JP2022512235A - 治療剤の送達のための組成物並びにその使用及び製造方法 - Google Patents
治療剤の送達のための組成物並びにその使用及び製造方法 Download PDFInfo
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Abstract
Description
本出願は、2019年10月17日出願の米国特許仮出願第62/916,754号、2019年8月21日出願の米国特許仮出願第62/889,824号、2019年6月5日出願の米国特許仮出願第62/857,567号、2019年5月10日出願の米国特許仮出願第62/846,474号、及び2018年12月11日出願の米国特許仮出願第62/778,132号に対する優先権の利益を主張し、これらの各出願の開示は参照によりその全体が本明細書に組み込まれる。優先権主張が本出願とともに提出されたものとして出願データシートで特定されているありとあらゆる出願もまた、37 CFR1.57に基づいてその全体が参照により本明細書に組み込まれる。
場合にそれを固化させる他の薬剤を欠いている。例えば、いくつかの実施形態では、CBD粉末は、CBDの固化をもたらすマルトデキストリン又は他の添加剤を欠いている。
る。いくつかの実施形態では、脂質は、トリカプリン、トリラウリン、トリミリスチン、トリパルミチン、及びトリステアリンのうちの1つ又は複数を含む。いくつかの実施形態では、1つ又は複数の脂質(例えば、MCT、LCT、又はその両方)は、集合的又は個別に、約400mg/ml、300mg/ml、200mg/ml、150mg/ml、100mg/ml、93mg/ml、75mg/ml、50mg/ml、25mg/ml以下、又は前述の値を含む及び/若しくはそれらにまたがる範囲の濃度で、水性組成物中に存在する。いくつかの実施形態では、1つ又は複数の脂質は、(集合的又は個別に)約2.5%、5%、10%、15%、20%、30%、40%、50%、60%以下、又は前述の値を含む及び/若しくはそれらにまたがる範囲の乾燥wt%で、組成物中に存在する。いくつかの実施形態では、1つ又は複数の脂質は、(集合的又は個別に)約2.5%、5%、7.5%、10%、12.5%、15%、20%、30%、40%以下、又は前述の値を含む及び/若しくはそれらにまたがる範囲の湿潤wt%で、組成物中に存在する。いくつかの実施形態では、脂質は、約92.5%、95%、96%、98%、99%、99.9%以上、又は前述の値を含む及び/若しくはそれらにまたがる範囲の純度を有する。いくつかの実施形態では、脂質は、約8.5%、5%、4%、3.7%、2%、1%、0%以下、又は前述の値を含む及び/若しくはそれらにまたがる範囲の質量%総不純物含有量を有する。
以下は、本発明のある特定の実施形態を説明するために提供される。
製剤化する前に固体及び/又は粉末状態でナノ粒子組成物中に存在するのに十分な純度のカンナビジオール(CBD)と;
リン脂質と;
コレステロールと;
中鎖トリグリセリドと
を含むナノ粒子;及び
水
を含み、
ナノ粒子は、約75nm~約500nmの範囲の平均サイズを有し;
1か月の期間保存すると、ナノ粒子の平均サイズの変化は、約20%未満である、ナノ粒子組成物。
リン脂質と;
トリグリセリドと;
ステロールと;
フィトカンナビノイドと
を含むナノ粒子;及び
水
を含み、
少なくとも約12時間静置した場合、感知できる量のナノ粒子組成物は、水から沈降及び/又は分離しない、ナノ粒子組成物。
フィトカンナビノイドと1つ又は複数のリン脂質とを混合して溶液を提供する工程と、
溶液をマイクロフルイダイザーに通過させる工程と
を含む、方法。
フィトカンナビノイドと1つ又は複数のリン脂質とを混合して溶液を提供する工程と;
溶液を乾燥させて、実質的に固体製品を提供する工程と;
水中で製品を構成して再構成された溶液を提供する工程と;
再構成された溶液をマイクロフルイダイザーに通す工程と
を含む、方法。
組成物中1%~10%の範囲の質量パーセントの、製剤化する前に固体及び/又は粉末状態でナノ粒子組成物中に存在するのに十分な純度のカンナビジオール(CBD)と;
組成物中2.5%~15%の範囲の質量パーセントのホスファチジルコリンと;
