TWI468187B - 可吸入式藥劑 - Google Patents
可吸入式藥劑 Download PDFInfo
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- TWI468187B TWI468187B TW101148516A TW101148516A TWI468187B TW I468187 B TWI468187 B TW I468187B TW 101148516 A TW101148516 A TW 101148516A TW 101148516 A TW101148516 A TW 101148516A TW I468187 B TWI468187 B TW I468187B
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- tiotropium
- ethanol
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- 239000003814 drug Substances 0.000 title description 5
- 238000009472 formulation Methods 0.000 claims description 91
- 239000000203 mixture Substances 0.000 claims description 91
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 55
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 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 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 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 group 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 description 19
- 229960000257 tiotropium bromide Drugs 0.000 claims description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 18
- 239000003380 propellant Substances 0.000 claims description 18
- 229940110309 tiotropium Drugs 0.000 claims description 17
- 229910052782 aluminium Inorganic materials 0.000 claims description 9
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical group FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 8
- 235000011187 glycerol Nutrition 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229940071648 metered dose inhaler Drugs 0.000 claims description 3
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 description 12
- 229960004106 citric acid Drugs 0.000 description 12
- 150000005828 hydrofluoroalkanes Chemical class 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 230000002411 adverse Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000002144 chemical decomposition reaction Methods 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- -1 ascorbic acid Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
