JP7046237B2 - 手術部位感染の処置および予防のための組成物および方法 - Google Patents
手術部位感染の処置および予防のための組成物および方法 Download PDFInfo
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Description
本発明は一般に、手術部位感染の予防と処置のための徐放性組成物およびその使用に関する。
本発明のいくつかの実施形態による生分解性基材を含浸またはコーティングするために使用されるマトリックス組成物は、(a)生体適合性ポリマー、(b)生体適合性ポリマーと非共有結合した少なくとも1種のステロールを含む第1の脂質成分、(c)少なくとも12個の炭素の脂肪酸部分を有する少なくとも1種のリン脂質を含む第2の脂質成分、および(d)薬学的活性剤を含む。マトリックス組成物は、それを必要としている対象の身体の手術部位で薬学的活性剤の徐放をもたらす。
いくつかの実施形態では、コーティングマトリックス組成物は、ポリマーと結合コレステロールとが1つのタイプの層を形成し、リン脂質が第2のタイプの層を形成し、この2つのタイプの層が複数の交互層または疑似交互層の形態に組織化される、高度組織化多層構造を有する。
「リン脂質」は、グリセリン骨格上に単一のホスファチジル結合を有し、残りの2つの位置に脂肪酸を有するホスホグリセリドである。しかし、アルキル鎖、アルケニル鎖、または任意の他の少なくとも12個の炭素、あるいは、少なくとも14個の炭素の炭化水素鎖などの脂肪酸残基以外の炭化水素鎖を有するホスホグリセリドが、本発明の範囲内に含まれることを明確に理解されたい。結合は、リン脂質で認められるアシル結合に変わるエーテル結合であってよい。
別の実施形態では、本発明の方法および組成物のマトリックス組成物は、遊離脂肪酸をさらに含む。本発明のコーティングマトリックス組成物に組み込むことができる遊離脂肪酸の非制限的例は、オメガ-6脂肪酸、オメガ-9脂肪酸、14個以上の炭素原子を有する遊離脂肪酸、16個以上の炭素原子を有する遊離脂肪酸、16個の炭素原子を有する遊離脂肪酸、18個の炭素原子を有する遊離脂肪酸、16~22個の炭素原子を有する遊離脂肪酸、16~20個の炭素原子を有する遊離脂肪酸、16~18個の炭素原子を有する遊離脂肪酸、18~22個の炭素原子を有する遊離脂肪酸、18~20個の炭素原子を有する遊離脂肪酸、リノール酸、リノレン酸およびオレイン酸から選択される。別の実施形態では、遊離脂肪酸は、当該技術分野において既知の別の適切な遊離脂肪酸である。別の実施形態では、遊離脂肪酸は、マトリックス組成物に可撓性を付与する。別の実施形態では、遊離脂肪酸は、インビボ放出速度を遅らせる。別の実施形態では、遊離脂肪酸は、インビボ制御放出の一貫性を改善する。脂肪酸は不飽和であっても飽和していてもよい。別の実施形態では、少なくとも14個の炭素原子を有する飽和脂肪酸の組み込みが、得られるマトリックス組成物のゲル-液体遷移温度を高める。それぞれのタイプの脂肪酸は、本発明の別の実施形態を表す。
手術部位感染の予防および処置を目的とする本発明の方法は、現時点で効果的な解がなく、医学界で関心の高い医療ニーズに対処するものである。本発明の方法は、外科手術中および/またはその後に適用される局在型感染の処置および予防を提供する。本発明の方法は、全体的感染率を下げ、院内感染耐性菌を含む既存の感染を克服するまたは減らす。本発明の方法は、種々の組織および実質臓器における術後感染の処置および予防に使用してよい。
本発明の組成物を得るために、耐水性マトリックス中でポリマーと脂質の均一分散物が得られる任意の好適な方法を採用してよい。好都合にも、いくつかの実施形態では、用いられる方法は、製造プロセスのいずれの段階においても水の使用を回避する。
(a)第1の揮発性有機溶媒中に、(i)生分解性ポリエステルおよび(ii)ステロールを混合するステップと、
(b)第2の揮発性有機溶媒中に、(i)活性薬剤、(ii)ホスファチジルコリンまたはホスファチジルコリンの混合物、および任意で(iii)例えば、ホスファチジルエタノールアミンなどの追加の脂質成分を別々に混合するステップと、
(c)ステップ(a)および(b)から得られる生成物を混合するおよび均一化するステップと、
