JP2010526763A - Novel long-acting pharmaceutical composition for the treatment of respiratory diseases - Google Patents
Novel long-acting pharmaceutical composition for the treatment of respiratory diseases Download PDFInfo
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- JP2010526763A JP2010526763A JP2009511463A JP2009511463A JP2010526763A JP 2010526763 A JP2010526763 A JP 2010526763A JP 2009511463 A JP2009511463 A JP 2009511463A JP 2009511463 A JP2009511463 A JP 2009511463A JP 2010526763 A JP2010526763 A JP 2010526763A
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Abstract
本発明は、新規な抗コリン作用薬と新規な長時間作用型のベータ2作用薬とを基礎とした新規な医薬組成物、その製造方法及び呼吸器系疾患の治療における該医薬組成物の使用に関する。 The present invention relates to a novel pharmaceutical composition based on a novel anticholinergic agent and a novel long-acting beta-2 agonist, its production method and use of the pharmaceutical composition in the treatment of respiratory diseases About.
Description
本発明は、新規な抗コリン作用薬と新規な長時間作用型ベータ2作用薬とを基礎とした新規な医薬組成物、その製造方法ならびに呼吸器系障害の治療での該組成物の使用に関する。
(発明の説明)
本発明は、下記式1で表される抗コリン作用薬:
The present invention relates to a novel pharmaceutical composition based on a novel anticholinergic agent and a novel long-acting beta-2 agonist, a process for its preparation and the use of this composition in the treatment of respiratory disorders. .
(Description of the invention)
The present invention relates to an anticholinergic agent represented by the following formula 1:
(式中、
Aは下記から選択される基を示し、
(Where
A represents a group selected from the following:
R及びR1は水素を表すか、又は一緒になって単結合、-CH2-及び-O-から選択される基を表し、
X-は1個の負電荷を有するアニオンを示し、好ましくは、塩化物、臭化物、ヨウ化物、スルフェート、ホスフェート、メタンスルホネート、ニトレート、マレエート、アセテート、シトレート、フマレート、タルトレート、オキサレート、スクシネート、ベンゾエート及びp−トルエンスルホネートからなる群から選択されるアニオンを示す)と、
下記からなる群から選択される1種以上のベータ2作用薬:
R and R 1 represent hydrogen or together represent a single bond, a group selected from —CH 2 — and —O—,
X − represents one negatively charged anion, preferably chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate And an anion selected from the group consisting of p-toluenesulfonate)
One or more beta-2 agonists selected from the group consisting of:
であって、これらの医薬的に許容できる酸付加塩の形態であってもよく、また、鏡像異性体、鏡像異性体の混合物又はラセミ体の形態であってもよく、また、溶媒和物及び水和物の形態であってもよいベータ2作用薬とを含み、
さらに医薬的に許容できる賦形剤を混合してもよい、新規な医薬組成物に関する。
本発明による好適な組成物では、式1中、
Aが下記から選択される基を示し、
And may be in the form of their pharmaceutically acceptable acid addition salts, and may be in the form of enantiomers, mixtures of enantiomers or racemates, and solvates and A beta 2 agonist, which may be in the form of a hydrate,
Furthermore, it is related with the novel pharmaceutical composition which may mix a pharmaceutically acceptable excipient | filler.
In a preferred composition according to the invention, in formula 1,
A represents a group selected from:
R及びR1が水素を表すか、又は一緒になって単結合及び-O-から選択される基を表し、
X-が1個の負電荷を有するアニオンを示し、好ましくは、塩化物、臭化物、ヨウ化物、スルフェート、ホスフェート、メタンスルホネート、ニトレート、マレエート、アセテート、シトレート、フマレート、タルトレート、オキサレート、スクシネート、ベンゾエート及びp−トルエンスルホネートからなる群から選択されるアニオンを示す、式1の化合物が用いられる。
好ましくは、X-が塩化物、臭化物、4−トルエンスルホネート及びメタンスルホネートからなる群から選択される1個の負電荷を有するアニオン、好ましく臭化物を示す、式1で表される塩が用いられる。
特に好ましくは、X-が塩化物、臭化物及びメタンスルホネートからなる群から選択される1個の負電荷を有するアニオン、好ましく臭化物を示す、式1で表される塩が用いられる。
式1中、X-が臭化物を示す塩が本発明ではとりわけ好ましい。
本発明によると、式1中、Aが下記の基を示し、
R and R 1 represent hydrogen or together represent a group selected from a single bond and —O—;
X − represents one negatively charged anion, preferably chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate And a compound of formula 1 is used that represents an anion selected from the group consisting of p-toluenesulfonate.
Preference is given to salts of the formula 1 in which X − represents one negatively charged anion, preferably bromide, selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate.
Particular preference is given to using salts of the formula 1 in which X − represents one negatively charged anion, preferably bromide, selected from the group consisting of chloride, bromide and methanesulfonate.
In the formula 1, a salt in which X − represents bromide is particularly preferred in the present invention.
According to the present invention, in Formula 1, A represents the following group:
R、R1及びX-が本願明細書前記の定義のとおりである、式1の化合物が特に好適である。
式1中、Aが下記の基を示し、
Particularly preferred are compounds of formula 1, wherein R, R 1 and X − are as defined hereinbefore.
In Formula 1, A represents the following group,
R、R1及びX-が本願明細書前記の定義のとおりである、式1の化合物が本発明では特に好適である。
式1中、Aが下記の基を示し、
Especially preferred according to the invention are compounds of the formula 1, in which R, R 1 and X - are as defined hereinbefore.
In Formula 1, A represents the following group,
R、R1及びX-が本願明細書前記の定義のとおりである、式1の化合物が本発明では特に好適である。
式1中、R及びR1が水素を表し、A及びX-が本願明細書前記の定義のとおりである式1の化合物が本発明では特に好適である。
式1中、R及びR1が結合を表し、A及びX-が本願明細書前記の定義のとおりである式1の化合物が本発明では特に好適である。
式1中、R及びR1が-O-を表し、A及びX-が本願明細書前記の定義のとおりである式1の化合物が本発明では特に好適である。
式1の化合物は、WO02/32899、WO03/64419、WO03/64418及びWO03/64417より公知である。
式1の化合物が、トロペノール2,2-ジフェニルプロピオネート-メトブロマイド(1.1)、スコピン2,2-ジフェニルプロピオネート-メトブロマイド(1.2)、トロペノール9-メチル-フルオレン-9-カルボキシレート-メトブロマイド(1.3)、スコピン9-メチル-フルオレン-9-カルボキシレート-メトブロマイド(1.4)、トロペノール9-メチル-キサンテン-9-カルボキシレート-メトブロマイド(1.5)、スコピン9-メチル-キサンテン-9-カルボキシレート-メトブロマイド(1.6)、シクロプロピルトロピン2,2-ジフェニルプロピオネート-メトブロマイド(1.7)、シクロプロピルトロピン9-メチル-フルオレン-9-カルボキシレート-メトブロマイド(1.8)、シクロプロピルトロピン9-メチル-キサンテン-9-カルボキシレート-メトブロマイド(1.9)からなる群から選択され、これらの溶媒和物及び水和物の形態であってもよい化合物が本発明ではとりわけ好ましい。
Especially preferred according to the invention are compounds of the formula 1, in which R, R 1 and X - are as defined hereinbefore.
Particularly preferred in the present invention are compounds of formula 1 in which R and R 1 represent hydrogen and A and X − are as defined hereinbefore.
Particularly preferred in the present invention are compounds of formula 1 in which R and R 1 represent a bond, and A and X − are as defined hereinbefore.
Particularly preferred in the present invention are compounds of formula 1 in which R and R 1 represent —O—, and A and X − are as defined hereinbefore.
Compounds of formula 1 are known from WO 02/32899, WO 03/64419, WO 03/64418 and WO 03/64417.
