JP6495191B2 - 鎮痛薬の組合せおよびその使用 - Google Patents
鎮痛薬の組合せおよびその使用 Download PDFInfo
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- JP6495191B2 JP6495191B2 JP2015561736A JP2015561736A JP6495191B2 JP 6495191 B2 JP6495191 B2 JP 6495191B2 JP 2015561736 A JP2015561736 A JP 2015561736A JP 2015561736 A JP2015561736 A JP 2015561736A JP 6495191 B2 JP6495191 B2 JP 6495191B2
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- Prior art keywords
- weight
- acid
- opioid agonist
- dosage form
- pain
- Prior art date
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/49—Cinchonan derivatives, e.g. quinine
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本出願は、参照によってその全体を本明細書に組み入れる、2013年3月7日に出願した米国特許仮出願第61/774,113号の優先権を主張するものである。
以下の実施例は、本明細書に記載の方法および組成物を、例示するものであり、限定するものではない。治療において通常に遭遇する様々な条件およびパラメーターの他の適した修正および適応(adaptations)は、当業者には明らかであり、本明細書に記載の化合物および方法の精神および範囲内に属する。
キニジン/モルヒネ/デキストロメトルファンの投与が疼痛を治療する
ラットにおける、キニジン(Q)の、MS:DMの鎮痛効果を増強する能力、ならびにMSおよびMS:DMの耐性および依存性を低減する能力を決定した。成人Sprague−Dawlyラットを使用した。すべての実験のプロトコールは、国立衛生研究所(NIH)実験動物福祉部門(OLAW)に適合する施設内動物管理使用委員会(IACUC)を有する認定研究施設で実施した。
ラットのベースラインテールフリック潜時を3.5から4.5秒に設定した。組織の損傷を最小限に抑えるために、8秒後にテールフリックが起きない場合は、光(例えば熱)源を自動的に停止した。平均ベースライン潜時(BL)を測定するために、1分間の試験間隔で離れた3回のテールフリック試験の平均値を使用した。MS、MS:DM、およびMS:DM:Qの鎮痛効果、および耐性の発生を、薬物投与後の測定試験(テールフリック)潜時(TL)によって決定した。データは、式(%MPAE=[(TL−BL)/(8−BL)]×100)を用いて、最大可能鎮痛効果の百分率(%MPAE)として表すことができる。
ラットにおけるMSへの耐性を、テールフリック疼痛モデルを用いて測定し、ベースラインテールフリック潜時とMS、MS:DM、およびMS:DM:Q投与後の試験テールフリック潜時の間の時間の差異として測定した。試験の結果は、MS:DM:Qの3種の組合せは、ベースラインと比較して、ならびにMSおよびMS:DMおよび薬物なしの投与と比較して、テールフリック潜時の統計的に有意の増加を有するというものであった。さらに、依存を、腹腔内ナロキソン負荷(Naloxone challenge)の後10〜15分間、脱出跳躍(escape jumping)、歯をカチカチ言わせる、および身震いの3つの身体的特性を観察することによって決定した。
ラットにおけるMSの用量依存性の鎮痛効果を、上記のテールフリック疼痛モデルを用い、一連のMSの用量の経口投与を用いて決定した。MSの経口治療後1、2、および3時間において、テールフリック潜時を測定して、MSの最大鎮痛効果およびED50を決定した。耐性および依存に達するまで、経口MS投与を反復した。これを、ED50用量(約30mg/kg)におけるMSの1日当たり2回の投与によって、5、10、および15日間実行した。テールフリック潜時を、15日まで、各治療後90分測定した。テールフリック試験の後、ナロキソンをラットの1つの群に、5、10、および15日目に腹腔内で与え、禁断の徴候を、注射後10分間観察した。生理食塩水で処理されたラットの1つの群を、すべての時点で対照として使用した。