(d)ステップ(c)から得られる均一な混合物と基材を接触させるステップと、を含む。
(i)製造後、マトリックス組成物を水和し、遠心分離または濾過により単離する。マトリックス中に封入されない脂質は、ミセルまたはリポソームを形成し、上清中に特定される。上清およびマトリックスの全脂質含有物が定量化される。このようにして、異なる脂質:ポリマー初期比率の種々の配合物に対して、封入脂質含量対遊離脂質含量が最初に求められる。したがって、実際の実験的最大脂質/ポリマー比率が決定される。
(ii)製造後、マトリックス組成物をトリチウムタグ水を含む溶液で水和し、トリチウム不含溶液で洗浄し、遠心分離または濾過で単離して、ポリマー質量当たりの封入された水の量が定量化される。これを異なる脂質:ポリマー比率に対し繰り返すことにより、マトリックス組成物中の自由体積を飽和するのに必要な脂質の量が決定される。
使用した略語:ホスホエタノールアミン=PE;ホスファチジルコリン=PC;1,2-ジミリストイル-sn-グリセロ-3-ホスホエタノールアミン=DMPE(14:0);1,2-ジパルミトイル-sn-グリセロ-3-ホスホエタノールアミン=DPPE(16:0);1,2-ジステアロイル-sn-グリセロ-3-ホスホコリン=DSPC(18:0);1,2-ジパルミトイル-sn-グリセロ-3-ホスホコリン=DPPC(16:0);リン酸三カルシウム(TCP);ポリビニルアルコール(PVA)。
1.生分解性ポリマーおよび第1の脂質成分(例えば、ステロール)が揮発性有機溶媒と混合され、その示差走査熱量(DSC)プロファイルにより測定されるように、脂質飽和ポリマーマトリックスの溶液または懸濁液が得られる。
2.活性薬剤および第2の脂質成分(例えば、少なくとも1種のリン脂質)が第2の揮発性有機溶媒と混合されて第2の溶液または懸濁液が得られる。
3.2つの溶液または懸濁剤が組み合わされ、平衡に達するまで混合される。
4.基材(例えば、ゼラチンスポンジ、コラーゲン発泡体、鉱物基材)がその後、得られたステージ3の溶液と混合される。
5.有機溶媒がその後蒸発されて、薬剤含有脂質飽和ポリマーマトリックスでコーティングされたおよび/または含浸された基材が得られる。
下記の手順により、ドキシサイクリンの徐放に適するマトリックス組成物で平均直径100μmのリン酸三カルシウム粒子をコーティングした。
1.1.PLGA75/25のストック溶液(酢酸エチル中の300mg/ml)-PLGA75/25をメスフラスコ中に秤取した。酢酸エチルを、そのメスフラスコに添加した。全PLGA粒子が完全に溶解するまで、溶液を撹拌した。
1.2.コレステロールのストック溶液(酢酸エチル中の30mg/ml)-コレステロールをメスフラスコに秤取した。酢酸エチルを、そのメスフラスコに添加した。コレステロールが完全に溶解するまで、溶液をボルテックスした。
1.3.ドキシサイクリンのストック溶液(メタノール中の210mg/ml)-ドキシサイクリンをメスフラスコに秤取した。メタノールを、そのメスフラスコに添加した。ドキシサイクリンが完全に溶解するまで、溶液をボルテックスした。
1.4.DPPCのストック溶液(メタノール/酢酸エチル混合物(9/14)中の206mg/mlおよび69mg/mlのDSPC)-DPPCおよびDSPCをメスフラスコに秤取した。メタノール/酢酸エチル(9/14)を、そのメスフラスコに添加した。溶液を45℃で5分間インキュベートし、リン脂質が完全に溶解するまでボルテックスした。
溶液A-5体積部のコレステロールストック溶液を1体積部のPLGAストック溶液と混合した。この混合物は、50mg/mlのPLGAおよび25mg/mlのコレステロールを含有した。
溶液B-18容積部のドキシサイクリン溶液を82体積部のリン脂質溶液とうまく混合した(セクション1.4を参照)。この混合物は、225mg/mlのリン脂質(56mg/mlのDSPCおよび169mg/mlのDPPC)および37.5mg/mlのドキシサイクリンを含有した。
溶液AB-2体積部の溶液Bを3体積部の溶液Aと混合し、30mg/mlのPLGA75/25、15mg/mlのコレステロール、90mg/mlのリン脂質および15mg/mlのドキシサイクリンを含む溶液を得た。
