KR20040010552A - Inhalable formulation of a solution containing a tiotropium salt - Google Patents
Inhalable formulation of a solution containing a tiotropium salt Download PDFInfo
- Publication number
- KR20040010552A KR20040010552A KR10-2003-7006001A KR20037006001A KR20040010552A KR 20040010552 A KR20040010552 A KR 20040010552A KR 20037006001 A KR20037006001 A KR 20037006001A KR 20040010552 A KR20040010552 A KR 20040010552A
- Authority
- KR
- South Korea
- Prior art keywords
- pharmaceutical formulation
- weight
- pharmaceutical
- tiotropium
- acid
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 67
- 238000009472 formulation Methods 0.000 title claims abstract description 50
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 title claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 46
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 claims abstract description 29
- 229960000257 tiotropium bromide Drugs 0.000 claims abstract description 29
- 239000000443 aerosol Substances 0.000 claims abstract description 20
- MQLXPRBEAHBZTK-SEINRUQRSA-M tiotropium bromide hydrate Chemical compound O.[Br-].C[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 MQLXPRBEAHBZTK-SEINRUQRSA-M 0.000 claims abstract description 13
- 239000013543 active substance Substances 0.000 claims description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 22
- 229940110309 tiotropium Drugs 0.000 claims description 20
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical group 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- -1 monomethylsulfuric acid ester Chemical class 0.000 claims description 17
- 150000003431 steroids Chemical class 0.000 claims description 15
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 14
- 229960004436 budesonide Drugs 0.000 claims description 14
- 229940037001 sodium edetate Drugs 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 239000000654 additive Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 11
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 8
- 239000003755 preservative agent Substances 0.000 claims description 8
- 238000005507 spraying Methods 0.000 claims description 8
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 7
- 239000000739 antihistaminic agent Substances 0.000 claims description 7
- 229960002714 fluticasone Drugs 0.000 claims description 7
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 5
- 230000001387 anti-histamine Effects 0.000 claims description 5
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 5
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 5
- 239000008139 complexing agent Substances 0.000 claims description 5
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- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 4
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- 239000006184 cosolvent Substances 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical group CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 3
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 claims description 3
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- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 claims description 3
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 claims description 3
- 229960005127 montelukast Drugs 0.000 claims description 3
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- PSILZZNMGXTOOP-UHFFFAOYSA-N 2-[2-[[2-(4-tert-butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl]oxymethyl]phenyl]acetic acid Chemical compound CC(C)(C)C1=CSC(C=2OC3=CC=C(OCC=4C(=CC=CC=4)CC(O)=O)C=C3C=2)=N1 PSILZZNMGXTOOP-UHFFFAOYSA-N 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 229960000428 carbinoxamine Drugs 0.000 claims description 2
- OJFSXZCBGQGRNV-UHFFFAOYSA-N carbinoxamine Chemical compound C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-UHFFFAOYSA-N 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical group O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 229960005042 mequitazine Drugs 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 3
- 230000002335 preservative effect Effects 0.000 claims 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- AOPATQAZIRXNOX-UHFFFAOYSA-N 2-(1-methylcyclopropyl)acetic acid Chemical compound OC(=O)CC1(C)CC1 AOPATQAZIRXNOX-UHFFFAOYSA-N 0.000 claims 1
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 claims 1
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical group C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 claims 1
- 229960003449 epinastine Drugs 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 239000003380 propellant Substances 0.000 abstract description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
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- 230000005540 biological transmission Effects 0.000 description 12
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 11
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
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- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
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- 239000004147 Sorbitan trioleate Substances 0.000 description 3
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 3
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- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 3
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Abstract
본 발명은 물 또는 물과 에탄올로 이루어진 혼합물에 용해되어 있는, 티오트로퓸 브로마이드 또는 티오트로퓸 브로마이드 1수화물의 무추진제 흡입 제형 및 이로부터 생성된 무추진제 흡입 에어로졸에 관한 것이다.The present invention relates to a propellant inhalation formulation of tiotropium bromide or tiotropium bromide monohydrate, dissolved in water or a mixture of water and ethanol, and to a propellant inhalation aerosol produced therefrom.
Description
본 발명은 바람직하게는 흡입에 의해 투여되는 하나 이상의 기타 활성 물질과 결합하여, 물 또는 물과 에탄올의 혼합물에 용해된 티오트로퓸의 약제학적으로 허용가능한 염의 무추진제(propellant-free) 흡입성 제형 및 이로부터 제조된 무추진제 흡입성 에어로졸에 관한 것이다. 본 발명에 따른 제형은 흡입에 의해 활성 물질을 투여하기에 적합하며, 특히 천식과 COPD를 치료하기에 적합하다.The present invention preferably is a propellant-free inhalable formulation of thiotropium in water or a pharmaceutically acceptable salt of tiotropium dissolved in a mixture of water and ethanol, in combination with one or more other active substances administered by inhalation. And to propellant inhalable aerosols prepared therefrom. The formulations according to the invention are suitable for the administration of the active substance by inhalation, in particular for the treatment of asthma and COPD.
화학적으로는 (1α,2β,4β,5α,7β)-7-[(하이드록시-디-2-티에닐아세틸)옥시]-9,9-디메틸-3-옥사-9-아조니아트리사이클로[3.3.1.02,4]노난으로 표현되는, 티오트로퓸은 유럽 공개특허공보 제418 716 A1호의 티오트로퓸 브로마이드로서 공지되어 있다. 티오트로퓸의 브로마이드 염은 하기 화학식 I의 구조를 갖는다.Chemically, (1α, 2β, 4β, 5α, 7β) -7-[(hydroxy-di-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo Tiotropium, represented by [3.3.1.0 2,4 ] nonane, is known as tiotropium bromide of EP 418 716 A1. The bromide salt of tiotropium has the structure of formula (I)
티오트로퓸 브로마이드란 명칭으로 공지되어 있는 본 화합물은 유효한 약리학적 특성을 나타낸다. 티오트로퓸 및 이의 염은 매우 효과적인 항콜린성제이며, 천식 또는 COPD(만성 폐색성 폐질환)의 치료에 치료학적 이점을 제공할 수 있다. 또한, 티오트로퓸 브로마이드의 1수화물도 약리학적으로 가치가 있다. 두 화합물 모두가 본 발명의 바람직한 목적이다.The compound, known under the name tiotropium bromide, exhibits effective pharmacological properties. Tiotropium and its salts are very effective anticholinergic agents and can provide therapeutic benefits in the treatment of asthma or COPD (chronic obstructive pulmonary disease). The monohydrate of tiotropium bromide is also pharmacologically valuable. Both compounds are a preferred object of the present invention.
본 발명은 흡입에 의해 투여할 수 있는 위와 같은 화합물의 액체 활성 물질 제형에 관한 것이며, 본 발명에 따르는 액체 제형은 고품질의 표준을 만족시킨다.The present invention relates to liquid active substance formulations of such compounds which can be administered by inhalation, wherein the liquid formulations according to the invention meet high quality standards.
폐에 활성 물질을 최적으로 분배하기 위해서는, 액체 제형을 적합한 흡입기를 사용하여 추진제 기체 없이 투여해야 할 것이다. 치료학적인 목적에 필요한 투여량으로 소량의 액체 제형을 수초 이내에 치료학적인 흡입에 적합한 에어로졸로 분무시킬 수 있는 흡입기가 특히 적합하다. 본 발명의 범주내에서, 바람직한 분무기는 100㎕ 미만, 바람직하게는 50㎕ 미만, 가장 바람직하게는 20㎕ 미만의 활성 물질 용액을 1회 작동에 의해 분무시켜 평균 직경이 20μ미만, 바람직하게는 10μ미만인 에어로졸을 형성할 수 있으므로, 에어로졸의 흡입성 부분은 치료학적으로효과적인 양에 상응한다.In order to optimally distribute the active substance to the lungs, the liquid formulation will need to be administered without a propellant gas using a suitable inhaler. Particularly suitable are inhalers, which can spray a small amount of liquid formulation into aerosols suitable for therapeutic inhalation within a few seconds at dosages necessary for therapeutic purposes. Within the scope of the present invention, preferred nebulizers are sprayed by one operation of less than 100 μl, preferably less than 50 μl, most preferably less than 20 μl of active substance solution, with an average diameter of less than 20 μm, preferably 10 μl. Since less than one can form an aerosol, the inhalable portion of the aerosol corresponds to a therapeutically effective amount.
흡입용 액체 약제학적 조성물의 계량된 양을 추진제 없이 투여하는 이러한 종류의 장치는 예를 들면, "분무 장치 및 방법"이란 국제공개공보 제WO 91/14468호 및 국제공개공보 제WO 97/12687호(참조: 도 6a 및 6b 및 첨부된 설명)에 상세히 기재되어 있다. 이러한 유형의 분무기내에서, 약제학적 용액은 500bar 이하의 고압에 의해 폐에 사용되는 에어로졸로 전환된다. 상술한 문헌의 전체 내용이 참조문헌으로서 본 명세서의 범주내에 포함된다.Devices of this kind in which a metered amount of liquid pharmaceutical composition for inhalation is administered without a propellant is described, for example, in WO 91/14468 and WO 97/12687, entitled “Spraying Devices and Methods”. (See FIGS. 6A and 6B and the accompanying description) in detail. In this type of nebulizer, the pharmaceutical solution is converted to the aerosol used for the lungs by high pressure up to 500 bar. The entire contents of the foregoing documents are incorporated by reference into the scope of this specification.
이러한 유형의 분무기에서, 액체 제형은 저장소내에 저장된다. 사용되는 활성 물질 제형은 저장중 충분히 안정해야 하며, 아울러 이들의 의학적 목적에 따라, 어떤 추가 조작없이도 직접 투여할 수 있어야만 한다는 사실이 중요하다. 또한, 이들은 흡입기 또는, 용액 또는 제조된 에어로졸의 약제학적 양을 손상시키는 방식으로 흡입기와 상호작용할 수 있는 성분을 절대 함유해서는 안된다.In this type of nebulizer, the liquid formulation is stored in a reservoir. It is important that the active substance formulations to be used must be sufficiently stable during storage and, depending on their medical purpose, to be directly administrable without any further manipulation. In addition, they should never contain ingredients that can interact with the inhaler or in a way that would damage the pharmaceutical amount of the solution or the aerosol produced.