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- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 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 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- DQHNAVOVODVIMG-UHFFFAOYSA-M Tiotropium bromide Chemical compound [Br-].C1C(C2C3O2)[N+](C)(C)C3CC1OC(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 DQHNAVOVODVIMG-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 229920005549 butyl rubber Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229920005555 halobutyl Polymers 0.000 description 1
- 125000004968 halobutyl group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960001361 ipratropium bromide Drugs 0.000 description 1
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229940124818 soft mist inhaler Drugs 0.000 description 1
- 229940046810 spiriva Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- Chemical Kinetics & Catalysis (AREA)
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- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本發明係關於一種可吸入式藥劑，且更特定言之，係關於噻托銨(tiotropium)之溶液調配物。
噻托銨為一種抗膽鹼激導性劑且顯示為緩解慢性阻塞性肺病(COPD)患者之症狀的維持性支氣管擴張藥治療。噻托銨以呈吸入式粉末或供吸入之溶液形式的Spiriva®售出。
本發明係關於噻托銨調配物。噻托銨含有四級銨陽離子且通常以具有以下結構之溴化物鹽形式使用：
用於調配供急診室外使用的可吸入式藥劑之兩種最常見手段為乾粉吸入器(DPI)及加壓定劑量吸入器(pMDI)。DPI之一個實例為市售吸入式粉末。吸入式粉末含有儲存於硬膠囊中的一水合噻托溴銨及乳糖且使用HandiHaler®乾粉吸入器投與。然而，pMDI為遞送噻托溴銨至肺中的替代手段。通常，由於pMDI使用起來更容易，所以患者使用pMDI的順應性更大。此外，DPI之缺點在於，粉狀活性成
分中僅有一小部分實際吸入肺中。
pMDI調配物可以懸浮液或溶液形式呈現。WO 03/082252提供一水合噻托溴銨於HFA 134a或227中調配為懸浮液之實例。在溶液調配物中，活性成分溶於推進劑系統中且因此避免諸如pMDI分配噴嘴口之潛在堵塞、懸浮粒子之物理不穩定性及需要使用諸如界面活性劑之懸浮劑的問題。溶液調配物亦更容易製備。然而，與將噻托銨鹽調配為溶液調配物有關的一個重要問題為，活性成分在共溶劑(諸如乙醇)存在下，在化學上不穩定，需要將活性成分溶於HFA推進劑中。
市售供吸入之溶液藉由避開pMDI而完全解決此問題。該產品改為使用Respimat®「軟霧吸入器」。該調配物含有噻托溴銨、氯化苯甲烴銨、乙二胺四乙酸二鈉、純化水及3.6%鹽酸(用於調節pH值)。Respimat®吸入器係藉由吸入器內之彈簧的作用而非使用液化推進劑來產生霧。然而，pMDI為較佳手段且已嘗試將噻托銨調配為pMDI調配物。
