JP6113878B2 - ナノ粒子組成物及びその合成方法 - Google Patents
ナノ粒子組成物及びその合成方法 Download PDFInfo
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- JP6113878B2 JP6113878B2 JP2016034479A JP2016034479A JP6113878B2 JP 6113878 B2 JP6113878 B2 JP 6113878B2 JP 2016034479 A JP2016034479 A JP 2016034479A JP 2016034479 A JP2016034479 A JP 2016034479A JP 6113878 B2 JP6113878 B2 JP 6113878B2
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Description
キャリア・マトリックスを所望量除去して、治療効果のあるナノ粒子を放出させる前記工程は、選択的溶解、洗浄、昇華等の手段によって実施可能である。
当業者ならば、本明細書に記載の発明は、明細書に具体的に記載のしたもの以外のように変更、変形され得ることを理解するであろう。本発明は、そのような変更、変形の全てを含むものであることを理解されたい。本発明はまた、明細書で参照又は記載された全ての工程、特徴、組成物、及び化合物を単独又は集合的に含み、且つ、該工程又は特徴の任意及び全ての組み合わせ、若しくは任意の2種以上を含む。
「メカノケミカル合成(MCS)」とは、例えば、反応混合物をミリング媒体存在下で攪拌して機械的エネルギーを該反応混合物に伝えることによって、物質又は物質混合物中の化学反応、結晶構造変換、又は相変化を活性化、開始、又は促進するために機械的エネルギーを使用することを言い、「メカノケミカルアクティベーション」、「メカノケミカルプロセッシング」、「反応性ミリング」、及び関連工法が挙げられるが、これらに限定されない。反応混合物は閉じた容器又はチャンバーに投入する。本明細書中において「攪拌(agitating, agitation)」とは、並進運動(横移動振とう等)、回転(スピン等)、及び反転(上下反転等)等の基本的な動的動作の少なくとも1種、又はこれらの2種以上の任意の組み合わせを反応混合物に対して印加することを意味する。好ましくは、反応混合物に対して3種全ての動作を印加する。このような攪拌は、外部からの反応混合物とミリング媒体の混和(stir)を行って、或いは行わないで達成可能である。
本発明は、上記固体化学反応によって機械化学的に調製した、治療効果のあるナノ粒子を有する改良ナノコンポジット微構造組成物を提供する。一形態において、本発明は、上記固体化学反応によって機械化学的に調製した、キャリア・マトリックスに分散した治療効果のあるナノ粒子を有する改良ナノコンポジット微構造組成物を提供する。メカノケミカル反応中の固体化学を利用してナノコンポジット微構造組成物を生成することにより、出願人は、キャリア・マトリックス内の治療効果のあるナノ粒子の濃度及び分布、並びに該ナノ粒子のサイズ、場合によっては多形構造を制御することができる。
本発明は、改良ナノコンポジット微構造組成物の調製方法を含み、該方法は、メカノケミカル合成条件下で前駆体化合物を共反応物質と接触させて、該前駆体化合物と該共反応物質との間に固体化学反応を発生させ、キャリア・マトリックス中に分散した治療効果のあるナノ粒子を生成する工程を含む。この方法により製造されたキャリア・マトリックスは、無毒であることが好ましくは、或いは治療効果のあるナノ粒子から単離及び/又は実質的に除去可能でなくてはならない。
(式1)
A + B → C + D
式中、Aは前駆体化合物、Bは共反応物質、Cはキャリア・マトリックス、Dはキャリア・マトリックス中に分散された、所望の本発明の治療効果のあるナノ粒子であり、本発明の改良ナノコンポジット微構造組成物が得られる。
(式2)
A + B + E → C + D
式中、Eは希釈剤、表面安定化剤等の1種以上の促進剤、経口投与用のタブレットの一部を形成し得る他の物質、下記「薬剤及び医薬組成物」の項に列挙した作用薬及び媒体等、他の特定の薬物送達に必要なその他の物質、又はその組み合わせであり、したがって、キャリア・マトリックスCは1種以上の促進剤を有し得る。
本発明で好適に使用される前駆体化合物としては、固体メカノケミカル反応で共反応物質と反応して治療薬を生成可能な全ての化合物が挙げられ、該治療薬は、作用薬と、不活性キャリア・マトリックス、ガス、高揮発性液体、溶解度の違い等により容易に単離可能とする化学的性質を有する物質等の、容易に実質的に除去可能な副生成物の一部分を形成し得る反応副産物とを生成する化学反応を起こし、且つナノ粒子として存在可能なものである。尚、前記副生成物は、キャリアの構成成分を提供し得るが、必ずしもしなくともよい(例えば、CO2又はH2Oは、ガスとして容易に除去される副生成物である)。前駆体化合物は、通常、粒径を小さくする等の当業者が性質を改善したい医薬品化合物であり。前駆体化合物は、通常、従来の作用薬又は薬剤であるが、本発明の方法は、元の従来品と比べて既に粒子サイズを小さくした薬剤配合物に対して用いてもよい。所望の前駆体化合物が、80°Cを超えることもある、冷却前のメカノケミカル処理の通常温度に耐えることが出来ることが好都合である。したがって、融点が約80°C以上の化合物が好適である。低融点の前駆体化合物に対しては、反応容器を冷却することで、低融点化合物の処理を可能とする。例えば、簡易な水冷ミルで温度を50°C未満に保持でき、或いは冷却水を用いてミリング温度を低下させることが可能である。当業者ならば、反応ミルを任意の温度度、例えば−190°C〜500°Cの間で動作するように設計可能であることが理解されよう。ある反応においては、ミリング温度を前駆体化合物及び/又は共反応物質の融点よりも大幅に小さい温度に制御するのが有利であり得る。
本発明に好適な共反応物質は、反応で使用する前駆体化合物に対する適用性、及び該前駆体物質の性質に主に基づいて選択する。例えば、前駆体化合物が塩基の場合、適切な共反応物質は薬学的に許容可能な酸であり得る。前駆体化合物が酸の場合、適切な共反応物質は薬学的に許容可能な塩基であり得る。前駆体化合物が塩である場合、適切な共反応物質は酸又は塩基であり得る。この点に関して、共反応物質は下記検討事項に基づいて選択する。
(1)ナノスケールの微構造体の処理中の形成を促進する機械的性質
処理中に粒子を確実に破壊してナノコンポジット微構造体をミリング中に形成させるには、固体状態の前駆体化合物は低硬度(通常はMohs硬度7未満)であることが望ましい。
(2)低研削性
生成物粉体の粉砕ボール(即ちミリング媒体)とミル容器による汚染を最小限にするために、低研削性であることが望ましい。間接的な研削性の指標は、ミリングに基づいた異物の量を測定することで得られる。
(3)熱特性
前駆体化合物は、熱分解される確率を減らすために比較的低温で治療薬に変換されなければならない。実際の温度は、選んだ前駆体化合物の性質に依存する。
(4)凝集性
ミリング中、特には少量の水の存在下では、共反応物質の凝集性は小さくなければならない。ミリング中の凝集性を定量するのは困難である。ミリング中の共反応物質のミリング媒体及びミル容器への「固化」量を観察することによって、主観的な尺度を得ることが出来る。
(5)ナノ粒子組成物との未反応性
共反応物質は、プロセスの全ての段階でナノ粒子組成物(C+D)内のナノ粒子Dと反応しないことが好ましい。
(6)溶解特性
共反応物質の少なくとも一部を除去することが望ましい場合、該共反応物質は、その送達又は選択的除去を促進するために、生体液及び/又は水、アルコール等の一般的な溶媒に対して溶解性が高いことが好ましい。更に、共反応物質は、生体液及び/又は水、アルコール等の一般的な溶媒に対して少なくとも10mg/mlまで可溶であることが好ましい。