용액을 분무시키기 위해서, 예를 들면, 국제공개공보 제WO 94/07607호 또는 제WO 99/16530호에 기재된 것과 같은 특수 노즐이 사용된다. 본 문헌은 둘 다 본원에 참조문헌으로 인용된다.To spray the solution, special nozzles are used, for example as described in WO 94/07607 or WO 99/16530. Both of these documents are incorporated herein by reference.
국제공개공보 제WO 98/27959호에는 에디트산(나트륨 에데테이트)의 이나트륨 염을 첨가제로서 함유하는 상술한 흡입기용 액체 제형이 기재되어 있다. 상술한 흡입기를 사용하여 흡입성 에어로졸로 전환시키려는 용액의 수성 제형에 있어서, 분무 특이성의 발생을 저하시키기 위해서, 50mg/100㎖의 나트륨 에데테이트의 최소 농도가 바람직하다. 상기 공개공보에 기재된 실시예 중에서 티오트로퓸 브로마이드를 함유하는 제형이 있다. 이러한 제형에서, 활성 물질은 물에 용해되어 있다. 마찬가지로, 나트륨 에데테이트의 비율은 50mg/100㎖이다.WO 98/27959 describes liquid formulations for inhalers as described above which contain the disodium salt of edic acid (sodium edetate) as an additive. In aqueous formulations of solutions to be converted to inhalable aerosols using the inhalers described above, a minimum concentration of 50 mg / 100 ml of sodium edetate is preferred to reduce the occurrence of spray specificity. Among the examples described in this publication there is a formulation containing tiotropium bromide. In such formulations, the active substance is dissolved in water. Likewise, the proportion of sodium edetate is 50 mg / 100 ml.
놀랍게도, 첨가제인 나트륨 에데테이트의 비율이 50mg/100㎖ 미만인, 물 또는 물-에탄올 혼합물내의 티오트로퓸 염 용액의 제형은 선행 기술에 공지된 티오트로퓸 브로마이드를 함유하는 제형에 비해, 전달되는 조성물의 산포의 저하를 나타낸다는 사실이 밝혀졌다. 또한, 분무 품질도 매우 우수하다. 생성된 에어로졸은 흡입에 의해 투여하는데 있어서 매우 우수한 특성을 나타낸다.Surprisingly, formulations of the tiotropium salt solution in water or water-ethanol mixtures with a proportion of the additive sodium edetate of less than 50 mg / 100 ml are compared to formulations containing tiotropium bromide known in the prior art. It has been found that this indicates a decrease in the dispersion of. In addition, the spray quality is also very good. The resulting aerosols exhibit very good properties for administration by inhalation.
이러한 제형의 또 다른 이점은 활성 물질 제형내의 첨가제 아데테이트 나트륨의 부재 또는 저하로 인해, 용액 제형의 pH를 낮출 수 있다는 사실이다. 낮은 pH 수준은 제형내의 티오트로퓸 염의 장기간의 안정성에 있어서 필수적이다.Another advantage of such formulations is the fact that the pH of the solution formulation can be lowered due to the absence or drop of additive adetate sodium in the active substance formulation. Low pH levels are essential for the long term stability of the tiotropium salt in the formulation.
따라서, 본 발명의 목적은 상술한 흡입기를 사용하여 용액을 최적으로 분무하는데 요구되는 높은 기준을 만족시키는 약제학적으로 허용되는 티오트로퓸 염을 함유하는 수성 활성 물질 제형을 제공하는 것이다. 본 발명에 따르는 활성 물질 제형은 충분히 높은 약제학적 품질을 가져야만 한다. 즉, 이들은 수 년의 저장 기간, 바람직하게는 1년 이상, 보다 바람직하게는 2년 이상 동안 약제학적으로 안정해야만 한다.It is therefore an object of the present invention to provide an aqueous active substance formulation containing a pharmaceutically acceptable tiotropium salt that meets the high standards required for optimal spraying of solutions using the inhalers described above. The active substance formulations according to the invention must have a sufficiently high pharmaceutical quality. That is, they must be pharmaceutically stable for a storage period of several years, preferably at least one year, more preferably at least two years.
또 다른 목적은 흡입기를 사용하여 가압하에 분무되는 티오트로퓸 염을 함유하는 용액의 무추진제 제형을 제공하는 것인데, 여기서 당해 조성물은 특정 범위 이내에서 반복적으로 제조되는 에어로졸에 의해 운반된다.Another object is to provide a propellant formulation of a solution containing a tiotropium salt sprayed under pressure using an inhaler, wherein the composition is carried by an aerosol that is repeatedly produced within a certain range.
또 다른 목적은 흡입에 의해 투여될 수 있는, 티오트로퓸 및 또 다른 활성물질을 포함하는 용액의 제형을 제공하는 것이다.Yet another object is to provide a formulation of a solution comprising tiotropium and another active substance which can be administered by inhalation.
본 발명에 따라, 티오트로퓸의 임의의 약제학적으로 허용되는 염을 본 발명의 제형에 사용할 수 있다. 용어 티오트로퓸 염이 본 발명의 범주내에서 사용되는 경우, 이를 티오트포륨에 대한 기준으로 간주한다. 본 발명에 따라, 자유 암모늄 양이온인 티오트로퓸에 관한 기준은 반대 이온으로서 음이온을 함유하는 염(티오트로퓸 염)의 형태인 티오트로퓸에 관한 기준에 상응한다. 본 발명의 범주내에서 사용될 수 있는 티오트로퓸 염은 바람직하게는 티오트로퓸 이외에, 반대 이온(음이온)으로서 클로라이드, 브로마이드, 요오다이드, 메탄설포네이트, 파라-톨루엔설포네이트 및/또는 메틸설페이트를 함유하는 화합물이다.According to the invention, any pharmaceutically acceptable salt of tiotropium can be used in the formulation of the invention. When the term tiotropium salt is used within the scope of the present invention, it is regarded as a reference for tiophorium. According to the invention, the criteria for tiotropium, which is a free ammonium cation, correspond to the criteria for tiotropium in the form of salts (thiotropium salts) containing anions as counter ions. Tiotropium salts which can be used within the scope of the present invention are preferably chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate and / or methylsulfate as counter ions (anions), in addition to tiotropium. It is a compound containing.
본 발명의 범주내에서, 티오트로퓸 브로마이드는 바람직하게는 염으로서 존재한다. 본 발명의 범주내의 티오트로퓸 브로마이드에 관한 참조는 반드시 티오트로퓸 브로마이드의 모든 가능한 무정형 및 결정성 변형물에 대한 참조로서 이해되어야 한다. 이들은 예를 들면, 이들의 결정성 구조내에 용매 분자를 함유할 수 있다. 티오트로퓸 브로마이드의 모든 결정성 변형물중에서, 물을 함유하는 것(수화물)도 본 발명에 따라서 바람직하다. 본 발명의 범주내에서는 티오트로퓸 브로마이드 1수화물을 사용하는 것이 특히 바람직하다.Within the scope of the present invention, tiotropium bromide is preferably present as a salt. References to tiotropium bromide within the scope of the present invention must be understood as references to all possible amorphous and crystalline modifications of tiotropium bromide. These may contain, for example, solvent molecules in their crystalline structure. Of all the crystalline modifications of tiotropium bromide, those containing water (hydrates) are also preferred in accordance with the present invention. It is particularly preferred to use tiotropium bromide monohydrate within the scope of the present invention.
본 발명에 따르는 제형중에서, 티오트로퓸 염과 하나의 기타 활성 물질과의 배합물이 바람직하다.Among the formulations according to the invention, combinations of tiotropium salts with one other active substance are preferred.
본 발명에 따른 제형내에서, 티오트로퓸 염은 용매에 용해된다. 이러한 용매는 단순한 물일 수 있으며, 또는 물과 에탄올의 혼합물일 수도 있다. 첨가제 또는 티오트로퓸 염 이외의 기타 활성 물질, 바람직하게는 티오트로퓸 브로마이드 또는 티오트로퓸 브로마이드 1수화물의 용해도를 증가시키기 위해서, 당해 제형에 에탄올을 첨가할 수 있다. 에탄올 대 물의 상대 비율은 제한되지 않는데, 예를 들면, 90용적%일 수 있다. 바람직하게는, 에탄올의 최대 한도는 70용적%, 특히 60용적%, 가장 바람직하게는 30용적%이다. 나머지 용적%는 물로 이루어진다. 바람직한 용매는 에탄올을 첨가하지 않은 물이다.In the formulations according to the invention, the tiotropium salt is dissolved in a solvent. Such a solvent may be simple water or may be a mixture of water and ethanol. Ethanol may be added to the formulation in order to increase the solubility of the additives or other active materials other than tiotropium salts, preferably tiotropium bromide or tiotropium bromide monohydrate. The relative ratio of ethanol to water is not limited, for example 90% by volume. Preferably, the maximum limit of ethanol is 70% by volume, in particular 60% by volume and most preferably 30% by volume. The remaining volume% consists of water. Preferred solvent is water without the addition of ethanol.
티오트로퓸의 비율을 기준으로 한 최종 약제학적 제형내의 티오트로퓸 염의 농도는 목적하는 치료학적 효과에 좌우된다. 티오트로퓸에 반응하는 대부분의 질환에 있어서, 티오트로퓸의 농도는 0.0005 내지 5중량%, 바람직하게는 0.001 내지 3중량%이다.The concentration of tiotropium salt in the final pharmaceutical formulation based on the proportion of tiotropium depends on the desired therapeutic effect. In most diseases responsive to tiotropium, the concentration of tiotropium is from 0.0005 to 5% by weight, preferably from 0.001 to 3% by weight.
본 발명에 따르는 제형의 pH는 2.0 내지 4.5, 바람직하게는 2.5 내지 3.5, 보다 바람직하게는 2.7 내지 3.5 특히 바람직하게는 2.7 내지 3.2이다. pH의 상한은 3.1이 가장 바람직하다.The pH of the formulations according to the invention is from 2.0 to 4.5, preferably from 2.5 to 3.5, more preferably from 2.7 to 3.5 and particularly preferably from 2.7 to 3.2. The upper limit of the pH is most preferably 3.1.
pH는 약리학적으로 허용되는 산을 첨가함으로써 조절된다. 이러한 목적에 바람직한 무기 산의 예로는 염산, 브롬산, 질산, 황산 및/또는 인산이 있다.pH is adjusted by adding pharmaceutically acceptable acids. Examples of preferred inorganic acids for this purpose are hydrochloric acid, bromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
특히 적합한 유기 산의 예로는 아스코르빈산, 시트르산, 말산, 타르타르산, 말레산, 석신산, 푸마르산, 아세트산, 포름산 및/또는 프로피온산 등이 있다. 바람직한 무기 산은 염산 및 황산이다. 또한, 활성 물질 또는 배합 제제인 경우, 활성 물질중 어느 하나와의 산 첨가 염을 형성하는 산을 사용할 수도 있다. 유기 산중에서, 아스코르빈산, 푸마르산 및 시트르산이 바람직하며, 특히 시트르산이 바람직하다. 경우에 따라, 상술한 산의 혼합물도 사용할 수 있으며, 특히 이들의 산성화 특성 이외의 기타 특성을 나타내는 산의 경우, 예를 들면, 항료 또는 항산화제로서 작용하는 시트르산 또는 아스코르빈산과 같은 것들을 사용할 수 있다. 무기 산으로서는 특히 염산을 언급할 수 있다.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. Preferred inorganic acids are hydrochloric acid and sulfuric acid. In addition, in the case of an active substance or a combination preparation, an acid which forms an acid addition salt with any of the active substances may be used. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, and citric acid is particularly preferred. In some cases, mixtures of the above-mentioned acids may also be used, especially in the case of acids exhibiting properties other than their acidifying properties, for example, citric acid or ascorbic acid, which act as a medicament or antioxidant. have. As the inorganic acid, mention may be made in particular of hydrochloric acid.
경우에 따라, pH를 정확히 조정하기 위해 약리학적으로 허용되는 염기를 사용할 수 있다. 적합한 염기로는 예를 들면, 알칼리 금속 하이드록사이드 및 알칼리 금속 카보네이트가 있다. 바람직한 알칼리 이온은 나트륨이다. 이러한 종류의 염기가 사용되는 경우, 최종 약제학적 제형내에 함유되어 있는 생성된 염이 상술한 산과 약리학적으로 혼화성이 되도록 특히 주의해야 한다.In some cases, pharmacologically acceptable bases can be used to precisely adjust the pH. Suitable bases are, for example, alkali metal hydroxides and alkali metal carbonates. Preferred alkali ions are sodium. When bases of this kind are used, particular care should be taken to ensure that the resulting salts contained in the final pharmaceutical formulation are pharmacologically compatible with the above-mentioned acids.
본 발명에 따르면, 본 발명의 제형에 안정화제 또는 착물화제로서 에디트산(EDTA) 또는 이들의 공지된 염중 하나인 나트륨 에데테이트를 첨가할 필요가 없다.According to the present invention, there is no need to add sodium edetate, which is one of their known salts, as the stabilizer or complexing agent to the formulation of the present invention.
또 다른 바람직한 양태는 에디트산 및/또는 이들의 염을 함유한다.Another preferred embodiment contains editic acid and / or salts thereof.
나트륨 에데테이트를 포함하는 바람직한 양태에서, 나트륨 에데테이트를 기준으로 하는 함량은 10mg/100㎖ 미만이다. 이 경우, 5mg/100㎖ 내지 10mg/100㎖의 범위 또는 0 내지 5mg/100㎖ 이상이 바람직하다.In a preferred embodiment comprising sodium edetate, the content based on sodium edetate is less than 10 mg / 100 ml. In this case, the range of 5 mg / 100 ml-10 mg / 100 ml or 0-5 mg / 100 ml or more is preferable.
또 다른 양태에서, 나트륨 에데테이트의 함량은 10 내지 30mg/100㎖, 바람직하게는 25mg/100㎖ 이하이다.In another embodiment, the content of sodium edetate is 10 to 30 mg / 100 ml, preferably 25 mg / 100 ml or less.
바람직한 양태에서, 이러한 첨가제를 완전히 생략한다.In a preferred embodiment, such additives are omitted completely.
또한, 나트륨 에데테이트에 관한 주의점이 착물 특성을 나타내는 기타 비교가능한 첨가제에도 유사하게 적용되는데, 예를 들면, 니트릴로트리아세트산 및 이의 염과 같은 것을 대신 사용할 수도 있다.In addition, the caveats regarding sodium edetate also apply similarly to other comparable additives that exhibit complex properties, for example, such as nitrilotriacetic acid and salts thereof may be used instead.
착물화제라 함은 본 발명의 범주내에 착물 결합내로 유입될 수 있는 분자를 의미한다. 바람직하게는, 이러한 화합물은 착물화 양이온의 효과를 나타내어야 하며, 가장 바람직하게는 금속 양이온이다.By complexing agent is meant a molecule that can be introduced into the complex bond within the scope of the present invention. Preferably, such compounds should exhibit the effect of complexing cations, most preferably metal cations.
배합된 제제내의 티오트로퓸 염 이외의 기타 활성 물질은 특히 항히스타민제, 항알레르기제, 류코트리엔 길항제 및/또는 스테로이드 중에서 선택된다.Other active substances other than tiotropium salts in the formulated formulations are in particular selected from antihistamines, antiallergic agents, leukotriene antagonists and / or steroids.
이러한 활성 물질로는Such active materials include
스테로이드:steroid:
알클로메타손,플루니솔리드,Alclomethasone, Flunisolid,
알클로메타손-디프로피오네이트,플루오시놀론 아세토나이드,Alclomethasone-Dipropionate, Fluorcinolone Acetonide,
알리삭타이드,플루오시노나이드,Alisactide, Fluorinide,
암시노나이드,플루오코르틴,Amcinononide, fluorocortin,
아미노글루테트이미드,플루오코르톨론 카프로네이트,Aminoglutetimide, fluorocortolone caponate,
아리스토코르트-디아세테이트,플루오덱산,Aristocort-diacetate, fluorexic acid,
베클로메타손,플루오로메톨론,Beclomethasone, fluorometholone,
베클로메타손, 더글라스,플루티카손,Beclomethasone, Douglas, fluticasone,
베클로메타손-17,21-디프로피오네이트,플루티카손-프로피오네이트,Beclomethasone-17,21-dipropionate, fluticasone-propionate,
베타메타손 발레레이트,포르메볼론,Betamethasone valerate, formmebolone,
베타메타손 아다만토에이트,포르모코르탈,Betamethasone adamantatoate, formocortal,
부데소나이드,할시노나이드,Budesonide, Halsinoid,
부틱소코르트,할로메타손,Butoxysocort, Halometason,
카네스텐-HC,할로프레돈-아세테이트,Carnetsten-HC, halopredone-acetate,
시클로메타손,하이드로코르티손,Cyclomethasone, hydrocortisone,
클로베타솔,하이드로코르티손-17-부티레이트,Clobetasol, hydrocortisone-17-butyrate,
클로베타손,하이드로코르티손-아세포네이트,Clobetason, hydrocortisone-aselate,
클로프레드놀,하이드로코르티손-부티레이트 프로피오네이트,Cloprednol, hydrocortisone-butyrate propionate,
클로프로드놀,이코메타손 엔부테이트,Cloprodnol, icomethasone enbutate,
플루오코르틴 부틸,시클로메타손,Fluorocortin butyl, cyclomethasone,
코르티바졸,로트리손,Cortibazole,
데플라자코르트,마지프레돈,Deplazacort,
데플라자코르트,메드리손,Deplazacort,
데메텍스,메프레드니손,Demetex,
데프로돈,메틸프로드니솔론-아세토네이트,Deprodone, methylprodisolone-acetonate,
데프로돈 프로피오네이트,모메타손,Deprodone propionate, mometasone,
덱사메타손,모메타손 플루오레이트,Dexamethasone, mometasone fluorate,
덱사메타손-21-이소니코티네이트,미코페놀레이트 모페틸,Dexamethasone-21-isonicotinate, mycophenolate mofetil,
덱사메타손 이소니코티네이트,프란루카스트,Dexamethasone isicotinate, franlukast,
디플로라손,파라메타손-아세테이트,Diflorason, Paramethasone-Acetate,
디플루프레드네이트,프레드니카베이트,Diflufredate, Prednica Bate,
엔드리손,프로메드롤,Endlessone, Promedol,
플루아자코르트,세라트로다스트,Fluzazacort,
플루클로론 아세토나이드,티프레단,Fluclolone Acetonide, Tipredan,
틱소코르톨-피발레이트,트리마시놀론 베네토나이드,Thixocortol-pivalate, trimascinolone bentonide,
트리암시놀론,울오베타솔-프로피오네이트,Triamcinolone, woolbetasol-propionate,
트리암시놀론-헥사아세토나이드,질레우톤,Triamcinolone-hexaacetonide, zileuton,
트릴로스탄,Trilostan,
메틸 9-알파-클로로-6-알파-플로오로-11-베타-17-알파-디하이드록시-16알파-메틸-3-옥소-1,4-안드로스타디엔-17-베타-카복실레이트-17-프로피오네이트가 있다.Methyl 9-alpha-chloro-6-alpha-fluoro-10-beta-17-alpha-dihydroxy-16alpha-methyl-3-oxo-1,4-androstadiene-17-beta-carboxylate- 17-propionate.
티오트로퓸 브로마이드, 또는 트리트로퓸 브로마이드-1수화물 및 부데소나이드, 플루니솔라이드, 베클로메타손 디프로피오네이트 또는 플루티카손의 배합물과 이의 약제학적으로 허용되는 염(가능한 다른 것)이 특히 바람직하다.Tiotropium bromide, or a combination of tritropium bromide-1 hydrate and budesonide, flunisolide, beclomethasone dipropionate, or fluticasone and pharmaceutically acceptable salts thereof (other possible) Particularly preferred.
바람직한 배합물은 티오트로퓸 브로마이드 또는 티오트로퓸 브로마이드 1수화물 및 부데소나이드를 포함한다.Preferred combinations include tiotropium bromide or tiotropium bromide monohydrate and budesonide.
본 발명에 따른 제형내의 스테로이드(예: 부데노사이드, 플루니솔라이드, 베클로메타손 디프로피오네이트 또는 플루티카손)의 농도는 바람직하게는 0.05 내지 10중량%, 바람직하게는 5중량% 이하, 보다 바람직하게는 0.1 내지 2.5중량%, 특히 바람직하게는 0.2 내지 2.5중량%이다. 본 제형을 상술한 흡입기와 함께 사용하는 경우, 1회 분무당 바람직하게는 12.5 내지 250㎍의 스테로이드가 분배되도록 스테로이드의 농도를 조절한다. 약리학적으로 활성인 투여량이 1회 또는 2회 분무로투여되는 농도가 특히 바람직하다.The concentration of steroids (eg, budenosides, flunisolide, beclomethasone dipropionate or fluticasone) in the formulations according to the invention is preferably from 0.05 to 10% by weight, preferably up to 5% by weight. More preferably 0.1 to 2.5% by weight, particularly preferably 0.2 to 2.5% by weight. When the formulation is used with the inhaler described above, the concentration of the steroid is adjusted so that preferably 12.5 to 250 μg of steroid is dispensed per spray. Particularly preferred are concentrations in which the pharmacologically active dose is administered in one or two sprays.
배합된 제형이 류코트리엔 길항제를 함유하는 경우, 이는 바람직하게는 몬테루카스트, 프란루카스트, 자피르루카스트, 1-(((R)-(3-(2-(6,7-디플루오로-2-퀴놀리닐)에테틸)페닐)-3(2-(2-하이드록시-2-프로필)페닐)티오)-메틸사이클로프로판-아세트산, 1-(((R)-3-(3-(2-(2,3-디클로로티에노[3,2-b]피리딘-5-일)-(E)-에테닐)페닐)-3-(2-(1-하이드록시-1-메틸에틸)페닐)프로필)티오)메틸)-사이클로프로판-아세트산 또는 [2-[[2-(4-3급-부틸-2-티아졸릴)-5-벤조푸라닐]옥시메틸]페닐]아세트산으로 이루어진 그룹으로부터 선택된다. 몬테루카스트, 프란루카스트 및/또는 자피르루카스트가 바람직하다.If the formulated formulation contains a leukotriene antagonist, it is preferably montelukast, franlukast, zafirlukast, 1-(((R)-(3- (2- (6,7-difluoro-2) -Quinolinyl) ethetyl) phenyl) -3 (2- (2-hydroxy-2-propyl) phenyl) thio) -methylcyclopropane-acetic acid, 1-(((R) -3- (3- ( 2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl)-(E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) Phenyl) propyl) thio) methyl) -cyclopropane-acetic acid or [2-[[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid Is selected from. Montelukast, franlukast and / or zafirlukast are preferred.
류코트리엔 길항제의 농도는 0.05 내지 10중량%, 바람직하게는 5중량% 이하, 보다 바람직하게는 0.1 내지 3.5중량%이다.The concentration of the leukotriene antagonist is from 0.05 to 10% by weight, preferably up to 5% by weight, more preferably from 0.1 to 3.5% by weight.
항히스타민제 및 항알레르기제의 예를 다음에 나타낸다:Examples of antihistamines and antiallergic agents are shown below:
아젤라스틴,Azelastine,
아스테미졸,Asemizol,
바미핀,Bamifin,
카르비녹사민 수소 말레에이트,Carbinoxamine hydrogen maleate,
세트리진,Set Ligin,
섹클로르페니르아민,Secchlorpheniramine,
클로르페녹사민,Chlorphenoxamine,
클레마스틴,Clemastine,
클레마스틴 수소 푸마레이트,Clemastine hydrogen fumarate,
데슬로라티딘,Desloratidine,
디멘히드리네이트,Dimenhydrinate,
디메틴덴,Dimethineden,
이나트륨 크로모글리케이트,Disodium chromoglycate,
디페닐히드라민,Diphenylhydramine,
독실아민,Doxylamine,
에바스틴,Evastin,
에메다스틴,Emedastine,
에피나스틴,Epineast,
펙소페나딘,Fexofenadine,
케토티펜,Ketotifen,
레보카바스틴,Levocavastin,
로라타딘,Loratadine,
메클로진,Meclozin,
메퀴타진,Methagezine,
미졸라스틴,Mizolastin,
네도크로밀,Nedochromil,
페니르아민 및/또는 프로메타진.Phenyramine and / or promethazine.
에피나스틴, 네도크로밀, 이나트륨 크로모글리케이트, 아스테미졸, 메퀴타진, 카비녹사민 및/또는 클레마스틴 및/또는 상응하는 약제학적으로 허용가능한 염이 바람직하다.Preference is given to efinastin, nedochromyl, disodium chromoglycate, asemizole, mequitazine, carbinoxamine and / or clemastine and / or corresponding pharmaceutically acceptable salts.
배합된 제제에서, 항알레르기제 및/또는 항히스타민제의 농도는 바람직하게는 0.05 내지 15중량%, 바람직하게는 10중량% 이하, 보다 바람직하게는 0.1 내지 10중량%, 가장 바람직하게는 0.1 내지 7중량%이다.In the formulated formulations, the concentration of antiallergic and / or antihistamine is preferably from 0.05 to 15% by weight, preferably up to 10% by weight, more preferably from 0.1 to 10% by weight and most preferably from 0.1 to 7 Weight percent.
또한, 상술한 모든 활성 물질은 이들의 약리학적으로 허용되는 염 형태로 임의로 사용될 수 있다.In addition, all the active substances mentioned above may optionally be used in the form of their pharmacologically acceptable salts.
배합된 제제는 바람직하게는 티오트로퓸이 용액내에 존재하는 제형이다. 기타 활성 물질을 용해시키거나 또는 현탁시킬 수 있으며, 이는 일반적으로 기타 활성 물질 및 특히 사용된 용매에 의해 결정된다.The formulated formulation is preferably a formulation in which tiotropium is present in solution. Other active substances can be dissolved or suspended, which is generally determined by the other active substances and in particular the solvent used.
추가의 활성 물질이 낮은 pH에서 손상될 수 있는 것일 경우, 이를 바람직하게는 현탁액으로서 제형화시킨다. 현탁된 형태의 이점은 pH를 보다 산성으로 만들 수 있다는 점인데, 이는 용해된 티오트로퓸의 안정성의 이점을 위한 것이다. 티오트로퓸의 바람직한 pH 범위는 2.0 내지 4.5, 바람직하게는 2.5 내지 3.5, 가장 바람직하게는 2.7 내지 3.2이다.If the additional active substance is capable of being damaged at low pH, it is preferably formulated as a suspension. The advantage of the suspended form is that the pH can be made more acidic, which is for the benefit of the stability of the dissolved tiotropium. The preferred pH range of tiotropium is from 2.0 to 4.5, preferably from 2.5 to 3.5 and most preferably from 2.7 to 3.2.
스테로이드의 경우, 이들은 바람직하게는 현탁된 형태로 사용되며, 특히 플루티카손이다. 이는 특히 사용된 용매가 에탄올이 없이 단지 물인 경우에 그러하다. 에탄올을 첨가하는 경우, 스테로이드를 용액으로 제형화시킬 수도 있다. 그러나, 예를 들면, 부데소나이드가 물과 에탄올의 혼합물에 용해되는 경우 pH 3.5에서 충분히 안정한 것으로 밝혀졌다.In the case of steroids, they are preferably used in suspended form, in particular fluticasone. This is especially the case when the solvent used is only water without ethanol. If ethanol is added, the steroid can also be formulated in solution. However, it has been found, for example, that budesonide is sufficiently stable at pH 3.5 when it is dissolved in a mixture of water and ethanol.
본 발명의 범주내에 기재된 흡입기내의 본 발명에 따른 제형을 사용함에 있어서, 제형의 모든 성분이 용액으로 존재하는 경우에 유리할 수 있다.In using the formulation according to the invention in an inhaler described within the scope of the invention, it may be advantageous if all the components of the formulation are present in solution.
에탄올 뿐만 아니라, 기타 공용매 및/또는 기타 보조제를 본 발명에 따른 제형에 첨가할 수 있다.In addition to ethanol, other cosolvents and / or other auxiliaries may be added to the formulations according to the invention.
기타 바람직한 공용매는 하이드록실 그룹 또는 기타 극성 그룹을 함유하는 것으로서, 예를 들면, 알코올-특히 이소프로필알코올, 글리콜-특히 프로필렌글리콜, 폴리에틸렌글리콜, 폴리프로필렌글리콜, 글리콜에테르, 글리세롤, 폴리옥시에틸렌 알코올 및 폴리옥시에틸렌 지방산 에스테르가 있다.Other preferred cosolvents contain hydroxyl groups or other polar groups, for example alcohols, in particular isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohol and Polyoxyethylene fatty acid esters.
본 명세서내에서 보조제 및 첨가제란 활성 물질 제형의 품질을 향상시키기 위해, 활성 물질을 포함하지는 않지만, 활성 물질과 함께 약리학적으로 적합한 용매내에서 제형화될 수 있는 임의의 약리학적으로 허용가능하며 치료학적으로 유용한 물질을 의미한다. 바람직하게는, 이러한 물질은 목적하는 치료의 범주내에서 어떠한 약리학적 효과 또는 측정가능한 약리학적 효과 또는 적어도 바람직하지 않은 약리학적 효과를 나타내지 않는다. 보조제 및 첨가제로는 예를 들면, 대두 레시틴, 올레산, 소르비탄 에스테르(예: 소르비탄 트리올레에이트), 폴리비닐피롤리돈과 같은 계면활성제, 기타 안정화제, 착물화제, 항산화제 및/또는 최종 약제학적 제형의 저장 수명을 연장시키는 보존제, 향료, 비타민 및/또는 기타 당해 기술분야에 공지된 첨가제가 있다. 또한, 첨가제는 예를 들면, 염화나트륨과 같은 약리학적으로 허용되는 염을 포함한다.Adjuvants and excipients herein are any pharmacologically acceptable and therapeutic agents that do not include the active substance but may be formulated in a pharmacologically suitable solvent with the active substance to improve the quality of the active substance formulation. It means a scientifically useful substance. Preferably, such substances do not exhibit any pharmacological effect or measurable pharmacological effect or at least undesirable pharmacological effect within the scope of the desired treatment. Auxiliaries and additives include, for example, soy lecithin, oleic acid, sorbitan esters (eg sorbitan trioleate), surfactants such as polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or final Preservatives, flavorings, vitamins and / or other additives known in the art which extend the shelf life of pharmaceutical formulations. In addition, the additives include pharmacologically acceptable salts such as, for example, sodium chloride.
적합한 계면활성제 또는 현탁-안정화제로는 친지질성 탄화수소 그룹 및 하나이상의 관능성 친수성 그룹, 특히 C5-20지방 알코올, C5-20지방산, C5-20지방산 에스테르, 레시틴, 글리세라이드, 프로필렌글리콜 에스테르, 폴리옥시에틸렌, 폴리소르베이트, 솔비탄 에스테르 및/또는 탄수화물을 갖는 모든 약리학적으로 허용되는 물질이 있다. C5-10지방산, 프로필렌글리콜 디에스테르 및/또는 트리글리세라이드 및/또는 C5-20지방산의 소르비탄이 바람직하며, 올레산 및 소르비탄 모노, 디- 또는 트리올레에이트가 특히 바람직하다. 또한, 독성학적으로 허용가능하며, 약제학적으로 허용가능한 중합체 및/또는 블록 중합체를 현탁 안정화제로서 사용할 수 있다.Suitable surfactants or suspension-stabilizers include lipophilic hydrocarbon groups and one or more functional hydrophilic groups, in particular C 5-20 fatty alcohols, C 5-20 fatty acids, C 5-20 fatty acid esters, lecithins, glycerides, propylene glycol There are all pharmacologically acceptable materials having esters, polyoxyethylene, polysorbates, sorbitan esters and / or carbohydrates. Sorbitans of C 5-10 fatty acids, propylene glycol diesters and / or triglycerides and / or C 5-20 fatty acids are preferred, with oleic acid and sorbitan mono, di- or trioleate being particularly preferred. In addition, toxicologically acceptable and pharmaceutically acceptable polymers and / or block polymers may be used as suspension stabilizers.
계면활성제의 양은 현탁된 활성 물질의 중량비를 기준으로 하여 1:1 이하일 수 있으며, 0.0001:1 내지 0.5:1의 양이 바람직하며, 0.0001:1 내지 0.25:1의 양이 특히 바람직하다.The amount of surfactant may be 1: 1 or less, based on the weight ratio of the suspended active substance, with an amount of 0.0001: 1 to 0.5: 1 being preferred, with an amount of 0.0001: 1 to 0.25: 1 being particularly preferred.
바람직한 부형제로는 pH를 조정하는데 이미 사용하지 않았다면, 예를 들면, 아스코르빈산과 같은 항산화제, 비타민 A, 비타민 E, 토코페롤 및 유사한 비타민 또는 인체내에서 발생되는 프로비타민이 있다.Preferred excipients are, for example, antioxidants such as ascorbic acid, vitamin A, vitamin E, tocopherol and similar vitamins or provitamins occurring in the human body, if not already used to adjust the pH.
본 제형을 병원성 박테리아에 의한 오염으로부터 보호하기 위해 보존제를 첨가할 수 있다. 적합한 보존제는 당해 기술분야에 공지되어 있으며, 특히 선행 기술에 공지된 농도의 벤즈알코늄 클로라이드 또는 벤조산 또는 벤조에이트(예: 나트륨 벤조에이트)가 있다.Preservatives may be added to protect the formulation from contamination by pathogenic bacteria. Suitable preservatives are known in the art and in particular benzalkonium chloride or benzoic acid or benzoate (eg sodium benzoate) at concentrations known in the prior art.
바람직한 제형은 용매인 물 및/또는 물/에탄올 및 티오트로퓸 염 이외에, 단지 벤즈알코늄 클로라이드, pH 조정용 산 및 나트륨 아데테이트만을 함유한다. 또 다른 바람직한 양태에서, 나트륨 에데테이트가 생략된다. 또한, 이러한 양태는 염화나트륨을 함유할 수도 있다.Preferred formulations contain only benzalkonium chloride, pH-adjusting acid and sodium adetate, in addition to the solvents water and / or water / ethanol and tiotropium salts. In another preferred embodiment, sodium edetate is omitted. This embodiment may also contain sodium chloride.
이미 여러차례 상술한 바와 같이, 티오트로륨 브로마이드는 유럽 공개특허공보 제418 716A1호에 기재되어 있으며, 결정성 티오트로퓸 브로마이드 1수화물을 하기에 보다 상세히 설명한 방법을 사용하여 수득할 수 있다.As already described several times, tiotropium bromide is described in EP-A-418 716A1, and crystalline tiotropium bromide monohydrate can be obtained using the method described in more detail below.
본 발명에 따르는 결정성 1수화물을 제조하기 위해서는, 유럽 공개특허공보 제418 716A1호에 기재된 방법에 의해 수득된 티오트로퓸 브로마이드를 예를 들면, 우선 물에 침지시켜, 가열하고, 활성탄으로 정제하고, 활성탄을 제거한 후, 티오트로퓸 브로마이드 1수화물을 서서히 냉각시키면서, 서서히 결정화시킨다.To prepare the crystalline monohydrate according to the present invention, tiotropium bromide obtained by the method described in EP-418 716A1, for example, is first immersed in water, heated and purified with activated carbon After the activated carbon is removed, the tiotropium bromide monohydrate is slowly crystallized while gradually cooling.
절차는 바람직하게는 다음과 같다:The procedure is preferably as follows:
적합한 치수의 반응 용기내에서, 용매를 예를 들면, 유럽 공개특허공보 제418 716A1호에 기재된 방법에 의해 수득된 티오트로퓸 브로마이드와 혼합한다. 티오트로퓸 브로마이드 1몰당 물을 0.4 내지 1.5kg, 바람직하게는 0.6 내지 1kg, 가장 바람직하게는 약 0.8kg을 용매로서 사용한다. 수득된 혼합물을 교반하면서 바람직하게는 50℃ 이상, 가장 바람직하게는 60℃ 이상으로 가열한다. 선택할 수 있는 최대 온도는 사용된 용매의 비점에 따라 좌우된다. 바람직하게는, 혼합물을 80 내지 90℃ 범위로 가열한다.In a reaction vessel of suitable dimensions, the solvent is mixed with tiotropium bromide obtained by the method described, for example, in EP 418 716A1. 0.4 to 1.5 kg, preferably 0.6 to 1 kg and most preferably about 0.8 kg of water per mole of tiotropium bromide is used as the solvent. The resulting mixture is heated to preferably 50 ° C. or higher, most preferably 60 ° C. or higher with stirring. The maximum temperature that can be selected depends on the boiling point of the solvent used. Preferably, the mixture is heated to the range of 80 to 90 ° C.
본 용액에 무수 또는 물로 습윤시킨 활성탄을 첨가한다. 바람직하게는, 사용된 티오트로퓸 브로마이드 1몰당 10 내지 50g, 보다 바람직하게는 15 내지 35g,가장 바람직하게는 약 25g의 활성탄을 첨가한다. 경우에 따라, 활성탄을 티오트로퓸 브로마이드를 함유하는 용액에 첨가하기 전에 물에 현탁시킨다. 활성탄을 현탁시키기 위해서, 사용된 티오트로퓸 브로마이드 1몰당 70 내지 200g, 바람직하게는 100 내지 160g, 보다 바람직하게는 약 135g의 물을 첨가한다. 활성탄을 티오트로퓸 브로마이드를 함유하는 용액에 첨가하기 전, 미리 물에 현탁시키는 경우, 동일한 양의 물로 다시 한번 세척하는 것이 바람직하다. 활성탄을 첨가한 후, 5 내지 60분 동안, 바람직하게는 10 내지 30분 동안, 보다 바람직하게는 약 15분 동안 일정한 온도에서 교반을 계속하고, 수득된 혼합물을 여과하여 활성탄을 제거한다. 그 다음, 여과기를 물로 세척한다. 이때, 사용된 티오트로퓸 브로마이드 1몰당 140 내지 400g, 바람직하게는 200 내지 320g, 가장 바람직하게는 약 270g의 물을 사용한다. 그 다음, 여과물을 서서히 냉각시키고, 바람직하게는 20 내지 25℃의 온도로 냉각시킨다. 이러한 냉각은 바람직하게는 매 10 내지 30분 동안 1 내지 10℃, 바람직하게는 매 10 내지 30분 동안 2 내지 8℃, 보다 바람직하게는 매 10 내지 20분 동안 3 내지 5℃, 가장 바람직하게는 약 매 20분 동안 3 내지 5℃의 속도로 수행된다. 냉각이 완료된 후, 교반을 20분 내지 3시간, 바람직하게는 40분 내지 2시간, 보다 바람직하게는 약 1시간 동안 결정화가 완료될 때까지 지속한다. 그 다음, 수득된 결정을 여과 또는 흡인 여과에 의해 분리하여 용매를 제거한다. 수득된 결정을 추가로 세척할 필요가 있는 경우, 세척 용매로서 물 또는 아세톤을 사용할 것이 권장된다. 수득된 티오트로퓸 브로마이드 1수화물 결정을 세척하기 위해, 사용된 티오트로퓸 브로마이드 1몰당 0.1 내지 1.0L, 바람직하게는 0.2 내지0.5L, 보다 바람직하게는 약 0.3L의 용매를 첨가한다. 필요한 경우에 세척 단계를 반복할 수 있다. 수득된 생성물을 진공하에 건조시키거나 또는 물 함량이 2.5 내지 4.0%가 수득될 때까지 가열된 공기를 순환시킴으로써 건조시킨다.To this solution is added activated carbon wetted with anhydrous or water. Preferably, 10 to 50 g, more preferably 15 to 35 g, most preferably about 25 g of activated carbon is added per mole of tiotropium bromide used. If desired, activated carbon is suspended in water prior to addition to the solution containing tiotropium bromide. To suspend activated charcoal, 70 to 200 g, preferably 100 to 160 g, more preferably about 135 g of water is added per mole of tiotropium bromide used. If the activated carbon is previously suspended in water before addition to the solution containing tiotropium bromide, it is preferred to wash once again with the same amount of water. After adding activated carbon, stirring is continued at a constant temperature for 5 to 60 minutes, preferably for 10 to 30 minutes, more preferably for about 15 minutes, and the obtained mixture is filtered to remove activated carbon. Then, the filter is washed with water. At this time, 140 to 400 g, preferably 200 to 320 g, most preferably about 270 g of water is used per mole of tiotropium bromide used. The filtrate is then cooled slowly and preferably to a temperature of 20-25 ° C. Such cooling is preferably 1 to 10 ° C. for every 10 to 30 minutes, preferably 2 to 8 ° C. for every 10 to 30 minutes, more preferably 3 to 5 ° C. for every 10 to 20 minutes, most preferably At a rate of 3-5 ° C. for about every 20 minutes. After cooling is complete, stirring is continued for 20 minutes to 3 hours, preferably 40 minutes to 2 hours, more preferably about 1 hour until crystallization is complete. The crystals obtained are then separated by filtration or suction filtration to remove the solvent. If the obtained crystals need to be washed further, it is recommended to use water or acetone as the washing solvent. To wash the obtained tiotropium bromide monohydrate crystals, 0.1 to 1.0 L, preferably 0.2 to 0.5 L, more preferably about 0.3 L of solvent is added per mole of tiotropium bromide used. If necessary, the washing step can be repeated. The product obtained is dried under vacuum or by circulating heated air until a water content of 2.5 to 4.0% is obtained.
