TW201618759A - Dry powder for inhalation formulation having improved stability of combined active ingredients - Google Patents
Dry powder for inhalation formulation having improved stability of combined active ingredients Download PDFInfo
- Publication number
- TW201618759A TW201618759A TW104132119A TW104132119A TW201618759A TW 201618759 A TW201618759 A TW 201618759A TW 104132119 A TW104132119 A TW 104132119A TW 104132119 A TW104132119 A TW 104132119A TW 201618759 A TW201618759 A TW 201618759A
- Authority
- TW
- Taiwan
- Prior art keywords
- diluent
- dry powder
- weight
- powder
- micronized
- Prior art date
Links
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
-
- 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
- A61P11/06—Antiasthmatics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Otolaryngology (AREA)
- Emergency Medicine (AREA)
- Biochemistry (AREA)
- Medicinal Preparation (AREA)
- Biophysics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
一或多個例示實施例係有關於一種用於吸入型調配物之乾粉末，此乾粉末包括選自沙美特羅(salmeterol)、替托比銨(tiotropium)、氟替皮質醇(fluticasone)，及其等之藥學上可接受鹽類之至少二組合型活性成分，且更特別地，係有關於一種用於吸入型調配物之乾粉末，此乾粉末具有經改善之組合型活性成分之穩定性，此組合型活性成分因為微米化及係組合型而一般會具有差的穩定性，且係有關於一種含有此乾粉末之吸入型調配物。 One or more exemplified embodiments relate to a dry powder for use in an inhaled formulation comprising a salmeterol, tiotropium, fluticasone, And at least a combination active ingredient of a pharmaceutically acceptable salt thereof, and more particularly, a dry powder for use in an inhaled formulation having an improved stability of the combined active ingredient The combination active ingredient generally has poor stability due to micronization and combination, and is related to an inhalation formulation containing the dry powder.
用於治療呼吸疾病(例如，氣喘及慢性阻塞性肺病(COPD))之呈一吸入型調配物型式之各種藥劑係於市場上可獲得。特別地，諸如短效型β致效劑(SABAs)、長效型β致效劑(LABAs)、吸入型皮質類固醇(ICS)，或長效型拮 抗劑(LAMAs)之藥物係廣泛用於預防及治療諸如氣喘或COPD之呼吸疾病。SABAs、LABAs，及LAMAs基於其等之藥理機構會具有支氣管擴張功效，且ICS會緩和已知為氣喘原因之炎症。由於此等功效，SABAs、LABAs、LAMAs，及ICS會改善一秒用力呼氣量(FEV1)、呼吸窘迫，及COPD之惡化。SABAs之經常使用例子係沙丁胺醇(salbutamol)及特布他林(terbutaline)。LABAs之例子係沙美特羅、福莫特羅(formoterol)，及茚達特羅(indacaterol)。ICS之例子係氟替皮質醇及布***(budesonide)。LAMA之例子係替托比銨及吡咯醣(glycopyrronium)。 Various agents in an inhaled formulation for the treatment of respiratory diseases (eg, asthma and chronic obstructive pulmonary disease (COPD)) are commercially available. In particular, such as short-acting beta agonists (SABAs), long-acting beta agonists (LABAs), inhaled corticosteroids (ICS), or long-acting antagonists Anti-drugs (LAMAs) are widely used to prevent and treat respiratory diseases such as asthma or COPD. SABAs, LABAs, and LAMAs have bronchodilating effects based on their pharmacological mechanisms, and ICS alleviates inflammation known to be a cause of asthma. Because of these effects, SABAs, LABAs, LAMAs, and ICS improve the forced expiratory volume (FEV1), respiratory distress, and COPD deterioration in one second. Examples of frequent use of SABAs are salbutamol and terbutaline. Examples of LABAs are salmeterol, formoterol, and indacaterol. Examples of ICS are fluticacorin and budesonide. Examples of LAMA are tetoprofen and glycopyrronium.
全球慢性阻塞性肺病倡議組織(Global Initiative for Chronic Obstructive Lung Disease(GOLD))對於COPD之治療指南建議使用用於同時吸入具有不同或互補作用機構的藥物之一組合型調配物。例如，LABA大部份係處方給具有少於80%之FEV1量之COPD患者，及具有少於50%之FEV1量之COPS患者，或遭受經常性急性惡化者除LABA外係進一步被處方ICS。來自此等同時吸入具有互補作用機構之藥物的預期改善治療功效已基於各種研究結果而被證明(Aaron,Shawn D.等人，Annals of internal medicine 146.8(2007)：545-555；J.Y.Sohn等人，Tuberculosis and Respiratory Diseases 67.6(2009)：536-544；Hanania,Nicola A.等人，CHEST Journal 124.3(2003)：834-843)。 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a combination of ones for the simultaneous inhalation of drugs with different or complementary mechanisms for the treatment of COPD. For example, most LABAs are prescribed to COPD patients with less than 80% of FEV1, and COPS patients with less than 50% of FEV1, or those who suffer from frequent acute exacerbations are further prescribed ICS in addition to LABA. The expected improved therapeutic efficacy of these drugs simultaneously inhaled with complementary mechanisms has been demonstrated based on various findings (Aaron, Shawn D. et al., Annals of internal medicine 146.8 (2007): 545-555; JYSohn et al. , Tuberculosis and Respiratory Diseases 67.6 (2009): 536-544; Hanania, Nicola A. et al., CHEST Journal 124.3 (2003): 834-843).
如上所述之二藥物的組合型調配物係已於廣泛臨床使用。此等組合之一典型例子係包括沙美特羅及氟替 皮質醇之Seretide®。由於同時吸入LABA及ICS，Seretide®於呼吸道伸縮及炎症治療提供一有效治療功效。但是，雖然以作為一LABA藥物而著稱，沙美特羅具有約5.5小時之半衰期且無法持續一足夠時期提供一呼吸道伸縮功效。 The combination formulation of the two drugs as described above has been widely used clinically. One typical example of such a combination system comprises salmeterol and fluticasone Seretide of cortisol ®. Because while LABA and inhaled ICS, Seretide ® in the treatment of respiratory tract inflammation and stretching provide an effective therapeutic efficacy. However, although known as a LABA drug, salmeterol has a half-life of about 5.5 hours and cannot last for a sufficient period of time to provide a respiratory retraction effect.