前駆体化合物Aと共反応物質Bの組み合わせ及び/又は促進剤Eによるが、副生成物は、存在する場合、塩酸ナトリウム、炭酸水素ナトリウム、アンモニア、二酸化炭素、水蒸気、及び除去が容易なその他ガスを含み得る。副生成物の少なくとも一部を除去することが望ましい場合、該副生成物は、その送達又は選択的除去を促進するために、生体液及び/又は水、アルコール等の一般的な溶媒に対して溶解性が高く、且つ昇華温度はナノ粒子の融点よりも低いことが好ましい。更に、副生成物は、生体液及び/又は水、アルコール等の一般的な溶媒に対して少なくとも10mg/mlまで可溶であることが好ましい。
改良ナノコンポジット微構造組成物(C+D)内における、所望の治療効果のあるナノ粒子Dの凝集を防ぐことが望ましい場合、希釈剤、表面安定化剤、又はそれらの組み合わせ等の促進剤が使用可能である。
本発明の方法により直接製造された改良ナノ粒子組成物は、キャリア・マトリックスに分散した薬剤(活性薬)のナノ粒子を有する(該キャリア・マトリックスの少なくとも一部を除去することも場合によってはある)。薬剤ナノ粒子の平均粒径は、直径で200nm未満、好ましくは100nm未満、より好ましくは75nm未満、更に好ましくは50nm未満、またある場合は30nmである。ナノ粒子のサイズは、少なくとも50%が平均範囲内のサイズとなり、好ましくは少なくとも60%、より好ましくは少なくとも70%、更に好ましくは少なくとも75%が平均範囲内のサイズとなるように分布していることが好ましい。
改良ナノコンポジット微構造組成物が一旦所望どおり形成されたら、前駆体化合物Aから生成物Dを峻別する必要があり得る。AとDは、融点、溶解度、又はサイズ等の測定可能な物性の変化に基づいて当業者に知られた手法で峻別可能であることが理想的である。生成物から前駆体化合物を峻別するための他の分析手法としては、示差走査熱量測定法(DSC)、X線回折法、赤外線分光法(IRS)等が挙げられる。
本発明はまた、本発明のナノコンポジット微構造組成物を使用して製造した薬剤及び医薬組成物を提供する。そのような組成物は、組成物単独(C+Dの形態、又はキャリア・マトリックスの一部分又は全てを除去した形態)で含んでもよく、或いは、より好ましくは、1種以上の薬学的に許容可能なキャリア、並びに薬学的に許容可能な組成物の調製に一般的に使用される他の作用薬と併用してもよい。
(1)作用薬表面に付着可能であるが該作用薬自身との化学反応には関わらず且つ反応を起こさない、ポリエチレングリコール(PEG)、ポリビニルピロリドン(PVP)、ポリビニルアルコール、クロスポビドン、ポリビニルピロリドン−ポリビニルアクリレートコポリマー、セルロース誘導体、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、カルボキシメチルエチルセルロース、フタル酸ヒドロキシプロピルメチルセルロース、ポリアクリレート、ポリメタクリレート、尿素、糖類、ポリオール及びそのポリマー、乳化剤、糖ゴム、スターチ、有機酸及びその塩、ビニルピロリドン、酢酸ビニル等の高分子表面安定化剤、及び/又は
(2)種々のセルロース、架橋ポリビニルピロリドン、微晶性セルロース等の結着剤、及び/又は
(3)ラクトース一水和物、無水ラクトース、種々のスターチ等の充填剤、及び/又は
(4)コロイド状二酸化シリコン、タルク、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、シリカゲル等、圧縮する粉体の流動性に作用を及ぼす作用物質等の滑剤、及び/又は
(5)スクロース、キシリトール、サッカリンナトリウム、チクロ、アスパルテーム、アクスルフェイム(accusulfame)K等、任意の天然又は人工の甘味剤、及び/又は
(6)香料添加剤、及び/又は
(7)ソルビン酸カリウム、メチルパラベン、プロピルパラベン、安息香酸及びその塩、ブチルパラベン等の他のパラヒドロキシ安息香酸エステル、エチルアルコール、ベンジルアルコール等のアルコール、フェノール等のフェノール化合物、塩化ベンズアルコニウム等の四級化合物等の保存剤、及び/又は