WO 94/13262揭示使用無機酸或有機酸使溶液調配物穩定化。然而，其中之揭示內容主要關於異丙托溴銨且尚未明瞭應如何改進該手段以適用於噻托銨。
US 2005/0058606亦使用無機酸或有機酸解決使噻托溴銨溶液調配物穩定化的問題。
然而，對於使用酸使溶液調配物穩定化存在極大擔憂，因為酸本身可與罐之金屬表面反應，使得金屬鹽浸析至調
配物中，導致活性成分之進一步不穩定性及/或調配物污染。舉例而言，EP 1 666 029揭示pMDI溶液調配物，其中吸入器之內表面係由不鏽鋼或陽極化鋁組成，或其中內表面襯有惰性有機塗層，以使罐對活性成分之化學不穩定性的影響最小。另外，EP 2 201 934描述含有噻托銨鹽、HFA推進劑、一或多種共溶劑及無機酸的pMDI調配物。該文獻教示使用配備有密封環及密封墊之氣溶膠罐的重要作用，該等密封環及密封墊與調配物接觸，其係由丁基橡膠或鹵丁基橡膠製成，以避免含酸調配物與密封環及密封墊之材料發生不利的相互作用。
因此，此項技術中仍需要在化學上穩定且與吸入器之內表面不發生不利反應之噻托銨鹽的pMDI溶液調配物。
因此，本發明提供包含噻托銨鹽、12-20%乙醇、0.1-1.5%水、0.05-0.10%檸檬酸及HFA推進劑的溶液調配物，其中百分比為以調配物總重量計的重量百分比。
此調配物在乙醇、水及檸檬酸之絕對及相對量上具有嚴格的限制，以便得到關於活性成分之高度化學穩定性而對吸入器材料無不利影響。
本發明之調配物為溶液調配物且因此該調配物具有單一均相。因此將噻托銨鹽及檸檬酸溶於推進劑/乙醇/水相中。可將調配物冷卻至4℃且接著再加熱至周圍溫度而活性成分不會沈澱。
由於調配物為溶液，因此調配物無需界面活性劑之存在
(其用於使懸浮液調配物中所懸浮之活性成分粒子穩定化)。因此，不必向調配物中添加界面活性劑，且因此本發明之調配物較佳實質上不含界面活性劑(例如以調配物總重量計，調配物含有小於0.0001 wt%界面活性劑)。
調配物含有噻托銨鹽、12-20%乙醇、0.1-1.5%水、0.05-0.10%檸檬酸及HFA推進劑。所有百分比為以調配物總重量(亦即，活性成分與所存在之所有賦形劑的總重量)計的重量百分比。調配物較佳含有0.15%至0.75%水。
本發明一般適用於噻托銨鹽，但本發明調配物較佳含有噻托溴銨，噻托溴銨為最常用的鹽且此鹽目前可市購。本文所列之賦形劑之較佳量特別(但不排他)是針對與作為噻托銨鹽的噻托溴銨一起使用所設計。
噻托銨鹽之存在量將根據特定產品所需的噻托銨之劑量而變。通常，噻托銨鹽(較佳為噻托溴銨)以每次啟動經閥提供1-10微克噻托銨鹼的量存在。較佳為每次啟動經閥提供2-6微克噻托銨鹼。亦即，定劑量的游離鹼等效物之量係在其離開閥時量測。此對應於0.00422-0.02110 wt%之噻托溴銨之較佳量。
根據USP，乙醇較佳為脫水乙醇。乙醇存在主要是為了溶解噻托銨鹽。在一個較佳實施例中，乙醇之量為12-15%。根據USP，水較佳為純化水。水較佳以0.30-0.60%存在。根據USP，檸檬酸較佳為無水檸檬酸。在另一個較佳實施例中，檸檬酸之量為0.05-0.08%。咸信，相對較高濃度之檸檬酸為噻托銨鹽提供所需的化學穩定性。然而，
保留含量相對較低的水可防止檸檬酸使罐降解。
特別較佳的是，該等量同時為12-15%乙醇、0.30-0.60%水及0.05-0.08%檸檬酸。更佳地，該等組分以約15%乙醇、約0.5%水及約0.06%檸檬酸存在。
調配物亦含有氫氟烷烴(HFA)推進劑。此等推進劑在此項技術中已熟知。本發明之較佳HFA為HFA 134a及/或HFA 227。較佳使用HFA 134a。
一旦啟動吸入器，吸入器即釋放定劑量之調配物。定劑量之調配物通過閥桿及桿體，經由桿體之分配噴嘴中之孔口排入吹嘴中且由此送至患者。一經釋放，推進劑即快速蒸發，留下溶於乙醇及水之小液滴中的活性成分，乙醇及水之小液滴會再部份蒸發。液滴之粒度將取決於許多因素，包括乙醇及水的使用量、分配噴嘴中之孔口尺寸、噴射力、噴霧幾何學等。然而，液滴直徑通常小於5微米。在一些應用中，液滴尺寸對於最佳肺沈積而言太小。在此類情況下，可向調配物中添加甘油。甘油揮發性小於乙醇且因此在啟動時較少蒸發，從而得到較大液滴(較大意謂其具有較高空氣動力學質量中值，如藉由NGI所量測)。因此，在一個較佳實施例中，本發明之調配物進一步包含甘油。在一個特別較佳實施例中，本發明之調配物由噻托銨鹽(較佳為噻托溴銨)、12-20%乙醇、0.1-1.5%水、0.05-0.10%檸檬酸、HFA推進劑及視情況存在之甘油(較佳量為0.5-5%)組成。上文所列之賦形劑之較佳量同樣適用於此實施例。
