを使用して実施した。カンナビジオールは、化学的に非常に反応性が高いと報告されている(Mechoulam,R.およびJanus,L,Cannabidiol:an overview of some chemical and pharmacological aspects.Part I;chemical aspects(2002)Chem Phys Lipids 121(1-2):35-43)。例えば、酸素の存在下で塩基に含まれるカンナビジオールは、単量体および二量体のヒドロキノンに酸化されることが報告されている(同文献)。酸化された化合物の陰イオンは、深い紫色を有し、大麻の識別に使用されたビーム反応の基礎である(同文献)。O-H…N水素結合を潜在的に活用するために、イミダゾールなどの薬学的に許容される塩基とカンナビジオールとの共結晶を形成する試みは、おそらくビーム反応の結果として、溶液の変色をもたらした。したがって、使用した塩基のpKaは、実験条件を調整する際に考慮に入れた。芳香族窒素を含有するような塩基性の低い化合物は、O-H…N水素結合を活用するために評価した。実験は、約1:1、2:1、または1:2のAPI:コフォーマー比で設定し、過剰量のコフォーマーを使用した追加の実験を行った。実験は、冷却、蒸発、スラリー化、および溶媒支援粉砕を含む様々な結晶化技術を使用して行った。共結晶スクリーニング実験から得られた固体は、典型的には、偏光顕微鏡(PLM)およびX線粉末回折(XRPD)によって分析した。単離された固体のXRPDパターンを、カンナビジオールおよびコフォーマーの既知の形態のXRPDパターンと比較した。
独特の結晶性物質は、L-プロリンとのカンナビジオールの共結晶を対象とした実験から識別した。L-プロリンの潜在的な首位は、MeOHの存在下でのカンナビジオールとL-プロリンの比率が異なるいくつかの異なる実験条件から得た。MeOH中のカンナビジオールおよび過剰のL-プロリンを含有する溶液の蒸発は、XRPDに基づいてL-プロリンとの混合物として単離された独特の結晶性物質をもたらした(図2)。MeOHでのカンナビジオールおよびL-プロリンの溶媒支援粉砕、ならびにカンナビジオールおよびL-プロリンを含有する(1:1および2:1のモル比)MeOH溶液の蒸発は、同じ独特の結晶性物質をもたらした。カンナビジオール:L-プロリン(1:1)形態Aの特徴を表4に示す。
カンナビジオール(87.76mg、0.28mmol)およびL-プロリン(33.8、0.29mmol)mgを、室温(RT)でメタノール(350μL)に溶解した。透明な溶液を室温で約3時間攪拌した。溶液を窒素下で1日間蒸発させた。
カンナビジオールL-プロリン形態Aの水溶解度は、アリコート添加法を使用して<1mg/mlと推定した
カンナビジオールおよびD-プロリンのMeOHとの溶媒支援粉砕がXRPD(図7)により独特の物質を生成した、ならびに等モル量のカンナビジオールおよびD-プロリンを含有するMeOH溶液の蒸発、の2つの条件下でカンナビジオールD-プロリン形態Aを生成した。カンナビジオールD-プロリン形態Aの特性評価を表5に示す。
カンナビジオールとD-プロリン形態Aとの共結晶の調製:
カンナビジオールテトラメチルピラジン物質Aは、等モル量のカンナビジオールおよびテトラメチルピラジン(TMP)を1:1でMeOHと溶媒支援粉砕することにより、不規則物質として単離した。カンナビジオールおよびTMPを1:2のモル比で含有する第2の溶媒支援粉砕実験では、同じ不規則物質が得られ、追加のピークが存在した。等モル量のカンナビジオールおよびTMPを含有する、実験から単離された固体を、XRPD(図12)、1H NMR、DSC、およびFT-IR分光法により分析した。さらに、水溶解度の視覚的推定を実施し、カンナビジオールテトラメチルピラジン物質Aの固体を95%RHに曝露した後、XRPDにより分析した。
カンナビジオール(51.0mg、0.16mmol)とテトラメチルピラジン(22.1mg、0.16mmol)とを合わせ、少量のMeOHと接触させ、濃いペーストを生成した。試料をメノウ乳鉢/乳棒で軽く粉砕し、白色粉末を生成した。固体を収集し、分析した。
カンナビジオール4,4’-ジピリジル物質Aは、等モル量ならびにMeOHの存在下での2モル当量の4,4-ジピリジルを含む溶媒支援粉砕実験から識別した(XRPD、図16)。カンナビジオール4,4’-ジピリジル物質Aの特性評価を表7にまとめる。
カンナビジオール(55.4mg、0.18mmol)と4,4’-ジピリジル(27.4mg、0.18mmol)とを合わせ、少量のMeOHと接触させ、濃厚なペーストを生成した。試料をメノウ乳鉢/乳棒で軽く粉砕し、白色粉末を生成した。固体を収集して分析した。
Claims (12)
- カンナビジオールと、コフォーマーテトラメチルピラジンと、を含み、9.1、14.6、18.3、および19.6度2θ±0.2にピークを含むX線回折パターンを有する、固体形態。
- カンナビジオール対テトラメチルピラジンのモル比が、1:1である、請求項1に記載の固体形態。