(8)バッファー、及び/又は
(9)微晶性セルロース、ラクトース、リン酸水素カルシウム、サッカライド、及び/又はそれらの任意の混合物等の、薬学的に許容可能な不活性フィラー等の希釈剤、及び/又は
(10)コーンスターチ、ポテトスターチ、メイズスターチ、改変スターチ、クロスカルメロースナトリウム、クロスポビドン、デンプングリコール酸ナトリウム、その混合物等の湿潤剤、及び/又は
(11)分解剤、及び/又は
(12)有機酸(クエン酸、酒石酸、マレイン酸、フマル酸、アジピン酸、コハク酸、アルギン酸、無水物及び酸塩化物等)、炭酸塩(炭酸ナトリウム、炭酸カリウム、炭酸マグネシウム、炭酸グリシンナトリウム、炭酸L−リジン、炭酸アルギニン等)、又は重炭酸塩(重炭酸ナトリウム、重炭酸カリウム等)等の発泡剤カップル等の発泡剤、及び/又は
(13)他の薬学的に許容可能な賦形剤、を含んでよい。
本発明の医薬組成物は、経口投与、直腸投与、肺投与、膣内投与、局所投与(粉体、軟膏、又はドロップ)、経皮投与等の任意の薬学的に許容可能な方法で、或いは口腔又は鼻腔スプレーとして、ヒト及び動物に投与可能である。
本発明はまた、動物の治療方法であって、本発明の方法で製造したナノコンポジット微構造組成物を有する組成物を前記動物に対して治療効果量投与する工程を含む治療方法を対象とする。
本発明の他の実施形態は、(i)メカノケミカル合成条件下で前駆体化合物を共反応物質と接触させて該前駆体化合物と該共反応物質との間に固体化学反応を発生させ、キャリア・マトリックスに分散した治療効果のあるナノ粒子を生成する工程と、(ii)該キャリア・マトリックスの少なくとも一部分を除去して、該治療効果のあるナノ粒子を放出させる工程とを含む、精製ナノ粒子治療薬の調製方法に関する。
過剰量の硫酸水素ナトリウムとのジクロフェナクナトリウムのメカノケミカル処理
過剰量の硫酸水素ナトリウムとのジクロフェナクナトリウム塩のメカノケミカル処理によってジクロフェナク酸の超微細粒子(1000nm未満)を製造した。この実施例では、硫酸水素ナトリウム試薬は化学反応物質と希釈剤の両方として作用する。
硫酸ナトリウム存在下での硫酸水素ナトリウムとのジクロフェナクナトリウムのメカノケミカル処理
硫酸ナトリウム存在下での硫酸水素ナトリウムとのジクロフェナクナトリウムのメカノケミカル処理によってジクロフェナク酸の超微細粒子を製造した。この実施例では、硫酸ナトリウム試薬は不活性な希釈剤のみとして作用する。
ジクロフェナク酸と過剰量炭酸塩のメカノケミカル処理
過剰量の炭酸ナトリウムとのジクロフェナクナトリウムのメカノケミカル処理によって炭酸水素ナトリウム及び過剰量の炭酸ナトリウムのマトリックスに分散したジクロフェナクナトリウム超微細粒子を製造した。
示差走査熱量測定法(DSC)、及びX線回折法(XRD)によって反応生成物を分析した。DSCにおいて、ナトリウム塩のジクロフェナクと、酸のジクロフェナクでは加熱中の挙動は異なった。ナトリウム塩は、275°C付近の分解反応が起こるまで変化が無かったのに対し、酸では、140°C付近から始まった二つの熱イベントと、昇華による連続的な質量放出が見られた。酸及び塩形態のXRDパターンは、文献に詳しく記載されている。
Na2CO3に分散させたジクロフェナクナトリウム塩のナノ粒子組成物
Na2CO3を有するキャリア・マトリックスに分散させたジクロフェナクナトリウム塩のナノ粒子組成物を以下のように調製した。
前駆体化合物として、構造式
NH4Clに分散させたジクロフェナク酸のナノ粒子組成物
NH4Clを有するキャリア・マトリックスに分散させたジクロフェナク酸のナノ粒子組成物は以下のように調製した。
前駆体化合物として、構造式