따라서, 하나의 양태에 따르면, 본 발명은 상술한 절차에 의해 수득될 수 있는 결정성 티오트로퓸 브로마이드 1수화물을 사용하는 상술한 유형의 용액의 제형에 관한 것이다.Thus, according to one embodiment, the present invention relates to the formulation of a solution of the above-mentioned type using crystalline tiotropium bromide monohydrate obtainable by the above-described procedure.
본 발명에 따르는 무추진제 에어로졸을 제조하기 위해 본 발명에 따르는 티오트로퓸 염을 함유하는 약제학적 제형을 바람직하게는 상술한 유형의 흡입기내에서 사용한다. 여기서, 본 발명자들은 선행 기술에 발표된 특허 문헌을 본원에 참조문헌으로 이용한다는 사실을 명시한다.Pharmaceutical formulations containing the tiotropium salt according to the invention for the preparation of propellant-free aerosols according to the invention are preferably used in an inhaler of the type described above. Here, the inventors specify the fact that the patent documents published in the prior art are used herein by reference.
서론 부분에서 언급한 바와 같이, 바람직한 흡입기의 추가 발전된 양태가 국제공개공보 제WO 97/12687호 및 이의 도 6에 기재되어 있다. 이러한 분무기[레스피맷(RespimatTM)]를 유리하게는 활성 물질로서 티오트로퓸 염을 함유하는 본 발명에 따르는 흡입성 에어로졸을 제조하는데 사용할 수 있다. 길이가 9 내지 15cm 미만이며, 폭이 2 내지 4cm인 원통형 모양의 알맞은 크기로 인하여, 환자는 어디든 본 장치를 소지할 수 있다. 본 분무기에 의해서 고압에서 작은 노즐을 통해 약제학적 제형의 한정된 용적이 분무되어 흡입성 에어로졸이 제조된다.As mentioned in the introduction, further developments of preferred inhalers are described in WO 97/12687 and its FIG. 6. Such nebulizers (Respimat ™ ) can advantageously be used to prepare the inhalable aerosols according to the invention which contain the tiotropium salt as the active substance. Due to the suitable size of the cylindrical shape of less than 9-15 cm in length and 2-4 cm in width, the patient can carry the device anywhere. A limited volume of pharmaceutical formulation is sprayed by the nebulizer through a small nozzle at high pressure to produce an inhalable aerosol.
바람직한 분무기는 본질적으로 상부 하우징부(housing part), 펌프 하우징, 노즐, 록킹 클램프, 스프링 하우징, 스프링 및 저장 용기로 이루어지는데, 다음과같은 특징을 갖는다:Preferred nebulizers consist essentially of an upper housing part, a pump housing, a nozzle, a locking clamp, a spring housing, a spring and a storage container, having the following characteristics:
- 상부 하우징부에 고정되어 있으며, 한쪽 말단에 노즐 또는 노즐 배열을 갖는 노즐 바디를 가지고 있는 펌프 하우징,A pump housing fixed to the upper housing part and having a nozzle body at one end with a nozzle or nozzle arrangement,
- 밸브 바디를 갖는 중공(hollow) 피스톤,Hollow piston with valve body,
- 중공 바디가 고정되어 있으며, 상부 하우징부내에 위치하는 동력 전달 플랜지,A power transmission flange fixed in the hollow body and located in the upper housing part;
- 상부 하우징부에 위치한 록킹 클램핑 장치,-Locking clamping device located in the upper housing part,
- 회전 베어링에 의해 상부 하우징부에 회전식으로 장착되어 있는, 스프링이 내장된 스프링 하우징,A spring housing with built-in spring, which is rotatably mounted on the upper housing part by means of a rotating bearing,
- 축 방향으로 스프링 하우징 위에 설치되어 있는 하부 하우징부.Lower housing part mounted on the spring housing in the axial direction.
밸브 바디를 포함하는 중공 피스톤은 국제공개공보 제WO 97/12687호에 기재된 장치에 상응한다. 이는 부분적으로 펌프 하우징의 실린더내로 투과하여 실린더내에서 축 방향으로 이동가능하도록 배치되어 있다. 도 1 내지 도 4, 특히 도 3 및 상세한 설명의 관련된 부분을 참조한다. 스프링이 이완되는 순간, 밸브 바디를 갖는 중공 피스톤에 의해 이의 고압 말단부에서 활성 물질 용액의 측정된 양인 유체에 5 내지 60MPa(약 500 내지 600bar), 바람직하게는 10 내지 60MPa(약 100 내지 600bar)의 압력이 가해진다. 10 내지 50㎕의 용적이 바람직하며, 10 내지 20㎕의 용적이 보다 바람직하며, 1회 작동당 15㎕의 용적이 특히 바람직하다.The hollow piston comprising the valve body corresponds to the device described in WO 97/12687. It is partly arranged to penetrate into the cylinder of the pump housing and move axially within the cylinder. Reference is made to FIGS. 1 to 4, in particular FIG. 3 and related parts of the description. At the moment the spring relaxes, the fluid, measured by the hollow piston having the valve body at its high pressure end, is 5 to 60 MPa (about 500 to 600 bar), preferably 10 to 60 MPa (about 100 to 600 bar) Pressure is applied. A volume of 10 to 50 μl is preferred, a volume of 10 to 20 μl is more preferred, and a volume of 15 μl per operation is particularly preferred.
밸브 바디는 바람직하게는 노즐 바디에 마주하는 중공 피스톤의 말단부에 장착된다.The valve body is preferably mounted at the distal end of the hollow piston facing the nozzle body.
노즐 바디내의 노즐은 바람직하게는 미세구조인데, 즉 마이크로 엔지니어링에 의해 제작된다. 미세구조화된 노즐 바디는 본원에 그 내용이 참조문헌으로 인용된, 국제공개공보 제WO 94/07607호 및 제WO 99/16530호의 실시예, 특히 국제공개공보 제WO 94/07607호의 도 1 및 관련 설명에 기재되어 있다. 이러한 노즐 바디는 예를 들어, 유리 및/또는 실리콘으로 서로 밀봉된 2장의 시트로 이루어져 있는데, 2장의 시트중 하나 이상은 노즐 주입구 말단을 노즐 배출구 말단에 연결시켜주는 하나 이상의 미세구조화된 채널을 갖는다. 노즐 배출구 말단에는 깊이가 2 내지 10μ이며, 폭이 5 내지 15μ인, 바람직하게는 깊이가 4.5 내지 6.5μ이며, 길이가 7 내지 9μ인 하나 이상의 원형 또는 비원형 개구가 있다.The nozzle in the nozzle body is preferably microstructured, ie produced by micro engineering. Microstructured nozzle bodies are described in the examples of WO 94/07607 and WO 99/16530, in particular WO 94/07607, the disclosures of which are incorporated herein by reference. Described in the description. Such a nozzle body consists of, for example, two sheets sealed with glass and / or silicone, one or more of which have one or more microstructured channels connecting the nozzle inlet end to the nozzle outlet end. . At the nozzle outlet end there are one or more circular or non-circular openings of 2 to 10 microns in depth, 5 to 15 microns in width, preferably 4.5 to 6.5 microns in depth and 7 to 9 microns in length.
다수의 노즐 개구(바람직하게는 2개)가 있는 경우라면, 노즐 바디내의 노즐의 분무 방향은 서로 평행하게 작동할 수 있거나, 또는 노즐 개구의 방향이 서로 기울어져 있을 수 있다. 배출구 말단에 2개 이상의 노즐 개구를 갖는 노즐 바디의 경우, 분무 방향은 서로 20°내지 160°, 바람직하게는 60 내지 150°, 가장 바람직하게는 80 내지 100°의 각을 가질 수 있다. 노즐 개구는 바람직하게는 10 내지 200μ의 간격, 보다 바람직하게는 10 내지 100μ의 간격, 보다 더욱 바람직하게는 30 내지 70μ의 간격으로 위치한다. 간격은 50μ가 가장 바람직하다. 따라서, 분무 방향은 노즐 개구의 영역내에서 만난다.If there are multiple nozzle openings (preferably two), the spraying directions of the nozzles in the nozzle body may operate in parallel to each other, or the directions of the nozzle openings may be inclined to each other. In the case of a nozzle body having two or more nozzle openings at the outlet end, the spraying directions may have an angle of 20 ° to 160 °, preferably 60 to 150 °, most preferably 80 to 100 ° from each other. The nozzle openings are preferably located at intervals of 10 to 200 μ, more preferably at intervals of 10 to 100 μ, even more preferably at intervals of 30 to 70 μ. The interval is most preferably 50 mu. Thus, the spray direction meets in the region of the nozzle opening.
상술한 바와 같이, 액체 약제학적 제제는 600bar 이하, 바람직하게는 200 내지 300bar의 주입 압력에서 노즐 바디에 충돌하고, 노즐 개구를 통해 흡입성 에어로졸로 분무된다. 에어로졸의 바람직한 입자 크기는 20μ이하, 바람직하게는 3 내지 10μ이다.As mentioned above, the liquid pharmaceutical formulation impinges on the nozzle body at an injection pressure of 600 bar or less, preferably 200 to 300 bar, and is sprayed with the inhalable aerosol through the nozzle opening. The preferred particle size of the aerosol is 20 μm or less, preferably 3 to 10 μm.