本發明之溶液調配物意欲使用加壓定劑量吸入器(pMDI)進行投與。pMDI在此項技術中已熟知；詳情參見例如Drug Delivery to the Respiratory Tract,D.Ganderton及T.Jones編,VCH Publishers,1987,第87-88頁，或Pharmaceutics-The Science of Dosage Form Design,第2版,M.E.Aulton編,Churchill Livingstone,2002,第476頁及其後)。
pMDI通常具有含有藥劑之罐及具有吹嘴之啟動器外殼。罐一般由具有卷邊蓋之鋁杯形成，此卷邊蓋攜有定量閥組件。定量閥組件具備突出閥桿，此閥桿以推入配合方式插入啟動器外殼之桿體中。
啟動時，使用者向罐之封閉端施加壓力。定量閥組件之內部構件為受載彈簧，因此啟動裝置通常需要15 N至30 N之壓力。回應此壓力，罐相對於閥桿軸向移動，移動量在約2 mm與4 mm之間變化。此軸向移動程度足以啟動定量閥且促使定量的調配物經由閥桿排出。接著此調配物經由桿體之分配噴嘴之孔口釋入吹嘴中。使用者此時經由裝置之吹嘴吸入，將因此接受一定劑量之活性成分。
為了防止不慎啟動進入患者之眼中，以吸入啟動式吸入器(亦稱為呼吸啟動式吸入器)特別較佳。合適吸入器揭示於WO 92/09323、GB 2 264 238及WO 01/93933中。本發明最佳使用如參考WO 92/09323之圖3至圖5所述的吸入器。
本發明進一步提供包含罐的加壓定劑量吸入器，其中該罐含有如本文所述之溶液調配物。罐位於如上文論述之啟
動器外殼中。罐較佳含有100次啟動或少於100次啟動，較佳為約60次啟動(亦即供給一個月，根據每劑啟動兩次)。此為相當低量，且因此罐中之頂部空間傾向於大於習知pMDI，習知pMDI使噻托銨鹽化學降解的傾向增加。然而，即使在此更具挑戰性的環境中，本發明之調配物亦能夠提供所需程度之化學穩定性。舉例而言，10 mL滿邊容量罐可具有2.5-6.3 mL之裝填體積及7.5-3.7 mL之相應頂部空間體積。閥較佳為25-63微升閥，更佳為25或50微升閥。
現已驚人地發現，本發明之調配物不僅能夠減少或防止活性成分之化學降解，而且不會顯著影響罐之材料(參見下文所述之實例2及3)。由此提供的重要優點在於，可使用未經塗佈的鋁罐，從而降低pMDI之成本而不會對調配物有不利影響。因此，根據本發明之一個較佳實施例，pMDI包含內表面未經塗佈的由鋁構成之罐。預計可使用其他有機酸(諸如抗壞血酸)，使用噻托溴銨之類似調配物達成類似穩定特性。
因此，在另一態樣中，本發明提供包含噻托銨鹽、12-20%乙醇、0.1-1.5%水、0.05-0.10%有機酸(較佳為抗壞血酸)及HFA推進劑的溶液調配物，其中百分比為以調配物總重量計的重量百分比。
調配物較佳含有0.15%至0.75%水。此態樣之其他較佳實施例在隨附申請專利範圍中鑑別。
本發明現參考以下實例加以描述，該等實例不欲具限制
性。
使用HFA 134a及乙醇(乙醇濃度僅為8-15%)製備噻托溴銨溶液調配物。一種此類調配物由0.08% w/w噻托溴銨、12% w/w乙醇及88% w/w HFA 134a組成。將溶液冷卻至4℃且接著再加熱至CRT而藥物不會沈澱。觀測到噻托溴銨發生快速化學降解。
藉由將噻托溴銨、乙醇、水及檸檬酸合併及將各組分混合直至形成溶液來製備多批溶液調配物。所有調配物含有0.0071% w/w噻托溴銨及HFA 134a(直至100% w/w)。將溶液裝填至鋁罐中，接著用50微升閥密封且填充HFA 134a。除批次H外，皆使用經FEP塗佈之鋁罐。賦形劑之量列於下表中。
3個月之後，僅對批次A、I、C、E及H進行連續測試。
結果顯示於下表(其中CRT表示所控制之室溫，亦即，25℃/60%相對濕度，且ACC表示加速穩定性測試條件，亦即40℃、75%相對濕度)中。
結果顯示6個月之後化學降解程度可接受地低。批次E及H亦顯示基本相同的結果，表明本發明之調配物在未經塗佈罐中可耐受。