ミリング装置(70cm3のステンレス製ボールミル容器)に過剰量(2.6g)の共反応物質NH4Clと共に投入し、含有量がそれぞれ13.7重量%、86.3重量%(15体積%、85体積%に相当)である反応混合物を合計2cm3得た。10gの10mmクロム鋼ボール(10個)のミリング媒体を容器に入れた。圧縮空気(100kcpa)をミリング容器内に流入して冷却を行った。MCS後に得られた組成物は、たった15分後で、NH4ClとNaClのキャリア・マトリックス(NH4Cl:84.7重量%、84.8体積%、NaCl:2.5重量%、1.8体積%)に分散された下記構造式のジクロフェナクナトリウムのナノ粒子(12.9重量%、13.4体積%)を有しており、アンモニアガスが副生成物として生成した。
Na2CO3に分散させたナプロキセンナトリウム塩のナノ粒子組成物
Na2CO3を有するキャリア・マトリックスに分散させたナプロキセンナトリウム塩のナノ粒子組成物を以下のように調製した。
前駆体化合物として、構造式
の従来のナプロキセン酸粉体0.6014gを、ミリング装置(70cm3のステンレス製ボールミル容器)に過剰量(3.401g)の共反応物質Na2CO3と共に投入し、含有量がそれぞれ15重量%、85重量%(27.4体積%、72.6体積%に相当)である反応混合物を合計1.85cm3得た。10gの10mmスチール製ボール(10個)のミリング媒体を容器に入れた。圧縮空気流(100kcpa)を用いて冷却を行った。MCS後に得られた組成物は、Na2CO3とNaHCO3のキャリア・マトリックス(Na2CO3:68.2重量%、81.1体積%、NaHCO3:5.0重量%、5.5体積%)に分散された下記構造式のナプロキセンナトリウム塩のナノ粒子(16.5重量%、26.3体積%)を有していた。
NH4Clに分散させたナプロキセン酸のナノ粒子組成物
NH4Clを有するキャリア・マトリックスに分散させたナプロキセン酸のナノ粒子組成物を以下のように調製した。
前駆体化合物として、構造式
NH4Clに分散された塩酸オランザピンのナノ粒子組成物
NH4Clを有するキャリア・マトリックスに分散された塩酸オランザピンのナノ粒子組成物を以下のように調製した。
前駆体化合物として、従来のオランザピン粉体(フリーベース)0.386gを、ミリング装置(70cm3の硬化ステンレス製ボールミル容器)に過剰量(2.596g)の共反応物質NH4Clと共に投入し、含有量がそれぞれ13重量%、87重量%(15体積%、85体積%に相当)である反応混合物を合計2cm3得た。10gの10mmスチール製ボール(10個)のミリング媒体を容器に入れた。圧縮空気流(100kcpa)を用いて冷却を行った。MCS時間は、0分、5分、30分、60分を評価した。MCS後に得られた組成物は、NH4Clのキャリア・マトリックス(NH4Cl:85重量%、83体積%)に分散された塩酸オランザピンのナノ粒子(14.3重量%、17体積%)を有しており、副生成物としてアンモニアガスが生成した。
クエン酸マトリックスに分散させたシルデナフィルクエン酸塩のナノ粒子組成物
クエン酸を有するキャリア・マトリックスに分散されたシルデナフィルのナノ粒子組成物を以下のように調製した。
まず、従来のクエン酸シルデナフィル2gを重炭酸ナトリウム存在下でCH2Cl2(DCM)で抽出して、シルデナフィル遊離塩基1.35g及びクエン酸ナトリウムを得た。以下のように、本発明のMCS反応に前駆体化合物としてこのシルデナフィル遊離塩基を使用した。
下記構造式のシルデナフィル遊離塩基
Claims (42)
- 治療薬のナノ粒子を有するナノ粒子組成物の製造方法であって、
固体キャリア・マトリックスに分散された治療薬のナノ粒子を有するナノ粒子組成物を製造するのに十分な反応時間で、前駆体化合物と少なくとも1種の共反応物質との混合物をミリング媒体を使用したミリング装置内でメカノケミカル合成する工程を含み、
前記前駆体化合物と前記少なくとも1種の共反応物質とのメカノケミカル反応が、前記治療薬と少なくとも1種の副生成物の前記メカノケミカル合成をもたらし、
前記固体キャリア・マトリックスが前記メカノケミカル合成の副生成物及び/又は過剰な共反応物質であり、
前記メカノケミカル合成が、前記前駆体化合物と前記少なくとも1種の共反応物質との酸/塩基反応、又は前記前駆体化合物と前記少なくとも1種の共反応物質との金属イオン置換のいずれかであることを特徴とするナノ粒子組成物の製造方法。 - 前記ナノ粒子の平均サイズが200nm未満である請求項1に記載の方法。
- 前記ナノ粒子の平均サイズが100nm未満である請求項1に記載の方法。
- 前記ナノ粒子の平均サイズが75nm未満である請求項1に記載の方法。
- 前記ナノ粒子の平均サイズが50nm未満である請求項1に記載の方法。
- 前記ナノ粒子の平均サイズが40nm未満である請求項1に記載の方法。
- 少なくとも50%の前記ナノ粒子の粒子サイズが、前記平均サイズの範囲内である請求項1〜6のいずれかに記載の方法。
- 少なくとも75%の前記ナノ粒子の粒子サイズが、前記平均サイズの範囲内である請求項7に記載の方法。
- 前記反応時間が5分間〜2時間である請求項1〜8のいずれかに記載の方法。
- 前記反応時間が5分間〜1時間である請求項9に記載の方法。
- 前記反応時間が5分間〜45分間である請求項9に記載の方法。
- 前記反応時間が5分間〜30分間である請求項9に記載の方法。
- 前記反応時間が10分間〜20分間である請求項12に記載の方法。
- 前記ミリング媒体がスチール製ボールを有する請求項1〜13のいずれかに記載の方法。
- 前記スチール製ボールの直径が1〜20mmである請求項14に記載の方法。
- 前記スチール製ボールの直径が2〜15mmである請求項14に記載の方法。
- 前記スチール製ボールの直径が3〜10mmである請求項14に記載の方法。
- 前記前駆体化合物が、医薬品、又は活性薬剤である請求項1〜17のいずれかに記載の方法。
- 前記前駆体化合物が、抗肥満薬、中枢神経系興奮剤、カロテノイド、コルチコステロイド、エステラーゼ阻害剤、抗菌薬、腫瘍治療薬、抗嘔吐薬、鎮痛薬、心臓血管作動薬、NSAID及びCOX−2阻害剤等の抗炎症薬、駆虫薬、不整脈治療薬、抗生物質(ペニシリン等)、抗凝固剤、抗うつ薬、抗糖尿病薬、抗てんかん薬、抗ヒスタミン薬、抗高血圧薬、抗ムスカリン様作用薬、抗マイコバクリア薬、抗新生物薬、免疫抑制剤、抗甲状腺薬、抗ウィルス薬、抗不安薬、鎮痛剤(睡眠薬、神経安定薬)、収れん薬、α−アドレナリン受容体遮断薬、β−アドレナリン受容体遮断薬、血液製剤及び代用血液、強心薬、造影剤、コルチコステロイド、咳止め剤(排痰薬、粘液溶解薬)、診断薬、診断造影剤、利尿薬、ドパミン作動薬(抗パーキンソン病薬)、止血剤、免疫薬、脂質制御薬、筋弛緩剤、副交感神経興奮薬、副甲状腺カルシトニン、ビスフォスフォネート、プロスタグランジン、放射性医薬品、性ホルモン(ステロイド等)、抗アレルギー薬、刺激薬、食欲抑制薬、交感神経興奮薬、甲状腺薬、血管拡張薬、及びキサンチンからなる群から選択される請求項1〜18のいずれかに記載の方法。
- 前記前駆体化合物が、ハロペリドール、DLイソプロテレノール塩酸塩、テルフェナジン、塩酸プロプラノロール、塩酸デシプラミン、サルメテロール、クエン酸シルデナフィル、タダラフィル、バルデナフィル、フェナム酸、ピロキシカム、ナプロキセン、ボルタレン(ジクロフェナク)、ロフェコキシブ、イブプロフェン、オンダンステトロン、スマトリプタン、ナラトリプタン、酒石酸エルゴタミン+カフェイン、メチルセルジド、及びオランザピンからなる群から選択される請求項19に記載の方法。
- 前記共反応物質が、Na 2 CO 3 、NaHCO 3 、NH 4 Cl、硫酸水素ナトリウム、水酸化ナトリウム、フマル酸、マレイン酸、酒石酸、クエン酸、塩酸メチルアミン、臭化アンモニウム及び炭酸水素カリウムからなる群から選ばれる請求項1〜20のいずれかに記載の方法。
- 前記固体キャリア・マトリックスの少なくとも一部を除去する工程を更に含む請求項1〜21のいずれかに記載の方法。
- 前記固体キャリア・マトリックスの少なくとも25%を除去する請求項22に記載の方法。
- 前記固体キャリア・マトリックスの少なくとも50%を除去する請求項23に記載の方法。
- 前記固体キャリア・マトリックスの少なくとも75%を除去する請求項24に記載の方法。