以LABA、ICS，及LAMA同時投藥可提供一進一步改善之治療功效的報導研究結果為基礎，對於此等三種組合型調配物之研究已被進行(Singh,Dave等人，Thorax 63.7(2008)：592-598)。例如，WO13/187626揭露一種用於治療呼吸疾病之吸入型調配物，包含沙美特羅昔奈酸鹽(LABA)、氟替皮質醇丙酸鹽(ICS)，及替托比銨溴化物(LAMA)。WO13/187626揭露一種乾粉末吸入型調配物，其具有約30μm至120μm之平均顆粒尺寸，以確保使三活性成分可信賴地遞送至一目標位置，此調配物具有良好內容物均勻性，且對於隨流速變化而改變之動態顆粒尺寸分佈具有小變化。但是，WO13/187626未教示發展一種具有經改善之組合型活性成分之穩定性的調配物。 Based on the results of a report that provides a further improved therapeutic efficacy by concurrent administration of LABA, ICS, and LAMA, studies have been conducted on these three combination formulations (Singh, Dave et al., Thorax 63.7 (2008): 592-598). For example, WO 13/187626 discloses an inhaled formulation for the treatment of respiratory diseases, comprising salmeteri tropamate (LABA), flutica cortisol propionate (ICS), and tetolbium ammonium bromide (LAMA). ). WO 13/187626 discloses a dry powder inhalation formulation having an average particle size of from about 30 [mu]m to 120 [mu]m to ensure reliable delivery of the three active ingredients to a target site, the formulation having good content uniformity and The dynamic particle size distribution that changes as the flow rate changes has a small change. However, WO 13/187626 does not teach the development of a formulation having improved stability of the combined active ingredient.
吸入型調配物之一典型特徵係其等活性成分被微米化成約5μm或更少之顆粒尺寸。因此，由於微米化，一吸入型調配物之活性成分會具有大表面積。因此，活性成分對於一起使用之稀釋劑及/或外部環境可能不具有確保之穩定性。一吸入型調配物之活性成分的穩定性於藥物品質控制係極重要，因為活性成分之單位劑量係小。活性成分之穩定性問題於含有如上所述之至少二活性成分的組合之一吸入型調配物係特別重要，因為具有大表面積之活 性成分的交互作用會加速產生相關化合物(雜質)。因此，需要確保含有至少二活性成分之組合的用於呼吸疾病治療之一吸入型調配物中之個別活性成份的經改善之穩定性的藥學研究。 One of the typical characteristics of inhaled formulations is that their active ingredients are micronized to a particle size of about 5 [mu]m or less. Thus, due to micronization, the active ingredient of an inhaled formulation will have a large surface area. Thus, the active ingredient may not have a guaranteed stability for the diluent and/or external environment used together. The stability of the active ingredient of an inhaled formulation is extremely important in the quality control of the drug because the unit dosage of the active ingredient is small. The stability of the active ingredient is particularly important in an inhalation-type formulation containing a combination of at least two active ingredients as described above, because of the large surface area The interaction of sexual components accelerates the production of related compounds (impurities). Accordingly, there is a need for a pharmaceutical study that ensures improved stability of individual active ingredients in an inhaled formulation for treatment of a respiratory disease comprising a combination of at least two active ingredients.
一或多個例示實施例包括一種用於吸入型調配物之乾粉末，此乾粉末包括具有經改善之穩定性的有效用於治療呼吸疾病之至少二組合型活性成分。 One or more exemplified embodiments include a dry powder for use in an inhaled formulation comprising at least two combination active ingredients effective for treating respiratory diseases with improved stability.
一或多個例示實施例包括一種吸入型調配物，其包括此乾粉末。 One or more exemplary embodiments include an inhalation formulation that includes such a dry powder.
一或多個例示實施例包括一種製備用於吸入型調配物之乾粉末之藥學方法，此乾粉末包括具有經改善之穩定性之活性成分。 One or more exemplary embodiments include a pharmaceutical method of preparing a dry powder for use in an inhaled formulation comprising an active ingredient having improved stability.
依據一或多個例示實施例，一種用於吸入型調配物之乾粉末包括：選自由沙美特羅或其一藥學上可接受鹽、替托比銨或其一藥學上可接受鹽，及氟替皮質醇或其一藥學上可接受鹽所組成之組群之至少二組合型活性成分；及一稀釋劑，其中，以此稀釋劑總重量為基準，此稀釋劑包括約0.1重量%至約50重量%之具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末，使得此等活性成分之至少一者之穩定性係高於具有超過50重量%之經微米化的粉末含量之一乾粉末的穩定性。 According to one or more exemplary embodiments, a dry powder for use in an inhaled formulation comprises: selected from salmeterol or a pharmaceutically acceptable salt thereof, tetolbium ammonium or a pharmaceutically acceptable salt thereof, and fluorine a at least two combination active ingredient of the group consisting of cortisol or a pharmaceutically acceptable salt thereof; and a diluent, wherein the diluent comprises from about 0.1% by weight to about the total weight of the diluent 50% by weight of the micronized powder having an average particle diameter (X 50 ) of about 30 μm or less such that at least one of the active ingredients has a stability higher than that of more than 50% by weight of the micronized The stability of one of the powder contents of the dry powder.
依據一或多個例示實施例，提供一種使用一稀釋 劑用於製備用於吸入型調配物之乾粉末之方法，以此稀釋劑總重量為基準，此稀釋劑包括約0.1重量%至約50重量%之具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末，此乾粉末具有至少一活性成分之更高穩定性，且包括：選自由沙美特羅或其一藥學上可接受鹽、替托比銨或其一藥學上可接受鹽，及氟替皮質醇或其一藥學上可接受鹽所組成之組群之至少二組合型活性成分；及一稀釋劑。 According to one or more exemplified embodiments, there is provided a method of preparing a dry powder for use in an inhalation formulation using a diluent comprising from about 0.1% to about 50% by weight based on the total weight of the diluent a micronized powder having an average particle diameter (X 50 ) of about 30 μm or less, the dry powder having a higher stability of at least one active ingredient, and comprising: selected from salmeterol or a pharmaceutical thereof An at least two combination active ingredient of the group consisting of an acceptable salt, tetolamine or a pharmaceutically acceptable salt thereof, and fluticacorol or a pharmaceutically acceptable salt thereof; and a diluent.
依據一或多個例示實施例，一種吸入型調配物包括上述乾粉末。 In accordance with one or more exemplary embodiments, an inhaled formulation includes the above dry powder.