組成物中0.5%~5%の範囲の質量パーセントのステロールと;
組成物中2.5%~15%の範囲の質量パーセントの中鎖トリグリセリドと
を含むナノ粒子、及び
組成物中60%~80%の範囲の質量パーセントの水
を含み、
ナノ粒子は、約75nm~約175nmの範囲の平均サイズを有し;
1か月の期間保存すると、ナノ粒子の平均サイズの変化は、約20%未満である、脂質系粒子組成物。
組成物中5%~15%の範囲の質量パーセントの、製剤化する前に固体及び/又は粉末状態でナノ粒子組成物中に存在するのに十分な純度のカンナビジオール(CBD)と;
組成物中35%~60%の範囲の質量パーセントのホスファチジルコリンと;
組成物中2.5%~10%の範囲の質量パーセントのステロールと;
組成物中35%~50%の範囲の質量パーセントの中鎖トリグリセリドと
を含むナノ粒子を含み、
組成物は、15mg/kgの経口投与後、80ng/mlのCmaxを有する、脂質系粒子組成物。
フィトカンナビノイドを提供する工程と;
ホスファチジルコリンを提供する工程と;
中鎖トリグリセリドを提供する工程と;
中鎖トリグリセリド、ホスファチジルコリン、及びフィトカンナビノイドを混合して溶液を提供する工程と;
溶液をマイクロフルイダイザーに通過させて、脂質系粒子組成物を提供する工程と
を含む、方法。
組成物の実施形態の調製
材料及び方法
別途注記のない限り、本明細書で使用される成分は、以下のベンダーから入手した:ヒマワリ由来のホスファチジルコリン及び中鎖トリグリセリドを、American Lecithin社(Lipoid社、「MCT」としてリストされている)から購入し、ソルビン酸カリウム、ペパーミント油、ビタミンE、リンゴ酸、及びコレステロールを、Spectrum Chemicals社から購入し、CBD単離物を、Botanical&Bioscience Laboratories社から購入し、ラカンカ(Luo Han Guo)(モンクフルーツ)抽出物を、GLG Life Tech社から購入し、注射用水を、Rocky Mountain Biologicals社から購入し、クエン酸一水和物及び安息香酸ナトリウムを、JT Baker社から購入した。使用したCBD単離物は、質量対質量(w/w)で0.3%以下のTHCを含んでいた。ホスファチジルコリンは、96.3%又は99.9%を超えるホスファチジルコリン(水素化)を含むH100-3グレードであった。ホスファチジルコリン及び1.1%未満のリゾホスファチジルコリン及び2.0%未満のトリグリセリド。これは高純度のホスファチジルコリン(96%超の純粋なホスファチジルコリン(水素化))であり、発明者の知る限り、現在のCBD製品では使用されていない。
安定性試験
この実施例は、実施例1で調製されたいくつかの実施形態の安定性試験及び貯蔵寿命データを開示する。実施例1で調製されたバッチを、冷却すると、7.0~9.0重量ポンドインチの必要な除去トルクで取り付けられたチャイルドプルーフキャップを備えた20mLの琥珀色のバイアルに充填した。密閉ボトルを、2~8℃、25℃/60%相対湿度、40℃/75%相対湿度、又は50℃及び非制御湿度で保存した。0、1、2、3、6、及び11か月目に特性評価のために、最小限に試料を引き出した。特性評価には、動的光散乱による粒径分析及びUPLCによるCBD濃度が含まれていた。結果を図3及び4に示す。
ナノ粒子のイメージング
この実施例は、実施例1で先に記載されたように調製された脂質ナノ粒子の代表的な画像を開示する。バッチ1及び3で概説した成分組成と一致する試料を、水で10倍に希釈した。3マイクロリットルを、先にグロー放電された薄い銅グリッド(Cu-200CN、Pacific Grid-Tech社)上に配置した。グリッドの準備のために、試料を、湿度制御(100%)下で低温(0~5℃)にて凍結チャンバー内に入れた。濾紙で2秒間吸い取った後、試験体を凍結剤、すなわち液体窒素で冷却した液体エタンにより急速に凍結させた。調製した乾燥物を、200kV FEI Talos C200C電子顕微鏡にマウントした。顕微鏡画像を、45Kの倍率で収集した。例示的な画像を図5に示す。
組成物の実施形態の調製
以下には、噴霧乾燥及び凍結乾燥によって調製された脂質ナノ粒子粉末のいくつかの実施形態を記載する。CBD単離物含有脂質ナノ粒子を、実施例1の製造プロセスに記載されている方法に従って調製した。乾燥CBD含有脂質ナノ粒子を噴霧するために、最終製品を、リオプロテクタントとして機能する追加の賦形剤、例として、0%、5%、10%、15%、又は20%の、以下のラクトース、デキストロース、トレハロース、アルギニン、グリシン、及び/又はヒスチジン単独と、又はそれらの組合せと混合した。賦形剤を最終製品溶液に加え、溶解するまで混合(200RPM)した。材料の平衡化によって、室温での追加のインキュベーションが可能であった。
組成物の実施形態の調製
以下では、CBD単離脂質ナノ粒子組成物の実施形態を製造するための無溶媒アプローチの実施形態について記載する。CBD脂質ナノ粒子を、高剪断インラインミキサーを利用した無溶媒法を使用し、続いて高圧均質化を使用して調製した。水溶性香味剤を含むすべての水溶性製剤成分を、指定された濃度で注射用水に溶解させた。水溶液を、更に使用する前に加熱及び濾過した。温水溶液を、高剪断インラインミキサー(Silverson Versoミキサー)の入口に供給する容器の底の出口を備えた混合容器に移した。高剪断ミキサーの出口には、混合容器の上部に液体を戻すチューブが利用されている。温水溶液を混合容器に移すと、インラインミキサーが作動し、ミキサーの自己ポンピング動作によって液体がシステム内を移動する。
ナノ粒子のサイズ及び安定性に対する脂質及びCBDの濃度の影響
CBD含有脂質ナノ粒子を、ナノ粒子粒径分布及び短期安定性に対するそれらの影響を決定するために、種々の脂質濃度により100mLバッチで溶媒系製造プロセスを使用して調製した。ナノ粒子を、透明ガラス容器中に20mL以上のアリコートにし、2~8℃、25℃、相対湿度60%で、40℃、相対湿度75%で保存した。一定の間隔で粒径分布を決定し、Z平均、多分散指数、及びD90粒径を記録した。以下の表に、研究された製剤の成分の質量パーセントをまとめている。
CBD脂質ナノ粒子溶液及び粉末の薬物動態
CBD含有脂質ナノ粒子を、実施例1のバッチ2及び4に概説されている配合成分を使用して、溶媒系製造プロセスに従って調製した。CBD含有脂質ナノ粒子の粉末を、実施例4に概説されている方法に従って調製した。
CBD含有脂質ナノ粒子の防腐剤系
CBD含有脂質ナノ粒子を、溶媒系製造プロセスを使用して調製したが、脂質フィルムの水和及び混合の前に、異なる濃度の防腐剤を水溶液中に溶解した。クエン酸一水和物及びリンゴ酸を、それぞれ6.10及び5.73mMで製剤1に加えた。製剤2では、クエン酸を4.88mMで加え、リンゴ酸は加えなかった。製剤3では、クエン酸を0.16mMで加え、リンゴ酸は加えなかった。製剤4では、クエン酸もリンゴ酸も加えなかった。すべての製剤は、8.53mMのソルビン酸カリウム及び8.90mMの安息香酸ナトリウムを含有していた。製剤を、2~8℃、相対湿度60%で25℃、及び相対湿度75%で40℃にて6か月又は7か月間保存した後、pH、粒径分布、ゼータ電位、CBD濃度、及び粒径について特性評価し、防腐効果チャレンジを行った。以下の表には、製剤の初期特徴付けデータをまとめている。
脂質ナノ粒子製剤中のより高い濃度のCBD
CBD含有脂質ナノ粒子を、上記に概説された溶媒系製造プロセスを使用して調製した。本実施例では、脂質比を相互に固定し、CBD濃度を変化させた。製剤組成は、以下の表に概説されている。製剤を、2~8℃、相対湿度60%で25℃、及び相対湿度75%で40℃にて100日間保存し、粒径分布を測定した。報告された結果は、0日目に記録された初期条件からの平均パーセント変化である(n=試料ごと、時点ごとに3回の測定)。正の数は、0日目に対して増加した粒径パラメーターを示し、負の数は、0日目に対して減少したパラメーターを示す。
CBD含有脂質ナノ粒子を濾過することができる