록킹 클램핑 장치는 스프링, 바람직하게는 원통형의 나선형 압축 스프링을 기계적 에너지의 저장소로서 함유한다. 이러한 스프링은 스프링 성분으로서 동력 전달 플랜지에 작용하는데, 이러한 운동은 록킹 성분의 위치에 의해 결정된다. 동력 전달 플랜지의 이동 거리는 상부 정지부와 하부 정지부에 의해 정확하게 한정된다. 스프링은 바람직하게는 상부 하우징부가 하부 하우징부내의 스프링 하우징에 대하여 압축되는 경우 발생되는 외부 토크에 의해, 스텝핑-업 기어(stepping-up gear)(예: 나선형 슬라이딩 기어)에 의해 압축된다. 이 경우, 상부 하우징부 및 동력 전달 플랜지는 단일 속도 또는 다중 속도 스플라인(spline) 기어를 함유한다.The locking clamping device contains a spring, preferably a cylindrical helical compression spring, as a reservoir of mechanical energy. This spring acts on the power transmission flange as a spring component, the movement of which is determined by the position of the locking component. The travel distance of the power transmission flange is precisely defined by the upper stop and the lower stop. The spring is preferably compressed by a stepping-up gear (eg helical sliding gear) by the external torque generated when the upper housing portion is compressed against the spring housing in the lower housing portion. In this case, the upper housing portion and the power transmission flange contain a single speed or multi speed spline gear.
인게이징(engaging) 록킹 표면을 갖는 록킹 성분은 동력 전달 플랜지 둘레에 환상 배열로 배치되어 있다. 이는 예를 들면, 고유 방사상으로 탄성적으로 변형가능한 플라스틱 또는 금속의 고리로 이루어져 있다. 스프링을 잠군 후에, 록킹 성분의 록킹 표면이 동력 전달 플랜지의 경로에 삽입되어, 스프링의 풀림을 방지한다. 록킹 성분은 단추에 의해 작동된다. 작동 단추는 록킹 성분에 연결되어 있거나 커플링되어 있다. 록킹 클램핑 장치를 작동시키기 위해, 작동 단추를 환상 면에 대하여 평행하게, 바람직하게는 분무기내로 이동시키고, 이에 의해 변형성 고리가 환상 면내에서 변형된다. 록킹 클램핑 장치의 구조의 상세한 설명은 국제공개공보 제WO 97/20590호에 기재되어 있다.The locking components with an engaging locking surface are arranged in an annular arrangement around the power transmission flange. It consists, for example, of rings of plastic or metal which are inherently radially elastically deformable. After locking the spring, the locking surface of the locking component is inserted in the path of the power transmission flange to prevent the spring from loosening. The locking element is operated by the button. The actuation button is connected or coupled to the locking component. To actuate the locking clamping device, the actuation button is moved parallel to the annular face, preferably into the sprayer, whereby the deformable ring is deformed in the annular face. A detailed description of the structure of the locking clamping device is given in WO 97/20590.
하부 하우징부는 스프링 하우징에 걸쳐 축방향으로 압축되며, 베어링, 스핀들용 드라이브 및 유체용 저장 용기를 포함한다.The lower housing portion is axially compressed over the spring housing and includes a bearing, a drive for the spindle and a reservoir for the fluid.
압축기가 작동되는 경우, 하우징의 상부는 하부에 대하여 회전하는데, 하부는 이의 스프링 하우징를 포함한다. 한편, 스프링이 압축되고, 나선형 슬라이딩 기어에 의해 편향되면, 클램핑 장치가 자동적으로 맞물린다. 회전각은 바람직하게는 360°의 전체 부분이며, 예를 들면, 180°이다. 스프링이 압축됨과 동시에, 상부 하우징부내의 동력 전달 성분은 소정의 양 만큼 이동하고, 중공 피스톤이 펌프 하우징내의 실린더 내부에서 뒤로 당겨져, 결과적으로 저장 용기로부터 유체의 일부가 노즐 전방의 고압 챔버내로 흡입된다.When the compressor is operated, the upper part of the housing rotates with respect to the lower part, the lower part comprising its spring housing. On the other hand, when the spring is compressed and deflected by the helical sliding gear, the clamping device is automatically engaged. The rotation angle is preferably an entire portion of 360 °, for example 180 °. As the spring is compressed, the power transmission component in the upper housing portion moves by a predetermined amount and the hollow piston is pulled back inside the cylinder in the pump housing, resulting in a portion of the fluid from the reservoir being drawn into the high pressure chamber in front of the nozzle. .
경우에 따라, 분무시키려는 유체를 함유하는 다수의 교체가능한 저장 용기를 연속해서 분무기내로 삽입하여 사용할 수 있다. 이러한 저장 용기는 본 발명에 따르는 수성 에어로졸 제제를 함유한다.If desired, multiple replaceable reservoirs containing the fluid to be sprayed may be inserted into the sprayer in succession. Such storage containers contain an aqueous aerosol formulation according to the invention.
분무 방법은 작동 단추를 가볍게 누름으로써 개시된다. 그 다음, 클램핑 장치에 의해 동력 전달 성분용 경로가 개방된다. 이러한 편향된 스프링에 의해 피스톤이 폄프 하우징내의 실린더내로 압축된다. 유체는 분무기 형태의 분무기의 노즐로부터 분사된다.The spraying method is initiated by lightly pressing the actuation button. The path for the power transmission component is then opened by the clamping device. This biased spring compresses the piston into the cylinder in the pump housing. The fluid is injected from the nozzle of the nebulizer in the form of a nebulizer.
구조에 관한 추가의 상세한 설명이 본원에 참조문헌으로 인용되는, PCT 출원 국제공개공보 제WO 97/12683호 및 제WO 97/20590호에 기재되어 있다.Further details regarding the structure are described in PCT applications WO 97/12683 and WO 97/20590, which are incorporated herein by reference.
분무기(분사기)의 성분은 이들의 기능에 적합한 물질로 제조된다. 분무기의 하우징 및 기타 성분들은 (작동이 된다면) 바람직하게는 예를 들면, 사출 성형에 의해 플라스틱으로 제조된다. 의료 분야에 있어서는, 생리학적으로 허용가능한 물질이 사용된다.The components of the nebulizer (injector) are made of materials suitable for their function. The housing and other components of the nebulizer (if operated) are preferably made of plastic, for example by injection molding. In the medical field, physiologically acceptable substances are used.
국제공개공보 제WO 97/12687호의 도 6a/b와 동일한, 도 1a/b는 본 발명에 따르는 수성 에어로졸 제제가 유리하게 흡입될 수 있는 레스피맷TM분무기를 나타낸 것이다.1A / B, identical to FIG. 6A / B of WO 97/12687, shows a Respite ™ nebulizer with which an aqueous aerosol formulation according to the invention can be advantageously inhaled.
도 1a는 스프링이 압축되어 있는 분무기의 단면도를 나타낸 것이며, 도 1b는 스프링이 이완되어 있는 분무기의 단면도를 나타낸 것이다.FIG. 1A shows a cross sectional view of the nebulizer with the spring compressed, and FIG. 1B shows a cross sectional view of the nebulizer with the spring relaxed.
상부 하우징부(51)는 펌프 하우징(52)을 함유하는데, 이의 한쪽 말단에는 분무기 노즐용 홀더(53)가 장착되어 있다. 홀더내에는 노즐 바디(54)와 여과기(55)가 위치한다. 록킹 클램핑 장치의 동력 전달 플랜지(56)내에 고정된 중공 피스톤(57)은 펌프 하우징의 실린더내로 일부 돌출되어 있다. 이의 말단에서 중공 피스톤은 밸브 바디(58)를 가지고 있다. 중공 피스톤은 개스킷(59)에 의해 밀봉되어 있다. 상부 하우징부 내부에는 스프링이 이완되는 경우에 동력 전달 플랜지가 정지되는 곳에 정지부(61)가 있다. 동력 전달 플랜지에는 스프링이 신장되는 경우에 동력 전달 플랜지가 정지되는 곳에 정지부(61)가 위치한다. 스프링이 신장되는 경우, 록킹 성분(62)이 상부 하우징부내의 정지부(61)와 지지체(63) 사이에 유입된다. 작동 단추(64)는 록킹 성분과 연결되어 있다. 상부 하우징부는 마우스피스(65)에서 종료되며, 이동성 보호 마개(66)에 의해 밀폐된다.The upper housing portion 51 contains a pump housing 52, on one end of which is mounted a holder 53 for the spray nozzle. The nozzle body 54 and the filter 55 are located in the holder. The hollow piston 57 fixed in the power transmission flange 56 of the locking clamping device partially protrudes into the cylinder of the pump housing. At its end, the hollow piston has a valve body 58. The hollow piston is sealed by the gasket 59. Inside the upper housing part there is a stop 61 where the power transmission flange is stopped when the spring is relaxed. In the power transmission flange, a stop 61 is located where the power transmission flange is stopped when the spring is extended. When the spring is extended, the locking component 62 flows between the stop 61 and the support 63 in the upper housing portion. The actuation button 64 is connected with the locking component. The upper housing portion terminates at the mouthpiece 65 and is closed by a movable protective cap 66.
압축 스프링(68)을 포함하는 스프링 하우징(67)은 스냅-피트 러그(snap-fit lug)(69)와 회전 베어링에 의해 상부 하우징부에 회전식으로 설치되어 있다. 하부 하우징부(70)는 스프링 하우징 위에 압축된다. 스프링 하우징 내부에는 분무시키려는 유체(72)용 교체가능한 저장 용기(71)가 위치한다. 이러한 저장 용기는 마개(73)에 의해 밀폐되는데, 이를 통해 중공 피스톤이 저장 용기로 돌출되며, 피스톤의 말단이 유체에 잠긴다(활성 물질 용액의 공급).The spring housing 67 including the compression spring 68 is rotatably mounted to the upper housing portion by a snap-fit lug 69 and a rotating bearing. The lower housing portion 70 is compressed above the spring housing. Inside the spring housing is a replaceable storage container 71 for the fluid 72 to be sprayed. This storage container is sealed by a stopper 73 through which a hollow piston protrudes into the storage container, the end of the piston being immersed in the fluid (supply of active substance solution).
기계적 카운터용 스핀들(74)이 스프링 하우징의 외부에 장착된다. 구동 톱니바퀴(75)가 상부 하우징부에 마주하는 스핀들의 말단에 위치한다. 스핀들 위에는 활자(slider)(76)가 위치한다.A mechanical counter spindle 74 is mounted on the outside of the spring housing. A drive gear 75 is located at the distal end of the spindle facing the upper housing portion. On the spindle a slider 76 is located.