1.5gの基材(例えば、リン酸三カルシウム粉末(100μmの粒子)、ポリビニルアルコール(PVA)粉末、ポリ乳酸(PLA)粉末)を30mmのガラスペトリ皿中に秤取した。
1.5mlの溶液ABをその皿に加えた。
ペトリ皿を45℃に設定した真空オーブン中に入れ、全溶媒が蒸発するまで(溶媒の存在が検出されなくなるまで)軽真空(約610mm/Hg)にし、オーブンの電源を切り、完全真空にして全ての残留溶媒を除去した(一晩)。
乾燥後のコーティングしたリン酸三カルシウム粉末を明色保護バイアル中に移し、4℃で貯蔵した。
薬物放出プロファイル:コーティングされた基材を水和し(37℃で5%血清)、マトリックス組成物で含浸された/コーティングされたリン酸三カルシウム粒子からのドキシサイクリンの放出をHPLCで追跡し、定量した。放出プロファイルを図1に示す。
手術前準備:動物は、外科手術の約1~2時間前に皮下注射によりオピオイド鎮痛薬(投与量レベル約0.075mg/kgのブプレノルフィン)を投与される。全ての場合について、動物はイソフルラン吸入(酸素中2~4%、流量0.8~1.2L/分)により全身麻酔を受ける。
それぞれの試験部位を無菌のはさみを使って無菌状態で小片に切断し、ポケットの内容を露出させる。
一般に、両TCP処置群(すなわち、群番号2および4)に割付けられたほとんど全ての動物で、0.5~2cmの直径の隆起が試験部位の中央で観察された。さらに、群2および4の試験部位のほとんどにおいて、皮膚の内側組織への癒着は認められなかった。
群2および4のそれぞれの動物番号7および18-1x107または1x108CFU/mlの細菌と組み合わされたTCP:殿筋中の筋肉内ポケットは、肉芽腫性(すなわち、マクロファージ、巨細胞)反応物に取り囲まれた多形核細胞(膿瘍形成)、壊死およびビークル要素(TCP)顆粒の集合物を含有していた。全体反応部位は、初期成熟莢膜反応物によりに取り囲まれている。多数の細菌コロニーもまた、膿瘍に密接して、および膿瘍内で特定されている。膿瘍形成は、等級3にスコア化される。
希釈/誘発培地:1,000xTSB+10%ヒト血清 24時間;成長培地/寒天:トリプチックソイブロス/リプチックソイ寒天培地、好気条件で24時間。
低温ストック(-70℃)を使って、黄色ブドウ球菌の最初の継代培養をOSA(生物体特異的寒天)上で画線培養により行った。プレートを適切な増殖条件下で20±2.0時間インキュベートし、4℃でさらに貯蔵した。
LOG10(CFU/ペグ)=LOG10[(X/B)(D)]式中、X=平均CFU;B=播種量(0.02mL);D=希釈。
ニュージーランド白ウサギに対し、半胸骨深さでの胸骨欠損を生じさせる。12匹のニュージーランド白ウサギは6匹の動物の2つの同等の群に無作為に分割される。それらは胸骨正中切開を受け、所定の較正された細菌接種用量と混合され形成された間隙(例えば、胸骨欠損)中に置かれた「対照品」(非コーティングTCP)または「試験品」(実施例1に記載のように調製されたマトリックス組成物でコーティングされた/含浸されたTCP粒子)のいずれかを適用された。
Claims (18)
- 外科手術に関連する軟部組織切開部位感染の処置または予防において使用するための医薬組成物であって、(a)生分解性ポリエステルと、(b)コレステロールを含む第1の脂質成分と、(c)少なくとも14個の炭素の脂肪酸部分を有する少なくとも1種のホスファチジルコリンを含む第2の脂質成分と、(d)ドキシサイクリンおよびドキシサイクリンヒクラートから選択される抗生物質と、を含むマトリックス組成物で、含浸されたまたは完全にもしくは部分的に表面コーティングされた生分解性鉱物基材を含み、前記生分解性鉱物基材がβ-リン酸三カルシウム(β-TCP)粒子からなり、前記医薬組成物が軟部組織切開部位への局所投与用である、医薬組成物。
- 前記感染が、表層切開部感染、深部切開部感染および臓器/体腔感染を含む、請求項1に記載の医薬組成物。
- 全体の術後感染率の低減、手術前に存在し得る軟部組織感染の根絶、前記軟部組織切開部位でのバイオフィルム形成の抑制および前記軟部組織切開部位での既存のバイオフィルムの根絶の内の少なくとも1つに対し有用である、請求項1に記載の医薬組成物。
- 前記感染が、メチシリン耐性黄色ブドウ球菌(MRSA)により引き起こされる、請求項1に記載の医薬組成物。