- 結晶性である、請求項1に記載の固体形態。
- 共結晶である、請求項1に記載の固体形態。
- 89.9℃のピーク開始または92.8℃でピーク最大値を有するDSCサーモグラムを有する、請求項1に記載の固体形態。
- 請求項1~5のいずれか1項に記載の固体形態を含む、医薬組成物。
- 薬学的に許容される賦形剤または担体をさらに含む、請求項6に記載の医薬組成物。
- 請求項6又は7記載の医薬組成物から成る、カンナビジオールによる治療に適した疾患または状態の治療剤。
- 前記疾患または状態が、中枢神経系障害、心血管障害、神経血管障害、癌、多発性硬化症、多発性硬化症に関連する筋けいれん、パーキンソン病、精神病、早期発症てんかんによって引き起こされる発作を含むてんかん(けいれんおよび発作)、精神障害、炎症、疼痛、線維筋痛症、肝炎、表皮水疱症、神経変性疾患における痙性、悪液質および拒食症、緑内障における高眼圧症、運動障害、神経筋障害、プラダーウィリ症候群、トゥレット症候群のけいれん、疑似球の影響、薬物依存の軽減、喫煙、中毒の治療、糖尿病、グラフト対宿主病(GVHD)、アテローム性動脈硬化、炎症性腸疾患、クローン病、潰瘍性大腸炎、全身性エリテマトーデス(SLE)、皮膚エリテマトーデス、乾癬、自己免疫疾患、後天性免疫不全症候群、サルコイドーシス、関節リウマチ、間質性肺疾患(ILD)、強皮症、皮膚炎、虹彩炎、結膜炎、角結膜炎、特発性両側進行性感音難聴、再生不良性貧血、赤芽球癆、特発性血小板減少症、多発性軟骨炎、墓眼症、筋萎縮性側索硬化症(ALS)およびALSに関連する症状、原発性胆汁性肝硬変、回腸炎、慢性炎症性腸疾患、セリアック病、過敏性腸症候群、アルツハイマー病、プリオン関連疾患、脂肪肝、不眠症(発症および維持)および他の睡眠障害、心的外傷後ストレス障害、にきび、大麻離脱症状、OCD、外傷後ストレス症候群、吐き気、癌治療に関連する吐き気、嘔吐(vomiting)、嘔吐(emesis)、乗り物酔い、ならびに低酸素虚血(急性脳卒中)から選択される1又は2種以上である、請求項8記載の治療剤。
- 前記疾患または状態が、中枢神経系障害、心血管障害、神経血管障害、神経筋障害、がん、自己免疫疾患、外傷後ストレス症候群、吐き気及び低酸素虚血からから選択される1又は2種以上である、請求項8又は9記載の治療剤。
- 前記疾患または状態が、固形腫瘍、癌転移、多発性硬化症、多発性硬化症に関連する筋けいれん、パーキンソン病、パーキンソン病、精神病、てんかん、治療抵抗性てんかん、結節性硬化症複合体におけるてんかん、ドラベート症候群、急性および慢性期の熱性感染症関連てんかん症候群(ファイアーズ)、スタージウェーバー症候群、てんかん重積、悪性移動性部分発作、脳腫瘍関連てんかん、レノックス・ガストー症候群、精神障害、認知機能障害、統合失調症における認知障害、不安、うつ病、双極性障害、線維筋痛症、肝炎、表皮水疱症、神経変性疾患における痙性、悪液質、拒食症、緑内障における高眼圧症、運動障害、神経筋障害、プラダーウィリ症候群、トゥレット症候群のけいれん、中毒、喫煙中毒、オピオイド中毒、糖尿病、グラフ対宿主病(GVHD)、アテローム性動脈硬化、炎症性腸疾患、クローン病、潰瘍性大腸炎、全身性エリテマトーデス、皮膚エリテマトーデス、乾癬、自己免疫性ブドウ膜炎、自己免疫性肝炎、過敏性肺疾患、過敏性肺炎、遅延型過敏症、シェーグレン病、後天性免疫不全症候群、サルコイドーシス、関節リウマチ、間質性肺疾患、強皮症、皮膚炎、虹彩炎、結膜炎、角結膜炎、特発性両側進行性感音難聴、再生不良性貧血、赤芽球癆、特発性血小板減少症、多発性軟骨炎、墓眼症、筋萎縮性側索硬化症(ALS)およびALSに関連する症状、原発性胆汁性肝硬変、回腸炎、慢性炎症性腸疾患、セリアック病、過敏性腸症候群、アルツハイマー病、プリオン関連疾患、脂肪肝、不眠症(発症および維持)、パーキンソン病の睡眠障害、心的外傷後ストレス障害、にきび、大麻離脱症状、OCD、吐き気、癌治療に関連する吐き気、嘔吐、乗り物酔い、及び低酸素虚血(急性脳卒中)から選択される1又は2種以上である、請求項8又は9記載の治療剤。
- 前記がんが、未分化上衣腫、DIPG、多形性膠芽腫、膀胱、乳房、頭頸部、前立腺、神経内分泌、非ホジキンリンパ腫、非小細胞肺、結腸、直腸、膵臓及び卵巣のがんである、請求項8又は9記載の治療剤。
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US20190177258A1 (en) | 2019-06-13 |
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US20230404939A1 (en) | 2023-12-21 |
US20210299048A1 (en) | 2021-09-30 |
TW201927733A (zh) | 2019-07-16 |
WO2019118360A1 (en) | 2019-06-20 |
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