상술한 분무기는 흡입하기에 적합한 에어로졸을 형성시키기 위한 본 발명에 따른 에어로졸 제제를 분무하는데 적합하다.The nebulizer described above is suitable for spraying an aerosol formulation according to the invention for forming an aerosol suitable for inhalation.
본 발명에 따른 제형을 상술한 방법을 사용하여 분무하는 경우, 흡입기의 전체 작동(퍼프)의 97% 이상, 바람직하게는 98% 이상으로 배출된 양은 이러한 양의 25% 이하, 바람직하게는 20%의 오차 범위를 갖는 한정된 양에 상응해야 한다. 바람직하게는, 5 내지 30mg, 보다 바람직하게는 5 내지 20mg의 제형이 퍼프당 정의된 양으로 운반된다.When the formulations according to the invention are sprayed using the method described above, the amount emitted in at least 97%, preferably at least 98% of the total operation (puff) of the inhaler is not more than 25%, preferably 20% Must correspond to a finite amount with a margin of error. Preferably, 5 to 30 mg, more preferably 5 to 20 mg of the formulation is delivered in a defined amount per puff.
목적하는 양에 비하여 25% 이하의 오차 한계를 벗어나는 운반된 양의 비율은 1.5% 미만, 바람직하게는 1.2% 미만이어야 한다.The proportion of conveyed amount outside the margin of error of 25% or less relative to the desired amount should be less than 1.5%, preferably less than 1.2%.
그러나, 본 발명에 따른 제형을 상술한 것 이외의 분무기(예: 제트-스트림 분무기)를 사용하여 분무시킬 수도 있다.However, the formulations according to the invention may also be sprayed using a nebulizer other than those described above (eg a jet-stream nebulizer).
I. 티오트로퓸 브로마이드 1수화물의 합성 실시예I. Synthesis Examples of Tiotropium Bromide Monohydrate
티오트로퓸 브로마이드 15.0kg을 적합한 반응 용기내의 물 25.7kg에 첨가한다. 혼합물을 80 내지 90℃로 가열하고, 투명한 용액이 형성될 때까지 일정한 온도에서 교반한다. 물로 습윤시킨 활성탄(0.8kg)을 물 4.4kg에 현탁시키고, 본 혼합물을 티오트로퓸 브로마이드를 함유하는 용액에 첨가하고, 물 4.3kg으로 세척한다. 이렇게 수득된 혼합물을 80 내지 90℃의 온도에서 15분 이상 동안 교반한 다음, 가열된 여과기를 통해 외부 온도가 70℃인 예비가열된 장치로 여과한다. 여과기를 물 8.6kg으로 세척한다. 장치의 내용물을 매 20분당 3 내지 5℃의 속도로 20 내지 25℃의 온도로 냉각시킨다. 냉수를 사용하여 장치를 10 내지 15℃로 추가로 냉각시키고, 추가로 1시간 이상 동안 교반하여 결정화를 완료시킨다. 결정을 흡인 여과 건조기를 사용하여 분리하고, 분리한 결정 슬러리를 물 9ℓ(10 내지 15℃)와 냉 아세톤(10 내지 15℃)으로 세척한다. 수득된 결정을 25℃에서 2시간 동안 질소 기류하에 건조시킨다. 수율: 티오트로퓸 브로마이드 1수화물 13.4kg(계산치의 86%).15.0 kg of tiotropium bromide is added to 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C. and stirred at a constant temperature until a clear solution is formed. Activated carbon wetted with water (0.8 kg) is suspended in 4.4 kg of water, and the mixture is added to a solution containing tiotropium bromide and washed with 4.3 kg of water. The mixture thus obtained is stirred at a temperature of 80-90 ° C. for at least 15 minutes and then filtered through a heated filter with a preheated device having an external temperature of 70 ° C. The filter is washed with 8.6 kg of water. The contents of the device are cooled to a temperature of 20-25 ° C. at a rate of 3-5 ° C. every 20 minutes. The apparatus is further cooled to 10-15 [deg.] C. with cold water and stirred for an additional 1 hour or more to complete the crystallization. The crystals are separated using a suction filtration dryer, and the separated crystal slurry is washed with 9 L of water (10 to 15 DEG C) and cold acetone (10 to 15 DEG C). The obtained crystals are dried at 25 ° C. for 2 hours under a stream of nitrogen. Yield: 13.4 kg tiotropium bromide monohydrate (86% of calculated value).
II. 제형의 실시예II. Examples of Formulations
약제학적 제제 100g의 함유 성분:Ingredients of 100 g of pharmaceutical preparation:
나머지는 선행 기술에 공지된 양인 물 또는 물/에탄올과, 상술한 활성 물질중 하나이다.The remainder is water or water / ethanol in an amount known in the prior art and one of the active substances described above.
실시예 9 내지 12: 부데소나이드Examples 9-12: budesonide
실시예 1 내지 8 각각은 추가로 다음을 함유할 수 있다:Each of Examples 1-8 may further contain:
실시예 9a: 부데소나이드 0.3g, HCl로 조정한 pH 3.0, 용매 물, 에탄올 없음,Example 9a: 0.3 g of budesonide, pH 3.0 adjusted with HCl, without solvent water, ethanol,
실시예 9b: 부데소나이드 0.3g, HCl로 조정한 pH 3.5.Example 9b: 0.3 g of budesonide, pH 3.5 adjusted with HCl.
실시예 9c: 부데소나이드 0.3g, HCl로 조정한 pH 4.0.Example 9c: 0.3 g of budesonide, pH 4.0 adjusted with HCl.
실시예 10: 부데소나이드가 0.6g이며, 실시예 9a 내지 9c와 유사함Example 10 Budesonide is 0.6 g, similar to Examples 9a-9c
실시예 11: 부데소나이드가 1.3g이며, 실시예 9a 내지 9c와 유사함Example 11: Budesonide is 1.3 g, similar to Examples 9a-9c
실시예 12: 부데소나이드가 2.0g이며, 실시예 9a 내지 9c와 유사함Example 12 Budesonide is 2.0 g, similar to Examples 9a-9c
실시예 9 내지 12에서 스테로이드는 현탁액내에 제형으로 존재한다. 소르비탄 트리올레이트가 계면활성제로서 사용될 수 있다.In Examples 9 to 12 the steroids are in dosage form in suspension. Sorbitan trioleate can be used as the surfactant.
실시예 13 내지 15Examples 13-15
실시예 9 내지 12와 유사함. 벤즈아코늄 클로라이드가 나트륨 벤조에이트로 대체된다.Similar to Examples 9-12. Benzaconium chloride is replaced by sodium benzoate.
실시예 16 내지 19Examples 16-19
실시예 9 내지 12와 유사함. 염산 대신에, pH를 조정하는데 시트르산을 단독으로 사용한다.Similar to Examples 9-12. Instead of hydrochloric acid, citric acid is used alone to adjust the pH.
실시예 20 내지 30Examples 20-30
성분 및 양은 실시예 9 내지 19와 유사하다. 물 대신에, 물(10용적%)과 에탄올(90용적%)의 혼합물을 사용한다. 부데소나이드가 용액내에 존재한다.Ingredients and amounts are similar to Examples 9-19. Instead of water, a mixture of water (10% by volume) and ethanol (90% by volume) is used. Budesonide is present in solution.
기타 실시예Other Example
상술한 실시예 9 내지 30과 유사하게, 소량의 플루니솔라이드, 베클로메타손 디프로피오네이트 또는 플루티카손을 부데소나이드 대신 사용한다. 플루티카손의 경우, 현탁액 제제의 경우, 소르비탄 트리올레이트 대신 레시틴을 첨가한다. 사용된 용매가 물인 경우, 스테로이드가 현탁액으로서 형성된다. 물과 에탄올의 혼합물인 경우, 스테로이드가 용액내에 존재할 수 있다.Similar to Examples 9-30 described above, small amounts of flunisolide, beclomethasone dipropionate or fluticasone are used in place of budesonide. For fluticasone, for suspension formulations, lecithin is added instead of sorbitan trioleate. If the solvent used is water, the steroid is formed as a suspension. In the case of a mixture of water and ethanol, the steroid may be present in solution.
실시예 31Example 31
에피나스틴: 0.2gEpineast: 0.2 g
EDTA: 25mgEDTA: 25 mg
티오트로퓸 브로마이드 1수화물: 29mgTiotropium bromide monohydrate: 29 mg
0.1N의 염산으로 pH를 3.0으로 조정함.PH was adjusted to 3.0 with 0.1 N hydrochloric acid.
물을 첨가하여 100㎖로 만듬.Add 100 ml of water.
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US20030235538A1 (en) | 2002-04-09 | 2003-12-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Method for the administration of an anticholinergic by inhalation |
GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
CA2544733A1 (en) * | 2003-10-09 | 2005-04-21 | Inverseon, Inc. | Methods for treating diseases and conditions with inverse agonists and for screening for agents acting as inverse agonists |
SE0303269L (en) * | 2003-12-03 | 2005-06-04 | Microdrug Ag | Medical product |
AU2006224842B2 (en) * | 2005-03-16 | 2011-09-29 | Meda Pharma Gmbh & Co Kg | The combination of anticholinergics and leukotriene receptor antagonists for the treatment of respiratory diseases |
AU2007267523B2 (en) * | 2006-05-26 | 2012-02-09 | Dey, L.P. | Nebulizable compositions of quaternary ammonium muscarinic receptor antagonists |
CN100446770C (en) * | 2007-01-10 | 2008-12-31 | 上海现代药物制剂工程研究中心有限公司 | Water aerosol containing beclomethasone dipropionate |
TR200907237A2 (en) * | 2009-09-23 | 2011-04-21 | Bi̇lgi̇ç Mahmut | Tiotropium dry powder combination |
CN116173025A (en) * | 2018-07-26 | 2023-05-30 | 四川海思科制药有限公司 | Aerosol pharmaceutical composition containing glycopyrronium salt and indacaterol salt, and preparation method and application thereof |
WO2020019953A1 (en) * | 2018-07-26 | 2020-01-30 | 四川海思科制药有限公司 | Aerosol pharmaceutical composition containing a glycopyrrolate salt, preparation method therefor, and uses thereof |
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US5824669A (en) * | 1996-03-22 | 1998-10-20 | Nitromed, Inc. | Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders |
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