- 前記軟部組織切開が、
整形外科手術、脊椎外科手術、消化器系器官の外科手術、胃潰瘍手術、胃癌手術、開腹胃バイパス手術、虫垂切除手術、結腸切除手術、胆嚢摘出手術、迷走神経切除手術、開腹胆道手術、小腸手術、結腸直腸手術、心臓手術、ヘルニア修復、血管手術、帝王切開、前立腺切除、産婦人科外科手術、頭頸部癌手術、移植手術、神経系外科手術、および形成手術
からなる群から選択される外科手術に関連する、請求項1~4のいずれか1項に記載の医薬組成物。 - 前記外科手術が、消化器系器官の外科手術である、請求項5に記載の医薬組成物。
- 前記軟部組織切開が心臓手術に関連する、請求項5に記載の医薬組成物。
- 適正な手術部位準備、全身性の予防的抗生物質投与、細胞療法、ならびに手術前後の酸素補給、正常体温の維持および血糖コントロールによる宿主の強化からなる群より選択される種菌を減らすための標準的なケア手順に追加して実施される、請求項1~7のいずれか1項に記載の医薬組成物。
- 前記生分解性鉱物基材が、約200ミクロン(μm)未満、好ましくは約150μm未満、の平均粒径を有する粒子からなり、より好ましくは、前記生分解性鉱物基材が、50~150μmの範囲の平均粒径を有する粒子からなり、さらにより好ましくは、大部分の粒子が球状および/または楕円状である、請求項1~8のいずれか1項に記載の医薬組成物。
- 前記少なくとも1種のホスファチジルコリンが、14~18個の炭素を有する脂肪酸部分を有するホスファチジルコリンまたはホスファチジルコリンの組み合わせである、請求項1~9のいずれか1項に記載の医薬組成物。
- 前記マトリックス組成物中の前記生分解性ポリエステルが、PLA(ポリ乳酸)、PGA(ポリグリコール酸)およびPLGA(ポリ(乳酸-co-グリコール酸))からなる群より選択される、
請求項1~10のいずれか1項に記載の医薬組成物。 - 更に前記マトリックス組成物が、防腐剤、抗炎症剤、抗真菌剤およびこれらの任意の組み合わせからなる群から選択される活性剤を含むか、または;
更に前記マトリックス組成物が、少なくとも1種の抗炎症剤を含む、
請求項1~11のいずれか1項に記載の医薬組成物。 - 脂質の総量の前記生分解性ポリエステルに対する重量比が、1:1~9:1(両端含む)である、請求項1~12のいずれか1項に記載の医薬組成物。
- 前記コーティングされた生分解性鉱物基材が、約60~90%(w/w)の前記生分解性鉱物基材および10~40%(w/w)の前記マトリックス組成物を含み、好ましくは、前記コーティングされた生分解性鉱物基材が、約70~90%(w/w)の前記生分解性鉱物基材および10~30%(w/w)の前記マトリックス組成物を含む、請求項1~13のいずれか1項に記載の医薬組成物。
- 前記マトリックス組成物が、水を実質的に含まない、請求項1~14のいずれか1項に記載の医薬組成物。
- 前記コーティングされた生分解性鉱物基材が水性環境中で維持される場合、前記マトリックス組成物が前記抗生物質の徐放をもたらし、好ましくは、少なくとも30%の前記抗生物質が前記組成物からゼロ次反応速度で放出される、請求項1~15のいずれか1項に記載の医薬組成物。
- 前記マトリックス組成物が、(a)15~25%(w/w)のポリ(乳酸-co-グリコール酸)(PLGA);(b)5~15%(w/w)のコレステロール;(c)50~70%(w/w)の、1,2-ジパルミトイル-sn-グリセロ-3-ホスホコリン(DPPC)と1,2-ジステアロイル-sn-グリセロ-3-ホスホコリン(DSPC)との混合物であってDPPCのDSPCに対する比が約5:1~2:1である混合物;および(d)7~12%(w/w)のドキシサイクリンまたはドキシサイクリンヒクラート、を含み、
前記生分解性鉱物基材が前記コーティングされた生分解性鉱物基材の合計重量の約80~90%(w/w)を構成し且つ前記マトリックス組成物が前記コーティングされた生分解性鉱物基材の合計重量の約10~20%(w/w)を構成する、
請求項1~9のいずれか1項に記載の医薬組成物。 - 前記医薬組成物が、感染部位へのその適用の前にペーストとして処方される、請求項1~17のいずれか1項に記載の医薬組成物。
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