CBD含有脂質ナノ粒子を、10リットルのバッチサイズで、溶媒系方法を使用して調製した。更なる研究の前に、ナノ粒子を、粒径分布及びCBD濃度について特性評価した。材料を濾過するために、ナノ粒子溶液をステンレス鋼のサイドアームを含む加圧容器に移した。サイドアームには、Pharmed BPTチューブを使用して、3M betafineインラインフィルターを用いて、加圧容器を受入容器に接続した。ナノ粒子溶液を濾過するために、窒素ガスを加圧容器に充填して溶液を置換し、溶液を強制的にフィルターに通して受入容器に入れた。この研究では、2つの3M betafineフィルター、すなわち0.2ミクロン及び0.65ミクロンのポリプロピレンフィルターを評価した。濾過後、粒径分布及びCBD濃度を再度測定し、開始時の測定値と比較した。すべての測定を、3回実行した。
動作圧力及び通過回数によって得られた粒径分布
CBD含有脂質ナノ粒子を、100mLのバッチサイズで溶媒系製造プロセスを使用して調製した。研究の目的の第1の部分は、通過回数が初期粒径分布に与える影響、及び相対湿度60%で25℃にて6か月間保存した後の何らかの変化を決定することであった。脂質スラリーの全量を、10回マイクロ流動化して、各回の後分析のために試料収集した。以下の図15に、Z平均及びD90の粒径を示す。マイクロフルイダイザーを1回通過した後、Z平均は200nm未満であったが、D90粒径は1.0ミクロンであった。マイクロフルイダイザーを2回通過した後、Z平均とD90は両方とも200nm未満であった。粒径間の差は、通過5までの後続の通過により減少した。通過6からそれ以降、2つの粒径は差が大きくなった。興味深いことに、通過1~5では、相対湿度60%で25℃にて6か月間保存した後、粒径パラメーターのパーセント変化がわずかに減少した(図16)。しかし、同じ保存条件及び時間において通過6~10で、D90及びPDIの有意な増加が観察された。D90の粒径は、通過6~10で少なくとも300%増加した。
いくつかのCBD単離物で調製されたCBD含有脂質ナノ粒子
CBD含有脂質ナノ粒子を、100mLバッチでの溶媒系製造プロセス又は無溶媒高剪断混合プロセスを使用して調製した。脂質ナノ粒子を、様々な製造元製のCBD単離物を使用して調製し、これらはすべて、99%を超えるCBD純度を有し、検出可能なTHCを有していなかった。ナノ粒子を20mg/mLで調製し、最終濃度をUHPLCで検証した。すべての調製物は、85.4nm~105.6nmの間のZ平均粒径、113.0nm~153.2nmのD90粒径、及び0.105~0.169の多分散指数を有していた。Gen Canna社、Global Cannabinoids社、及びMile High Labs社製CBD単離物により調製された脂質ナノ粒子は、Boulder Botanicals社製CBD単離物で調製されたものと有意差はなく、CBD単離物の起源に関係なく同様のナノ粒子属性が達成可能であることを示している。この実施例の結果は、以下の表にまとめられている。
フルスペクトル又は広域スペクトルCBD材料で調製されたCBD含有脂質ナノ粒子
CBD含有脂質ナノ粒子を、0.1リットルのバッチで溶媒系及び/又は無溶媒製造プロセスにより調製した。この実施例では、CBDの起源は、CBD含有量が44.25%~86.6%でばらつきのあるフルスペクトル又は広域スペクトルのヘンプ抽出物に由来していた。THC含有量は0.3%未満であるか、又は検出可能ではなかった。すべての製剤を、20mg/mLCBDの最終濃度に調製し、UHPLCによって確認した。製剤中の残りの脂質を改変して、フル/広域スペクトルヘンプ抽出物中のより低濃度のCBDに適応させた。すべての製剤は、94.88nm~178.0nmの間のZ平均粒径、132.0nm~265.0nmの間のD90粒径、及び0.100~0.221の多分散指数を有していた。得られた粒径の属性は、CBD単離物で調製されたものと異なっておらず、このことは、脂質ナノ粒子製剤において、広域又はフルスペクトルCBDを、CBD単離物と交換することができることを示している。この研究の結果は、以下の表にまとめられている。
CBG単離物、CBN留出物、及びCBDa油により調製された脂質ナノ粒子