Compounds of formula 1 are tropenol 2,2-diphenylpropionate-methobromide (1.1), scopine 2,2-diphenylpropionate-methobromide (1.2), tropenol 9-methyl-fluorene-9-carboxylate- Metobromide (1.3), Scopine 9-methyl-fluorene-9-carboxylate-methobromide (1.4), Tropenol 9-methyl-xanthene-9-carboxylate-methobromide (1.5), Scopine 9-methyl-xanthene-9 -Carboxylate-methobromide (1.6), cyclopropyltropin 2,2-diphenylpropionate-methobromide (1.7), cyclopropyltropin 9-methyl-fluorene-9-carboxylate-methobromide (1.8), cyclopropyl The group consisting of tropine 9-methyl-xanthene-9-carboxylate-methobromide (1.9) Are al selected, may also be compound in the form of their solvates and hydrates are particularly preferred in the present invention.
驚いたことに、式1の抗コリン作用薬を式2で表される化合物と一緒に投与すると、例えば気道の炎症性疾患又は閉塞性疾患の治療において、予期しなかった有効な治療効果が見られる。この有用な効果を鑑みると、それぞれの化合物を従来の単剤療法で使用した場合と比べると、本発明の医薬組成物は少ない用量で使用することができる。本発明のもう一つの良い面は、例えば、ベータ受容体刺激薬(betamimetics)の投与時などに起きるおそれのある望ましくない副作用が低減されることである。本件では特筆しておくべき望ましくない副作用とは、ベータ受容体刺激薬によって引き起こされる可能性のある心臓への興奮作用で、特に、頻脈や、心臓の搏動が強くなったり、狭心症に似た痛み及び不整脈である。前記の作用は、この2種の有効成分を単一の有効成分製剤にして同時に投与した場合も、別々の製剤にして2種の有効成分を順次投与した場合もどちらの場合にも見られる。本発明では、この2種の有効成分を単一製剤にして同時に投与することが好ましい。
本発明の範囲において、化合物1’に言及する場合は、塩1に含まれる下記式で表される薬理学的に有効なカチオンを示すものと解釈される。
Surprisingly, when an anticholinergic agent of formula 1 is administered together with a compound of formula 2, an unexpected effective therapeutic effect is seen, for example, in the treatment of inflammatory or obstructive diseases of the respiratory tract. It is done. In view of this useful effect, the pharmaceutical composition of the present invention can be used in a smaller dose than when each compound is used in conventional monotherapy. Another good aspect of the present invention is that it reduces unwanted side effects that can occur, for example, during administration of beta receptor stimulants. An undesirable side effect that should be noted in this case is the excitement of the heart that can be caused by beta-receptor stimulants, especially for tachycardia, increased heart perturbation, and angina. Similar pain and arrhythmia. The above-mentioned action can be seen both when the two active ingredients are administered simultaneously as a single active ingredient formulation and when the two active ingredients are administered sequentially as separate formulations. In the present invention, it is preferable to administer these two active ingredients simultaneously as a single preparation.
In the scope of the present invention, reference to compound 1 ′ is taken to indicate a pharmacologically effective cation represented by the following formula contained in salt 1.
前記医薬組成物において、有効成分は2種が単一製剤に含有されていてもよいし、あるいは、2つの別個の製剤に含有されていてもよい。有効成分1及び2を単一製剤中に含有する医薬組成物が本発明では好ましい。
ベータ受容体刺激薬2に言及する場合は、鏡像異性体(RもしくはS)又はその混合物も包含するものであり、本発明の範囲においては化合物のR鏡像異性体が特に重要である。式2で表される化合物の鏡像異性体のエナンチオ選択的調製方法については、この分野では公知である。また、本発明ではベータ受容体刺激薬2はその塩ならびに水和物又は溶媒和物の形態で存在してもよい。
本発明の組成物の一部を形成するベータ受容体刺激薬2の好適な鏡像異性体及びジアステレオ異性体を以下に示す。
In the pharmaceutical composition, two active ingredients may be contained in a single preparation or may be contained in two separate preparations. A pharmaceutical composition containing active ingredients 1 and 2 in a single formulation is preferred in the present invention.
Reference to beta receptor stimulant 2 also includes enantiomers (R or S) or mixtures thereof, and the R enantiomer of a compound is particularly important within the scope of the present invention. Methods for enantioselective preparation of enantiomers of compounds of formula 2 are known in the art. In the present invention, the beta receptor stimulant 2 may be present in the form of its salt and hydrate or solvate.
Preferred enantiomers and diastereoisomers of Beta Receptor Stimulant 2 that form part of the composition of the present invention are shown below.
本発明の好適な医薬組成物の例は、化合物1.1と2.1、1.1と2.2、1.1と2.3、1.1と2.4、1.1と2.5、1.1と2.6、1.1と2.7、1.1と2.8、1.2と2.1、1.2と2.2、1.2と2.3、1.2と2.4、1.2と2.5、1.2と2.6、1.2と2.7、1.2と2.8、1.3と2.1、1.3と2.2、1.3と2.3、1.3と2.4、1.3と2.5、1.3と2.6、1.3と2.7、1.3と2.8、1.4と2.1、1.4と2.2、1.4と2.3、1.4と2.4、1.4と2.5、1.4と2.6、1.4と2.7、1.4と2.8、1.5と2.1、1.5と2.2、1.5と2.3、1.5と2.4、1.5と2.5、1.5と2.6、1.5と2.7、1.5と2.8、1.6と2.1、1.6と2.2、1.6と2.3、1.6と2.4、1.6と2.5、1.6と2.6、1.6と2.7、1.6と2.8、1.7と2.1、1.7と2.2、1.7と2.3、1.7と2.4、1.7と2.5、1.7と2.6、1.7と2.7、1.7と2.8、1.8と2.1、1.8と2.2、1.8と2.3、1.8と2.4、1.8と2.5、1.8と2.6、1.8と2.7、1.8と2.8、1.9と2.1、1.9と2.2、1.9と2.3、1.9と2.4、1.9と2.5、1.9と2.6、1.9と2.7、1.9と2.8を含む組合わせで、それぞれ、ラセミ体、鏡像異性体またはジアステレオ異性体の形態であってもよく、また、医薬的に許容できる酸付加塩、溶媒和物及び/又は水和物の形態であってもよい。
また、本発明の範囲では、ベータ受容体刺激薬という用語をさす場合、ベータ2作用薬を示すものと解釈される。ベータ受容体刺激薬2を指す場合、その薬理学的に許容できる酸付加塩も含まれる。ベータ受容体刺激薬2の薬理学的に許容できる酸付加塩とは、塩酸、臭化水素酸、硫酸、リン酸、メタンスルホン酸、酢酸、フマル酸、コハク酸、乳酸、クエン酸、酒石酸、1-ヒドロキシ-2-ナフタレンカルボン酸又はマレイン酸の塩をはじめとする薬理学的に許容できる塩を本発明では意味する。所望であれば、前記酸の混合物を用いて塩2を調製することもできる。本発明によると、塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩、フマル酸塩、メタンスルホン酸塩、マレイン酸塩及びキシナホ酸塩から選択される2の塩が好ましい。
本発明の態様の1つは、治療有効量の有効成分1及び2に加えて医薬的に許容できる賦形剤を含む前記医薬組成物に関する。別の態様では、本発明は治療有効量の有効成分1及び2のほかに医薬的に許容できる賦形剤を含まない前記医薬組成物に関する。
さらに、本発明は、炎症性及び閉塞性の呼吸器系疾患の治療、産科学における早産の予防(陣痛抑制)、房室心ブロックの場合における心臓の洞調律の修復、徐脈性の心調律障害の回復(抗不整脈薬)、循環器系ショックの治療(血管拡張及び心臓の増大)ならびに皮膚の痒みや炎症の治療用の、1種以上、好ましくは1種の有効成分2を含む医薬組成物を製造するための治療上有効量の有効成分1の使用に関するものである。
Examples of suitable pharmaceutical compositions of the present invention are compounds 1.1 and 2.1, 1.1 and 2.2, 1.1 and 2.3, 1.1 and 2.4, 1.1 and 2.5, 1.1 and 2.6, 1.1 and 2.7, 1.1 and 2.8, 1.2 and 2.1, 1.2. And 2.2, 1.2 and 2.3, 1.2 and 2.4, 1.2 and 2.5, 1.2 and 2.6, 1.2 and 2.7, 1.2 and 2.8, 1.3 and 2.1, 1.3 and 2.2, 1.3 and 2.3, 1.3 and 2.4, 1.3 and 2.5, 1.3 and 2.6 1.3 and 2.7, 1.3 and 2.8, 1.4 and 2.1, 1.4 and 2.2, 1.4 and 2.3, 1.4 and 2.4, 1.4 and 2.5, 1.4 and 2.6, 1.4 and 2.7, 1.4 and 2.8, 1.5 and 2.1, 1.5 and 2.2, 1.5 And 2.3, 1.5 and 2.4, 1.5 and 2.5, 1.5 and 2.6, 1.5 and 2.7, 1.5 and 2.8, 1.6 and 2.1, 1.6 and 2.2, 1.6 and 2.3, 1.6 and 2.4, 1.6 and 2.5, 1.6 and 2.6, 1.6 and 2.7 1.6, 2.8, 1.7 and 2.1, 1.7 and 2.2, 1.7 and 2.3, 1.7 and 2.4, 1.7 and 2.5, 1.7 and 2.6, 1.7 and 2.7, 1.7 and 2.8, 1.8 and 2.1, 1.8 and 2.2, 1.8 and 2.3, 1.8 And 2.4, 1.8 and 2.5, 1.8 and 2.6, 1.8 and 2.7, 1.8 and 2.8, 1.9 and 2.1, 1.9 and 2.2, 1.9 and 2.3, 1.9 and 2.4, 1.9 and 2.5, 1.9 and 2.6, 1.9 and 2.7, 1.9 and 2.8 In combination with racemates, enantiomers or May be in the form of A stereo isomers and pharmaceutically acceptable acid addition salts may be in the form of solvates and / or hydrates thereof.
Also, within the scope of the present invention, the term beta receptor stimulant is taken to indicate a beta 2 agonist. When referring to beta receptor stimulant 2, pharmacologically acceptable acid addition salts thereof are also included. The pharmacologically acceptable acid addition salts of beta receptor stimulant 2 are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, In the present invention, pharmaceutically acceptable salts including salts of 1-hydroxy-2-naphthalenecarboxylic acid or maleic acid are meant in the present invention. If desired, salt 2 can be prepared using a mixture of the acids. According to the invention, two salts selected from hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate, maleate and xinafoate are preferred.
One aspect of the present invention relates to said pharmaceutical composition comprising a pharmaceutically acceptable excipient in addition to a therapeutically effective amount of active ingredients 1 and 2. In another aspect, the present invention relates to said pharmaceutical composition which does not contain a pharmaceutically acceptable excipient in addition to a therapeutically effective amount of active ingredients 1 and 2.
Further, the present invention provides treatment of inflammatory and obstructive respiratory diseases, prevention of preterm birth in obstetrics (suppression of labor), repair of cardiac sinus rhythm in the case of atrioventricular heart block, bradycardic heart rhythm Pharmaceutical composition comprising one or more, preferably one active ingredient 2, for the recovery of disorders (antiarrhythmic drugs), the treatment of circulatory shock (vasodilation and heart enlargement) and the treatment of skin itching and inflammation The use of a therapeutically effective amount of active ingredient 1 to produce a product.
本発明の好ましい態様として、様々な原因による閉塞性肺疾患、様々な原因による肺気腫、拘束性肺疾患、間質性肺疾患、嚢胞性線維症、様々な原因による気管支炎、気管支拡張症、成人呼吸窮迫症候群(ARDS)及びすべての種類の肺浮腫を含む群から選択される呼吸器系疾患治療用の、1種以上、好ましくは1種の有効成分2を含む医薬組成物を製造するための、治療上有効量の有効成分1の使用に関するものである。
前記のとおり、本発明の医薬組成物は、気管支喘息、小児喘息、重篤な喘息、急性喘息の発作、慢性気管支炎及び慢性閉塞性肺疾患(COPD)から選択される閉塞性肺疾患の治療用医薬組成物を製造するために好ましくは使用される。なかでも気管支喘息及びCOPDの治療用医薬組成物を製造するために使用することがとりわけ本発明では好ましい。
また、その原因が慢性閉塞性肺疾患(COPD)又はα1−プロテイナーゼ阻害剤の欠如にある肺気腫の治療用医薬組成物を製造するための、本発明の医薬組成物の使用も好ましい。
また、アレルギー性歯槽骨炎、石綿症又は珪肺症等の職業に関連した有害物質に誘発される拘束性肺疾患、及び、例えば癌性リンパ管症、細気管支肺胞上皮癌、リンパ腫などのような肺腫瘍が原因となる狭窄から選択される拘束性肺疾患の治療用医薬組成物を製造するために、本発明の医薬組成物を使用することも好ましい。
また、例えば、ウイルス、細菌、真菌類、原生動物、蠕虫又は他の病原体による感染を原因とする肺炎、例えば、吸引や左心不全などといった様々な要素を原因とする肺臓炎、放射線照射による肺臓炎又は線維症、例えば紅斑性狼瘡、全身性硬皮症又はザルコイドーシス等の膠原病、例えば、ベック病等の肉芽腫症、特発性の間質性肺炎又は特発性肺線維症(IPF)から選択される間質性肺疾患の治療用医薬組成物を製造するために、本発明の医薬組成物を使用することも好ましい。
Preferred embodiments of the present invention include obstructive pulmonary disease due to various causes, emphysema due to various causes, restrictive lung disease, interstitial lung disease, cystic fibrosis, bronchitis due to various causes, bronchiectasis, adult For producing a pharmaceutical composition comprising one or more, preferably one active ingredient 2, for the treatment of respiratory diseases selected from the group comprising respiratory distress syndrome (ARDS) and all types of pulmonary edema The use of a therapeutically effective amount of active ingredient 1.
As described above, the pharmaceutical composition of the present invention treats obstructive pulmonary disease selected from bronchial asthma, childhood asthma, severe asthma, acute asthma attack, chronic bronchitis and chronic obstructive pulmonary disease (COPD). It is preferably used to produce a pharmaceutical composition for use. Among them, it is particularly preferable in the present invention to use it for producing a pharmaceutical composition for treating bronchial asthma and COPD.
Also preferred is the use of the pharmaceutical composition of the present invention for the manufacture of a pharmaceutical composition for the treatment of pulmonary emphysema whose cause is chronic obstructive pulmonary disease (COPD) or lack of an α1-proteinase inhibitor.
Also, restrictive lung diseases induced by occupational harmful substances such as allergic alveolar osteomyelitis, asbestosis or silicosis, and cancerous lymphangiopathy, bronchioloalveolar carcinoma, lymphoma, etc. It is also preferred to use the pharmaceutical composition of the present invention for the manufacture of a pharmaceutical composition for the treatment of restrictive lung disease selected from stenosis caused by various lung tumors.
Also, for example, pneumonia caused by infection by viruses, bacteria, fungi, protozoa, helminths or other pathogens, for example, pneumonia caused by various factors such as aspiration or left heart failure, pneumonitis caused by radiation irradiation Or from fibrosis, eg collagen disease such as lupus erythematosus, systemic scleroderma or sarcoidosis, eg granulomatosis such as Beck disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF) It is also preferred to use the pharmaceutical composition of the present invention to produce a selected pharmaceutical composition for the treatment of interstitial lung disease.
また、嚢胞性線維症又は膵線維症の治療用医薬組成物を製造するための、本発明の医薬組成物の使用も好ましい。
また、例えば、細菌もしくはウイルス感染による気管支炎、アレルギー性気管支炎、及び中毒性気管支炎等の気管支炎の治療用医薬組成物を製造するための、本発明の医薬組成物の使用も好ましい。
また、気管支拡張症の治療用医薬組成物を製造するための、本発明の医薬組成物の使用も好ましい。
また、成人呼吸窮迫症候群(ARDS)の治療用医薬組成物を製造するための、本発明の医薬組成物の使用も好ましい。
また、例えば毒性物質や異物の吸引による中毒性肺浮腫等の肺浮腫の治療用医薬組成物を製造するための、本発明の医薬組成物の使用も好ましい。
喘息又はCOPDの治療用医薬組成物を製造するために、前記詳述の化合物を使用することがとりわけ好ましい。また、炎症性及び閉塞性の呼吸器系疾患の1日1回の治療、特に、喘息又はCOPDの1日1回治療用の医薬組成物を製造するための、本発明の医薬組成物の前記使用がとりわけ重要である。
さらに、本発明は、前記記載の疾病のなかの1つの治療用医薬組成物を製造するために、治療上有効量の式1で表される有効成分を、治療上有効量の有効成分2と共に使用することに関する。
また、本発明は前記疾病の1つの治療方法に関するもので、治療上有効量の式1で表される有効成分を治療上有効量の有効成分2と共に投与することを特徴とする。
本発明の範囲において、化合物1及び2は同時に投与しても順次投与してもよいが、化合物1と2とを同時に投与することが好ましい。
Also preferred is the use of the pharmaceutical composition of the present invention for the manufacture of a pharmaceutical composition for the treatment of cystic fibrosis or pancreatic fibrosis.
Also preferred is the use of the pharmaceutical composition of the present invention for producing a pharmaceutical composition for the treatment of bronchitis such as bronchitis due to bacterial or viral infection, allergic bronchitis, and toxic bronchitis.
The use of the pharmaceutical composition of the present invention for producing a pharmaceutical composition for the treatment of bronchiectasis is also preferred.
Also preferred is the use of the pharmaceutical composition of the present invention for the manufacture of a pharmaceutical composition for the treatment of adult respiratory distress syndrome (ARDS).
In addition, the use of the pharmaceutical composition of the present invention for producing a pharmaceutical composition for treating pulmonary edema such as toxic pulmonary edema caused by inhalation of toxic substances or foreign substances is also preferred.
It is particularly preferred to use the compounds detailed above for the preparation of a pharmaceutical composition for the treatment of asthma or COPD. The pharmaceutical composition of the present invention for producing a pharmaceutical composition for once-daily treatment of inflammatory and obstructive respiratory diseases, particularly for once-daily treatment of asthma or COPD. Use is particularly important.
Furthermore, the present invention provides a therapeutically effective amount of the active ingredient represented by formula 1 together with a therapeutically effective amount of active ingredient 2 to produce a therapeutic pharmaceutical composition for one of the diseases described above. About using.
The present invention also relates to a method for treating the above-mentioned diseases, wherein a therapeutically effective amount of the active ingredient represented by Formula 1 is administered together with a therapeutically effective amount of the active ingredient 2.
Within the scope of the present invention, compounds 1 and 2 may be administered simultaneously or sequentially, but compounds 1 and 2 are preferably administered simultaneously.
本発明の有効成分組合せにおいて使用可能な有効成分1及び2の比率は様々に変えることができる。有効成分1及び2は溶媒和物又は水和物の形態であってもよい。1及び2は塩の選択次第によって、その様々な塩の形態により分子量が違うため、本発明の範囲内で用いることができる質量比は変化する。そこで、以下に示す質量比はカチオン1’と遊離塩基の化合物2を基準としている。
本発明の有効成分組合せは、1’と式2の遊離塩基化合物とを例えば約1:30〜400:1、好ましくは1:25〜200:1、好ましくは1:20〜100:1、特に好ましくは1:15〜50:1の範囲の質量比で含むとよい。
例えば、本発明の範囲を限定するものではないが、本発明による1と2との好適な組合わせにはカチオン1’と遊離塩基の化合物2とを以下の質量比で含むとよい。1:15、1:14、1:13、1:12、1:11、1:10、1:9、1:8、1:7、1:6、1:5、1:4、1:3、1:2、1:1、2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1、11:1、12:1、13:1、14:1、15:1、16:1、17:1、18:1、19:1、20:1、21:1、22:1、23:1、24:1、25:1、26:1、27:1、28:1、29:1、30:1、31:1、32:1、33:1、34:1、35:1。
1と2との組合せを含む本発明の医薬組成物は、通常、単回投与ごとにカチオン1’及び化合物2をあわせて5〜5000μg、好ましくは10〜2000μg、より好ましくは15〜1000μg、さらに好ましくは20〜800μg、本発明でより好ましくは30〜750μg、好ましくは40〜700μgの用量中に一緒に含んで投与する。この全用量は、化合物2は遊離塩基の状態を基準としている。
The ratio of active ingredients 1 and 2 that can be used in the active ingredient combination of the present invention can be varied. Active ingredients 1 and 2 may be in the form of solvates or hydrates. Depending on the choice of salt, 1 and 2 have different molecular weights depending on the various salt forms, so that the mass ratio that can be used within the scope of the present invention varies. Therefore, the mass ratio shown below is based on the cation 1 ′ and the free base compound 2.
The active ingredient combination according to the invention comprises 1 ′ and a free base compound of formula 2, for example from about 1:30 to 400: 1, preferably from 1:25 to 200: 1, preferably from 1:20 to 100: 1, in particular Preferably, it may be contained at a mass ratio in the range of 1:15 to 50: 1.
For example, but not limiting the scope of the present invention, suitable combinations of 1 and 2 according to the present invention may include cation 1 ′ and free base compound 2 in the following mass ratio. 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1: 9, 1: 8, 1: 7, 1: 6, 1: 5, 1: 4, 1: 3, 1: 2, 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, 26: 1, 27: 1, 28: 1, 29: 1, 30: 1, 31: 1, 32: 1, 33: 1, 34: 1, 35: 1.
The pharmaceutical composition of the present invention comprising a combination of 1 and 2 is usually 5 to 5000 μg, preferably 10 to 2000 μg, more preferably 15 to 1000 μg, in addition to cation 1 ′ and compound 2, for each single administration. It is preferably administered together in a dose of 20-800 μg, more preferably 30-750 μg, preferably 40-700 μg in the present invention. This total dose is based on the free base state of Compound 2.
例えば、本発明による1と2との組合せには、1回の投与での総用量が約5μg、10μg、15μg、20μg、25μg、30μg、35μg、40μg、45μg、50μg、55μg、60μg、65μg、70μg、75μg、80μg、85μg、90μg、95μg、100μg、105μg、110μg、115μg、120μg、125μg、130μg、135μg、140μg、145μg、150μg、155μg、160μg、165μg、170μg、175μg、180μg、185μg、190μg、195μg、200μg、205μg、210μg、215μg、220μg、225μg、230μg、235μg、240μg、245μg、250μg、255μg、260μg、265μg、270μg、275μg、280μg、285μg、290μg、295μg、300μg、305μg、310μg、315μg、320μg、325μg、330μg、335μg、340μg、345μg、350μg、355μg、360μg、365μg、370μg、375μg、380μg、385μg、390μg、395μg、400μg、405μg、410μg、415μg、420μg、425μg、430μg、435μg、440μg、445μg、450μg、455μg、460μg、465μg、470μg、475μg、480μg、485μg、490μg、495μg、500μg、505μg、510μg、515μg、520μg、525μg、530μg、535μg、540μg、545μg、550μg、555μg、560μg、565μg、570μg、575μg、580μg、585μg、590μg、595μg、600μg、605μg、610μg、615μg、620μg、625μg、630μg、635μg、640μg、645μg、650μg、655μg、660μg、665μg、670μg、675μg、680μg、685μg、690μg、695μg、700μg等となるような量の1’の化合物と式2の化合物が含まれる。ここでも規定の用量は、本発明の医薬組成物で化合物2は遊離塩基の量を基準としている。前記の1回の投与ごとの推奨投与量が、明示されている数値に限定されないということは当業者であれば明らかである。また、およそ±2.5μgの範囲内の増減、とりわけ小数範囲の増減が含まれることも当業者であれば明らかであろう。こうした用量範囲において、有効成分1’及び2を上記の質量比で含ませることができる。
本発明による1と2との有効成分組成物は吸入による投与が好ましい。そのためには、成分1及び2を吸入に適した形態で提供する必要がある。吸入可能な調剤としては、吸入可能粉末、噴射剤含有定量エアロゾル又は噴射剤を含有しない吸入液が挙げられる。有効成分1及び2の組合せを含有する本発明の吸入粉末は、有効成分のみから構成されていてもよいし、あるいは、有効成分と医薬的に許容できる賦形剤との混合物で構成されていてもよい。本発明の範囲において、噴射剤を含有しない吸入液という言葉には、濃縮物又は直ぐに使用できる無菌吸入用溶液が含まれる。本発明の調剤は、有効成分1及び2の組合せを、1つの製剤中に一緒に含有させるか、又は2つの別個の製剤に含有させるかのいずれでもよい。本発明の範囲において使用できるこうした製剤については、明細書の次のパートでより詳細に説明する。
For example, the combination of 1 and 2 according to the present invention includes a total dose of about 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 90 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg, 305μg, 310μg 320μg, 325μg, 330μg, 335μg, 340μg, 345μg, 350μg, 355μg, 360μg, 365μg, 370μg, 375μg, 380μg, 385μg, 390μg, 395μg, 400μg, 405μg, 410μg, 415μg, 420μg, 425μg, 430μg, 435μg, 440μg 445μg, 450μg, 455μg, 460μg, 465μg, 470μg, 475μg, 480μg, 485μg, 490μg, 495μg, 500μg, 505μg, 510μg, 5 15μg, 520μg, 525μg, 530μg, 535μg, 540μg, 545μg, 550μg, 555μg, 560μg, 565μg, 570μg, 575μg, 580μg, 585μg, 590μg, 595μg, 600μg, 605μg, 610μg, 615μg, 620μg, 630μg, 635μg The amount of 1 ′ compound and the compound of formula 2 are included such as 640 μg, 645 μg, 650 μg, 655 μg, 660 μg, 665 μg, 670 μg, 675 μg, 680 μg, 685 μg, 690 μg, 695 μg, 700 μg, etc. Again, the prescribed dose is based on the amount of free base in compound 2 of the pharmaceutical composition of the invention. It will be apparent to those skilled in the art that the recommended dosage for each administration is not limited to the stated values. It will also be apparent to those skilled in the art that an increase / decrease within the range of approximately ± 2.5 μg, particularly an increase / decrease in the decimal range, is included. In such a dose range, the active ingredients 1 ′ and 2 can be included in the above-mentioned mass ratio.
The active ingredient compositions 1 and 2 according to the present invention are preferably administered by inhalation. This requires that components 1 and 2 be provided in a form suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered dose aerosols or inhalants containing no propellant. The inhalable powder of the present invention containing a combination of active ingredients 1 and 2 may be composed only of the active ingredient or a mixture of the active ingredient and a pharmaceutically acceptable excipient. Also good. Within the scope of the invention, the term propellant-free inhalation solution includes concentrates or ready-to-use sterile inhalation solutions. The preparations of the present invention may contain the combination of active ingredients 1 and 2 either together in one formulation or in two separate formulations. Such formulations that can be used within the scope of the present invention are described in more detail in the next part of the specification.
A)本発明の組成物を含む吸入可能粉末:
本発明による吸入粉末は、1及び2のみを含むか、又は、医薬的に許容できる適当な賦形剤と共に含むかのいずれでもよい。有効成分1及び2が医薬的に許容できる賦形剤と共に存在する場合、以下の医薬的に許容できる賦形剤を使用して本発明による吸入粉末を調製することができる。単糖類(例えば、グルコース又はアラビノース)、二糖類(例えば、ラクトース、サッカロース、マルトース、トレハロース)、オリゴ糖類及び多糖類(例えば、デキストラン)、多価アルコール類(例えば、ソルビトール、マンニトール、キシリトール)、塩類(例えば、塩化ナトリウム、炭酸カルシウム)あるいは、これら賦形剤の混合物。好ましくは、単糖類又は二糖類が使用され、なかでもラクトース又はグルコースの使用が好ましく、限定はされないが、その水和物の形が特に好ましい。
本発明による吸入粉末の範囲では、賦形剤の最大平均粒径は250μmまで、好ましくは10〜150μm、最も好ましくは15〜80μmの範囲である。上記の賦形剤に平均粒径1〜9μmのより微細な賦形剤画分を添加することが適切と考えられる場合もあろう。より微細な賦形剤も、本願明細書中で前記に列挙した使用可能な賦形剤の群から選択される。最終的に、本発明の吸入可能粉末を調製するには、平均粒径が好ましくは0.5〜10μm、より好ましくは1〜5μmの微分化した有効成分1および2を賦形剤混合物に添加する。粉砕及び微分化を行い、最後にすべての成分を混合することによる本発明の吸入粉末の製造方法は、従来技術より公知である。本発明の吸入粉末は、成分1及び2の両方を含有する単一の粉末混合物の状態、或いは、1又は2のみを含有する別個の吸入粉末のいずれかの状態に調製し投与することができる。
A) Inhalable powder comprising the composition of the invention:
Inhalable powders according to the present invention may contain only 1 and 2 or together with suitable pharmaceutically acceptable excipients. When active ingredients 1 and 2 are present together with pharmaceutically acceptable excipients, the following pharmaceutically acceptable excipients can be used to prepare inhalable powders according to the present invention. Monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, saccharose, maltose, trehalose), oligosaccharides and polysaccharides (eg dextran), polyhydric alcohols (eg sorbitol, mannitol, xylitol), salts (For example, sodium chloride, calcium carbonate) or a mixture of these excipients. Preferably, monosaccharides or disaccharides are used, among which lactose or glucose is preferred, and without limitation, the hydrate form is particularly preferred.
In the range of inhalable powders according to the invention, the maximum average particle size of the excipient is up to 250 μm, preferably 10 to 150 μm, most preferably 15 to 80 μm. It may be considered appropriate to add a finer excipient fraction with an average particle size of 1-9 μm to the excipient. Finer excipients are also selected from the group of usable excipients listed herein above. Finally, to prepare the inhalable powder of the present invention, differentiated active ingredients 1 and 2 having an average particle size of preferably 0.5 to 10 μm, more preferably 1 to 5 μm, are added to the excipient mixture. The process for producing the inhalable powder according to the invention by grinding and differentiating and finally mixing all the components is known from the prior art. The inhalable powders of the present invention can be prepared and administered either as a single powder mixture containing both components 1 and 2, or as separate inhalable powders containing only 1 or 2. .
本発明の吸入粉末は、従来技術から公知の吸入器を用いて投与することができる。1及び2に加えて医薬的に許容できる賦形剤を含む本発明の吸入粉末は、例えば、US4570630Aに記載されているような計量チャンバーを用いた供給源から1回分の用量を放出する吸入器によって、あるいは、DE3625685Aに記載されているような他の手段によって投与することができる。1及び2を含み、さらに医薬的に許容できる賦形剤を含有していてもよい本発明の吸入粉末は、例えば、Turbuhaler(登録商標)という商品名で知られている吸入器を使って投与してもよいし、又は、EP237507Aに開示されているような吸入器を使って投与することもできる。好ましくは、1及び2に加えて医薬的に許容できる賦形剤を含有する本発明の吸入粉末は、例えばWO94/28958に記載されているように、カプセルに充填(所謂インハレット(inhalettes)形成)したものを吸入器で使用する。
図1に、カプセルに充填した本発明の医薬組成物を投与するのに特に好適な吸入器を示す。カプセルから粉末状の医薬組成物を吸入するためのこの吸入器(ハンディヘラー)は、2個の窓2を含むハウジング1、空気導入口を有し、スクリーンハウジング4を介して固定されたスクリーン5を備えたデッキ3、デッキ3に連結し、2本の尖ったピン7を備えバネ8に対して可動型の押しボタン8を有する吸入チャンバー6、スピンドル10を介してハウジング1、デッキ3及びカバー11と連結し、跳ね上げ式で開閉可能なマウスピース12、ならびに、流動抵抗を調整するための空気穴13とによって特徴づけられる。
The inhalable powders according to the invention can be administered using inhalers known from the prior art. An inhaler powder according to the invention comprising pharmaceutically acceptable excipients in addition to 1 and 2 is an inhaler that releases a single dose from a source using, for example, a metering chamber as described in US Pat. Or by other means as described in DE 3625685A. Inhalable powders according to the invention comprising 1 and 2 and which may further contain pharmaceutically acceptable excipients are administered, for example, using an inhaler known under the trade name Turbuhaler® Alternatively, it can be administered using an inhaler as disclosed in EP237507A. Preferably, the inhalable powders according to the invention containing pharmaceutically acceptable excipients in addition to 1 and 2 are filled into capsules (so-called inhalette formation) as described, for example, in WO 94/28958 Use with inhaler.
FIG. 1 shows an inhaler that is particularly suitable for administering the pharmaceutical composition of the present invention filled in a capsule. This inhaler (handy heller) for inhaling a powdered pharmaceutical composition from a capsule has a housing 1 including two windows 2, an air inlet, and a screen 5 fixed via a screen housing 4. A deck 3, which is connected to the deck 3, a suction chamber 6 which has two pointed pins 7 and a movable push button 8 with respect to a spring 8, a
B)本発明の組成物を含む噴射剤ガス駆動型吸入エアロゾル:
本発明による噴射剤ガス含有吸入エアロゾルには、有効成分1及び2が噴射剤ガス中に溶解又は分散状態で含まれていればよい。1及び2は別々の製剤又は単一調剤中に存在させることができ、その中で1及び2は両方とも溶解又は分散されているか、あるいは、一方の成分のみが溶解され他方の成分が分散されているかのいずれかである。本発明の吸入エアロゾルの調製に使用できる噴射剤ガスについては従来技術から既知である。好適な噴射剤ガスは、n−プロパン、n−ブタン又はイソブタン等の炭化水素化合物、及び、メタン、エタン、プロパン、ブタン、シクロプロパン又はシクロブタンの好ましくは塩素化及びフッ素化誘導体等のハロ炭化水素化合物から選択される。上記噴射剤ガスは単独で、又はその混合物として使用できる。特に好ましい噴射剤ガスは、TG11、TG12、TG134a(1,1,1,2-テトラフルオロエタン)、TG227(1,1,1,2,3,3,3-ヘプタフルオロプロパン)及びこれらの混合物から選択されるハロゲン化アルカン誘導体で、TG134a、TG227及びその混合物が好適である。
また、本発明の噴射剤駆動型吸入エアロゾルには、補助溶剤、安定剤、界面活性剤、酸化防止剤、滑剤及びpH調節剤等の他の成分も含ませることができる。これらの成分はすべて、当分野において公知である。
本発明による噴射剤ガス含有吸入エアロゾルには、有効成分1及び/又は2を5質量%まで含有させるとよい。例えば、本発明のエアロゾルは、有効成分1及び/又は2を0.002〜5質量%、0.01〜3質量%、0.015〜2質量%、0.1〜2質量%、0.5〜2質量%又は0.5〜1質量%含む。
B) Propellant gas driven inhalation aerosol comprising the composition of the invention:
In the propellant gas-containing inhalation aerosol according to the present invention, the active ingredients 1 and 2 may be contained in the propellant gas in a dissolved or dispersed state. 1 and 2 can be present in separate formulations or single preparations, in which both 1 and 2 are either dissolved or dispersed, or only one component is dissolved and the other component is dispersed Either. Propellant gases that can be used for the preparation of the inhaled aerosols according to the invention are known from the prior art. Suitable propellant gases include hydrocarbon compounds such as n-propane, n-butane or isobutane, and halohydrocarbons such as methane, ethane, propane, butane, cyclopropane or cyclobutane, preferably chlorinated and fluorinated derivatives. Selected from compounds. The propellant gas can be used alone or as a mixture thereof. Particularly preferred propellant gases are TG11, TG12, TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. TG134a, TG227 and mixtures thereof are preferred with halogenated alkane derivatives selected from
The propellant-driven inhalation aerosol of the present invention can also contain other components such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All of these components are known in the art.
The propellant gas-containing inhalation aerosol according to the present invention may contain up to 5% by mass of active ingredient 1 and / or 2. For example, the aerosol of the present invention contains 0.002 to 5% by mass, 0.01 to 3% by mass, 0.012 to 2% by mass, 0.1 to 2% by mass, 0.5 to 2% by mass, or 0.5 to 1% by mass of the active ingredient 1 and / or 2. % Is included.
有効成分1及び/又は2が分散状態で存在する場合は、該有効成分粒子の平均粒子径は10μmまでが好ましく、さらに好ましくは0.1〜6μm、より好ましくは1〜5μmである。
前述の本発明による噴射剤駆動型吸入エアロゾルは、当該分野において公知の吸入器(定量噴霧吸入器(MDI))を用いて投与することができる。従って、本発明の別の態様としては、前述の噴射剤駆動型エアロゾルを投与するのに適した1種以上の吸入器と組み合わせた、噴射剤駆動型エアロゾル状態の医薬組成物に関する。更に、本発明は、前述の本発明による噴射剤ガス含有エアロゾルを収容することを特徴とする吸入器に関するものである。また、本発明は、適切なバルブが設けられ、適当な吸入器で使用可能であり、かつ、本発明による上記噴射剤ガス含有吸入エアロゾルの1種を収容する、カートリッジに関する。好適なカートリッジ、さらには本発明による噴射剤ガス含有吸入エアロゾルをカートリッジに充填する方法については、従来技術から公知である。
C)本発明の組成物を含む、噴射剤を含有しない吸入溶液又は懸濁液:
本発明の噴射剤を含有しない吸入用溶液は、例えば水性溶媒又はアルコール系溶媒、好ましくはエタノール系溶媒を含むが、エタノール系溶媒と水性溶媒とを混合したものを含有してもよい。水性/エタノール系混合溶媒の場合、水に対するエタノールの相対的割合は限定されないが、最大限70容量%まで、より詳細にはエタノールは60容量%までである。残りの容量を水で構成する。有効成分1及び2を別個に又は一緒に含有する溶液又は懸濁液は、適当な酸を用いてpH2〜7、好ましくはpH2〜5に調整する。pH値は無機酸又は有機酸から選択される酸を用いて調整すればよい。とりわけ好適な無機酸の例としては、塩酸、臭化水素酸、硝酸、硫酸及び/又はリン酸が挙げられる。特に好適な有機酸の例としては、アスコルビン酸、クエン酸、リンゴ酸、酒石酸、マレイン酸、コハク酸、フマル酸、酢酸、ギ酸及び/又はプロピオン酸等が挙げられる。推奨される無機酸は塩酸及び硫酸である。また、有効成分の一方とともに酸付加塩をすでに形成している酸を使用することも可能である。有機酸の中では、アスコルビン酸、フマル酸及びクエン酸が好ましい。所望であれば、上記酸の混合物を用いることもでき、特に、酸性化特性に加えて、例えば香料、酸化防止剤又は錯化剤としての特性を有する酸、例えばクエン酸又はアスコルビン酸等の場合は、混合して用いるとよい。本発明によると、塩酸を用いてpH値を調整することが特に好ましい。
When the active ingredients 1 and / or 2 are present in a dispersed state, the average particle diameter of the active ingredient particles is preferably up to 10 μm, more preferably 0.1 to 6 μm, more preferably 1 to 5 μm.
The propellant-driven inhalation aerosol according to the present invention described above can be administered using an inhaler known in the art (metered dose inhaler (MDI)). Accordingly, another aspect of the present invention relates to a propellant-driven aerosol pharmaceutical composition in combination with one or more inhalers suitable for administering the propellant-driven aerosol described above. Furthermore, the present invention relates to an inhaler characterized in that it contains the propellant gas-containing aerosol according to the present invention. The invention also relates to a cartridge provided with a suitable valve, usable with a suitable inhaler, and containing one of the propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges, as well as methods for filling the cartridges with the propellant gas-containing inhalation aerosol according to the invention are known from the prior art.
C) A propellant-free inhalation solution or suspension comprising the composition of the invention:
The inhalation solution containing no propellant of the present invention contains, for example, an aqueous solvent or an alcohol solvent, preferably an ethanol solvent, but may contain a mixture of an ethanol solvent and an aqueous solvent. In the case of an aqueous / ethanol-based mixed solvent, the relative ratio of ethanol to water is not limited, but up to 70% by volume, more specifically, up to 60% by volume of ethanol. The remaining volume is made up of water. Solutions or suspensions containing active ingredients 1 and 2 separately or together are adjusted to pH 2-7, preferably pH 2-5, using a suitable acid. The pH value may be adjusted using an acid selected from inorganic acids or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid. Recommended inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids that have already formed acid addition salts with one of the active ingredients. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids can also be used, especially in the case of acids having properties as perfumes, antioxidants or complexing agents, for example citric acid or ascorbic acid, in addition to acidifying properties. May be used as a mixture. According to the invention, it is particularly preferred to adjust the pH value with hydrochloric acid.
本発明では、エデト酸(EDTA)又はその公知の塩の1つであるエデト酸ナトリウムを安定剤又は錯化剤として添加することは、本発明の処方においては不要である。実施形態によっては、この化合物を1種以上含んでもよい場合もある。推奨実施形態は、エデト酸ナトリウムを基準とした含有量が、100mg/100ml未満、好ましくは50mg/100ml未満、さらに好ましくは20mg/100ml未満である。一般に、エデト酸ナトリウムの含有量が0〜10mg/100mlの範囲となる吸入液が好ましい。
本発明の噴射剤を含有しない吸入液には、補助溶剤及び/又は他の賦形剤を添加することができる。好ましい補助溶剤は、ヒドロキシル基又は他の極性基を含むもので、例えばアルコール類、特にイソプロピルアルコール、グリコール類、特にプロピレングリコール、ポリエチレングリコール、ポリプロピレングリコール、グリコールエーテル、グリセロール、ポリオキシエチレンアルコール類及びポリオキシエチレン脂肪酸エステル類である。本明細書における賦形剤及び添加剤という用語は、それ自体は活性物質ではないが、活性物質を含む調剤の定性的特性を改善するために、医薬的に好適な溶媒中で1種またはそれより多くの活性物質と共に処方できる、薬理的に許容できる任意の物質を意味する。これらの物質は薬理的作用を持たないことが好ましいが、所望の療法との関連において容易に認識できるような薬理作用は持たないか、少なくとも望ましくない薬理作用を有していないことが好ましい。賦形剤及び添加剤としては、例えば、大豆レシチン、オレイン酸、ポリソルベートなどのソルビタンエステル類、ポリビニルピロリドンなどの界面活性剤、他の安定剤、錯化剤、最終的な医薬製剤の品質保持期間を保証又は延長する酸化防止剤及び/又は防腐剤、香味付与剤、ビタミン類及び/又は当分野で公知の他の添加剤が挙げられる。また、添加剤には塩化ナトリウム等の医薬的に許容できる塩も等張剤として含まれる。
In the present invention, it is not necessary in the formulation of the present invention to add edetic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complexing agent. In some embodiments, one or more of this compound may be included. A preferred embodiment has a content based on sodium edetate of less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, more preferably less than 20 mg / 100 ml. In general, an inhalation solution with a sodium edetate content in the range of 0 to 10 mg / 100 ml is preferred.
Co-solvents and / or other excipients can be added to the inhalation solution containing no propellant of the present invention. Preferred cosolvents are those containing hydroxyl groups or other polar groups such as alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and poly Oxyethylene fatty acid esters. The terms excipients and additives herein are not active substances per se, but may be one or more in a pharmaceutically suitable solvent in order to improve the qualitative properties of a formulation containing the active substance. It means any pharmacologically acceptable substance that can be formulated with more active substance. These substances preferably have no pharmacological action, but preferably have no pharmacological action that can be easily recognized in the context of the desired therapy, or at least have no undesirable pharmacological action. Examples of excipients and additives include soy lecithin, oleic acid, sorbitan esters such as polysorbate, surfactants such as polyvinylpyrrolidone, other stabilizers, complexing agents, and quality retention period of the final pharmaceutical preparation. Antioxidants and / or preservatives, flavoring agents, vitamins and / or other additives known in the art to guarantee or prolong the protection. Additives also include pharmaceutically acceptable salts such as sodium chloride as isotonic agents.
好ましい賦形剤としては、例えば、pHの調整に使用されていないのであればアスコルビン酸、さらにはビタミンA、ビタミンE、トコフェロール及び人体内で産生する同様なビタミン類及びプロビタミン類等の酸化防止剤が挙げられる。
防腐剤を使用して病原体による汚染から調剤を保護することができる。適当な防腐剤は当該分野において公知のものであり、特に従来技術からわかっている濃度の、塩化セチルピリジニウム、塩化ベンザルコニウム又は安息香酸もしくは安息香酸ナトリウムなどの安息香酸塩である。上記防腐剤は、好ましくは50mg/100mlまで、より好ましくは5〜20mg/100mlの濃度で存在しているとよい。
好ましい製剤は、溶剤としての水及び有効成分1及び2の組合せのほかに、塩化ベンザルコニウム及びエデト酸ナトリウムのみを含むものである。エデト酸ナトリウムを含有させない推奨実施形態もある。
本発明の噴射剤を含有しない吸入液の投与は、治療用量である少量の液体製剤を数秒間以内で霧状にして治療用吸入に適したエアロゾルを生成することができるタイプの吸入器を用いて行う。本発明の範囲では、好ましくは1回のスプレー操作で100μL未満、好ましくは50μL未満、より好ましくは10〜30μLの量の有効成分溶液を霧状にして、平均粒径20μm未満、好ましくは10μm未満のエアロゾルを形成することができ、エアロゾルの吸入可能分が治療上の有効量に相当するようにできる噴霧器が好ましい噴霧器である。
吸入用液状医薬組成物の定量を噴射剤を使用せずに放出するタイプの装置については、例えば国際特許出願WO91/14468及びWO97/12687(特に図6a及び図6b参照)に記載されている。これらに記載されているネブライザー(装置)は、Respimat(登録商標)という名称で知られている。
Preferred excipients include, for example, antioxidants such as ascorbic acid if not used for pH adjustment, and vitamin A, vitamin E, tocopherol and similar vitamins and provitamins produced in the human body. Agents.
Preservatives can be used to protect the formulation from contamination by pathogens. Suitable preservatives are known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoates such as benzoic acid or sodium benzoate in concentrations known from the prior art. The preservative is preferably present in a concentration of up to 50 mg / 100 ml, more preferably 5-20 mg / 100 ml.
Preferred formulations are those containing only benzalkonium chloride and sodium edetate in addition to the combination of water as solvent and active ingredients 1 and 2. There are also recommended embodiments in which no sodium edetate is included.
