JP6027708B2 - 安定な液体製剤 - Google Patents
安定な液体製剤 Download PDFInfo
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- JP6027708B2 JP6027708B2 JP2016524250A JP2016524250A JP6027708B2 JP 6027708 B2 JP6027708 B2 JP 6027708B2 JP 2016524250 A JP2016524250 A JP 2016524250A JP 2016524250 A JP2016524250 A JP 2016524250A JP 6027708 B2 JP6027708 B2 JP 6027708B2
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- BPKAHTKRCLCHEA-UBFJEZKGSA-N paricalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-UBFJEZKGSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
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- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- 239000001384 succinic acid Substances 0.000 description 1
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- 150000003892 tartrate salts Chemical class 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 210000001519 tissue Anatomy 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
Images
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
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- F04D—NON-POSITIVE-DISPLACEMENT PUMPS
- F04D25/00—Pumping installations or systems
- F04D25/02—Units comprising pumps and their driving means
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- F04D25/0606—Units comprising pumps and their driving means the pump being electrically driven the electric motor being specially adapted for integration in the pump
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F01—MACHINES OR ENGINES IN GENERAL; ENGINE PLANTS IN GENERAL; STEAM ENGINES
- F01D—NON-POSITIVE DISPLACEMENT MACHINES OR ENGINES, e.g. STEAM TURBINES
- F01D15/00—Adaptations of machines or engines for special use; Combinations of engines with devices driven thereby
- F01D15/10—Adaptations for driving, or combinations with, electric generators
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Description
本出願は、2013年6月28日出願の米国仮出願第61/840,618号の利益を主張し、その開示の全体を参照することにより本出願に含める。
技術分野
本開示は、カルシウム感知受容体のペプチド作動薬を含む液体製剤、さらに詳しくは、長期間貯蔵後に安定なままである製剤に関する。本開示は、該製剤の製造方法および使用方法にも関する。
AMG 416などのカルシウム感知受容体のペプチド作動薬を含む液体製剤を提供する。
もう1つの実施態様において、製剤は、2.5〜4.0のpHを有する。もう1つの実施態様において、製剤は、3.0〜3.5のpHを有する。もう1つの実施態様において、製剤は、3.0〜4.0のpHを有する。もう1つの実施態様において、製剤は、2.8〜3.8のpHを有する。