脂質ナノ粒子を、溶媒系製造プロセスを使用して他の市販のカンナビノイドを用いて調製し、粒径分布について特性評価した。Global cannabinoids社製CBG単離物は、CBGが93.34質量%であり、他のカンナビノイドは検出されなかった(製造元のCOAに基づく)。Z平均粒径は105.6nmであり、D90粒径は241.0nmであり、多分散指数は0.206であった。脂質ナノ粒子を、Global cannabinoids社製CBN留出物を用いて調製した。CBN留出物は80.5質量%のCBNであり、3.1質量%のCBCを含有していたが、他のカンナビノイドは検出できなかった(製造元のCOAに基づく)。Z平均粒径は99.59nmであり、D90粒径は139.0nmであり、多分散指数は0.138であった。脂質ナノ粒子も、製剤の脂質比を改変せずに、希釈CBDa油(Myriam's Hope社、Nevada)を使用して調製した(結果は示さず)。CBG及びCBNナノ粒子の結果は、以下の表にまとめられている。
CBD含有脂質ナノ粒子を調製するために使用されるコレステロールに対するフィトステロール代替物
CBD脂質ナノ粒子製剤を、0.1リットルのバッチで溶媒系製造プロセスを使用して調製した。本実施例では、コレステロールの代替物として様々なフィトステロールを使用して製剤を調製した。フィトステロール(physterosterols)は、BASF社から購入し、Vegapure 867 GN、Vegapure FS、及びVegapure 95DSという名称であった。フィトステロールによって、製剤中のコレステロールを同じ質量パーセントで置き換え、製剤に追加の改変は行わず、コレステロールを加えなかった。以下の表は、コレステロールの3つのフィトステロール代替物を使用した初期の粒径測定値についてまとめている。Vegapure 867 GNは、Z平均粒径が85.1nm、PDIが0.152であり、Vegapure FSは、Z平均粒径が87.6nm、PDIが0.168であり、Vegapure 95DSは、粒径が130.7nm、PDIが0.400であった。
中鎖トリグリセリドの代替物を用いたCBD脂質ナノ粒子の調製
パート1:CBD脂質ナノ粒子を、0.1リットルのバッチで溶媒系製造プロセスを使用して調製した。中鎖トリグリセリド(MCT)を、ABITEC社から入手可能な代替物に置き換えた。Captex 8000 NFは、カプリル酸のトリグリセリドであり、Captex GTOは、オレイン酸のトリグリセリドであり、Captex1000は、カプリン酸のトリグリセリドである。Captexトリグリセリドによって、以下の表に記載されている質量パーセントでMCTを置き換えた。この表はまた、初期粒径及び多分散指数についてまとめている。
組成物の実施形態の調製
CBDの送達のための組成物を、以下の方法を使用して調製した。組成物を調製するために、CBD(2.0g)を、中鎖トリグリセリド(9.3g)中に混合しながら溶解させた。この溶液に、コレステロール(1.0g)及びホスファチジルコリン(10.0g)を加えた。ビタミンEを撹拌しながら加え(0.05g)、油相において抗酸化剤として作用させた。その際、リンゴ酸(0.085g)、クエン酸(0.085mg)、ソルビン酸カリウム(0.1g)、安息香酸ナトリウム(0.1g)、及びモンクフルーツ抽出物(0.09g)を、水(76.07g)に混合しながら加えた。水相を混合しながら油相に加えた。
組成物の実施形態の調製
CBDの送達のための組成物を、以下の方法を使用して調製した。100mlのエタノールに、0.3質量対質量(w/w)%以下のTHCを含むCBD単離物(2.0g)を加えた。その際、中鎖トリグリセリド(9.3g)を混合しながら加えた。この溶液に、コレステロール(1.0g)、ホスファチジルコリン(10.0g)、及びビタミンE(0.05g)を加えた。
組成物の実施形態の試験
5リットルの製造バッチを高圧液体クロマトグラフィー(HPLC)によって分析して、試料中に存在するカンナビノイドを測定した。結果は、以下の表に示すとおりであった:
ヌーペプト及びCBD脂質ナノ粒子製剤
溶媒系脂質ナノ粒子製造プロセスを使用して、ヌーペプト(N-フェニルアセチルL-プロリルグリシンエチルエステル)(N-phenylacetyl-L-prolyglygice ethyl ester)の製剤を作製した。ヌーペプト及び脂質を、高温でエタノール中に溶解し、乾燥させてフィルムを形成した。フィルムを、乾燥窒素ガスで埋め戻し、4℃で12~24時間保存した後、続行した。フィルムを温水により水和し、30分間混合した後、マイクロ流動化を行い、最終製剤量は100mLであった。この実施例で研究された製剤は、以下の表にまとめられている。
メラトニン及びCBD脂質ナノ粒子製剤
メラトニン単独、並びにメラトニン及びCBDを含む脂質ナノ粒子製剤を、溶媒系製造プロセスを使用して調製した。メラトニン単独又はメラトニン及びCBDを、他の脂質成分とともに、エタノール中に部分的に~完全に溶解させ、その後乾燥させてフィルムにした。フィルムを窒素ガスで覆い、処理前に4℃で12~24時間保存した。固体脂質フィルムを温水で水和し、30分間混合して脂質スラリーを形成した後、マイクロ流動化した。すべての製剤を、100mLバッチで調製した。以下の表は、本実施例で作製された製剤についてまとめている。
CBD、メラトニン、及びGABAの脂質ナノ粒子粉末製剤
以下の脂質ナノ粒子製剤は、睡眠を促進するように設計されている。製剤を、200mLのバッチで溶媒系製造プロセスを使用して調製した。脂質、CBD、メラトニンすべてをエタノール中に溶解し、乾燥させてフィルムにした。フィルムを、安息香酸ナトリウムとソルビン酸カリウムをそれぞれ最大1.052mg/mL、及びクエン酸一水和物とリンゴ酸をそれぞれ最大0.622mg/mL含有する温媒体で水和した。処理後、GABA(ガンマアミノ酪酸)を脂質ナノ粒子懸濁液に溶解し、2時間混合した後、特性評価を行い、噴霧乾燥させた(上の概説のとおり)。
疑似胃液及び疑似腸液中のCBD脂質ナノ粒子の安定性
消化プロセスを通過したCBD脂質ナノ粒子の安定性を、2時間後に疑似胃液中の粒径分布を測定し、続いて4時間後に疑似腸液中で希釈及びインキュベーションすることによってシミュレートした。CBD脂質ナノ粒子を、100mLスケールの溶媒系製造プロセスを使用して調製した。疑似胃液を、1グラムの塩化ナトリウム(CAS7647-14-5)、21.5mgのタウロコール酸ナトリウム(CAS345909-26-4)、6.5mgのレシチン(CAS8002-43-5)、及び十分な塩酸(CAS7647-01-0)を、精製水(QS 500mL)中で溶解/分散させ、最終pHを1.6にすることによって調製した。疑似腸液を、1グラムの塩化ナトリウム(CAS7647-14-5)、806.5mgのタウロコール酸ナトリウム(CAS345909-26-4)、64.4mgのレシチン(CAS8002-43-5)、1.1グラムのマレイン酸(CAS110-16-7)、及び696mgの水酸化ナトリウム(CAS1310-73-2)を、精製水(QS500mL)中で溶解/分散させることによって調製した。必要に応じて、pHを6.5に調整した。疑似溶液は、直ちに使用するか、又は4℃にて1か月以内の間保存した。
油性で純度がより低いリン脂質を用いたCBD脂質ナノ粒子の調製
CBD含有脂質ナノ粒子を、0.1リットルのバッチで溶媒系製造プロセスを使用して調製した。脂質ナノ粒子を、油性リン脂質で調製して、99.0%純粋なホスファチジルコリン(H100-3)と比較した。油性リン脂質の組成(製造元のCOAから取得した情報)を、初期粒径分布測定値とともに、以下の表中の組成の下に示す。
甘味剤の実施例。
CBD脂質ナノ粒子を、100mLバッチサイズの溶媒系製造プロセスを使用して調製した。乾燥脂質フィルムを、防腐剤として、安息香酸ナトリウムとソルビン酸カリウムをそれぞれ最大1.052mg/mL、及びクエン酸一水和物とリンゴ酸をそれぞれ最大0.622mg/mL含有する水和媒体で水和した。甘味剤(0.09%w/w)を、水和媒体に溶解させた後、以下の配合表に基づいて乾燥フィルムに加え、製剤に追加の香味剤を加えなかった。処理の1日後、製剤を、初期粒径分布についてスクリーニングした(下の表に示す)。初期粒径測定は、Monkfruit社、GLG社、及びTate and Lyle社から評価されたすべての甘味剤が、CBD脂質ナノ粒子製剤に適合性があることを示している。
比較薬製品
共通の成分又はラベルを有するCBD比較薬製品を、内に記載された実施形態との粒径比較のために、元の製造元のウェブサイトから購入した。この検索で使用された主要な成分は、ホスファチジルコリン、リン脂質、レシチン、又はMCTであった。ラベルに見出されるキーワードには、ナノ、リポソーム系、及び水溶性が含まれる。製品を、濾過された超純水で、粒径測定に好適な計数が得られる光学密度に希釈した。以下の表は、比較薬製品から測定された粒径についてまとめている。測定されたすべての製品は、本明細書に記載の製剤を超える粒径及び多分散指数を有し、このことは、成分の選択及び製造プロセスが、安定なナノ粒子を製造するための鍵であることを更に支持している。