The administration of the inhalation liquid not containing the propellant of the present invention uses an inhaler of a type capable of generating an aerosol suitable for therapeutic inhalation by atomizing a small amount of liquid preparation as a therapeutic dose within a few seconds. Do it. Within the scope of the present invention, the active ingredient solution is preferably atomized in an amount of less than 100 μL, preferably less than 50 μL, more preferably 10-30 μL in a single spray operation, with an average particle size of less than 20 μm, preferably less than 10 μm. Nebulizers that are capable of forming an aerosol of the same amount such that the inhalable portion of the aerosol represents a therapeutically effective amount are preferred nebulizers.
Devices of the type that release a quantitative amount of a liquid pharmaceutical composition for inhalation without the use of a propellant are described, for example, in international patent applications WO 91/14468 and WO 97/12687 (see in particular FIGS. 6a and 6b). The nebulizers (devices) described therein are known by the name Respimat®.
このネブライザー(Respimat(登録商標))を効果的に利用して、有効成分1及び2の組合せを含む本発明の吸入エアロゾルを生成することができる。
従って、更なる本発明の態様は、上記のような噴射剤を含有しない吸入溶液又は懸濁液状態の医薬製剤の投与に適した装置、好ましくはRespimat(登録商標)と組み合わせた、噴射剤を含有しない吸入溶液又は懸濁液状態の医薬製剤に関する。好ましくは、Respimat(登録商標)という名称で公知の装置と組み合わせた、本発明による有効成分1及び2の組合せを特徴とする、噴射剤を含有しない吸入溶液又は懸濁液に関する。さらに、本発明は、本願明細書で前述したような本発明の噴射剤を含有しない吸入溶液又は懸濁液を収容することを特徴とする、前記吸入用装置、好ましくはRespimat(登録商標)に関するものである。
本発明では、有効成分1及び2を含有する単一調剤型の吸入溶液が好ましい。「単一調剤」という用語には、例えばWO00/23037に開示のごとく、2種の成分1及び2が2室型カートリッジに収容されている調剤も含まれる。この公報はその全体をもって本願明細書に引用するものである。
本発明による噴射剤を含有しない吸入溶液又は懸濁液は、濃縮物又は直ぐに使用できる無菌吸入用溶液もしくは懸濁液、ならびにRespimat(登録商標)での使用向けに設計された上記溶液及び懸濁液の状態とすることができる。直ぐに使用できる製剤は、例えば等張性の生理食塩水を添加することによって濃縮物から得られる。直ぐに使用できる無菌製剤は、ベンチュリの原理又は他の原理によって超音波又は圧縮空気を用いて吸入性エアロゾルを生成するエネルギー駆動型の固定式又は持運び可能なネブライザーを使用して投与することができる。
This nebulizer (Respimat®) can be effectively utilized to produce an inhalation aerosol of the present invention that includes a combination of active ingredients 1 and 2.
Accordingly, a further aspect of the present invention provides a propellant in combination with a device suitable for administration of a pharmaceutical formulation in the form of an inhalation solution or suspension that does not contain a propellant as described above, preferably Respimat®. The present invention relates to a pharmaceutical preparation containing no inhalation solution or suspension. Preferably, it relates to a propellant-free inhalation solution or suspension, characterized by the combination of active ingredients 1 and 2 according to the invention, in combination with a device known under the name Respimat®. Furthermore, the present invention relates to said inhalation device, preferably Respimat®, characterized in that it contains an inhalation solution or suspension which does not contain the propellant of the present invention as described herein above. Is.
In the present invention, a single-dose inhalation solution containing active ingredients 1 and 2 is preferred. The term “single preparation” also includes a preparation in which two components 1 and 2 are contained in a two-chamber cartridge, as disclosed for example in WO 00/23037. This publication is incorporated herein by reference in its entirety.
Propellant-free inhalation solutions or suspensions according to the invention include concentrates or ready-to-use sterile inhalation solutions or suspensions, as well as the above solutions and suspensions designed for use with Respimat®. It can be in a liquid state. Ready-to-use formulations are obtained from the concentrate, for example by adding isotonic saline. Ready-to-use sterile formulations can be administered using energy-driven fixed or portable nebulizers that generate inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles .
従って、本発明の別の態様は、濃縮物又は直ぐに使用可能な無菌製剤の形態をとる、前述の噴射剤を含有しない吸入溶液又は懸濁液状態の医薬組成物を、これらの液の投与に適した装置と組み合わせたもので、該装置が、ベンチュリの原理又は他の方法によって超音波又は圧縮空気を用いて吸入性エアロゾルを生成する、エネルギー駆動式の自立型又は持運び可能なネブライザーであることを特徴とする。
以下の実施例は本発明の範囲を限定することなく、本発明をより詳細に説明するためのものである。以下の製剤実施例については、この分野で公知の方法と同様にして得ることができる。
製剤の実施例
下表に粉末製剤の例がまとめてある。規定の量は1回の用量あたりのμgで表される量と解釈される。一例であるが、それぞれの用量は図1による吸入器で使用されるカプセルに充填することができた。
Accordingly, another aspect of the present invention provides for the administration of these liquids in the form of concentrates or ready-to-use sterile formulations, inhalable solutions or suspensions containing no propellants as described above. In combination with a suitable device, the device is an energy-driven self-supporting or portable nebulizer that generates inhalable aerosols using ultrasound or compressed air according to the Venturi principle or otherwise It is characterized by that.
The following examples serve to illustrate the invention in more detail without limiting the scope of the invention. The following formulation examples can be obtained in the same manner as known in this field.
Formulation Examples Examples of powder formulations are summarized in the table below. The specified amount is taken as the amount expressed in μg per dose. As an example, each dose could be filled into a capsule used in the inhaler according to FIG.
1)塩酸付加塩
2)マレイン酸付加塩
3)フマル酸付加塩
4)一水和物
1) Hydrochloric acid addition salt 2) Maleic acid addition salt 3) Fumaric acid addition salt 4) Monohydrate
Claims (14)
Aは、下記から選択される基を示し、
X-は1個の負電荷を有するアニオンを示し、好ましくは、塩化物、臭化物、ヨウ化物、スルフェート、ホスフェート、メタンスルホネート、ニトレート、マレエート、アセテート、シトレート、フマレート、タルトレート、オキサレート、スクシネート、ベンゾエート及びp−トルエンスルホネートからなる群から選択されるアニオンを示す)と、
下記からなる群から選択される1種以上のベータ2作用薬:
A represents a group selected from:
X − represents one negatively charged anion, preferably chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate And an anion selected from the group consisting of p-toluenesulfonate)
One or more beta-2 agonists selected from the group consisting of:
X-が1個の負電荷を有するアニオンを示し、好ましくは、塩化物、臭化物、ヨウ化物、スルフェート、ホスフェート、メタンスルホネート、ニトレート、マレエート、アセテート、シトレート、フマレート、タルトレート、オキサレート、スクシネート、ベンゾエート及びp−トルエンスルホネートからなる群から選択されるアニオンを示す、請求項1記載の医薬組成物。 In the compound of the formula 1, A represents a group selected from the following:
X − represents one negatively charged anion, preferably chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate And the anion selected from the group consisting of p-toluenesulfonate.
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PCT/EP2007/054700 WO2007135024A1 (en) | 2006-05-24 | 2007-05-15 | New long-acting drug combinations for the treatment of respiratory diseases |
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JP (1) | JP2010526763A (en) |
CA (1) | CA2650813A1 (en) |
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DE10323966A1 (en) * | 2003-05-27 | 2004-12-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New long-acting drug combinations for the treatment of respiratory diseases |
CA2533791C (en) * | 2003-07-28 | 2012-05-22 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising betamimetics and an anticholinergic agent |
US20050025718A1 (en) * | 2003-07-31 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a betamimetic |
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2007
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