鑒於酸性調配物會腐蝕鋁罐的風險顯著，因此進一步研究批次H的未經塗佈罐。首先，測定調配物在3個月之後的鋁含量。濃度記錄為1.59 ppm，表示無毒性危險。其次，藉由SEM對罐進行表面分析。自罐上剪切25 mm×15 mm尺寸之條帶且使用JEOL 840 SEM檢查其表面。使用兩種放大倍數(100倍及250倍)對三個不同位置(條帶之頂端、中部及底端)成像且與使用未用罐獲得的結果比較。觀測到與噻托溴銨調配物一起使用的罐未遭損壞。
三種適合的商用調配物如下：
經由50 μL定量閥，每次啟動以6.3 μg噻托溴銨(閥外)遞送5.25 μg噻托銨。
適用於集中小批次之混合方法如下：
適用於將集中小批次填充於pMDI罐中的方法如下：
分析及相關物質為藥物產品之化學穩定性的關鍵指標且已在ACC及CRT儲存條件下監測實例4中之第一及第三調配物。
測定實例4中之第三調配物在初始時及穩定時的分析資料(% w/w)(每個時間點n=3個單位之平均值)。在閥直立定向(「VU」)及閥倒下定向(「VD」)時測試調配物。此批次之目標濃度為0.0071%。結果列於下表中：
亦對實例4中之5批第一調配物進行測試。結果列於下表中：
N/A：彙編資料時，尚未達到穩定性時間點。
分析資料證明調配物濃度無變化。相關物質資料證實此等研究結果。
針對實例4之5批第一調配物在初始時及穩定時量測遞送劑量均一性。目標遞送劑量為每次啟動(啟動器外)排出4.5微克噻托銨(mcg)。在每個時間點，在各穩定條件下量測三個罐的使用期DDU。對各罐測定10種啟動器外劑量，3種在罐使用期之初期(BOL)，4種在罐使用期之中期(MOL)及3種在罐使用期之末期(EOL)。每個時間點之平均數值概括於下表中(每個時間點n=30之平均值)：
資料證明，在整個使用期期間，在所測試之所有儲存條件及時間點下，遞送劑量均為一致的，可變性極小。
使用下一代衝擊器(NGI-裝置E,Ph.Eur.)，對實例4之5批第一調配物在初始及穩定時的空氣動力學粒度分佈
(aPSD)進行量測。在罐使用期初期及末期時進行此等量測。該方法每次測定時使用20次啟動排入NGI中。該方法每次測定時使用20次啟動排入NGI中。結果如下(每個時間點n=6之平均值)：
結果顯示噻托銨HFA BAI具有一致的aPSD概況，不論批次、其儲存時間及條件如何。此結果與溶液調配物之效能一致。
Claims (18)
- 一種溶液調配物，其包含噻托銨鹽(tiotropium salt)、12-20%乙醇、0.1-1.5%水、0.05-0.10%檸檬酸及HFA推進劑，其中該等百分比為以該調配物之總重量計的重量百分比。
- 如請求項1之調配物，其中該噻托銨鹽為噻托溴銨(tiotropium bromide)。
- 如請求項1或2之調配物，其中該噻托銨鹽係以每次啟動時從閥送出1-10微克之噻托銨鹼的量存在。
- 如請求項1或2之調配物，其中該噻托銨鹽以係每次啟動時從閥送出2-6微克之噻托銨鹼的量存在。
- 如請求項1或2之調配物，其中該HFA推進劑為HFA 134a及/或HFA 227。
- 如請求項1或2之調配物，其中該調配物進一步包含甘油。
- 如請求項1或2之調配物，其中乙醇之量為12-15%。
- 如請求項1或2之調配物，其中水之量為0.30-0.60%。
- 如請求項1或2之調配物，其中檸檬酸之量為0.05-0.08%。
- 如請求項1或2之調配物，其包含約15%乙醇、約0.5%水及約0.06%檸檬酸及HFA推進劑。
- 如請求項1或2之調配物，其由以下組成：噻托銨鹽、12-20%乙醇、0.1-1.5%水、0.05-0.10%檸檬酸、HFA推進劑及視情況存在之0.5-5%甘油。
- 一種溶液調配物，其包含噻托銨鹽、12-20%乙醇、0.1-1.5%水、0.05-0.10%有機酸及HFA推進劑，其中該等百分比為以該調配物之總重量計的重量百分比。
- 如請求項12之調配物，其中該有機酸為抗壞血酸。
- 如請求項12之調配物，其中有機酸之量為0.05-0.08%。
- 如請求項12之調配物，其包含約15%乙醇、約0.5%水及約0.06%有機酸及HFA推進劑。
- 如請求項12之調配物，其由以下組成：噻托銨鹽、12-20%乙醇、0.1-1.5%水、0.05-0.10%有機酸、HFA推進劑及視情況存在之0.5-5%甘油。
- 一種包含罐的加壓定劑量吸入器，其中該罐含有如請求項1至11中任一項或請求項12至16中任一項之溶液調配物。
- 如請求項17之加壓定劑量吸入器，其中該罐由鋁構成，其中內表面未經塗佈。
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