CBD脂質ナノ粒子局所ローション
以下の表に示されているのは、表面の疼痛を緩和するためのローション/クリーム中のCBDの担体としてCBD脂質ナノ粒子システムを利用する局所製剤である。製剤のベース(A相)には、Lipoid社のSkin Lipid Matrix 2026テクノロジーが利用されており、最終製剤中に50%で存在している。CBD(50mg/mL)脂質ナノ粒子(B相)組成物は、他の実施形態に記載されているが、ここでは防腐剤及び香味料を含まず、最終製剤中に20%(1%CBD)で存在している。組成物のC相は、脂質/油性成分、又は油溶性成分からなり、皮膚浸透促進剤としてのCaptex 170 EP、アルガン油、メントール、アルニカ油、樟脳及び、グレープフルーツ種子油を含み、最終製剤中に合計19%で存在する。ここで、メントール、アルニカ油、樟脳及び、グレープフルーツ種子油は、局所鎮痛特性のために存在する。最後に、組成物のD相は水であり、11%で存在する。
ホット及びコールドコーヒー製品におけるCBD脂質ナノ粒子の安定性
CBD脂質ナノ粒子を、8オンスのコーヒー飲料あたり10mgのCBDの濃度でコーヒー飲料中に分散させた。ホットコーヒー飲料を、プアオーバー技術を使用して調製し、CBD脂質ナノ粒子を導入した時点で、得られた液体は130°Fであった。CBDナノ粒子を、ナイトロコールドブリューコーヒー(Parks Coffee社)にも分散させて、ナノ粒子を導入した時点で、コーヒー飲料は2~8℃であった。飲料中に30分間保存した後、粒径測定のためにコーヒーを希釈した。各溶液中の初期粒径測定値を、2つのコーヒー飲料に30分間保存した後の粒径と比較した。図21に示すように、粒径は、30分にわたってコールドコーヒー飲料及びホットコーヒー飲料において、それぞれ11.3%及び6.5%しか増加しておらず、このことは、CBD脂質ナノ粒子がコーヒー飲料中で安定であることを示している。
実施形態の粘度測定
CBD脂質ナノ粒子(上記の実施例1で調製された)の粘度を、LV-DV-II+Brookfield粘度計(Brookfield社、Middleboro、MA)に取り付けられた少量のアダプターを使用して測定した。粘度を、26℃で16mLの溶液を使用し、スピンドル速度60RPMを使用して、3分間にわたって測定し、決定した。CBD脂質ナノ粒子溶液の粘度は、5.096Cpであると決定された。
処置方法
本発明者の経験に基づいて、以下の予言的結果を、対照研究を使用して予測する。
処置方法
本発明者の経験に基づいて、以下の予言的結果を、対照研究を使用して予測する。
処置方法
本発明者の経験に基づいて、以下の予言的結果を、対照研究を使用して予測する。
処置方法
本発明者の経験に基づいて、以下の予言的結果を、対照研究を使用して予測する。
102 液体成分
103 水を加える
104 混合する
105 水中油型エマルジョン
106 高剪断混合
201 成分
202 溶媒
203 混合する
204 濃縮する
205 構成する
206 高剪断混合
Claims (23)
- 脂質系粒子組成物であって、
組成物中1%~10%の範囲の質量パーセントのカンナビジオール(CBD)と;
組成物中2.5%~15%の範囲の質量パーセントのホスファチジルコリンと;
組成物中0.5%~5%の範囲の質量パーセントのステロールと;
組成物中2.5%~15%の範囲の質量パーセントの中鎖トリグリセリドと
を含むナノ粒子、及び
組成物中60%~約80%の範囲の質量パーセントの水
を含み、
前記ナノ粒子は、約75nm~約200nmの範囲の平均サイズを有し;
1か月の期間保存すると、前記ナノ粒子の平均サイズの変化は、約20%未満である、脂質系粒子組成物。 - リポソーム及び/又は水中油型ナノエマルジョンを含む、請求項1に記載の脂質系粒子組成物。
- 室温で少なくとも約1か月静置した場合、感知できる量のナノ粒子組成物が、水から沈降及び/又は分離しない、請求項1に記載の脂質系粒子組成物。
- 乾燥するまで濃縮してナノ粒子の粉末製剤を得る場合、ナノ粒子の粉末が再構成されて、ナノ粒子組成物を提供できるように構成される、請求項1に記載の脂質系粒子組成物。
- CBDのTmaxが4.5時間未満である、請求項1に記載の脂質系粒子組成物。
- 1か月の期間保存すると、前記ナノ粒子の平均サイズの変化が、約20%未満である、請求項1に記載の脂質系粒子組成物。
- 組成物中の前記ナノ粒子の多分散度が、0.20以下である、請求項1に記載の脂質系粒子組成物。
- 25℃及び60%相対湿度で90日保存すると、前記ナノ粒子の多分散度の変化が、100%以下である、請求項1に記載の脂質系粒子組成物。
- 25℃及び60%相対湿度で90日保存すると、前記ナノ粒子の多分散度の変化が、0.1以下である、請求項1に記載の脂質系粒子組成物。
- 25℃及び60%相対湿度で18か月より長い貯蔵寿命を有する、請求項1に記載の脂質系粒子組成物。
- 25℃及び60%相対湿度で90日保存すると、前記ナノ粒子のD90の変化が、10%以下である、請求項1に記載の脂質系粒子組成物。
- 15mg/kgの経口投与後、80ng/mlの最大濃度(Cmax)を有する、請求項1に記載の脂質系粒子組成物。
- 脂質系粒子組成物であって、
組成物中5%~20%の範囲の質量パーセントのカンナビジオール(CBD)と;
組成物中35%~60%の範囲の質量パーセントのホスファチジルコリンと;
組成物中2.5%~10%の範囲の質量パーセントのステロールと;
組成物中35%~50%の範囲の質量パーセントの中鎖トリグリセリドと
を含む粒子
を含み、
対象への15mg/kgの経口投与後、80ng/mlのCmaxを有する、組成物。 - 乾燥粉末として提供される、請求項13に記載の脂質系粒子組成物。
- 前記粉末が、水中で再構成されて水溶液が得られるように構成されており、
再構成時に、水溶液内のナノ粒子が、約75nm~約200nmの範囲の平均サイズを有する、請求項15に記載の脂質系粒子組成物。 - 防腐剤を更に含む、請求項1又は13に記載の脂質系粒子組成物。
- 前記防腐剤が、リンゴ酸、クエン酸、ソルビン酸カリウム、安息香酸ナトリウム、及びビタミンEのうちの1つ又は複数を含む、請求項1に記載の脂質系粒子組成物。
- 前記ステロールがコレステロールである、請求項1又は13に記載の脂質系粒子組成物。
- 香味剤を更に含む、請求項1又は13に記載の脂質系粒子組成物。
- 処置を必要とする患者を処置する方法であって、有効量の請求項1又は13に記載の脂質系粒子組成物を患者に投与することを含む、方法。
- フィトカンナビノイドのナノ粒子組成物を製造する方法であって、
フィトカンナビノイドを提供する工程と;
ホスファチジルコリンを提供する工程と;
中鎖トリグリセリドを提供する工程と;
中鎖トリグリセリド、ホスファチジルコリン、及びフィトカンナビノイドを混合して溶液を提供する工程と;
前記溶液をマイクロフルイダイザーに通過させて、脂質系粒子組成物を提供する工程と
を含む、方法。 - 前記溶液に1つ又は複数のステロールを加えることを更に含む、請求項21に記載の方法。
- 前記溶液に水を加えることを更に含む、請求項21に記載方法。
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CN113382719B (zh) | 2023-10-31 |
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AU2021203006B2 (en) | 2023-06-08 |
KR20210114409A (ko) | 2021-09-23 |
CN117695226A (zh) | 2024-03-15 |
AU2019398117B2 (en) | 2021-04-15 |
BR112021011087A2 (pt) | 2021-08-31 |
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EP3840730A1 (en) | 2021-06-30 |
US20210251917A1 (en) | 2021-08-19 |
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