本明細書中で用いるセクションの見出しは、構成上の目的のみであり、記載される主題を制限するものとみなされるべきではない。
慣例にしたがって、本明細書で用いる「a」および「an」は、他に特記しない限り、「1つまたはそれ以上」を意味する。
本開示は、カルシウム感知受容体のペプチド作動薬を含む液体製剤であって、約2.0〜約5.0のpHを有する製剤に関する。好ましい実施態様において、本開示は、AMG 416を含む液体製剤であって、約2.0〜約5.0のpHを有する製剤に関する。AMG 416およびその製造は、国際公開公報WO 2011/014707に記載される。たとえば、AMG 416を、固相合成によって対応するFmoc-保護D-アミノ酸から作成されてもよい。樹脂から切断した後、Boc-L-Cys(NPyS)-OHで材料を処理して、ジスルフィド結合を形成してもよい。次いで、Boc基をトリフルオロ酢酸(TFA)で除去し、得られる生成物を逆相高圧液体クロマトグラフィー(HPLC)によって精製し、凍結乾燥によってTFA塩形態として単離することができる。TFA塩は、続いての塩交換手順を行うことによって医薬的に許容しうる塩に変換されうる。このような手順は、当技術分野では周知であり、たとえば、イオン交換技術などが挙げられ、必要に応じて得られる生成物の精製を行う(たとえば、逆同液体クロマトグラフィーまたは逆浸透により)。
行われた実験および達成された結果などの以下の実施例は、説明の目的のために提供され、請求の範囲を限定するものと解釈されるべきではない。
この実験では、コハク酸塩緩衝生理食塩水中のAMG 416の溶解度を研究した。AMG 416 HCl(103 mg 粉末、80 mg ペプチド)を、200 μLのコハク酸塩緩衝生理食塩水(25 mM コハク酸塩、0.9% 生理食塩水、pH 4.5)に溶解した。短時間ボルテックスした後、公称濃度400 mg/mLの透明な溶液を得た。溶液体積の膨張は決定されなかったので、AMG 416の溶解度を、保存的に、少なくとも200 mg/mLと述べることができる。この実験では、最大溶解度は決定されなかったが、AMG 416は、少なくとも200 mg/mLの濃度まで、pH 4.5のコハク酸緩衝生理食塩水に可溶である。
この試験では、コハク酸塩緩衝生理食塩水(pH 4.5)中のさまざまな濃度にわたるAMG 416の安定性を研究した。上述の実施例1からの200 mg/mL AMG 416の溶液を、200 μLのコハク酸塩緩衝生理食塩水(pH 4.5)で、公称濃度200 mg/mLまでさらに希釈し、コハク酸塩緩衝生理食塩水(pH 4.5)で、66、20、6.7、2.2および0.67 mg/mLに連続希釈した。サンプルを室温(すなわち、約25℃)に維持し、間隔を置いて29日まで、アリコートをHPLCによって分析した。20〜0.67 mg/mLの濃度範囲を有する第二の一連のAMG 416サンプルを、40℃にてインキュベートし、同じ方法で分析した。
この試験では、コハク酸塩緩衝生理食塩水中のpH範囲にわたる、10 mg/mLの濃度のAMG 416の液体製剤の安定性を決定する。AMG 416 HCl(257 mg 粉末)を、20 mlのpH 4.5のコハク酸塩緩衝生理食塩水に溶解して、10.0 mg/mlのペプチド濃度(粉末のペプチド含量に対して調節)を提供した。溶液を5つの4 mLポーションに均等に分割し、必要に応じてNaOHおよびHClでそれぞれpH 2、3、4、5および6に調節した。各ポーションから3つの1 mL溶液を分取し、それぞれ、2-8℃、室温(約25℃)および40℃にてインキュベートした。各アリコート中の残りの1 mL溶液を、pH 4.5のコハク酸塩緩衝生理食塩水で、4 mLの2.5 mg/mLペプチド濃度に希釈し、同じ方法でpHを調節し、インキュベートした。HPLC分析のために、スケジュールにしたがって、サンプルを回収し、脱イオン水で、1.0 mg/mLに希釈した。
この試験では、液体製剤中のAMG 416の安定性におけるさまざまな医薬的賦形剤の効果を決定した。AMG 416の10 mg/mL溶液および2倍等張濃度のマンニトール、グリシン、アルギニン、NaClおよびNa2SO4のストック溶液を調製した。AMG 416溶液および5つの賦形剤溶液および脱イオン水のpHを、HCl/NaOHを用いてpH 3.5に別々に調節した。6つの溶液の500 μLのアリコートをガラスバイアルに加え、500μLのAMG 416溶液を同じバイアルに加え、十分に混合した。この走査を3回繰り返して、それぞれ5 mg/mL AMG 416および等張濃度の賦形剤(または脱イオン水)を含む18個のサンプルバイアルを準備した。pH 4.5に調節した溶液のセットを用いて、この操作を繰り返し、さらに18個のサンプルバイアルを準備した。サンプルをインキュベートし、関連する時点でのHPLC分析用に移動させた。