- 実質的に全ての前記固体キャリア・マトリックスを除去する請求項25に記載の方法。
- 前記ナノ粒子組成物が、医薬組成物である請求項1〜26のいずれかに記載の方法。
- 前記治療薬が、ジクロフェナクである請求項1〜27のいずれかに記載の方法。
- 前記ナノ粒子の平均サイズが30nm未満である請求項28に記載の方法。
- 前記固体キャリア・マトリックスが、Na 2 CO 3 、NaHCO 3 、NH 4 Cl、及びNaClからなる群から選ばれる少なくとも1種を有する請求項28又は29に記載の方法。
- 前記固体キャリア・マトリックスが、Na 2 CO 3 を単独で、或いはNaHCO 3 と共に有しており、前記ジクロフェナクのナノ粒子がジクロフェナクナトリウム塩の形態で存在する請求項28〜30のいずれかに記載の方法。
- 前記固体キャリア・マトリックスが、NH 4 Clを単独で、或いはNaClと共に有しており、前記ジクロフェナクのナノ粒子がジクロフェナク酸の形態で存在する請求項30に記載の方法。
- 前記治療薬が、ナプロキセンである請求項1〜27のいずれかに記載の方法。
- 前記固体キャリア・マトリックスが、Na 2 CO 3 を単独で、或いはNaHCO 3 と共に有しており、前記ナプロキセンのナノ粒子がナプロキセンナトリウム塩の形態で存在する請求項33に記載の方法。
- 前記固体キャリア・マトリックスが、NH 4 Clを単独で、或いはNaClと共に有しており、前記ナプロキセンのナノ粒子がナプロキセン酸の形態で存在する請求項33に記載の方法。
- 前記治療薬が、オランザピンである請求項1〜27のいずれかに記載の方法。
- 前記固体キャリア・マトリックスがNH 4 Clを有する請求項36に記載の方法。
- 前記オランザピンのナノ粒子が、塩酸オランザピンの形態で存在する請求項36又は37に記載の方法。
- 前記治療薬が、シルデナフィルである請求項1〜27のいずれかに記載の方法。
- 前記固体キャリア・マトリックスがクエン酸を有する請求項39に記載の方法。
- 前記シルデナフィルのナノ粒子がシルデナフィル塩基の形態で存在する請求項39又は40に記載の方法。
- 治療効果量の請求項1〜41のいずれかに記載のナノ粒子組成物と、医薬的に許容可能なキャリア又は賦形剤とを組み合わせることを特徴とする医薬品を製造する方法。
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US20200360294A1 (en) | 2020-11-19 |
EP1830824A4 (en) | 2012-08-29 |
ZA200704613B (en) | 2008-05-28 |
CA2593862A1 (en) | 2006-07-06 |
WO2006069419A1 (en) | 2006-07-06 |
IL183843A (en) | 2017-01-31 |
CN101094659A (zh) | 2007-12-26 |
US20090028948A1 (en) | 2009-01-29 |
NZ555719A (en) | 2010-11-26 |
JP2008526689A (ja) | 2008-07-24 |
JP2016106123A (ja) | 2016-06-16 |
CN104083342A (zh) | 2014-10-08 |
US20180169028A1 (en) | 2018-06-21 |
IL183843A0 (en) | 2007-10-31 |
CA2858733C (en) | 2017-12-19 |
CA2858733A1 (en) | 2006-07-06 |
JP6091041B2 (ja) | 2017-03-08 |
BRPI0518101A (pt) | 2008-10-28 |
EP1830824A1 (en) | 2007-09-12 |
EP1830824B1 (en) | 2016-01-13 |
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