此等及/或其它方面由結合所附圖式之下列實施例說明會變明顯及更輕易瞭解，其中：圖1係於40℃及75%相對濕度(RH)貯存0、1、3，及6個月後於依據本發明範例及比較例之吸入型調配物之每一者中之氟替皮質醇丙酸鹽之未知相關化合物的總量之圖；圖2至4係於40℃及75% RH貯存0、1、3，及6個月後於依據本發明範例及比較例之吸入型調配物之每一者中之沙美特羅之作為相關化合物之GR97980X的量之圖；且圖5至7係於40℃及75% RH貯存0、1、3，及6個月後於依據本發明範例及比較例之吸入型調配物之每一者中之替托比銨之作為相關化合物之B Ⅱ H27SE的量之圖。 These and/or other aspects will become apparent and more readily apparent from the following description of the embodiments in which: FIG. 1 is stored at 40 ° C and 75% relative humidity (RH) 0, 1, 3, and A graph of the total amount of unknown related compounds of flutica cortisol in each of the inhaled formulations according to the examples and comparative examples of the invention after 6 months; Figures 2 to 4 are at 40 ° C and 75 % RH is a plot of salmeterol in each of the inhaled formulations according to the examples of the invention and the amount of GR97980X as a related compound after storage for 0, 1, 3, and 6 months; and FIG. 5 Up to 7 is a related compound in each of the inhaled formulations according to the examples and comparative examples of the present invention after storage for 0, 1, 3, and 6 months at 40 ° C and 75% RH. A graph of the amount of B II H27SE.
除非其它定義，此處使用之所有術語(包括技術及科學術語)具有熟習本發明所屬技藝者所普遍瞭解之相同意義。雖然例示之方法或材料於此處列示，其它相似或相等者亦係於本發明之範圍內。作為此處參考資料之揭露的所有公開案被完整併入以供參考。 Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning meaning Although the methods or materials illustrated are listed herein, other similar or equivalent aspects are within the scope of the invention. All publications disclosed herein are incorporated by reference in their entirety.
依據本揭露之一方面，一種用於吸入型調配物之乾粉末包括：選自由沙美特羅或其一藥學上可接受鹽、替托比銨或其一藥學上可接受鹽，及氟替皮質醇或其一藥學上可接受鹽所組成之組群之至少二組合型活性成分；及一稀釋劑，其中，以此稀釋劑總重量為基準，此稀釋劑包括約0.1重量%至約50重量%之具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末，使得此等活性成分之至少一者之穩定性係高於具有超過50重量%之經微米化的粉末含量之一乾粉末的穩定性。 According to one aspect of the present disclosure, a dry powder for use in an inhaled formulation comprises: selected from salmeterol or a pharmaceutically acceptable salt thereof, tetolamine or a pharmaceutically acceptable salt thereof, and fluorotype cortex a at least two combination active ingredient of the group consisting of an alcohol or a pharmaceutically acceptable salt thereof; and a diluent, wherein the diluent comprises from about 0.1% by weight to about 50% by weight based on the total weight of the diluent % of a micronized powder having an average particle diameter (X 50 ) of about 30 μm or less such that at least one of the active ingredients has a stability higher than a micronized powder content of more than 50% by weight One of the stability of dry powder.
依據本發明之一方面，此等活性成分之至少一者的更高穩定性可意指較低產生此等活性成分之此至少一者之相關化合物。 According to one aspect of the invention, a higher stability of at least one of the active ingredients may mean a lower relative compound that produces at least one of the active ingredients.
於此處使用時，術語“平均顆粒直徑(X50)”係指於一累積顆粒尺寸分佈圖中相對應於50%之一顆粒尺寸，其係意指總數量顆粒之50%係小於X50且剩餘50%係大於X50。 As used herein, the term "average particle diameter (X 50 )" means a particle size corresponding to 50% in a cumulative particle size distribution, which means that 50% of the total number of particles is less than X 50 . And the remaining 50% is greater than X 50 .
一般，為了使活性成分有效遞送至肺，用於吸入型調配物之乾粉末包括經微米化成約5μm或更少之顆粒尺寸的一活性成分。但是，此等經微米化之顆粒具有高的表 面積對體積比率，且因此係熱力學上不穩定而產生過量表面能量，且因此可能聚結。經微米化之顆粒的此聚結會導致經微米化之顆粒附著於一膠囊或吸入型裝置之內壁，於吸入時阻礙經微米化之顆粒的釋放。為解決此缺點，活性成分可與一適當載劑(即，稀釋劑顆粒)混合投藥。例如，稀釋劑可具有約30μm至約120μm之顆粒尺寸。稀釋劑可與具有約30μm或更少之顆粒尺寸的一經微米化之稀釋劑混合使用。此已知導致活性成分顆粒與稀釋劑顆粒均勻黏著，及增強活性成分顆粒自稀釋劑顆粒釋放。此被歸因於稀釋劑之降低且均勻之整體表面能量，其係由於小量之經微米化之稀釋劑顆粒主要係與稀釋劑之一不規則顆粒表面的一高表面能量區域黏著而造成，而降低稀釋劑顆粒之表面能量。雖然此藉由使一稀釋劑與一經微米化之稀釋劑組合製備用於吸入型調配物之一乾粉末以便有效遞送活性成分係此項技藝已知，但尚未企圖藉由控制經微米化之稀釋劑的百分率而改善活性成分之穩定性。 Generally, in order to effectively deliver the active ingredient to the lung, the dry powder for the inhaled formulation includes an active ingredient which is micronized to a particle size of about 5 μm or less. However, these micronized particles have a high table The area to volume ratio, and therefore thermodynamically unstable, produces excess surface energy and may therefore coalesce. This coalescence of the micronized particles causes the micronized particles to adhere to the inner wall of a capsule or inhalation device, which hinders the release of the micronized particles upon inhalation. To address this disadvantage, the active ingredient can be administered in admixture with a suitable carrier (i.e., diluent granules). For example, the diluent can have a particle size of from about 30 [mu]m to about 120 [mu]m. The diluent can be used in combination with a micronized diluent having a particle size of about 30 μm or less. This is known to result in a uniform adhesion of the active ingredient particles to the diluent particles and to enhance release of the active ingredient particles from the diluent particles. This is attributed to the reduced and uniform overall surface energy of the diluent due to the small amount of micronized diluent particles being primarily adhered to a high surface energy region of the irregular particle surface of one of the diluents, The surface energy of the diluent particles is reduced. Although it is known in the art to prepare a dry powder for use in an inhaled formulation for effective delivery of the active ingredient by combining a diluent with a micronized diluent, it has not been attempted to control the micronized diluent. The percentage of the active ingredient is improved.
於用於吸入型調配物之乾粉末中，以稀釋劑總重量為基準，與組合型活性成分一起使用之稀釋劑可包括約0.1重量%至約50重量%之具有約30μm或更少之平均顆粒直徑(X50)之經微米化的粉末，而與稀釋劑之經微米化的粉末之量超過50重量%時相比，改善活性成分之穩定性。 In a dry powder for use in an inhaled formulation, the diluent for use with the combined active ingredient may comprise from about 0.1% to about 50% by weight, based on the total weight of the diluent, having an average of about 30 [mu]m or less. The micronized powder having a particle diameter (X 50 ) improves the stability of the active ingredient as compared to when the amount of the micronized powder of the diluent exceeds 50% by weight.
用於吸入型調配物之乾粉末中的沙美特羅或其一藥學上可接受鹽、替托比銨或其一藥學上可接受鹽，及氟替皮質醇或其一藥學上可接受鹽已知受製備此乾粉末期 間一起使用之稀釋劑及/或外部環境影響而隨著時間產生一相關化合物。依據一測試結果，與稀釋劑中具有約30μm或更少之平均顆粒直徑(X50)之經微米化之粉末的量超過稀釋劑總重量之約50重量%時相比，依據一實施例之用於吸入型調配物之乾粉末被發現產生一顯著降低量之相關化合物。 Salmeterol or a pharmaceutically acceptable salt thereof, a tiotropium or a pharmaceutically acceptable salt thereof, and fluticacorol or a pharmaceutically acceptable salt thereof, in a dry powder for use in an inhaled formulation It is known to produce a related compound over time by the diluent and/or external environmental influences used together during the preparation of the dry powder. According to a test result, according to an embodiment, when the amount of the micronized powder having an average particle diameter (X 50 ) of about 30 μm or less in the diluent exceeds about 50% by weight based on the total weight of the diluent Dry powders for inhaled formulations have been found to produce a significant reduction in related compounds.
特別地，本發明之發明人藉由使稀釋劑中具有約30μm或更少之平均顆粒直徑(X50)之經微米化之粉末的量控制於稀釋劑總重量之約50重量%或更少之範圍的各種比例，於約40℃及約75%相對濕度(RH)之加速條件下，對使用沙美特羅昔奈酸鹽、替托比銨溴化物、氟替皮質醇丙酸鹽，及一稀釋劑製備之用於吸入型調配物之乾粉末的膠囊進行穩定性測試。結果，與於稀釋劑中含有多於約50重量%之經微米化之粉末的乾粉末之膠囊相比，於稀釋劑中含有約50重量%或更少之具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末的用於吸入型調配物之乾粉末的膠囊被發現產生明顯低含量之相關化合物。亦發現稀釋劑中具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末的量愈小，產生之相關化合物的量愈低。再者，與現今可購得之Seretide®及Spiriva®相比，於稀釋劑中含有約50重量%或更少之具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末的用於吸入型調配物之乾粉末的膠囊被發現產生明顯低含量之相關化合物(參考測試例2)。 In particular, the inventors of the present invention control about 50% by weight or less of the total weight of the diluent by making the amount of the micronized powder having an average particle diameter (X 50 ) of about 30 μm or less in the diluent. Various ratios of the range, at about 40 ° C and about 75% relative humidity (RH) acceleration conditions, the use of salmeteroloxifate, tetolbium ammonium bromide, flutica cortisol propionate, and A capsule prepared from a diluent for dry powder of the inhalation formulation was tested for stability. As a result, it contains about 50% by weight or less of an average particle having a size of about 30 μm or less in the diluent as compared with a capsule containing a dry powder of more than about 50% by weight of the micronized powder in the diluent. capsules for inhalation of a dry powder formulation of the powder was micronized diameter (X 50) for generating related compounds were found to significantly lower the content. It has also been found that the smaller the amount of the micronized powder having an average particle diameter (X 50 ) of about 30 μm or less in the diluent, the lower the amount of the relevant compound produced. Further, the micronized powder having an average particle diameter (X 50 ) of about 30 μm or less is contained in the diluent in comparison with Sereteride ® and Spiriva ® which are currently available in the diluent. Capsules for dry powders of inhaled formulations were found to produce significantly lower levels of related compounds (Reference Test Example 2).
例如，於依據一實施例之用於吸入型調配物之乾 粉末中，以稀釋劑總重量為基準，稀釋劑中具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末的量可於約10重量%至約35重量%之範圍，且於某些實施例，係約10重量%至約20重量%，且於某些其它實施例，係約13重量%至約18重量%。 For example, in the dry powder for the inhalation type formulation according to an embodiment, the micronized powder having an average particle diameter (X 50 ) of about 30 μm or less in the diluent based on the total weight of the diluent. The amount may range from about 10% to about 35% by weight, and in certain embodiments, from about 10% to about 20% by weight, and in certain other embodiments, from about 13% to about 18%. weight%.
於某些實施例，稀釋劑可為於製備用於治療呼吸疾病之吸入型調配物的乾粉末之技藝中可獲得之任何已知稀釋劑。例如，稀釋劑可選自由單醣類，諸如，葡萄糖或***糖；雙醣類，諸如，乳糖、麥芽糖，或蔗糖；多醣類，諸如，澱粉、糊清，或葡萄聚糖；多醇類，諸如，山梨醇、甘露醇，或木糖醇；及此等之水合物所組成之組群，但不限於此等。於某些實施例，稀釋劑可為一單醣或一雙醣。例如，稀釋劑可為乳糖。稀釋劑可具有約30μm至約120μm之平均顆粒直徑，以有效遞送一吸入型調配物中之活性成分。 In certain embodiments, the diluent can be any known diluent available in the art for preparing dry powders for use in the treatment of inhaled formulations of respiratory diseases. For example, the diluent may be selected from monosaccharides such as glucose or arabinose; disaccharides such as lactose, maltose, or sucrose; polysaccharides such as starch, paste, or glucomann; polyols , for example, sorbitol, mannitol, or xylitol; and a group of such hydrates, but are not limited thereto. In certain embodiments, the diluent can be a monosaccharide or a disaccharide. For example, the diluent can be lactose. The diluent can have an average particle diameter of from about 30 [mu]m to about 120 [mu]m to effectively deliver the active ingredient in an inhaled formulation.
於某些實施例，活性成分可為選自由沙美特羅昔奈酸鹽、替托比銨溴化物，及氟替皮質醇丙酸鹽所組成組群之至少二者。於某些其它實施例，活性成分可包括沙美特羅昔奈酸鹽、替托比銨溴化物，及氟替皮質醇丙酸鹽之全部三者。 In certain embodiments, the active ingredient can be at least two selected from the group consisting of salmeterol, tiotropium bromide, and flutica cortisol. In certain other embodiments, the active ingredient can include all three of salmeteri gluconate, tetolamine bromide, and fluticacoretate propionate.
依據本揭露之另一方面，提供一種使用稀釋劑用於製備用於吸入型調配物之乾粉末之方法，以稀釋劑總重量為基準，此稀釋劑包含約0.1重量%至約50重量%之具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末，此 乾粉末具有至少一活性成分之更高穩定性，且包括：選自由沙美特羅或其一藥學上可接受鹽、替托比銨或其一藥學上可接受鹽，及氟替皮質醇或其一藥學上可接受鹽所組成組群之至少二組合型活性成分；及一稀釋劑。 In accordance with another aspect of the present disclosure, there is provided a method of using a diluent for preparing a dry powder for use in an inhalation formulation, the diluent comprising from about 0.1% to about 50% by weight based on the total weight of the diluent a micronized powder having an average particle diameter (X 50 ) of about 30 μm or less, the dry powder having a higher stability of at least one active ingredient, and comprising: selected from salmeterol or a pharmaceutically acceptable thereof a salt, a tiotropium or a pharmaceutically acceptable salt thereof, and at least a combined active ingredient of the group consisting of fluticacorol or a pharmaceutically acceptable salt thereof; and a diluent.
上述用於吸入型調配物之乾粉末的實施例之詳細說明亦可應用於使用稀釋劑製備乾粉末之方法的實施例。 The detailed description of the above examples of dry powders for inhaled formulations can also be applied to embodiments of methods for preparing dry powders using diluents.
例如，於使用稀釋劑製備乾粉末之方法中，以稀釋劑總重量為基準，稀釋劑可包括約10重量%至約35重量%之經微米化之粉末，且於某些實施例，係約10重量%至約20重量%，且於某些其它實施例，係約13重量%至約18重量%。 For example, in a method of preparing a dry powder using a diluent, the diluent may comprise from about 10% to about 35% by weight, based on the total weight of the diluent, of the micronized powder, and in certain embodiments, From 10% by weight to about 20% by weight, and in certain other embodiments, from about 13% by weight to about 18% by weight.
於使用稀釋劑製備乾粉末之方法的某些實施例，稀釋劑可選自由單醣類，諸如，葡萄糖或***糖；雙醣類，諸如，乳糖、麥芽糖，或蔗糖；多醣類，諸如，澱粉、糊清，或葡萄聚糖；多醇類，諸如，山梨醇、甘露醇，或木糖醇；及此等之水合物所組成之組群，但不限於此等。於某些實施例，稀釋劑可為一單醣或一雙醣。例如，稀釋劑可為乳糖。 In certain embodiments of the method of preparing a dry powder using a diluent, the diluent may be selected from monosaccharides such as glucose or arabinose; disaccharides such as lactose, maltose, or sucrose; polysaccharides such as, Starch, paste, or glucomannan; a group of polyols such as sorbitol, mannitol, or xylitol; and hydrates thereof, but are not limited thereto. In certain embodiments, the diluent can be a monosaccharide or a disaccharide. For example, the diluent can be lactose.
依據本揭露之另一方面，提供一種吸入型調配物，其包括依據上述實施例之任何者的乾粉末。 In accordance with another aspect of the present disclosure, an inhalation formulation is provided comprising a dry powder according to any of the above embodiments.
於某些實施例，吸入型調配物可包括每單位劑量為約5毫克至約25毫克之稀釋劑，且於某些其它實施例，每單位劑量為15毫克至約25毫克之稀釋劑。當稀釋劑之量高 到超過上限，患者可能由於在吸入期間發生之不悅感而不情願服用吸入型調配物，且再者，作為一外部材料之稀釋劑會造成氣喘。另一方面，當稀釋劑的量小到超過下限，稀釋劑與活性成分間之均勻性不能被確保，且會難以將一單位劑量之乾粉末填充於一膠囊或泡殼內。當稀釋劑之量於上述範圍內，稀釋劑可藉由一般生產方法填充至一膠囊或泡殼內，且吸入型調配物可使用用於生產膠囊或泡殼之一般藥物生產設備製備，而無需用於生產此吸入型調配物之特別設備。 In certain embodiments, inhaled formulations may include from about 5 mg to about 25 mg of diluent per unit dose, and in certain other embodiments, from 15 mg to about 25 mg of diluent per unit dose. When the amount of thinner is high To the upper limit, the patient may be reluctant to take the inhaled formulation due to the unpleasantness that occurs during inhalation, and further, as a diluent for the external material, may cause asthma. On the other hand, when the amount of the diluent is as small as the lower limit, the uniformity between the diluent and the active ingredient cannot be ensured, and it is difficult to fill a unit dose of the dry powder in a capsule or a blister. When the amount of the diluent is within the above range, the diluent can be filled into a capsule or a blister by a general production method, and the inhalation type preparation can be prepared using a general pharmaceutical production apparatus for producing a capsule or a blister without Special equipment for the production of this inhalation formulation.
包括依據上述實施例之任何者的乾粉末之吸入型調配物可使用一傳統已知製備吸入型調配物之方法製備。例如，製備包括依據上述實施例之任何者的乾粉末之吸入型調配物之方法可包括：稱重及篩選適當量之活性成分、一稀釋劑，及一經微米化之稀釋劑，且混合經篩選之活性成分、稀釋劑，及經微米化之稀釋劑獲得一混合物；使此混合物穩定化；以經穩定化之混合物填充，例如，一膠囊。使混合物穩定化可包括使混合物於室溫留置約10小時至約20小時。 Inhalation formulations comprising a dry powder according to any of the above embodiments can be prepared using a conventionally known method of preparing inhaled formulations. For example, a method of preparing an inhaled formulation comprising a dry powder according to any of the above embodiments may comprise: weighing and screening an appropriate amount of active ingredient, a diluent, and a micronized diluent, and mixing and screening The active ingredient, diluent, and micronized diluent are used to obtain a mixture; the mixture is stabilized; and the stabilized mixture is filled, for example, a capsule. Stabilizing the mixture can include leaving the mixture at room temperature for from about 10 hours to about 20 hours.
於某些實施例，包括依據上述實施例之任何者的乾粉末之吸入型調配物可呈一膠囊、一卡匣，或一泡殼的型式。例如，依據上述實施例之任何者的用於吸入型調配物之乾粉末可被填充至用於乾粉末吸入器(DPIs)之由明膠或羥丙甲纖維素等製成之膠囊或卡匣內，或由鋁薄層等製成之一泡殼內。 In certain embodiments, the inhalation formulation comprising a dry powder according to any of the above embodiments may be in the form of a capsule, a cassette, or a blister. For example, a dry powder for an inhaled formulation according to any of the above embodiments may be filled into capsules or cartridges made of gelatin or hypromellose for use in dry powder inhalers (DPIs). Or one of the blister made of a thin layer of aluminum or the like.
於某些實施例，包括依據上述實施例之任何者的乾粉末之一吸入型調配物可呈一膠囊的型式。膠囊尺寸可為，例如，1號至4號。例如，膠囊尺寸可為3號。製備呈一膠囊型式之依據一實施例的吸入型調配物無需用於使乾粉末填充膠囊之特別裝置。例如，欲以乾粉末填充之一膠囊可為透明。使用一透明膠囊能使患者於吸入後立即看到膠囊內之乾粉末是否被吸入，及於吸入前以視覺檢視乾粉末之穩定性惡化或產品缺陷，諸如，聚結或變色。 In certain embodiments, one of the dry powder formulations, including any of the above embodiments, can be in the form of a capsule. The capsule size can be, for example, No. 1 to No. 4. For example, the capsule size can be number 3. The inhalation formulation according to one embodiment for preparing a capsule form does not require a special device for filling the dry powder into capsules. For example, one of the capsules to be filled with dry powder can be transparent. The use of a transparent capsule enables the patient to see if the dry powder in the capsule is inhaled immediately after inhalation, and visually examines the deterioration of the stability of the dry powder or product defects such as coalescence or discoloration prior to inhalation.
於某些實施例，吸入型調配物可藉由使用任何傳統已知乾粉末吸入器(DPI)投藥至一患者。例如，一DPI可包括使膠囊破裂或刺破之一裝置，或使用任何其它方法使膠囊打開以膠囊內之稱重乾粉末遞送至患者肺部。DPI可進一步包括一空氣入口，其產生一氣流使空氣供應至此裝置內；一空氣出口，其於患者吸入此吸入型調配物時使活性成分經此空氣出口排放；及一過濾器，其係用於過濾出任何雜質。現今於市場上可獲得之此等裝置的例子係ROTAHALER®(可得自GSK)、HANDIHALER®(可得自Boehringer Ingelheim)，及AEROLIZER®(可得自PLASTIAPE)。例如，此裝置可為AEROLIZER®(可得自PLASTIAPE)。AEROLIZER®包括於其一封蓋中之一孔洞，用以容納一膠囊，其中，當壓下一按鈕時，插針從孔洞相反側露出，使膠囊刺破。此裝置係小且可攜帶。 In certain embodiments, the inhaled formulation can be administered to a patient by using any conventionally known dry powder inhaler (DPI). For example, a DPI can include a device that ruptures or punctures the capsule, or the capsule is opened using any other method to deliver the weighed dry powder within the capsule to the patient's lungs. The DPI may further comprise an air inlet that produces an air flow to supply air into the device; an air outlet that discharges the active ingredient through the air outlet when the patient inhales the inhaled formulation; and a filter for use Filter out any impurities. Examples of such devices currently available on the market are ROTAHALER ® (available from GSK), HANDIHALER ® (available from Boehringer Ingelheim), and AEROLIZER ® (available from PLASTIAPE). For example, the device can be AEROLIZER ® (available from PLASTIAPE). AEROLIZER ® is included in one of the holes in one of the covers to accommodate a capsule, wherein when the button is pressed, the pin is exposed from the opposite side of the hole to pierce the capsule. This device is small and portable.
於依據上述實施例之任何者之吸入型調配物，活性成分的量可依一患者之種族、性別、年齡、重量，及呼 吸疾病狀況而改變。於某些實施例，吸入型調配物每單位劑量可包括約25μg至約100μg之沙美特羅昔奈酸鹽、約5μg至約50μg之替托比銨溴化物，及約25μg至約500μg之氟替皮質醇丙酸鹽作為自由鹼。 In the case of the inhalation formulation according to any of the above embodiments, the amount of the active ingredient may vary depending on the race, sex, age, weight, and call of the patient. Changed by the disease situation. In certain embodiments, the inhaled formulation may comprise from about 25 [mu]g to about 100 [mu]g of salmeteri gluconate, from about 5 [mu]g to about 50 [mu]g of tetobi ammonium bromide, and from about 25 [mu]g to about 500 [mu]g of fluorine per unit dose. Cortisol propionate is used as a free base.
依據上述實施例之任何者的吸入型調配物可用以治療或減輕此等組合型活性成分已知係有效之任何呼吸疾病。例如，吸入型調配物可有效控制支氣管收縮、炎症，及呼吸道黏液分泌，因此可廣泛用於治療呼吸疾病。例如，吸入型調配物可用於治療氣喘或慢性阻塞性肺病(COPD)。 Inhaled formulations according to any of the above embodiments may be used to treat or alleviate any respiratory disease in which such combination active ingredients are known to be effective. For example, inhaled formulations are effective in controlling bronchoconstriction, inflammation, and respiratory mucus secretion, and are therefore widely used to treat respiratory diseases. For example, inhaled formulations can be used to treat asthma or chronic obstructive pulmonary disease (COPD).
本揭露之一或多個實施例現將參考下列範例作說明。但是，此等範例僅係用於例示目的，且不打算用以限制本揭露之一或多個實施例的範圍。 One or more embodiments of the present disclosure will now be described with reference to the following examples. However, the examples are for illustrative purposes only and are not intended to limit the scope of one or more embodiments of the disclosure.
範例1至3：製備含有具約10重量%之經微米化的乳糖之一稀釋劑的乾粉末吸入型調配物 Examples 1 to 3: Preparation of a dry powder inhalation formulation containing one of about 10% by weight of micronized lactose diluent
沙美特羅昔奈酸鹽、氟替皮質醇丙酸鹽、替托比銨溴化物、乳糖，及具有約17μm之平均顆粒直徑(X50)的經微米化之乳糖(Respitose® ML006，可得自DMV)係依據表1中之組成物稱重，篩選，然後，於一混合器中混合約30分鐘。形成之混合物每一者被穩定化約12小時或更久，且藉由使用一膠囊填充裝置填充至一3號透明膠囊內。 Salmeterol gluconate, flutica cortisol propionate, tetolbium ammonium bromide, lactose, and micronized lactose having an average particle diameter (X 50 ) of about 17 μm (Respitose® ML006, available From DMV), the composition according to Table 1 was weighed, screened, and then mixed in a mixer for about 30 minutes. The resulting mixture was each stabilized for about 12 hours or longer and filled into a No. 3 clear capsule by using a capsule filling device.
範例4至6：製備包括具約30重量%之經微米化的乳糖之一稀釋劑的乾粉末吸入型調配物 Examples 4 to 6: Preparation of a dry powder inhalation formulation comprising a diluent having about 30% by weight of micronized lactose
乾粉末吸入型調配物係依據表2中之組成物以與範例1至3相同方式製備。 The dry powder inhalation formulation was prepared in the same manner as in Examples 1 to 3 according to the compositions in Table 2.
比較例1至3：製備包括具約50重量%之經微米化的乳糖之一稀釋劑的乾粉末吸入型調配物 Comparative Examples 1 to 3: Preparation of a dry powder inhalation formulation comprising a diluent having about 50% by weight of micronized lactose
乾粉末吸入型調配物係依據表3中之組成物以與範例1至3相同方式製備。 The dry powder inhalation formulation was prepared in the same manner as in Examples 1 to 3 according to the compositions in Table 3.
比較例4 Comparative example 4
使用一現今可購得之產物Seretide Diskus®，其含有沙美特羅昔奈酸鹽及氟替皮質醇丙酸鹽作為活性成分。 A currently available product, Seretide Diskus ® , containing salmeteri fluoxetate and flutica cortisol propionate is used as an active ingredient.
比較例5 Comparative Example 5
使用一現今可購得產品Spiriva HandiHaler®，其含有替托比銨溴化物作為一活性成分。 A now available product, Spiriva HandiHaler ® , is used as an active ingredient in tetobi ammonium bromide.
測試例1：顆粒尺寸分析 Test Example 1: Particle Size Analysis
範例1至6及比較例1至3之乾粉末吸入型調配物之每一者中除了活性成分外之乳糖及經微米化之乳糖的一混合物之顆粒尺寸分佈係使用一顆粒尺寸分析器(HELOS雷射繞射感應器，可得自Sympatec)於下列分析條件下測量，獲得於稀釋劑中具有約30μm或更少之平均顆粒直徑 (X50)之經微米化之粉末的百分率。結果係顯示於表4及5中。 The particle size distribution of a mixture of lactose and micronized lactose in addition to the active ingredient in each of the dry powder inhalation formulations of Examples 1 to 6 and Comparative Examples 1 to 3 was carried out using a particle size analyzer (HELOS). laser diffraction sensor, available from a Sympatec) measured under the following analysis conditions, a percentage of an average particle diameter of about 30μm or less of the micronized powder (X 50) was in the diluent. The results are shown in Tables 4 and 5.
-分析條件- - Analysis conditions -
測量鏡片：R5 Measuring lens: R5
分散壓力：2.5巴 Dispersion pressure: 2.5 bar
進料比率：65% Feed ratio: 65%
測試例2：穩定性測試 Test Example 2: Stability Test
穩定性測試係使用範例1至6及比較例1至5之吸入型調配物之每一者30個膠囊，藉由測量於下列條件下之活性成分的相關化合物之量而實施。比較例4之Seretide Diskus®之20個膠囊，及比較例5之Spiriva HandiHaler®之10個膠囊被使用。每一吸入型調配物之穩定性測試重複三次獲得一平均量。 The stability test was carried out using 30 capsules of each of the inhalation formulations of Examples 1 to 6 and Comparative Examples 1 to 5, by measuring the amount of the relevant compound of the active ingredient under the following conditions. Comparative Example Seretide Diskus ® 4 of the capsule 20, and Comparative Example HandiHaler ® Spiriva 5 of the capsule 10 is used. The stability test for each inhalation formulation was repeated three times to obtain an average amount.
-貯存條件：於40℃及75%相對濕度於Al-Al泡殼包裝內 - Storage conditions: in 40 ° C and 75% relative humidity in the Al-Al blister package
-測試時間：起始階段，1個月後，3個月後，6個月後 - Test time: initial stage, 1 month later, 3 months later, 6 months later
-分析標的：來自氟替皮質醇丙酸鹽之未知相關化合物 - Analytical target: unknown related compound from flutica cortisol propionate
來自沙美特羅之GR97980X From Salometro GR97980X
來自替托比銨之B Ⅱ H27SE B II H27SE from tetolbium
-未知相關化合物及GR97980X之分析方法 -Unknown related compounds and analysis method of GR97980X
檢測器：紫外線吸收檢測器(於228nm之吸收率) Detector: UV absorption detector (absorption at 228 nm)
管柱：Inertsil ODS-2(250mm×4.6mm,3.5μm) Column: Inertsil ODS-2 (250mm × 4.6mm, 3.5μm)
移動相A：以10%(v/v)磷酸調整至pH 2.9之0.05M磷酸二氫銨水溶液 Mobile phase A: 0.05 M aqueous ammonium dihydrogen phosphate solution adjusted to pH 2.9 with 10% (v/v) phosphoric acid
移動相B：乙腈 Mobile phase B: acetonitrile
流速：約1.0毫升/分鐘 Flow rate: about 1.0 ml / min
注射體積：50μL Injection volume: 50μL
管柱溫度：35℃ Column temperature: 35 ° C
-B Ⅱ H27SE之分析方法 -B II H27SE analysis method
檢測器：紫外線吸收檢測器(於240nm之吸收率) Detector: UV absorption detector (absorption at 240 nm)
管柱：用於層析術R之丙基矽烷基二氧化矽凝膠(150mm×3.0mm,3.5μm) Column: propyl decyl cerium oxide gel for chromatography R (150 mm × 3.0 mm, 3.5 μm)
移動相A：藉由使1.0克之甲烷磺酸鈉及5.0克之磷酸二氫鉀溶於980毫升之去離子水中，以稀磷酸使pH調整 至3.0，且加水達1000毫升體積而獲得之溶液。 Mobile phase A: pH adjustment by dilute phosphoric acid by dissolving 1.0 g of sodium methanesulfonate and 5.0 g of potassium dihydrogen phosphate in 980 ml of deionized water A solution obtained by adding water to a volume of 1000 ml to 3.0.
移動相B：甲醇：乙腈：移動相A=10：40：50(v/v/v) Mobile phase B: methanol: acetonitrile: mobile phase A = 10:40:50 (v/v/v)
流速：1.2毫升/分鐘 Flow rate: 1.2 ml / min
注射體積：15μL Injection volume: 15μL
管柱溫度：50℃ Column temperature: 50 ° C
測試結果係顯示於圖1至7。 The test results are shown in Figures 1 to 7.
圖1係氟替皮質醇丙酸鹽之未知相關化合物的總量之圖。參考圖1，未知相關化合物的量被發現於比較例1及2之吸入型調配物中隨著時間顯著增加，但於範例1至6之吸入型調配物中無顯著增加，指示依據本發明實施例之吸入型調配物具有顯著高的氟替皮質醇丙酸鹽穩定性。 Figure 1 is a graph of the total amount of unknown related compounds of fluticacoretate propionate. Referring to Figure 1, the amount of the unknown related compound was found to increase significantly over time in the inhaled formulations of Comparative Examples 1 and 2, but there was no significant increase in the inhaled formulations of Examples 1 to 6, indicating the implementation in accordance with the present invention. An inhaled formulation has a significantly higher flutica cortisol propionate stability.
圖2至4係為沙美特羅的相關化合物之GR97980X的量之圖。參考圖2至4中之結果，與比較例1至3之吸入型調配物相比，沙美特羅之相關化合物的量被發現於範例1至6之吸入型調配物中隨著時間變得顯著較低，且當與比較例4之可購得的產品相比係更低。 Figures 2 to 4 are graphs showing the amount of GR97980X of the related compound of salmeterol. Referring to the results in FIGS. 2 to 4, the amount of the related compound of salmeterol was found to be remarkable over time in the inhalation formulations of Examples 1 to 6 as compared with the inhaled formulations of Comparative Examples 1 to 3. It was lower and was lower when compared to the commercially available product of Comparative Example 4.
圖5至7係為替托比銨的相關化合物之B Ⅱ H27SE的量之圖。參考圖5至7中之結果，與比較例1至3之吸入型調配物相比，替托比銨之相關化合物的量被發現於範例1至 6之吸入型調配物中隨時間變顯著較低，且與比較例5之可購得產品相比係更低。 Figures 5 to 7 are graphs showing the amount of B II H27SE of the related compound of tetolamine. Referring to the results in Figures 5 to 7, the amount of related compounds of tetolamine was found in Example 1 as compared to the inhaled formulations of Comparative Examples 1 to 3. The inhaled formulation of 6 became significantly lower over time and was lower compared to the commercially available product of Comparative Example 5.
基於圖1至7之結果，當與可購得產品相比，以稀釋劑總重量為基準，含有約50重量%或更少之具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末的依據本發明一實施例之一吸入型調配物被發現具有經顯著改善之隨時間的活性成分穩定性。 Based on the results of Figures 1 to 7, containing about 50% by weight or less of the average particle diameter (X 50 ) of about 30 μm or less, based on the total weight of the diluent, based on the total weight of the diluent. Inhalation-type formulations according to one embodiment of the invention of micronized powders have been found to have significantly improved stability of the active ingredients over time.
如上所述，依據本揭露之一或多個實施例，由於以稀釋劑總重量為基準，與組合型活性成分一起使用之約0.1重量%至約50重量%之具有約30μm或更少之平均顆粒直徑(X50)的經微米化之粉末的存在，用於吸入型調配物之一乾粉末及含有此乾粉末之一吸入型調配物會具有經顯著改善之組合型活性成分穩定性。由於經改善之活性成分之穩定性，隨時間產生之活性成分的相關化合物之量可顯著降低。 As described above, in accordance with one or more embodiments of the present disclosure, from about 0.1% by weight to about 50% by weight, based on the total weight of the diluent, has an average of about 30 μm or less, based on the total weight of the diluent. the micronized powder is present through the particle diameter (X 50) for one of the dry powder inhalation formulation and one comprising a dry powder inhaler of this type will have a combination of type formulation stability of the active ingredient by significant improvement. Due to the stability of the improved active ingredient, the amount of the relevant compound of the active ingredient produced over time can be significantly reduced.
雖然本發明已特別參考其較佳實施例而顯示及說明，但熟習此項技藝者會瞭解於型式及節細之各種改變可於其內在未偏離如所附申請專利範圍中界定般之本發明的精神及範圍下進行。揭露之實施例需被認為僅係說明性之意義，而非用於限制目的。因此，本發明之範圍並非以本發明之詳細說明界定，而係以所附之申請專利範圍，且此範圍內之所有差異會被闡釋為包括於本發明內。 While the present invention has been shown and described with reference to the preferred embodiments of the preferred embodiments of the present invention, it will be understood that The spirit and scope of the conduct. The disclosed embodiments are considered to be illustrative only and not for purposes of limitation. Therefore, the scope of the invention is not intended to
Claims (13)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20140132006 | 2014-09-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW201618759A true TW201618759A (en) | 2016-06-01 |
Family
ID=55630875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW104132119A TW201618759A (en) | 2014-09-30 | 2015-09-30 | Dry powder for inhalation formulation having improved stability of combined active ingredients |
Country Status (5)
| Country | Link |
|---|---|
| KR (1) | KR20160038767A (en) |
| AR (1) | AR102108A1 (en) |
| TW (1) | TW201618759A (en) |
| UY (1) | UY36336A (en) |
| WO (1) | WO2016052897A1 (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0012260D0 (en) * | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel composition |
| GB0208609D0 (en) * | 2002-04-13 | 2002-05-22 | Glaxo Group Ltd | Compositions |
| KR20060135873A (en) * | 2004-03-12 | 2006-12-29 | 씨아이피엘에이 엘티디. | Salmeterol inhalation formulations |
| TR201000681A2 (en) * | 2010-01-29 | 2011-08-22 | B�Lg�� Mahmut | Dry powder formulations inhaled. |
| KR20130140358A (en) * | 2012-06-14 | 2013-12-24 | 한미약품 주식회사 | Dry powder for inhalation formulation comprising salmeterol xinafoate, fluticasone propionate and tiotropium bromide, and method for preparing the same |
-
2015
- 2015-09-22 KR KR1020150133883A patent/KR20160038767A/en not_active Application Discontinuation
- 2015-09-22 WO PCT/KR2015/009918 patent/WO2016052897A1/en active Application Filing
- 2015-09-29 UY UY0001036336A patent/UY36336A/en not_active Application Discontinuation
- 2015-09-29 AR ARP150103125A patent/AR102108A1/en unknown
- 2015-09-30 TW TW104132119A patent/TW201618759A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR102108A1 (en) | 2017-02-01 |
| UY36336A (en) | 2016-04-01 |
| KR20160038767A (en) | 2016-04-07 |
| WO2016052897A1 (en) | 2016-04-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI565481B (en) | Dry powder for inhalation formulation comprising salmeterol xinafoate, fluticasone propionate and tiotropium bromide, and method for preparing same | |
| EP1545634B1 (en) | Method of preparing dry powder inhalation compositions | |
| UA119773C2 (en) | Combinations of tiotropium bromide, formoterol and budesonide for the treatment of copd | |
| US9987229B2 (en) | Process for preparing a medicament | |
| CN107205936B (en) | Composition comprising at least one dry powder obtained by spray drying for increasing the stability of the formulation | |
| RU2422144C2 (en) | Application of tiotropium salts for treatment of severe forms of persistent asthma | |
| KR101728116B1 (en) | Dry powder composition for inhalation comprising tiotropium or pharmaceutically acceptable salt thereof | |
| JP2006517178A (en) | Inhalation composition with high drug ratio | |
| KR20210044336A (en) | Dry powder for inhalation formulation and preparation method thereof | |
| EA036153B1 (en) | Pharmaceutical composition for inhalation, packed dosage form, capsule, method of treating obstructive airway diseases and pharmaceutical kit | |
| EA015353B1 (en) | Use of tiotropium salts in the treatment of moderate persistent asthma | |
| US20050158248A1 (en) | Method of preparing dry powder inhalation compositions | |
| TW201618759A (en) | Dry powder for inhalation formulation having improved stability of combined active ingredients | |
| KR20180036459A (en) | Capsule for inhalation with improved content uniformity and delivered dose of combined active ingredients and preparing method thereof | |
| US20220331244A1 (en) | Novel carrier particles for dry powder formulations for inhalation | |
| KR20160117069A (en) | Capsule for inhalation with improved stability of combined active ingredients | |
| KR20170038571A (en) | Inhalation capsule with enhanced delivery rate of active ingredients |