この試験では、9日にわたって、4つの異なる緩衝剤において、AMG 416の液体製剤の溶液を評価した。ナトリウム塩形態:酢酸塩、クエン酸塩、乳酸塩およびコハク酸塩の4つの異なるアニオン性緩衝剤について、25 mM濃度、pH 4.5にて、緩衝生理食塩水溶液を調製した。AMG 416 HCl(粉末)を各緩衝溶液に溶解して、2.5 mg/mL溶液を準備し、HCl/NaOHでpHを4.5に調節する。溶液を、pH 4.5緩衝剤でさらに1.0 mg/mLおよび0.25 mg/mLに希釈する。得られる溶液のそれぞれを、2つのガラスHPLCバイアルに分け、1つを2-8℃にて貯蔵し、1つを室温(約25℃)にて貯蔵した。効力および純度を決定するために、0、4および9日にてHPLC分析を行った。
この試験では、低pH条件下でのAMG 416の液体製剤の安定性を研究した。59mgのコハク酸を45 mlの研究室処理した(脱イオン化)水に溶解し、必要に応じて1N HClおよび1N NaOHを用いてpHを3.5に調節し、適量50 mlにすることによって、コハク酸塩緩衝生理食塩水(10 mM、pH 3.5)を調製した。同じ方法で、10 mM、pH 3.5の乳酸ナトリウム(56 mg/50 mL)緩衝溶液を調製した。
67日後のAMG 416溶液(5 mg/mL)についての分解プロフィール
10 mM緩衝剤濃度:L=乳酸塩;S=コハク酸塩。張性調節剤:N=0.9% NaCl;M=5% マンニトール)。二量体に対する値 % は、出発値を引いた後の分解の増加を反映する。
67日までの時点におけ5 mg/mL溶液中のホモ二量体へのAMG 416の分解
(10 mM緩衝剤濃度:L=乳酸塩;S=コハク酸塩。張性調節剤:N=0.9% NaCl;M=5% マンニトール)。実験用に用いられたAPIが、かなりの量の二量体を含んでいたので、分解が(総二量体ではなく)二量体含量中の増加として表されることに留意。
この試験では、さまざまな製造および分析条件下でのAMG 416の液体製剤の安定性を調査した。それぞれ、pH(2.7、3.3または3.9)、ペプチド濃度(4、5または6 mg/mL)および塩濃度(0.7、0.85または1.0%)の異なる組合せを有する14の製剤試験グループを調製した。各製剤のオスモル濃度を同じに維持した(コハク酸塩 10 mM)。表16参照。
製剤試験グループ
製剤試験グループのそれぞれのサンプル(2.1 mL)を3mLのタイプ1Bのガラスバイアル(Schott、ドイツ)に分注し、密閉した(ゴム栓)。バイアルのセットを4℃、25℃または40℃の温度にて3ヶ月間直立させて貯蔵した。pH、オスモル濃度、AMG 416パーセントおよび分解を3ヶ月にわたって評価した。
この試験では、3.4 mg/mLの濃度におけるAMG 416の液体製剤の長期安定性を、コハク酸塩緩衝生理食塩水中のpHの範囲にわたって決定した。USP精製水(1200 mL)をガラスビーカーに分注した。コハク酸ナトリウム(4.05 g)および塩化ナトリウム(13.5 g)を加え、攪拌して溶解した。必要に応じて1N NaOHおよび/または1N HClでpHを2.5に調節した。AMG 416 HCl(5.5 g 粉末重量)を加え、攪拌して溶解し、精製水で1500 mLにして、3.4 mg/mL溶液(AMG 416)を提供する。溶液を、3つのポーションに分割し、各ポーションのpHをそれぞれ、2.5、3.0および3.5に調節した。各溶液を、0.22ミクロンPVDFフィルターを通して別々にろ過し、2 mL〜5-ccのバイアルに分注する。栓をし、密閉し、ラベリングした後、バイアルを、5℃±3、25℃±2および40℃±2に指定された安定性チャンバーに置いた。スケジュールにしたがってサンプルを回収し、HPLC分析用に脱イオン水で1.0 mg/mLに希釈した。0、1、2、3、5、12および24ヶ月における純度を表17に提供する(注:この試験では、出発純度値は、99.2%であった)。結果は、pHおよび温度の関数としてのAMG 416の3.4 mg/mL液体製剤の長期安定性プロフィールを提供する。
表17
AMG 416溶液についての24ヶ月までの時点における純度
Claims (15)
- 2.5〜4.5のpHを有する、請求項1に記載の製剤。
- 2.5〜4.0のpHを有する、請求項1に記載の製剤。
- 3.0〜3.5のpHを有する、請求項1に記載の製剤。
- pHが、医薬的に許容しうる緩衝剤によって維持される、請求項1に記載の製剤。
- 緩衝剤が、コハク酸塩である、請求項5に記載の製剤。
- AMG 416が、0.1 mg/mL〜20 mg/mLの濃度で製剤中に存在する、請求項1に記載の製剤。
- AMG 416が、1 mg/mL〜15 mg/mLの濃度で製剤中に存在する、請求項1に記載の製剤。
- AMG 416が、2.5 mg/mL〜10 mg/mLの濃度で製剤中に存在する、請求項1に記載の製剤。
- さらに医薬的に許容しうる張性調節剤を含む、請求項1に記載の製剤。
- 張性調節剤が、製剤がほぼ等張であるために十分な濃度で製剤中に存在する、請求項10に記載の製剤。
- 張性調節剤が、NaClである、請求項10に記載の製剤。
- 2-8℃にて2年間貯蔵された場合の分解が、10%未満である、請求項1に記載の製剤。
- 室温にて2年間貯蔵された場合の分解が、10%未満である、請求項1に記載の製剤。
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