モルヒネの耐性および依存性の発生を阻止するまたは軽減する、MS、DM、およびQの組合せ投与の治療的に有効な比率範囲。MSの様々な用量レベルによって誘発されたモルヒネ耐性および依存性の発生を防止する際に、MS/DM/Q比が類似しているかどうかを決定するために、MSの3種の用量(それぞれ、用量ED90、ED50、およびED30)を使用した。
モルヒネ、デキストロメトルファン、およびキニジンの組合せが、モルヒネ単独、またはデキストロメトルファンと組み合わせたモルヒネと比較して、疼痛の救済を増強する
モルヒネ、およびデキストロメトルファンの医薬組成物へのキニジンの添加を、Ugo Basileテールフリック法を用いて試験した。この方法は、鎮痛活性を有する複数の薬物のin vivoスクリーニングにしばしば使用される。動物を、尾部を赤外線光源を横切って真っすぐ後にして、Ugo Basileテールフリック計測器の表面上に置き、保持した。熱源およびタイマーは、足踏みペダル押下によってスイッチが入り、動物がその尾部を発光体から離して振ったとき、自動的にスイッチが切れた。潜時を測定し、鎮痛効果として解析した。各製剤を7匹のラットで試験した。ラットで試験した製剤は以下の通りであった。1)ビヒクル(対照)、2)モルヒネ(25mg/kgの用量);(3)デキストロメトルファン(25mg/kgの用量);4)1:1(重量:重量)の比のモルヒネ/デキストロメトルファン;5)1:1:0.1の比のモルヒネ/デキストロメトルファン/キニジン;6)1:1:0.5の比のモルヒネ/デキストロメトルファン/キニジン;および7)1:1:1の比のモルヒネ/デキストロメトルファン/キニジン。以下に示した結果は、1:1:1の比のモルヒネ/デキストロメトルファン/キニジンの組合せは、モルヒネ単独およびモルヒネとデキストロメトルファンの組合せの鎮痛効果を有意に増強したことを表している。さらに、1:1:1の比のモルヒネ/デキストロメトルファン/キニジンの3種の組合せは、モルヒネ単独またはモルヒネとデキストロメトルファンの組合せと比較して、投与の1時間以内に増強された鎮痛を引き起こした。1時間において、3種の組合せは17.90秒の平均値を有し、一方、モルヒネとデキストロメトルファンの組合せは6.84の平均値を有した。したがって、この組合せは、キニジンがない、モルヒネとデキストロメトルファンの組合せより2.6倍の鎮痛を有した。3種の組合せはまた、モルヒネ単独と比較して鎮痛の提供においてより有効であった。7匹の動物すべての平均値は、鎮痛のほとんど2倍の増加を示したが、異常値であったように見える1匹の動物を除いた場合、3種の組合せは、鎮痛を約2.7倍増加させた。
Claims (7)
- モルヒネ硫酸塩、デキストロメトルファン臭化水素酸塩一水和物及びキニジングルコン酸塩又はキニジン硫酸塩を含む医薬剤形であって、モルヒネ硫酸塩、デキストロメトルファン臭化水素酸塩一水和物及びキニジングルコン酸塩又はキニジン硫酸塩の割合は約1:1:1(重量:重量:重量)である、経口医薬剤形。
- 約10mg、約20mg、約30mg、約40mg、約50mg、または約60mgのモルヒネ硫酸塩を含む、請求項1に記載の経口医薬剤形。
- オピオイドアンタゴニストをさらに含む、請求項1に記載の経口医薬剤形。
- 前記剤形は速溶性フィルム剤である、請求項1に記載の経口医薬剤形。
- 剤形がそのままで投与された場合放出されない、隔離オピオイドアンタゴニストをさらに含む、請求項1に記載の経口医薬剤形。
- 前記隔離オピオイドアンタゴニストは、ナルトレキソン、ナロキソン、ナルメフェン、シクラゾシン、レバロルファン、もしくは薬学的に許容されるこれらの塩、またはこれらの任意の組合せの1つまたはそれ以上から選択される、請求項5に記載の経口医薬剤形。
- 請求項1〜6のいずれか1項に記載の経口医薬剤形であって、疼痛治療用である、前記経口医薬剤形。
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US201361774113P | 2013-03-07 | 2013-03-07 | |
US61/774,113 | 2013-03-07 | ||
PCT/US2014/022050 WO2014138669A1 (en) | 2013-03-07 | 2014-03-07 | Pain medicine combination and uses thereof |
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AU (2) | AU2014225422A1 (ja) |
CA (1) | CA2903757A1 (ja) |
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |