TW202404603A - Composition including cftr activator - Google Patents
Composition including cftr activator Download PDFInfo
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- TW202404603A TW202404603A TW112114740A TW112114740A TW202404603A TW 202404603 A TW202404603 A TW 202404603A TW 112114740 A TW112114740 A TW 112114740A TW 112114740 A TW112114740 A TW 112114740A TW 202404603 A TW202404603 A TW 202404603A
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- TW
- Taiwan
- Prior art keywords
- composition
- formula
- pharmaceutical composition
- optionally substituted
- surfactant
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 299
- 239000012190 activator Substances 0.000 title abstract description 18
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 63
- 150000001875 compounds Chemical class 0.000 claims description 84
- 239000008194 pharmaceutical composition Substances 0.000 claims description 73
- 239000004094 surface-active agent Substances 0.000 claims description 64
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 36
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- 239000002562 thickening agent Substances 0.000 claims description 30
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 29
- 235000002639 sodium chloride Nutrition 0.000 claims description 28
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- 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
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- 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
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Abstract
Description
本發明關於藥學組成物,其含有作為活性藥學成分而增加囊性纖維化穿膜電導調節劑(Cystic fibrosis transmembrane conductance regulator,CFTR)的活性的化合物,更特別關於改善溶解度與物理化學穩定性的藥學組成物。The present invention relates to pharmaceutical compositions, which contain compounds as active pharmaceutical ingredients that increase the activity of cystic fibrosis transmembrane conductance regulator (CFTR), and more particularly to pharmaceuticals that improve solubility and physicochemical stability. composition.
CFTR指的是CFTR基因編碼的膜蛋白和氯離子(Cl -)通道。當存在於細胞膜中的 CFTR活化時,可治療因CFTR 功能損失與退化所介導的數種疾病。舉例來說,活化CFTR的物質可活化Cl -通道以增加淚液產生量。綜上所述,可預期其可修正乾眼綜合症相關的異常淚膜。 CFTR refers to the membrane protein and chloride ion (Cl - ) channel encoded by the CFTR gene. When CFTR present in cell membranes is activated, several diseases mediated by loss and degeneration of CFTR function can be treated. For example, substances that activate CFTR can activate Cl channels to increase tear production. Taken together, it can be expected to correct the abnormal tear film associated with dry eye syndrome.
然而由於眼睛由多種複雜的組織組成,多種阻礙因素會阻擋組織之間的藥物傳遞,僅通過滴注藥學成分無法將活性藥學成分有效地傳遞至眼組織中。另外,考量到眼睛是體內最敏感的器官之一,為了將藥物輸送到眼睛,滴眼液必須具有物理化學穩定性,滴眼液的滲透壓或pH值必須與淚液的滲透壓或pH值相似,且須確保 微生物不會污染或腐蝕滴眼液。最重要的是,必須確保活性藥學成分的溶解度。在此考量下,滴眼液的研發困難重重的。此外,由於本發明的組成中的活性藥學成分包含的CFTR活化劑的原始溶解度低,需要許多配方研究以發展輸送至眼睛的滴眼液。However, since the eye is composed of a variety of complex tissues, various obstructive factors can block drug delivery between tissues, and active pharmaceutical ingredients cannot be effectively delivered to the eye tissue only by instilling pharmaceutical ingredients. In addition, considering that the eye is one of the most sensitive organs in the body, in order to deliver drugs to the eye, eye drops must have physical and chemical stability, and the osmotic pressure or pH value of the eye drops must be similar to that of tears. , and it must be ensured that microorganisms will not contaminate or corrode the eye drops. Most importantly, the solubility of the active pharmaceutical ingredients must be ensured. Under this consideration, the development of eye drops is very difficult. Furthermore, due to the low original solubility of the CFTR activator contained in the active pharmaceutical ingredient in the composition of the present invention, many formulation studies are required to develop eye drops for delivery to the eye.
本發明的發明人致力於開發了活化CFTR的物質,並進一步將其開發為具有改良溶解度和物理化學穩定性的滴眼液配方而完成了本發明。The inventor of the present invention devoted himself to developing a substance that activates CFTR, and further developed the substance into an eye drop formulation with improved solubility and physicochemical stability to complete the present invention.
先前技術文獻 專利文獻 韓國專利申請號:10-2018-0102590。 Prior technical literature patent documents Korean patent application number: 10-2018-0102590.
技術問題technical issues
一實施例需提供藥學組成物,其包括CFTR活化劑作為活性藥學成分並具有改良的溶解度與物理化學穩定性。One embodiment provides a pharmaceutical composition, which includes a CFTR activator as an active pharmaceutical ingredient and has improved solubility and physicochemical stability.
另一實施例需提供組成物以用於眼睛,其包括CFTR活化劑作為活性藥學成分,並具有改良的溶解度與物理化學穩定性。Another embodiment provides a composition for use in the eye, which includes a CFTR activator as an active pharmaceutical ingredient and has improved solubility and physicochemical stability.
另一實施例需由藥學組成物或眼用組成物,以預防、改善、或處理眼部相關的疾病或症狀。Another embodiment requires a pharmaceutical composition or ophthalmic composition to prevent, improve, or treat eye-related diseases or symptoms.
由下述的詳細內容與申請專利範圍,可更明顯地說明本發明的其他目的與優點。本發明的技術領域或類似技術領域中具有通常知識者,可充分認知推斷但未說明於此的內容將省略於此。Other objects and advantages of the present invention can be more clearly explained from the following detailed content and patent scope. Those with ordinary knowledge in the technical field of the present invention or similar technical fields can fully understand and infer that content that is not explained here will be omitted here.
解決問題的方法problem solving methods
一實施例提供的藥學組成物包括CFTR活化劑作為活性藥學成分;以及擇自聚山梨酯 80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑。An embodiment provides a pharmaceutical composition including a CFTR activator as an active pharmaceutical ingredient; and any selected from the group consisting of polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, and combinations thereof. A surfactant.
另一實施例提供的眼用組成物包括CFTR活化劑作為活性藥學成分;擇自聚山梨酯 80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑。Another embodiment provides an ophthalmic composition including a CFTR activator as an active pharmaceutical ingredient; selected from the group consisting of polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, and combinations thereof. Any kind of surfactant.
另一實施例提供的滴眼液包括眼用組成物以預防、改善、或處理眼部相關的疾病或症狀。Another embodiment provides eye drops including ophthalmic compositions to prevent, improve, or treat eye-related diseases or symptoms.
本發明的有利效果Advantageous effects of the present invention
本發明提供藥學組成物,其可確保改善的溶解度與物理化學穩定性,並確保生理等滲性。本發明的藥學組成物可改善溶解度不良且穩定性良好的CFTR活化劑的溶解度,因此品質隨著時間少量改變。此外,藥學組成物的形式可為處理眼部疾病所用的滴眼液,因此病患的藥物依從性高,可有效用於預防或治療CFTR活性相關的眼部疾病。此外,本發明簡化製造製程且放大到工業生產的規模,進而實現經濟的藥品生產。The present invention provides pharmaceutical compositions that ensure improved solubility and physicochemical stability and ensure physiological isotonicity. The pharmaceutical composition of the present invention can improve the solubility of a CFTR activator with poor solubility and good stability, so its quality changes slightly over time. In addition, the pharmaceutical composition can be in the form of eye drops for treating eye diseases, so patients have high drug compliance and can be effectively used to prevent or treat eye diseases related to CFTR activity. In addition, the present invention simplifies the manufacturing process and scales it up to the scale of industrial production, thereby achieving economical pharmaceutical production.
本發明將進一步詳述於下。The invention is described in further detail below.
除非另外定義,本說明書中所用的所有技術用語,與相關領域中具有通常知識者所理解的含義通常相同。此外,說明書說明合適的方法或樣品,但類似或相同的方法與樣品亦屬本說明書的範圍。Unless otherwise defined, all technical terms used in this specification generally have the same meanings as understood by those with ordinary knowledge in the relevant fields. In addition, the instructions describe suitable methods or samples, but similar or identical methods and samples also fall within the scope of the instructions.
此說明書所述的用語「CFTR活化劑」或「增加CFTR活性的化合物」指的是作用以增加CFTR活性的化合物。換言之,此化合物指的是藉由促進CFTR基因編碼的膜蛋白的產生和運動或藉由針對CFTR,而具有激活細胞膜的氯離子(Cl -)通道效果的化合物。舉例來說,「CFTR活化劑」可為式1所示的化合物或其藥學上可接受的鹽類。式1所示的化合物可包括其外消旋體、鏡像異構物、非鏡像異構物、溶劑化物、水合物、同質異晶物、或藥學上可接受的鹽類。舉例來說,式1所示的化合物可為式1a、1b、及1c所示的任何一種化合物。 The terms "CFTR activator" or "compound that increases CFTR activity" as used in this specification refer to compounds that act to increase CFTR activity. In other words, this compound refers to a compound that has the effect of activating the chloride ion (Cl - ) channel of the cell membrane by promoting the production and movement of the membrane protein encoded by the CFTR gene or by targeting CFTR. For example, the "CFTR activator" can be a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. The compound represented by Formula 1 may include its racemate, enantiomer, diastereomer, solvate, hydrate, isomer, or pharmaceutically acceptable salts. For example, the compound represented by Formula 1 can be any compound represented by Formula 1a, 1b, and 1c.
本發明一實施例提供的藥學組成物包括活性藥學成分如式1所示的化合物或其外消旋體、鏡像異構物、非鏡像異構物、溶劑化物、水合物、同質異晶物、或藥學上可接受的鹽類;以及The pharmaceutical composition provided by one embodiment of the present invention includes active pharmaceutical ingredients such as the compound represented by Formula 1 or its racemate, enantiomer, diastereomer, solvate, hydrate, isomer, or pharmaceutically acceptable salts; and
擇自聚山梨酯 80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑:Select from polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, and any surfactant in combination with the above:
式1Formula 1
其中,在式1中,Among them, in equation 1,
R 1及R 2可各自獨立地擇自H、視情況取代的C 1-C 10烷基、視情況取代的C 1-C 10烯基、視情況取代的芳基、視情況取代的雜芳基、視情況取代的芳基烷基、視情況取代的環烷基、視情況取代的雜環烷基、視情況取代的單環或雙環碳環、與視情況取代的單環或雙環雜環,或者 R 1 and R 2 may each be independently selected from H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 alkenyl, optionally substituted aryl, optionally substituted heteroaryl base, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted monocyclic or bicyclic carbocyclic ring, and optionally substituted monocyclic or bicyclic heterocycle ,or
R 1及R 2可與R 1及R 2所連接的氮原子環狀連接在一起,以形成視情況取代的單環或雙環雜環。 R 1 and R 2 may be cyclically linked together with the nitrogen atom to which R 1 and R 2 are attached to form an optionally substituted monocyclic or bicyclic heterocycle.
在一實施例中,式1所示的化合物可擇自式1a、1b、及1c所示的任何一種化合物。In one embodiment, the compound represented by Formula 1 can be selected from any compound represented by Formulas 1a, 1b, and 1c.
式1aFormula 1a
其中式1a的化合物亦可視作(S)-(4-苯甲醯基-3-甲基哌嗪-1-基)(7-(3,4-二甲氧基苯基)吡唑并[1,5-a]嘧啶-2-基)甲酮;The compound of formula 1a can also be regarded as (S)-(4-benzoyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo[ 1,5-a]pyrimidin-2-yl)methanone;
式1bFormula 1b
式1b的化合物亦可視作7-(3,4-二甲氧基苯基)-N-(4-羥基苯基)吡唑并[1,5-a]嘧啶-2-甲醯胺;以及The compound of formula 1b can also be regarded as 7-(3,4-dimethoxyphenyl)-N-(4-hydroxyphenyl)pyrazolo[1,5-a]pyrimidine-2-methamide; and
式1cFormula 1c
式1的化合物亦可視作7-(3,4-二甲氧基苯基)-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)吡唑并[1,5-a]嘧啶-2-甲醯胺鹽酸鹽。The compound of formula 1 can also be regarded as 7-(3,4-dimethoxyphenyl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyrimidine-2-methamide hydrochloride.
在此說明書中除非另外說明,主要藥學成分(API)指的是式1的化合物,或其所含的式1a、式1b、或式1c的化合物。In this specification, unless otherwise stated, the main pharmaceutical ingredient (API) refers to the compound of formula 1, or the compound of formula 1a, formula 1b, or formula 1c contained therein.
本發明的化合物可包括不對稱或手性中心,因此可由不同的立體異構物形式存在。本發明的化合物的所有立體異構物形式如非鏡像異構物、鏡像異構物、與外消旋體的混合物,被視作形成本發明的一部分。The compounds of the present invention may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, such as diastereomers, enantiomers, and racemic mixtures, are considered to form part of the present invention.
本發明的用語「鏡像異構物」指的是兩種立體異構物的化合物,其為彼此不可重疊的鏡像。本發明的用語「非鏡像異構物」指的是具有兩個或更多手性中心的兩個或兩個立體異構物,其分子彼此非鏡像。此外,鏡像異構物的 50:50 混合物稱作「外消旋體」或「外消旋混合物」。The term "enantiomer" as used herein refers to a compound of two stereoisomers that are non-superimposable mirror images of each other. The term "diastereomer" as used herein refers to two or more stereoisomers having two or more chiral centers whose molecules are not mirror images of each other. Additionally, a 50:50 mixture of enantiomers is called a "racemate" or "racemic mixture."
說明書的用語「藥學上可接受的鹽」指的是藥品工業中常用的鹽,其例子包括由鈣、鉀、鈉、鎂、或類似物製備的無機離子鹽;由鹽酸、硝酸、磷酸、氫溴酸、碘酸、過氯酸、酒石酸、硫酸、或類似物製備的無機酸鹽;由乙酸、三氟乙酸、檸檬酸、馬來酸、琥珀酸、草酸、苯甲酸、酒石酸、富馬酸、苦杏仁酸、丙酸、檸檬酸、乳酸、乙醇酸、葡萄糖酸、半乳醣醛酸、谷氨酸、戊二酸、葡萄醣醛酸、天冬氨酸、抗壞血酸、碳酸、香草酸、氫碘酸、或類似物製備的有機酸鹽;由甲磺酸、乙磺酸、苯磺酸、對甲苯磺酸、萘磺酸、或類似物製備的磺酸鹽;由甘氨酸、精氨酸、賴氨酸、或類似物製備的氨基酸鹽;或由三甲胺、三乙胺、氨、吡啶、甲基吡啶、或類似物製備的胺鹽。然而,實施例不具體限於此。The term "pharmaceutically acceptable salts" in the instructions refers to salts commonly used in the pharmaceutical industry. Examples include inorganic ionic salts prepared from calcium, potassium, sodium, magnesium, or the like; salts prepared from hydrochloric acid, nitric acid, phosphoric acid, hydrogen Inorganic acid salts prepared from bromic acid, iodic acid, perchloric acid, tartaric acid, sulfuric acid, or the like; from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid , mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydrogen Organic acid salts prepared from iodic acid, or the like; sulfonates prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, or the like; glycine, arginine, Amino acid salts prepared from lysine, or the like; or amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, or the like. However, the embodiment is not specifically limited thereto.
一實施例的藥學組成物可包含(S)-(4-苯甲醯基-3-甲基哌嗪-1-基)(7-(3,4-二甲氧基苯基)吡唑并[1,5-a]嘧啶- 2-基)甲酮作為活性藥學成分; 以及選自聚山梨醇酯80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑。The pharmaceutical composition of one embodiment may include (S)-(4-benzyl-3-methylpiperazin-1-yl)(7-(3,4-dimethoxyphenyl)pyrazolo [1,5-a]pyrimidin-2-yl)methanone as the active pharmaceutical ingredient; and selected from polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, and the above Any combination of surfactants.
一實施例的藥學組成物可包含7-(3,4-二甲氧基苯基)-N-(4-羥基苯基)吡唑并[1,5-a]嘧啶-2-甲醯胺作為活性藥學成分; 以及選自聚山梨醇酯80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑。The pharmaceutical composition of one embodiment may include 7-(3,4-dimethoxyphenyl)-N-(4-hydroxyphenyl)pyrazolo[1,5-a]pyrimidine-2-methamide As an active pharmaceutical ingredient; and any surfactant selected from the group consisting of polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, and combinations of the above.
一實施例的藥學組成物可包含7-(3,4-二甲氧基苯基)-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)吡唑并[1,5-a]嘧啶-2-甲醯胺鹽酸鹽作為活性藥學成分;以及選自聚山梨醇酯80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑。The pharmaceutical composition of one embodiment may include 7-(3,4-dimethoxyphenyl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrazolo [1,5-a]pyrimidine-2-methamide hydrochloride as the active pharmaceutical ingredient; and selected from polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, Any surfactant combined with the above.
本發明一實施例的藥學組成物可包括CFTR活化劑如活性藥學成分,其基於藥學組成物總量的含量可小於或等於1 % (w/v)。舉例來說,活性藥學成分量可大於或等於0.00001 % (w/v)且小於或等於1 % (w/v)、大於或等於0.00005 % (w/v)且小於或等於1 % (w/v)、大於或等於0.0001 % (w/v)且小於或等於1 % (w/v)、大於或等於0.0005 % (w/v)且小於或等於1 % (w/v)、或大於或等於0.001 % (w/v)且小於或等於1 % (w/v)。The pharmaceutical composition according to an embodiment of the present invention may include a CFTR activator such as an active pharmaceutical ingredient, and its content may be less than or equal to 1% (w/v) based on the total amount of the pharmaceutical composition. For example, the amount of active pharmaceutical ingredient may be greater than or equal to 0.00001% (w/v) and less than or equal to 1% (w/v), greater than or equal to 0.00005% (w/v) and less than or equal to 1% (w/ v), greater than or equal to 0.0001 % (w/v) and less than or equal to 1 % (w/v), greater than or equal to 0.0005 % (w/v) and less than or equal to 1 % (w/v), or greater than or Equal to 0.001 % (w/v) and less than or equal to 1 % (w/v).
舉例來說,CFTR活化劑如式1的化合物(比如式1a、1b、或1c的化合物)基於藥學成分總量的含量,可為小於或等於1 % (w/v)、0.001 % (w/v)至1 % (w/v)、0.005 % (w/v)至1 % (w/v)、0.005 % (w/v)至0.9 % (w/v)、0.005 % (w/v)至0.8 % (w/v)、0.005 % (w/v)至0.7% (w/v)、0.005 % (w/v)至0.6 % (w/v)、0.005 % (w/v)至0.5 % (w/v)、0.005 % (w/v)至0.4 % (w/v)、0.005 % (w/v)至0.3 % (w/v)、0.005 % (w/v)至0.2 % (w/v)、0.01 % (w/v)至0.9 % (w/v)、0.01 % (w/v)至0.8 % (w/v)、0.01 % (w/v)至0.7 % (w/v)、0.01 % (w/v)至0.6 % (w/v)、0.01 % (w/v)至0.5 % (w/v)、0.01 % (w/v)至0.4 % (w/v)、0.01 % (w/v)至0.3 % (w/v)、0.01 % (w/v)至0.2 % (w/v)、0.03 % (w/v)至0.5 % (w/v)、0.03 % (w/v)至0.4 % (w/v)、0.03 % (w/v)至0.3 % (w/v)、0.03 % (w/v)至0.2 % (w/v)、0.05 % (w/v)至0.9 % (w/v)、0.05 % (w/v)至0.5 % (w/v)、0.05 % (w/v)至0.4 % (w/v)、0.05 % (w/v)至0.3 % (w/v)、0.05 % (w/v)至0.2 % (w/v)、0.1 % (w/v)至0.9 % (w/v)、0.1 % (w/v)至0.8 % (w/v)、0.1 % (w/v)至0.7 % (w/v)、0.1 % (w/v)至0.6 % (w/v)、0.1 % (w/v)至0.5 % (w/v)、或0.1 % (w/v)至0.4 % (w/v)。本發明的式1的化合物如式1a、1b、或1c的化合物的溶解性不良,但在此處所述的含量範圍中可改善藥物的穩定性與儲存性,而不產生活性藥學成分的沉澱或改變活性藥學成分的外觀。For example, the content of the CFTR activator such as the compound of Formula 1 (such as the compound of Formula 1a, 1b, or 1c) based on the total amount of pharmaceutical ingredients can be less than or equal to 1% (w/v), 0.001% (w/ v) to 1 % (w/v), 0.005 % (w/v) to 1 % (w/v), 0.005 % (w/v) to 0.9 % (w/v), 0.005 % (w/v) to 0.8 % (w/v), 0.005 % (w/v) to 0.7% (w/v), 0.005 % (w/v) to 0.6 % (w/v), 0.005 % (w/v) to 0.5 % (w/v), 0.005 % (w/v) to 0.4 % (w/v), 0.005 % (w/v) to 0.3 % (w/v), 0.005 % (w/v) to 0.2 % ( w/v), 0.01 % (w/v) to 0.9 % (w/v), 0.01 % (w/v) to 0.8 % (w/v), 0.01 % (w/v) to 0.7 % (w/ v), 0.01 % (w/v) to 0.6 % (w/v), 0.01 % (w/v) to 0.5 % (w/v), 0.01 % (w/v) to 0.4 % (w/v) , 0.01 % (w/v) to 0.3 % (w/v), 0.01 % (w/v) to 0.2 % (w/v), 0.03 % (w/v) to 0.5 % (w/v), 0.03 % (w/v) to 0.4 % (w/v), 0.03 % (w/v) to 0.3 % (w/v), 0.03 % (w/v) to 0.2 % (w/v), 0.05 % ( w/v) to 0.9 % (w/v), 0.05 % (w/v) to 0.5 % (w/v), 0.05 % (w/v) to 0.4 % (w/v), 0.05 % (w/ v) to 0.3 % (w/v), 0.05 % (w/v) to 0.2 % (w/v), 0.1 % (w/v) to 0.9 % (w/v), 0.1 % (w/v) to 0.8 % (w/v), 0.1 % (w/v) to 0.7 % (w/v), 0.1 % (w/v) to 0.6 % (w/v), 0.1 % (w/v) to 0.5 % (w/v), or 0.1 % (w/v) to 0.4 % (w/v). The compound of formula 1 of the present invention, such as the compound of formula 1a, 1b, or 1c, has poor solubility, but within the content range described here, it can improve the stability and storage of the drug without causing precipitation of the active pharmaceutical ingredient. or alter the appearance of the active pharmaceutical ingredient.
此外,在此處說明的範圍內,本發明的藥學組成物可提供CFTR控制效果,比如預防、改善、或治療乾眼或結膜炎的效果而無副作用。Furthermore, within the scope described herein, the pharmaceutical compositions of the present invention can provide CFTR control effects, such as the effects of preventing, ameliorating, or treating dry eye or conjunctivitis without side effects.
說明書的用語「界面活性劑」指的是溶解於水或水溶液中用於降低界面張力或表面張力的物質。The term "surfactant" used in the specification refers to a substance dissolved in water or an aqueous solution to reduce interfacial tension or surface tension.
一實施例的界面活性劑可為選自聚山梨酯80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一者,且確認界面活性劑可進一步提高式1所示的化合物(如式1a、1b、或1c的化合物)的溶解度 (在磷酸鹽緩衝鹽水中的溶解度為34.1 μg/mL),並提高活性藥學成分的物理化學穩定性,因儲存一段時間後的界面活性劑不改變外觀。The surfactant in one embodiment can be any one selected from polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, and combinations of the above, and it is confirmed that the surfactant can Further improve the solubility of the compound represented by Formula 1 (such as the compound of Formula 1a, 1b, or 1c) (the solubility in phosphate buffered saline is 34.1 μg/mL), and improve the physical and chemical stability of the active pharmaceutical ingredient, because Surfactants do not change appearance after storage for a period of time.
說明書中的「聚山梨醇酯80」指的是經由加成聚合環氧乙烷至山梨醇酐油酸酯的游離羥基所得的非離子表面活性劑,且包括市售商品「Tween 80 (製造商:Croda)」。然而本發明不限於此種產品。"Polysorbate 80" in the specification refers to a nonionic surfactant obtained by the addition polymerization of ethylene oxide to the free hydroxyl group of sorbitan oleate, and includes the commercially available product "Tween 80 (manufacturer : Croda)". However, the present invention is not limited to such products.
說明書中的「聚氧乙烯-35蓖麻油」主要包含聚乙二醇蓖麻油酸酯以及游離二醇與乙氧基化甘油的三蓖麻油酸酯。舉例來說,其可得自環氧乙烷與蓖麻油酸甘油酯之間的反應。其通常為市售的「Kolliphor EL (製造商為BASF)」或「Kolliphor ELP (製造商為BASF)」,但不限於此種產品。The "polyoxyethylene-35 castor oil" in the instructions mainly contains polyethylene glycol ricinoleate and triricinoleate of free glycol and ethoxylated glycerin. It can be obtained, for example, from the reaction between ethylene oxide and ricinolein. It is usually the commercially available "Kolliphor EL (manufacturer: BASF)" or "Kolliphor ELP (manufacturer: BASF)", but is not limited to this product.
在一實施例中,界面活性劑可為聚氧乙烯-35蓖麻油。In one embodiment, the surfactant may be polyoxyethylene-35 castor oil.
在一實施例的藥學組成物中,界面活性劑的含量足以降低活性藥學成分在水溶液中的界面張力,並穩定維持活性藥學成分的溶解狀態,即其量足以改善活性藥學成分的溶解度。具體而言,即使使用少量的聚山梨醇酯80、聚乙二醇40-硬脂酸酯、及/或聚氧乙烯-35蓖麻油,也可改善活性藥學成分的溶解度至足以表現藥理效果的程度。In the pharmaceutical composition of one embodiment, the content of the surfactant is sufficient to reduce the interfacial tension of the active pharmaceutical ingredient in the aqueous solution and stably maintain the dissolved state of the active pharmaceutical ingredient, that is, the amount is sufficient to improve the solubility of the active pharmaceutical ingredient. Specifically, even using a small amount of polysorbate 80, polyethylene glycol 40-stearate, and/or polyoxyethylene-35 castor oil can improve the solubility of the active pharmaceutical ingredient to a level sufficient to exhibit pharmacological effects. degree.
本發明一實施例的藥學組成物可包括界面活性劑,其基於總組成的量可為小於或等於9 % (w/v)或小於或等於7 % (w/v)。具體而言,本發明的組成物的界面活性劑的量可為1 % (w/v)至9 % (w/v)、2 % (w/v)至9 % (w/v)、4 % (w/v)至9 % (w/v)、1 % (w/v)至7 % (w/v)、或2 % (w/v)至7 % (w/v)。當界面活性劑的含量在上述範圍內,本發明的藥學組成物可維持穩定外觀並充分維持液相的活性藥學成分的溶解度,因此可有效作為滴眼液所用的配方。The pharmaceutical composition of an embodiment of the present invention may include a surfactant, the amount of which may be less than or equal to 9% (w/v) or less than or equal to 7% (w/v) based on the total composition. Specifically, the amount of surfactant in the composition of the present invention can be 1% (w/v) to 9% (w/v), 2% (w/v) to 9% (w/v), 4 % (w/v) to 9 % (w/v), 1 % (w/v) to 7 % (w/v), or 2 % (w/v) to 7 % (w/v). When the content of the surfactant is within the above range, the pharmaceutical composition of the present invention can maintain a stable appearance and fully maintain the solubility of the active pharmaceutical ingredients in the liquid phase, and therefore can be effectively used as a formula for eye drops.
本發明一實施例的藥學組成物可包括界面活性劑,其基於總組成的量可為小於或等於9 % (w/v)、小於或等於7 % (w/v)、1 % (w/v)至9 % (w/v)、2 % (w/v)至9 % (w/v)、4 % (w/v)至9 % (w/v)、1 % (w/v)至7 % (w/v)、或1 % (w/v)至9 % (w/v);式1的CFTR活化劑化合物(如式1a、1b、或1c的化合物),其量可為小於或等於1% (w/v)、0.001 % (w/v)至1 % (w/v)、0.005 % (w/v)至1 % (w/v)、0.005 % (w/v)至0.9 % (w/v)、0.005 % (w/v)至0.8 % (w/v)、0.005 % (w/v)至0.7 % (w/v)、0.005 % (w/v)至0.6 % (w/v)、0.005 % (w/v)至0.5 % (w/v)、0.005 % (w/v)至0.4 % (w/v)、0.005 % (w/v)至0.3 % (w/v)、0.005 % (w/v)至0.2 % (w/v)、0.01 % (w/v)至0.9 % (w/v)、0.01 % (w/v)至0.8 % (w/v)、0.01 % (w/v)至0.7 % (w/v)、0.01 % (w/v)至0.6 % (w/v)、0.01 % (w/v)至0.5 % (w/v)、0.01 % (w/v)至0.4 % (w/v)、0.01 % (w/v)至0.3 % (w/v)、0.01 % (w/v)至0.2 % (w/v)、0.03 % (w/v)至0.5 % (w/v)、0.03 % (w/v)至0.4 % (w/v)、0.03 % (w/v)至0.3 % (w/v)、0.03 % (w/v)至0.2 % (w/v)、0.05 % (w/v)至0.9 % (w/v)、0.05 % (w/v)至0.5 % (w/v)、0.05 % (w/v)至0.4 % (w/v)、0.05 % (w/v)至0.3 % (w/v)、0.05 % (w/v)至0.2 % (w/v)、0.1 % (w/v)至0.9 % (w/v)、0.1 % (w/v)至0.8 % (w/v)、0.1 % (w/v)至0.7 % (w/v)、0.1 % (w/v)至0.6 % (w/v)、0.1 % (w/v)至0.5 % (w/v)、或0.1 % (w/v)至0.4 % (w/v)。The pharmaceutical composition according to an embodiment of the present invention may include a surfactant, and its amount based on the total composition may be less than or equal to 9% (w/v), less than or equal to 7% (w/v), 1% (w/ v) to 9 % (w/v), 2 % (w/v) to 9 % (w/v), 4 % (w/v) to 9 % (w/v), 1 % (w/v) to 7% (w/v), or 1% (w/v) to 9% (w/v); the CFTR activator compound of Formula 1 (such as the compound of Formula 1a, 1b, or 1c), the amount may be Less than or equal to 1% (w/v), 0.001 % (w/v) to 1 % (w/v), 0.005 % (w/v) to 1 % (w/v), 0.005 % (w/v) to 0.9 % (w/v), 0.005 % (w/v) to 0.8 % (w/v), 0.005 % (w/v) to 0.7 % (w/v), 0.005 % (w/v) to 0.6 % (w/v), 0.005 % (w/v) to 0.5 % (w/v), 0.005 % (w/v) to 0.4 % (w/v), 0.005 % (w/v) to 0.3 % ( w/v), 0.005 % (w/v) to 0.2 % (w/v), 0.01 % (w/v) to 0.9 % (w/v), 0.01 % (w/v) to 0.8 % (w/ v), 0.01 % (w/v) to 0.7 % (w/v), 0.01 % (w/v) to 0.6 % (w/v), 0.01 % (w/v) to 0.5 % (w/v) , 0.01 % (w/v) to 0.4 % (w/v), 0.01 % (w/v) to 0.3 % (w/v), 0.01 % (w/v) to 0.2 % (w/v), 0.03 % (w/v) to 0.5 % (w/v), 0.03 % (w/v) to 0.4 % (w/v), 0.03 % (w/v) to 0.3 % (w/v), 0.03 % ( w/v) to 0.2 % (w/v), 0.05 % (w/v) to 0.9 % (w/v), 0.05 % (w/v) to 0.5 % (w/v), 0.05 % (w/ v) to 0.4% (w/v), 0.05% (w/v) to 0.3% (w/v), 0.05% (w/v) to 0.2% (w/v), 0.1% (w/v) to 0.9 % (w/v), 0.1 % (w/v) to 0.8 % (w/v), 0.1 % (w/v) to 0.7 % (w/v), 0.1 % (w/v) to 0.6 % (w/v), 0.1 % (w/v) to 0.5 % (w/v), or 0.1 % (w/v) to 0.4 % (w/v).
在本發明一實施例的藥學組成物中,界面活性劑可作為形成奈米微胞的成分,以利角膜滲透而增加進入眼睛的奈米尺寸的藥物的吸收。本發明的實施例的藥學組成物可包括CFTR活化劑以及選自聚山梨酯80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑所形成的奈米微胞配方。In the pharmaceutical composition according to an embodiment of the present invention, the surfactant can be used as a component to form nanocells to facilitate corneal penetration and increase the absorption of nanometer-sized drugs entering the eye. Pharmaceutical compositions of embodiments of the present invention may include a CFTR activator and any interface activity selected from the group consisting of polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, and combinations thereof. Nanocell formula formed by the agent.
本發明基於奈米微胞配方技術所製備的藥學組成物含有CFTR活化劑和界面活性劑,且具有改善的溶解度。The pharmaceutical composition prepared based on the nanocell formulation technology of the present invention contains CFTR activator and surfactant, and has improved solubility.
說明書的用語「奈米微胞」指的是將臨界微胞濃度或更高濃度的界面活性劑滴入水性介質並攪拌所生成的自發奈米顆粒,其尺寸通常小於或等於200 nm。The term "nanocells" in the instructions refers to the spontaneous nanoparticles generated by dropping surfactant at a critical cell concentration or higher into an aqueous medium and stirring. Its size is usually less than or equal to 200 nm.
在一實施例中,本發明的奈米微胞顆粒的平均粒徑可小於或等於100 nm、小於或等於90 nm、小於或等於80 nm、小於或等於70 nm、小於或等於60 nm、小於或等於50 nm、小於或等於40 nm、小於或等於30 nm、或小於或等於20 nm。In one embodiment, the average particle diameter of the nanocell particles of the present invention can be less than or equal to 100 nm, less than or equal to 90 nm, less than or equal to 80 nm, less than or equal to 70 nm, less than or equal to 60 nm, less than Or equal to 50 nm, less than or equal to 40 nm, less than or equal to 30 nm, or less than or equal to 20 nm.
在一實施例中,奈米微胞顆粒的平均粒徑可為0.1 nm至100 nm、1 nm至100 nm、5 nm至50 nm、10 nm至30 nm、10 nm至20 nm、10 nm至15 nm、12 nm至14 nm、11 nm至14 nm、10.5 nm至13 nm、或11 nm至13 nm。在本發明一實施例的組成物中的奈米微胞顆粒中,就算製造時或在惡劣儲存條件下(如冷藏5天、60˚C下5天、以及60˚C下10天),粒徑變化可維持在±10 %以內。In one embodiment, the average particle diameter of the nanocell particles can be 0.1 nm to 100 nm, 1 nm to 100 nm, 5 nm to 50 nm, 10 nm to 30 nm, 10 nm to 20 nm, 10 nm to 15 nm, 12 nm to 14 nm, 11 nm to 14 nm, 10.5 nm to 13 nm, or 11 nm to 13 nm. In the nanocell particles in the composition of an embodiment of the present invention, even during production or under harsh storage conditions (such as refrigeration for 5 days, 60˚C for 5 days, and 60˚C for 10 days), the particles The diameter change can be maintained within ±10%.
在以滴眼液的形式施加藥學組成物時,本發明一實施例中含有奈米微胞的藥學組成物的優點為優異的角膜滲透性,並增加奈米尺寸的藥物的眼內吸收。本發明此實施例提供的眼用組成物包含:CFTR活化劑;以及選自聚山梨醇酯80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑。When the pharmaceutical composition is applied in the form of eye drops, the advantage of the pharmaceutical composition containing nanocells in one embodiment of the present invention is excellent corneal permeability and increased intraocular absorption of nano-sized drugs. The ophthalmic composition provided by this embodiment of the present invention includes: CFTR activator; and selected from the group consisting of polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, and combinations of the above. Any kind of surfactant.
在一實施例中,組成物可進一步包括擇自緩衝劑、等滲劑、增稠劑、pH調整劑、防腐劑、與抗氧化劑的至少一添加劑。In one embodiment, the composition may further include at least one additive selected from buffers, isotonic agents, thickeners, pH adjusters, preservatives, and antioxidants.
說明書的用語「緩衝劑」指的是用於穩定pH值於特定範圍中的物質。The term "buffer" in the specification refers to a substance used to stabilize the pH value within a specific range.
在一實施例中,緩衝劑可為選自磷酸鹽、三羥甲基胺基甲烷、檸檬酸鹽、與上述之組合的任何一者。In one embodiment, the buffering agent may be any one selected from the group consisting of phosphate, trishydroxymethylaminomethane, citrate, and combinations thereof.
舉例來說,磷酸鹽可為磷酸二鈉(磷酸氫二鈉,Na 2HPO 4)與磷酸單鈉(磷酸二氫鈉,NaH 2PO 4)的緩衝溶液。磷酸鹽可以作為酸酐或水合物提供。在一實施例中,緩衝劑可為Na 2HPO 4·7H 2O與NaH 2PO 4·2H 2O的混合物。 For example, the phosphate can be a buffer solution of disodium phosphate (disodium hydrogen phosphate, Na 2 HPO 4 ) and monosodium phosphate (sodium dihydrogen phosphate, NaH 2 PO 4 ). Phosphates can be provided as anhydrides or hydrates. In one embodiment, the buffer may be a mixture of Na 2 HPO 4 ·7H 2 O and NaH 2 PO 4 ·2H 2 O.
在一實施例中,緩衝劑可為檸檬酸鹽。舉例來說,緩衝劑可為檸檬酸與檸檬酸鹽的混合物。舉例來說,檸檬酸鹽可為檸檬酸鈉。檸檬酸鹽的形式可為酸酐或水合物(如檸檬酸鈉二水合物)。舉例來說,檸檬酸鹽可為檸檬酸鈉(如其二水合物)與檸檬酸的混合物。在一實施例中,需長時間儲存含有檸檬酸作為緩衝劑的組成物時,pH變化明顯降低且減少雜質產生,可提高組成物的物理化學穩定性。In one embodiment, the buffering agent may be citrate. For example, the buffer may be a mixture of citric acid and citrate salts. For example, the citrate salt may be sodium citrate. The citrate salt may be in the form of an anhydride or a hydrate (such as sodium citrate dihydrate). For example, the citrate salt may be a mixture of sodium citrate (eg its dihydrate) and citric acid. In one embodiment, when a composition containing citric acid as a buffer needs to be stored for a long time, the pH change is significantly reduced and the generation of impurities is reduced, which can improve the physical and chemical stability of the composition.
在一實施例的藥學組成物中,緩衝劑的含量足以穩定含有活性藥學成分的組成物的pH值。In one embodiment of the pharmaceutical composition, the content of the buffering agent is sufficient to stabilize the pH value of the composition containing the active pharmaceutical ingredient.
在一實施例的藥學組成物中,緩衝劑的含量可為0.1 % (w/v)至0.5 % (w/v)、0.15 % (w/v)至0.4 % (w/v)、0.2 % (w/v)至0.4 % (w/v)、0.2 % (w/v)至0.3 % (w/v)、0.25 % (w/v)至0.28 % (w/v)、0.27 % (w/v)至0.28 % (w/v)、0.1 % (w/v)、0.2 % (w/v)、0.25 % (w/v)、0.3 % (w/v)、或0.35 % (w/v)。In the pharmaceutical composition of one embodiment, the content of the buffer can be 0.1% (w/v) to 0.5% (w/v), 0.15% (w/v) to 0.4% (w/v), 0.2% (w/v) to 0.4 % (w/v), 0.2 % (w/v) to 0.3 % (w/v), 0.25 % (w/v) to 0.28 % (w/v), 0.27 % (w /v) to 0.28 % (w/v), 0.1 % (w/v), 0.2 % (w/v), 0.25 % (w/v), 0.3 % (w/v), or 0.35 % (w/ v).
說明書的用語「等滲劑」指的是以滴眼液、注射劑、噴霧劑、或類似物施用時,用於緩解疼痛或不適並防止紅血球細胞溶解而皺縮的物質。The term "isotonic agent" used in the instructions refers to a substance used to relieve pain or discomfort and prevent red blood cells from lysing and shrinking when administered as eye drops, injections, sprays, or the like.
在一實施例中,等滲劑可擇自甘露醇、山梨醇、氯化鈉、甘油、聚乙二醇、丙二醇、與上述之組合的任何一者,但不限於此。In one embodiment, the isotonic agent can be selected from mannitol, sorbitol, sodium chloride, glycerin, polyethylene glycol, propylene glycol, and any combination of the above, but is not limited thereto.
聚乙二醇是相對穩定且無毒的物質,且其形狀與性質在室溫下可隨分子量變化。舉例來說,聚乙二醇200 (PEG 200)、聚乙二醇300 (PEG 300)、聚乙二醇400 (PEG 400)、與聚乙二醇600 (PEG 600)在室溫下為透明液體形式。舉例來說,聚乙二醇1000 (PEG 1000)在室溫下為糊狀不透明白色固體。舉例來說,聚乙二醇4000 (PEG 4000)在室溫下是不透明的的固體如薄片、顆粒、或粉末。Polyethylene glycol is a relatively stable and non-toxic substance, and its shape and properties can change with molecular weight at room temperature. For example, polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), and polyethylene glycol 600 (PEG 600) are transparent at room temperature. Liquid form. For example, polyethylene glycol 1000 (PEG 1000) is a pasty, opaque white solid at room temperature. For example, polyethylene glycol 4000 (PEG 4000) is an opaque solid at room temperature such as flakes, granules, or powder.
可用於本發明組成物中的聚乙二醇為透明液體形式,其可與其他藥學成分均勻混合以作為滴眼液,且聚乙二醇的平均分子量為190至630。在一實施例中,可採用聚乙二醇200、聚乙二醇300、聚乙二醇400、或聚乙二醇600。The polyethylene glycol that can be used in the composition of the present invention is in the form of a transparent liquid, which can be evenly mixed with other pharmaceutical ingredients to be used as eye drops, and the average molecular weight of the polyethylene glycol is 190 to 630. In one embodiment, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, or polyethylene glycol 600 may be used.
在一實施例中,聚乙二醇可為聚乙二醇400。In one embodiment, the polyethylene glycol may be polyethylene glycol 400.
在一實施例中,等滲劑可為氯化鈉、丙二醇、或上述之組合。In one embodiment, the isotonicity agent may be sodium chloride, propylene glycol, or a combination thereof.
在一實施例中,組成物包括氯化鈉作為長時間儲存的緩衝劑,可明顯降低pH變化與雜質產生,以改善組成物的物理化學穩定性。In one embodiment, the composition includes sodium chloride as a buffer for long-term storage, which can significantly reduce pH changes and the generation of impurities, thereby improving the physical and chemical stability of the composition.
在一實施例中,藥學組成物所含的等滲劑的量,在活性藥學成分的組成物作為滴眼液施用時足以減輕疼痛或不適。In one embodiment, the pharmaceutical composition contains an isotonic agent in an amount sufficient to reduce pain or discomfort when the active pharmaceutical ingredient composition is administered as eye drops.
一實施例的藥學組成物可包含0 % (w/v)至10 % (w/v),比如0 % (w/v)至5.0 % (w/v)或0 % (w/v)至1.0 % (w/v)的等滲劑。舉例來說,藥學組成物中等滲劑的量可為0 % (w/v)至9 % (w/v)、0 % (w/v)至7 % (w/v)、0 % (w/v)至5 % (w/v)、0 % (w/v)至0.8 % (w/v)、0.00001 % (w/v)至9 % (w/v)、0.00001 % (w/v)至8 % (w/v)、0.0001 % (w/v)至0.8 % (w/v)、0.001 % (w/v)至0.8 % (w/v)、0.01 % (w/v)至0.8 % (w/v)、0.1 % (w/v)至0.8 % (w/v)、0.2 % (w/v)至0.8 % (w/v)、0.3 % (w/v)至0.8 % (w/v)、0.5 % (w/v)至0.8 % (w/v)、0.5 % (w/v)至0.75 % (w/v)、0.7 % (w/v)至0.8 % (w/v)、0.1 % (w/v)至0.75 % (w/v)、0.2 % (w/v)、0.3 % (w/v)、或0.75 % (w/v)。一實施例的組成物可不含等滲劑。The pharmaceutical composition of an embodiment may include 0% (w/v) to 10% (w/v), such as 0% (w/v) to 5.0% (w/v) or 0% (w/v) to 1.0 % (w/v) isotonic agent. For example, the amount of isotonic agent in the pharmaceutical composition can be 0% (w/v) to 9% (w/v), 0% (w/v) to 7% (w/v), 0% (w/v) /v) to 5 % (w/v), 0 % (w/v) to 0.8 % (w/v), 0.00001 % (w/v) to 9 % (w/v), 0.00001 % (w/v ) to 8 % (w/v), 0.0001 % (w/v) to 0.8 % (w/v), 0.001 % (w/v) to 0.8 % (w/v), 0.01 % (w/v) to 0.8 % (w/v), 0.1 % (w/v) to 0.8 % (w/v), 0.2 % (w/v) to 0.8 % (w/v), 0.3 % (w/v) to 0.8 % (w/v), 0.5 % (w/v) to 0.8 % (w/v), 0.5 % (w/v) to 0.75 % (w/v), 0.7 % (w/v) to 0.8 % (w /v), 0.1% (w/v) to 0.75% (w/v), 0.2% (w/v), 0.3% (w/v), or 0.75% (w/v). The composition of one embodiment may contain no isotonicity agent.
說明書的用語「增稠劑或增黏度劑」指的是增加液體藥品黏度所用的物質。The term "thickener or viscosity-increasing agent" in the instructions refers to substances used to increase the viscosity of liquid pharmaceutical products.
在一實施例中,增稠劑可為選自羥丙基甲基纖維素、聚乙烯醇、羧甲基纖維素鈉、羥乙基纖維素、聚乙烯吡咯烷酮、與上述之組合的任何一者,但不限於此。In one embodiment, the thickener may be any one selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, and combinations thereof. , but not limited to this.
一實施例採用增稠劑時,可改善活性藥學成分的物理化學穩定性。舉例來說,增稠劑可為羥丙基甲基纖維素。In one embodiment, when a thickener is used, the physical and chemical stability of the active pharmaceutical ingredient can be improved. For example, the thickening agent may be hydroxypropyl methylcellulose.
說明書的用語「羥丙基甲基纖維素」也可視作「羥丙甲纖維素」,亦可視作商品名「Pharmacoat」。然而本發明的增稠劑不限於此。The term "hydroxypropyl methylcellulose" in the instructions can also be regarded as "hypromellose" and the trade name "Pharmacoat". However, the thickener of the present invention is not limited to this.
說明書中的用語「聚乙烯吡咯烷酮」所指的物質可視作商品名「Kollidon 25」。然而本發明的增稠劑不限於此。The substance referred to by the term "polyvinylpyrrolidone" in the instructions can be regarded as the trade name "Kollidon 25". However, the thickener of the present invention is not limited to this.
在一實施例中,增稠劑可為羥丙基甲基纖維素或羧甲基纖維素鈉。In one embodiment, the thickener may be hydroxypropyl methylcellulose or sodium carboxymethylcellulose.
其他實施例的藥學組成物可不含增稠劑。The pharmaceutical compositions of other embodiments may contain no thickening agent.
一實施例的藥學組成物中,可包含適當量的增稠劑,使含有活性藥學成分的組成物的黏度適於施加滴眼液及/或維持藥品的外觀與物理化學的穩定性。The pharmaceutical composition of one embodiment may include an appropriate amount of thickener to make the viscosity of the composition containing active pharmaceutical ingredients suitable for applying eye drops and/or to maintain the appearance and physical and chemical stability of the drug.
一實施例的藥學組成物可包含0 % (w/v)至2.0 % (w/v) 的量的增稠劑。舉例來說,藥學組成物中增稠劑的量可為0.00001 % (w/v)至2.0 % (w/v)、0.0001 % (w/v)至2.0 % (w/v)、0.1 % (w/v)至2.0 % (w/v)、0.05 % (w/v)至1.0 % (w/v)、0.1 % (w/v)至1.0 % (w/v)、0.1 % (w/v)至0.6 % (w/v)、0.1 % (w/v)、0.6 % (w/v)、或0.015 % (w/v)。The pharmaceutical composition of one embodiment may include a thickening agent in an amount of 0% (w/v) to 2.0% (w/v). For example, the amount of thickener in the pharmaceutical composition can be 0.00001% (w/v) to 2.0% (w/v), 0.0001% (w/v) to 2.0% (w/v), 0.1% ( w/v) to 2.0 % (w/v), 0.05 % (w/v) to 1.0 % (w/v), 0.1 % (w/v) to 1.0 % (w/v), 0.1 % (w/ v) to 0.6% (w/v), 0.1% (w/v), 0.6% (w/v), or 0.015% (w/v).
說明書的用語「抗氧化劑」指的是避免藥品因氧化而劣化品質所用的物質。The term "antioxidants" used in the instructions refers to substances used to prevent the deterioration of drug quality due to oxidation.
在一實施例中,抗氧化劑可為擇自乙二胺四乙酸、亞硫酸鈉、亞硫酸氫鈉、焦亞硫酸鈉、與上述之組合的任何一者,但不限於此。In one embodiment, the antioxidant may be any one selected from the group consisting of ethylenediaminetetraacetic acid, sodium sulfite, sodium bisulfite, sodium metabisulfite, and combinations thereof, but is not limited thereto.
在一實施例中,抗氧化劑可為亞硫酸鈉或亞硫酸氫鈉。In one embodiment, the antioxidant may be sodium sulfite or sodium bisulfite.
在一實施例的藥學組成物中,可選擇抗氧化劑作為防止藥品氧化的適當成分。In the pharmaceutical composition of one embodiment, antioxidants can be selected as appropriate components to prevent oxidation of the drug.
在一實施例的藥學組成物中,抗氧化劑的含量足以避免藥品氧化。In the pharmaceutical composition of one embodiment, the content of antioxidants is sufficient to prevent oxidation of the drug.
一實施例的藥學組成物可包含0 % (w/v)至0.3 % (w/v)或0 % (w/v)至0.2 % (w/v)的量的抗氧化劑。舉例來說,組成物中的抗氧化劑含量可為0.1 % (w/v)。一實施例的組成物可不含抗氧化劑。The pharmaceutical composition of an embodiment may include an antioxidant in an amount of 0% (w/v) to 0.3% (w/v) or 0% (w/v) to 0.2% (w/v). For example, the antioxidant content in the composition may be 0.1% (w/v). The composition of one embodiment may not contain antioxidants.
一實施例的藥學組成物可不含抗氧化劑。一實施例中不含抗氧化劑的組成物,可減少pH變化與減少雜質而改善效果。The pharmaceutical composition of one embodiment may not contain antioxidants. In one embodiment, a composition that does not contain antioxidants can reduce pH changes and impurities to improve the effect.
一實施例的藥學組成物提供製備滴眼液配方所用的最佳化成分與組成物。The pharmaceutical composition of one embodiment provides optimized ingredients and compositions for preparing eye drop formulations.
一實施例的藥學組成物與活性藥學成分具有優異的混合相容性,可改善外觀、量、pH、粒徑、與雜質的演進結果中的物理化學穩定性,並改善溶解度與生理等滲性,且含有式1的化合物(如式1a、式1b、或式1c的化合物)可作為活性藥學成分的滴眼液藥品。The pharmaceutical composition of one embodiment has excellent mixing compatibility with active pharmaceutical ingredients, which can improve the physical and chemical stability in appearance, quantity, pH, particle size, and the evolution of impurities, and improve solubility and physiological isotonicity. , and eye drops containing compounds of formula 1 (such as compounds of formula 1a, formula 1b, or formula 1c) can be used as active pharmaceutical ingredients.
在一實施例中,藥學組成物可包括0.1 % (w/v)至0.4 % (w/v)的活性藥學成分。舉例來說,組成物中的活性藥學成分的量可為0.2 % (w/v)至0.3 % (w/v),或0.25 % (w/v)。In one embodiment, the pharmaceutical composition may include 0.1% (w/v) to 0.4% (w/v) of the active pharmaceutical ingredient. For example, the amount of active pharmaceutical ingredient in the composition may be 0.2% (w/v) to 0.3% (w/v), or 0.25% (w/v).
此說明書中採用的量的單位「% (w/v)」指的是基於組成物總量的量,比如組成物的總體基為100 mL時,其所含的成分重量(g)。The quantity unit "% (w/v)" used in this specification refers to the quantity based on the total amount of the composition. For example, when the total base of the composition is 100 mL, the weight (g) of the ingredients contained in it.
在一實施例中,藥學組成物可包括濃度小於或等於10 mg/mL的活性藥學成分。在更具體的例子中,本發明的組成物可包括濃度小於或等於2.7 mg/mL的活性藥學成分。在一實施例中,本發明的組成物可包括濃度為0.001 mg/mL至10 mg/mL或0.001 mg/mL至2.7 mg/mL的活性藥學成分。In one embodiment, the pharmaceutical composition may include an active pharmaceutical ingredient at a concentration of less than or equal to 10 mg/mL. In a more specific example, the compositions of the present invention may include an active pharmaceutical ingredient at a concentration of less than or equal to 2.7 mg/mL. In one embodiment, the composition of the present invention may include an active pharmaceutical ingredient at a concentration of 0.001 mg/mL to 10 mg/mL or 0.001 mg/mL to 2.7 mg/mL.
一實施例的藥學組成物可包括澄清與透明的外觀。The pharmaceutical composition of one embodiment may have a clear and transparent appearance.
在一實施例的藥學組成物中,奈米微胞維持形成時的原樣,而藥學組成物亦不隨時間改變外觀。In the pharmaceutical composition of one embodiment, the nanocells remain as they were when they were formed, and the pharmaceutical composition does not change its appearance over time.
一實施例的藥學組成物的滲透壓為150 mOsm/kg至450 mOsm/kg或200 mOsm/kg至400 mOsm/kg,比如250 mOsm/kg至343 mOsm/kg或260 mOsm/kg至360 mOsm/kg。The osmotic pressure of the pharmaceutical composition in one embodiment is 150 mOsm/kg to 450 mOsm/kg or 200 mOsm/kg to 400 mOsm/kg, such as 250 mOsm/kg to 343 mOsm/kg or 260 mOsm/kg to 360 mOsm/ kg.
在一或多個實施例中,藥學組成物可依需求而更包括添加劑如稀釋劑、溶劑、光遮罩劑、或類似物。舉例來說,組成物可為採用水作為溶劑(基質)的水性組成物,如水性滴眼液。In one or more embodiments, the pharmaceutical composition may further include additives such as diluents, solvents, photo-opaque agents, or the like as needed. For example, the composition may be an aqueous composition using water as a solvent (base), such as aqueous eye drops.
除了活性藥學成分與此說明書所術的添加劑以外,本技術領域中具有通常知識者可依據本發明的目的而進一步選擇合適的添加劑。In addition to the active pharmaceutical ingredients and the additives described in this specification, those with ordinary knowledge in the art can further select suitable additives according to the purpose of the present invention.
另一實施例提供的眼用組成物包括CFTR活化劑作為活性藥學成分,以及擇自聚山梨酯 80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑。眼用組成物意在包含經由眼睛局部施用物質的所有組成物。眼用組成物也可為滴眼液組成物。舉例來說,眼用組成物可用於預防、改善、或治療眼睛疾病、乾眼症、燒灼感、瘙癢、異物感、或粗糙感。Another embodiment provides an ophthalmic composition including a CFTR activator as an active pharmaceutical ingredient, and is selected from the group consisting of polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil, and combinations thereof. any kind of surfactant. Ophthalmic compositions are intended to include all compositions in which substances are administered topically via the eye. The ophthalmic composition may also be an eye drop composition. For example, ophthalmic compositions can be used to prevent, improve, or treat eye diseases, dry eye syndrome, burning sensation, itching, foreign body sensation, or roughness.
在一實施例中,眼用組成物可包括活性藥學成分(式1所示的化合物如式1a的化合物、式1b的化合物、或式1c的化合物),以及擇自聚山梨酯 80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油、與上述之組合的任何一種界面活性劑。In one embodiment, the ophthalmic composition may include an active pharmaceutical ingredient (a compound represented by Formula 1 such as a compound of Formula 1a, a compound of Formula 1b, or a compound of Formula 1c), and a compound selected from the group consisting of polysorbate 80, polyethylene Glycol 40-stearate, polyoxyethylene-35 castor oil, and any surfactant in combination with the above.
在一實施例中,藥學組成物包括的活性藥學成分的量小於或等於1% (w/v)、0.00001 % (w/v)至1 % (w/v)、0.00001 % (w/v)至0.9 % (w/v)、0.00001 % (w/v)至0.8 % (w/v)、0.00001 % (w/v)至0.7 % (w/v)、0.00001 % (w/v)至0.6 % (w/v)、0.00001 % (w/v)至0.5 % (w/v)、0.00001 % (w/v)至0.4 % (w/v)、0.00001 % (w/v)至0.3 % (w/v)、0.00001 % (w/v)至0.2 % (w/v)、0.00005 % (w/v)至1 % (w/v)、0.00005 % (w/v)至0.9 % (w/v)、0.00005 % (w/v)至0.8 % (w/v)、0.00005 % (w/v)至0.7 % (w/v)、0.00005 % (w/v)至0.6 % (w/v)、0.00005 % (w/v)至0.5 % (w/v)、0.00005 % (w/v)至0.4 % (w/v)、0.00005 % (w/v)至0.3 % (w/v)、0.00005 % (w/v)至0.2 % (w/v)、0.0001 % (w/v)至1 % (w/v)、0.0001 % (w/v)至0.9 % (w/v)、0.0001 % (w/v)至0.8 % (w/v)、0.0001 % (w/v)至0.7 % (w/v)、0.0001 % (w/v)至0.6 % (w/v)、0.0001 % (w/v)至0.5 % (w/v)、0.0001 % (w/v)至0.4 % (w/v)、0.0001 % (w/v)至0.3 % (w/v)、0.0001 % (w/v)至0.2 % (w/v)、0.0005 % (w/v)至1 % (w/v)、0.0005 % (w/v)至0.9 % (w/v)、0.0005 % (w/v)至0.8 % (w/v)、0.0005 % (w/v)至0.7 % (w/v)、0.0005 % (w/v)至0.6 % (w/v)、0.0005 % (w/v)至0.5 % (w/v)、0.0005 % (w/v)至0.4 % (w/v)、0.0005 % (w/v)至0.3 % (w/v)、0.0005 % (w/v)至0.2 % (w/v)、0.001 % (w/v)至1 % (w/v)、0.005 % (w/v)至1 % (w/v)、0.005 % (w/v)至0.9 % (w/v)、0.005 % (w/v)至0.8 % (w/v)、0.005 % (w/v)至0.7 % (w/v)、0.005 % (w/v)至0.6 % (w/v)、0.005 % (w/v)至0.5 % (w/v)、0.005 % (w/v)至0.4 % (w/v)、0.005 % (w/v)至0.3 % (w/v)、0.005 % (w/v)至0.2 % (w/v)、0.01 % (w/v)至0.9 % (w/v)、0.01 % (w/v)至0.8 % (w/v)、0.01 % (w/v)至0.7 % (w/v)、0.01 % (w/v)至0.6 % (w/v)、0.01 % (w/v)至0.5 % (w/v)、0.01 % (w/v)至0.4 % (w/v)、0.01 % (w/v)至0.3 % (w/v)、0.01 % (w/v)至0.2 % (w/v)、0.03 % (w/v)至0.5 % (w/v)、0.03 % (w/v)至0.4 % (w/v)、0.03 % (w/v)至0.3 % (w/v)、0.03 % (w/v)至0.2 % (w/v)、0.05 % (w/v)至0.9 % (w/v)、0.05 % (w/v)至0.5 % (w/v)、0.05 % (w/v)至0.4 % (w/v)、0.05 % (w/v)至0.3 % (w/v)、0.05 % (w/v)至0.2 % (w/v)、0.1 % (w/v)至0.9 % (w/v)、0.1 % (w/v)至0.8 % (w/v)、0.1 % (w/v)至0.7 % (w/v)、0.1 % (w/v)至0.6 % (w/v)、0.1 % (w/v)至0.5 % (w/v)、或0.1 % (w/v)至0.4 % (w/v)。在細胞為主的活性測試中,確認含有本發明的式1的化合物的藥學組成物在0.00001 % (w/v)的濃度下表現出活性。舉例來說,組成物中的活性藥學成分的量可為0.2 % (w/v)至0.3 % (w/v),或0.25 % (w/v)。In one embodiment, the pharmaceutical composition includes an active pharmaceutical ingredient in an amount less than or equal to 1% (w/v), 0.00001% (w/v) to 1% (w/v), 0.00001% (w/v) to 0.9 % (w/v), 0.00001 % (w/v) to 0.8 % (w/v), 0.00001 % (w/v) to 0.7 % (w/v), 0.00001 % (w/v) to 0.6 % (w/v), 0.00001 % (w/v) to 0.5 % (w/v), 0.00001 % (w/v) to 0.4 % (w/v), 0.00001 % (w/v) to 0.3 % ( w/v), 0.00001 % (w/v) to 0.2 % (w/v), 0.00005 % (w/v) to 1 % (w/v), 0.00005 % (w/v) to 0.9 % (w/ v), 0.00005 % (w/v) to 0.8 % (w/v), 0.00005 % (w/v) to 0.7 % (w/v), 0.00005 % (w/v) to 0.6 % (w/v) , 0.00005 % (w/v) to 0.5 % (w/v), 0.00005 % (w/v) to 0.4 % (w/v), 0.00005 % (w/v) to 0.3 % (w/v), 0.00005 % (w/v) to 0.2 % (w/v), 0.0001 % (w/v) to 1 % (w/v), 0.0001 % (w/v) to 0.9 % (w/v), 0.0001 % ( w/v) to 0.8 % (w/v), 0.0001 % (w/v) to 0.7 % (w/v), 0.0001 % (w/v) to 0.6 % (w/v), 0.0001 % (w/ v) to 0.5 % (w/v), 0.0001 % (w/v) to 0.4 % (w/v), 0.0001 % (w/v) to 0.3 % (w/v), 0.0001 % (w/v) to 0.2 % (w/v), 0.0005 % (w/v) to 1 % (w/v), 0.0005 % (w/v) to 0.9 % (w/v), 0.0005 % (w/v) to 0.8 % (w/v), 0.0005 % (w/v) to 0.7 % (w/v), 0.0005 % (w/v) to 0.6 % (w/v), 0.0005 % (w/v) to 0.5 % ( w/v), 0.0005 % (w/v) to 0.4 % (w/v), 0.0005 % (w/v) to 0.3 % (w/v), 0.0005 % (w/v) to 0.2 % (w/ v), 0.001 % (w/v) to 1 % (w/v), 0.005 % (w/v) to 1 % (w/v), 0.005 % (w/v) to 0.9 % (w/v) , 0.005 % (w/v) to 0.8 % (w/v), 0.005 % (w/v) to 0.7 % (w/v), 0.005 % (w/v) to 0.6 % (w/v), 0.005 % (w/v) to 0.5 % (w/v), 0.005 % (w/v) to 0.4 % (w/v), 0.005 % (w/v) to 0.3 % (w/v), 0.005 % ( w/v) to 0.2 % (w/v), 0.01 % (w/v) to 0.9 % (w/v), 0.01 % (w/v) to 0.8 % (w/v), 0.01 % (w/ v) to 0.7 % (w/v), 0.01 % (w/v) to 0.6 % (w/v), 0.01 % (w/v) to 0.5 % (w/v), 0.01 % (w/v) to 0.4 % (w/v), 0.01 % (w/v) to 0.3 % (w/v), 0.01 % (w/v) to 0.2 % (w/v), 0.03 % (w/v) to 0.5 % (w/v), 0.03 % (w/v) to 0.4 % (w/v), 0.03 % (w/v) to 0.3 % (w/v), 0.03 % (w/v) to 0.2 % ( w/v), 0.05 % (w/v) to 0.9 % (w/v), 0.05 % (w/v) to 0.5 % (w/v), 0.05 % (w/v) to 0.4 % (w/ v), 0.05 % (w/v) to 0.3 % (w/v), 0.05 % (w/v) to 0.2 % (w/v), 0.1 % (w/v) to 0.9 % (w/v) , 0.1 % (w/v) to 0.8 % (w/v), 0.1 % (w/v) to 0.7 % (w/v), 0.1 % (w/v) to 0.6 % (w/v), 0.1 % (w/v) to 0.5 % (w/v), or 0.1 % (w/v) to 0.4 % (w/v). In the cell-based activity test, it was confirmed that the pharmaceutical composition containing the compound of Formula 1 of the present invention exhibited activity at a concentration of 0.00001% (w/v). For example, the amount of active pharmaceutical ingredient in the composition may be 0.2% (w/v) to 0.3% (w/v), or 0.25% (w/v).
在本發明一實施例中,眼用組成物包括得主要藥學成分量可為小於或等於1 % (w/v)、0.00001 % (w/v)至1 % (w/v)、0.00001 % (w/v)至0.9 % (w/v)、0.00001 % (w/v)至0.8 % (w/v)、0.00001 % (w/v)至0.7 % (w/v)、0.00001 % (w/v)至0.6 % (w/v)、0.00001 % (w/v)至0.5 % (w/v)、0.00001 % (w/v)至0.4 % (w/v)、0.00001 % (w/v)至0.3 % (w/v)、0.00001 % (w/v)至0.2 % (w/v)、0.00005 % (w/v)至1 % (w/v)、0.00005 % (w/v)至0.9 % (w/v)、0.00005 % (w/v)至0.8 % (w/v)、0.00005 % (w/v)至0.7 % (w/v)、0.00005 % (w/v)至0.6 % (w/v)、0.00005 % (w/v)至0.5 % (w/v)、0.00005 % (w/v)至0.4 % (w/v)、0.00005 % (w/v)至0.3 % (w/v)、0.00005 % (w/v)至0.2 % (w/v)、0.0001 % (w/v)至1 % (w/v)、0.0001 % (w/v)至0.9 % (w/v)、0.0001 % (w/v)至0.8 % (w/v)、0.0001 % (w/v)至0.7 % (w/v)、0.0001 % (w/v)至0.6 % (w/v)、0.0001 % (w/v)至0.5 % (w/v)、0.0001 % (w/v)至0.4 % (w/v)、0.0001 % (w/v)至0.3 % (w/v)、0.0001 % (w/v)至0.2 % (w/v)、0.0005 % (w/v)至1 % (w/v)、0.0005 % (w/v)至0.9 % (w/v)、0.0005 % (w/v)至0.8 % (w/v)、0.0005 % (w/v)至0.7 % (w/v)、0.0005 % (w/v)至0.6 % (w/v)、0.0005 % (w/v)至0.5 % (w/v)、0.0005 % (w/v)至0.4 % (w/v)、0.0005 % (w/v)至0.3 % (w/v)、0.0005 % (w/v)至0.2 % (w/v)、0.001 % (w/v)至1 % (w/v)、0.005 % (w/v)至1 % (w/v)、0.005 % (w/v)至0.9 % (w/v)、0.005 % (w/v)至0.8 % (w/v)、0.005 % (w/v)至0.7 % (w/v)、0.005 % (w/v)至0.6 % (w/v)、0.005 % (w/v)至0.5 % (w/v)、0.005 % (w/v)至0.4 % (w/v)、0.005 % (w/v)至0.3% (w/v)、0.005 % (w/v)至0.2 % (w/v)、0.01 % (w/v)至0.9 % (w/v)、0.01 % (w/v)至0.8 % (w/v)、0.01 % (w/v)至0.7 % (w/v)、0.01 % (w/v)至0.6 % (w/v)、0.01 % (w/v)至0.5 % (w/v)、0.01 % (w/v)至0.4 % (w/v)、0.01 % (w/v)至0.3 % (w/v)、0.01 % (w/v)至0.2 % (w/v)、0.03 % (w/v)至0.5 % (w/v)、0.03 % (w/v)至0.4 % (w/v)、0.03 % (w/v)至0.3 % (w/v)、0.03 % (w/v)至0.2 % (w/v)、0.05 % (w/v)至0.9 % (w/v)、0.05 % (w/v)至0.5 % (w/v)、0.05 % (w/v)至0.4 % (w/v)、0.05 % (w/v)至0.3 % (w/v)、0.05 % (w/v)至0.2 % (w/v)、0.1 % (w/v)至0.9 % (w/v)、0.1 % (w/v)至0.8 % (w/v)、0.1 % (w/v)至0.7 % (w/v)、0.1 % (w/v)至0.6 % (w/v)、0.1 % (w/v)至0.5 % (w/v)、或0.1 % (w/v)至0.4 % (w/v)。在細胞為主的活性測試中,可確認含有本發明的式1的化合物的藥學組成物在0.00001 % (w/v)的濃度下表現出活性。In one embodiment of the present invention, the ophthalmic composition includes an amount of main pharmaceutical ingredients that is less than or equal to 1% (w/v), 0.00001% (w/v) to 1% (w/v), 0.00001% ( w/v) to 0.9 % (w/v), 0.00001 % (w/v) to 0.8 % (w/v), 0.00001 % (w/v) to 0.7 % (w/v), 0.00001 % (w/ v) to 0.6 % (w/v), 0.00001 % (w/v) to 0.5 % (w/v), 0.00001 % (w/v) to 0.4 % (w/v), 0.00001 % (w/v) to 0.3 % (w/v), 0.00001 % (w/v) to 0.2 % (w/v), 0.00005 % (w/v) to 1 % (w/v), 0.00005 % (w/v) to 0.9 % (w/v), 0.00005 % (w/v) to 0.8 % (w/v), 0.00005 % (w/v) to 0.7 % (w/v), 0.00005 % (w/v) to 0.6 % ( w/v), 0.00005 % (w/v) to 0.5 % (w/v), 0.00005 % (w/v) to 0.4 % (w/v), 0.00005 % (w/v) to 0.3 % (w/ v), 0.00005 % (w/v) to 0.2 % (w/v), 0.0001 % (w/v) to 1 % (w/v), 0.0001 % (w/v) to 0.9 % (w/v) , 0.0001 % (w/v) to 0.8 % (w/v), 0.0001 % (w/v) to 0.7 % (w/v), 0.0001 % (w/v) to 0.6 % (w/v), 0.0001 % (w/v) to 0.5 % (w/v), 0.0001 % (w/v) to 0.4 % (w/v), 0.0001 % (w/v) to 0.3 % (w/v), 0.0001 % ( w/v) to 0.2 % (w/v), 0.0005 % (w/v) to 1 % (w/v), 0.0005 % (w/v) to 0.9 % (w/v), 0.0005 % (w/ v) to 0.8 % (w/v), 0.0005 % (w/v) to 0.7 % (w/v), 0.0005 % (w/v) to 0.6 % (w/v), 0.0005 % (w/v) to 0.5 % (w/v), 0.0005 % (w/v) to 0.4 % (w/v), 0.0005 % (w/v) to 0.3 % (w/v), 0.0005 % (w/v) to 0.2 % (w/v), 0.001 % (w/v) to 1 % (w/v), 0.005 % (w/v) to 1 % (w/v), 0.005 % (w/v) to 0.9 % ( w/v), 0.005 % (w/v) to 0.8 % (w/v), 0.005 % (w/v) to 0.7 % (w/v), 0.005 % (w/v) to 0.6 % (w/ v), 0.005 % (w/v) to 0.5 % (w/v), 0.005 % (w/v) to 0.4 % (w/v), 0.005 % (w/v) to 0.3% (w/v) , 0.005 % (w/v) to 0.2 % (w/v), 0.01 % (w/v) to 0.9 % (w/v), 0.01 % (w/v) to 0.8 % (w/v), 0.01 % (w/v) to 0.7 % (w/v), 0.01 % (w/v) to 0.6 % (w/v), 0.01 % (w/v) to 0.5 % (w/v), 0.01 % ( w/v) to 0.4% (w/v), 0.01% (w/v) to 0.3% (w/v), 0.01% (w/v) to 0.2% (w/v), 0.03% (w/ v) to 0.5 % (w/v), 0.03 % (w/v) to 0.4 % (w/v), 0.03 % (w/v) to 0.3 % (w/v), 0.03 % (w/v) to 0.2 % (w/v), 0.05 % (w/v) to 0.9 % (w/v), 0.05 % (w/v) to 0.5 % (w/v), 0.05 % (w/v) to 0.4 % (w/v), 0.05 % (w/v) to 0.3 % (w/v), 0.05 % (w/v) to 0.2 % (w/v), 0.1 % (w/v) to 0.9 % ( w/v), 0.1 % (w/v) to 0.8 % (w/v), 0.1 % (w/v) to 0.7 % (w/v), 0.1 % (w/v) to 0.6 % (w/ v), 0.1 % (w/v) to 0.5 % (w/v), or 0.1 % (w/v) to 0.4 % (w/v). In the cell-based activity test, it can be confirmed that the pharmaceutical composition containing the compound of Formula 1 of the present invention exhibits activity at a concentration of 0.00001% (w/v).
在一實施例中,眼用組成物可為奈米微胞技術為主的配方。本發明的眼用組成物可包括奈米微胞。In one embodiment, the ophthalmic composition may be a formulation based on nanocell technology. The ophthalmic composition of the present invention may include nanocells.
在一實施例中,奈米微胞的平均粒徑可小於或等於100 nm,比如小於或等於90 nm、小於或等於80 nm、小於或等於70 nm、小於或等於60 nm、小於或等於50 nm、小於或等於40 nm、小於或等於30 nm、或者小於或等於20 nm。In one embodiment, the average particle size of the nanocells can be less than or equal to 100 nm, such as less than or equal to 90 nm, less than or equal to 80 nm, less than or equal to 70 nm, less than or equal to 60 nm, less than or equal to 50 nm. nm, less than or equal to 40 nm, less than or equal to 30 nm, or less than or equal to 20 nm.
在一實施例中,奈米微胞顆粒的平均粒徑可為0.1 nm至100 nm、1 nm至100 nm、5 nm至50 nm、10 nm至30 nm、10 nm至20 nm、10 nm至15 nm、12 nm至14 nm、11 nm至14 nm、10.5 nm至13 nm、或11 nm至13 nm。在本發明一實施例中,組成物中的奈米微胞顆粒的粒徑變化可維持在±10 %以內,就算在製造時與惡劣的儲存條件中(比如冷藏5天、在60˚C下5天,以及在60˚C下10天)。In one embodiment, the average particle diameter of the nanocell particles can be 0.1 nm to 100 nm, 1 nm to 100 nm, 5 nm to 50 nm, 10 nm to 30 nm, 10 nm to 20 nm, 10 nm to 15 nm, 12 nm to 14 nm, 11 nm to 14 nm, 10.5 nm to 13 nm, or 11 nm to 13 nm. In one embodiment of the present invention, the particle size variation of the nanocell particles in the composition can be maintained within ±10%, even during manufacturing and under harsh storage conditions (such as refrigeration for 5 days, at 60˚C 5 days, and 10 days at 60˚C).
在一實施例中,眼用組成物的pH值可為6.0至8.0。In one embodiment, the pH value of the ophthalmic composition may be 6.0 to 8.0.
眼用組成物可為眼部施用途徑所用的組成物。眼用組成物可用於藥學或獸醫施用的目的,且可作為藥品以及準藥物。The ophthalmic composition may be a composition for use by an ocular route of administration. Ophthalmic compositions may be used for pharmaceutical or veterinary administration purposes and may serve as pharmaceuticals as well as quasi-drugs.
在一實施例中,眼用組成物可為局部吸收或全身吸收的眼用組成物。舉例來說,眼用組成物可為局部用於眼睛上的組成物。In one embodiment, the ophthalmic composition may be a topically absorbed or systemically absorbed ophthalmic composition. For example, an ophthalmic composition can be a composition for topical application to the eye.
在一實施例中,眼用組成物可為依據醫生處方使用(或無需醫生處方即可使用)於眼科中的任何型態的配方。In one embodiment, the ophthalmic composition can be any type of formulation used in ophthalmology according to a doctor's prescription (or can be used without a doctor's prescription).
在一實施例中,眼用組成物可為液體組成物或半固體組成物。在一實施例中,眼用組成物的型態可為滴眼溶液、軟膏、凝膠、乳霜、洗劑、乳液、懸浮液、或噴霧劑。舉例來說,眼用組成物的型態可為滴眼液或軟膏。一實施例的滴眼液的主要優勢為使用簡單方便。滴眼液可為溶液型態或懸浮液型態的滴眼液。一實施例的眼睛軟膏的優點可為長時間維持於眼球中。此外,眼用組成物可由人工淚液或眼睛清潔劑的形式提供。In one embodiment, the ophthalmic composition may be a liquid composition or a semi-solid composition. In one embodiment, the ophthalmic composition may be in the form of an eye drop solution, ointment, gel, cream, lotion, emulsion, suspension, or spray. For example, the ophthalmic composition may be in the form of eye drops or ointment. The main advantage of the eye drops of one embodiment is that it is simple and convenient to use. The eye drops may be in the form of solution or suspension. An advantage of the eye ointment of one embodiment may be that it remains in the eyeball for a long time. Additionally, the ophthalmic composition may be provided in the form of artificial tears or eye cleansers.
可依據本技術領域的已知方法製備本發明一實施例的眼用組成物。本技術領域中具有通常知識者依據欲製備的配方型態,可輕易確認合適的賦形劑及/或載體與其用量。The ophthalmic composition of an embodiment of the present invention can be prepared according to known methods in the art. A person with ordinary knowledge in the art can easily confirm the appropriate excipients and/or carriers and their dosage according to the formulation to be prepared.
眼用組成物可包含或儲存於多種材料所製造的容器中。舉例來說,容器的組成可為聚乙烯或聚丙烯(包括低密度聚乙烯(LDPE)或類似物),或者玻璃容器。當此處揭露的組成物為滴眼液時,其包含於滴眼液容器中,更具體包含於多劑量型滴眼液容器或單位劑量型的滴眼液容器中。Ophthalmic compositions may be contained or stored in containers made of a variety of materials. For example, the container may be composed of polyethylene or polypropylene (including low density polyethylene (LDPE) or the like), or a glass container. When the composition disclosed here is an eye drop, it is contained in an eye drop container, more specifically, a multi-dose eye drop container or a unit dose eye drop container.
多劑量型滴眼液容器具有容器主體與附接至容器主體的蓋,其中蓋可自由打開與重新密封。在多劑量型滴眼液容器中通常含有多個劑量的滴眼液溶液,以在一定時間內使用。單位劑量型的滴眼液容器指的熔合與密封蓋於瓶口處的滴眼劑容器。使用時拉開蓋與瓶體之間的熔合部分。在單位劑量型的滴眼液容器中,含有單次或多次使用的滴眼液。此外,單位劑量型的滴眼液容器中所含的滴眼液可不含或基本上不含防腐劑如苯扎氯銨。The multi-dose eye drop container has a container body and a lid attached to the container body, wherein the lid can be freely opened and resealable. Multi-dose eye drop containers typically contain multiple doses of eye drop solution for use over a set period of time. Unit dose eye drop containers refer to eye drop containers with a fused and sealed cap at the mouth of the bottle. During use, pull apart the fused part between the cap and the bottle body. Unit-dose eye drop containers contain eye drops for single or multiple use. Additionally, the eye drops contained in unit dose eye drop containers may be free or substantially free of preservatives such as benzalkonium chloride.
一實施例的眼用組成物可具有以下特徵。用肉眼直接觀察時,本發明一實施例的眼用組成物可為無色或淺黃色的透明液體。The ophthalmic composition of one embodiment may have the following characteristics. When directly observed with the naked eye, the ophthalmic composition according to an embodiment of the present invention may be a colorless or light yellow transparent liquid.
本發明一實施例的眼用組成物適用於依據HPLC-PDA與HPLC的測試法進行測試。The ophthalmic composition according to one embodiment of the present invention is suitable for testing based on HPLC-PDA and HPLC testing methods.
本發明一實施例的眼用組成物的pH值可為6.0至8.0,其量測方法可為美國藥典的一般測試方法中的pH量測法。The pH value of the ophthalmic composition according to an embodiment of the present invention can be from 6.0 to 8.0, and the measurement method can be the pH measurement method in the general test methods of the United States Pharmacopeia.
本發明一實施例的眼用組成物的滲透壓可為260 mOsm/kg至360 mOsm/kg,其量測方法可為美國藥典的一般測試方法中的滲透壓量測法。The osmotic pressure of the ophthalmic composition according to an embodiment of the present invention may be 260 mOsm/kg to 360 mOsm/kg, and the measurement method may be the osmotic pressure measurement method in the general test methods of the United States Pharmacopoeia.
依據美國藥典一般測試方法中的滴眼液所用的不溶性顆粒測試法進行測試時,本發明一實施例的眼用組成物中,粒徑大於或等於10 μm的顆粒含量小於或等於50 顆粒/mL,粒徑大於或等於25 μm的顆粒含量小於或等於5 顆粒/mL,且粒徑大於或等於50 μm的顆粒含量小於或等於2 顆粒/mL。When tested according to the insoluble particle test method used for eye drops in the general test methods of the United States Pharmacopoeia, in the ophthalmic composition of one embodiment of the present invention, the content of particles with a particle size greater than or equal to 10 μm is less than or equal to 50 particles/mL. , the content of particles with a particle size greater than or equal to 25 μm is less than or equal to 5 particles/mL, and the content of particles with a particle size greater than or equal to 50 μm is less than or equal to 2 particles/mL.
依據美國藥典的一般測試方法中的滲透壓量測法進行測試時,本發明一實施例的眼用組成物中觀察不到微生物生長。When tested according to the osmotic pressure measurement method in the general test methods of the United States Pharmacopoeia, no microbial growth was observed in the ophthalmic composition of one embodiment of the present invention.
此外,除非另外明確定義,否則說明書中對藥學組成物的說明亦可用於眼用組成物。反之,對眼用組成物的說明亦可用於藥學組成物。In addition, unless otherwise clearly defined, descriptions of pharmaceutical compositions in the instructions may also apply to ophthalmic compositions. Conversely, descriptions given for ophthalmic compositions may also apply to pharmaceutical compositions.
另一實施例採用所述藥學組成物或眼用組成物,以預防、改善、或治療眼睛相關疾病或症狀。在一個實施例中,所述眼睛相關疾病或症狀可包括乾眼症、角膜結膜炎、眼睛乾澀、燒灼感、瘙癢、或眼球中的任何異物感或粗糙感。藥學組成物或眼用組成物可以包CFTR活化劑,即式1的化合物如式1a、式1b、或式1c的化合物,其用量適用於前述目的(如治療有效量)。Another embodiment uses the pharmaceutical composition or ophthalmic composition to prevent, improve, or treat eye-related diseases or symptoms. In one embodiment, the eye-related disease or symptom may include dry eye, keratoconjunctivitis, dry eyes, burning sensation, itching, or any foreign body or rough sensation in the eyeball. The pharmaceutical composition or ophthalmic composition may contain a CFTR activator, that is, a compound of Formula 1 such as a compound of Formula 1a, Formula 1b, or Formula 1c, in an amount suitable for the aforementioned purposes (such as a therapeutically effective amount).
可依據配方、症狀的嚴重程度、待用藥患者的年齡與體重、醫生判斷、或類似物適當地改變組成物的劑量。舉例來說,當組成物的配方選擇為滴眼液時,用藥至眼中的每一劑量可為1滴至5滴,較佳為1滴至3滴。此外,採用此組成物時,可一天施加組成物1次至數次,比如一天1次至4次,一天1次至3次,一天1次至2次,或一天1次,或者依需要經常或不定期地施加。The dosage of the composition may be appropriately changed depending on the formulation, severity of symptoms, age and weight of the patient to be treated, physician's judgment, or the like. For example, when the formula of the composition is eye drops, each dose applied to the eyes can be 1 drop to 5 drops, preferably 1 drop to 3 drops. In addition, when using this composition, the composition can be applied from 1 to several times a day, such as from 1 to 4 times a day, from 1 to 3 times a day, from 1 to 2 times a day, or once a day, or as often as needed. or applied irregularly.
上述內容僅用於說明本發明,對本技術領域中具有通常知識者而言,此處揭露的實施例可輕易調整成其他具體形式而不改變技術精神或基本特徵。因此,此處所述的實施例在所有方面都是說明性而非限制性。此處用於表示成分的量、性質如分子量、反應條件、或類似物的所有數字,應理解為在所有情況下都可由用語「約」調整,除非另外說明。綜上所述,說明書中的上述數字是近似值,其變化取決於本發明所需的性質。The above content is only used to illustrate the present invention. For those with ordinary knowledge in the art, the embodiments disclosed herein can be easily adjusted into other specific forms without changing the technical spirit or basic characteristics. Accordingly, the embodiments described herein are in all respects illustrative and not restrictive. All numbers used herein to express amounts of ingredients, properties such as molecular weight, reaction conditions, or the like, are to be understood to be modified in all instances by the term "about" unless otherwise stated. In summary, the above numbers in the specification are approximations and may vary depending on the properties required for the invention.
說明書中的用語「約」指的是給定值或範圍其5%內的值,較佳為1%至2%內的值。舉例來說,「約10%」指的是9.5%至10.5%,較佳為9.8%至10.2%。在另一例中,「約100˚C」指的是95˚C至105˚C之間的溫度,較佳為98˚C至102˚C之間的溫度。The term "about" in the specification refers to a value within 5% of a given value or range, preferably a value within 1% to 2%. For example, "about 10%" refers to 9.5% to 10.5%, preferably 9.8% to 10.2%. In another example, "about 100˚C" refers to a temperature between 95˚C and 105˚C, preferably between 98˚C and 102˚C.
說明書中的表述「具有」、「可具有」、「包括」、「可包括」、或類似用語指的是對應特徵(如數值或成分)的存在,其非用於排除額外特徵的存在。舉例來說,描述一種結構時,應理解除非另外說明,否則包含所有視情況存在的立體異構物與互變異構物形式。The expressions "has", "can have", "includes", "can include", or similar terms in the specification refer to the presence of corresponding features (such as numerical values or components), and are not used to exclude the presence of additional features. For example, when a structure is described, it is understood that all stereoisomers and tautomeric forms, as applicable, are included unless otherwise stated.
此外,說明書中說明的範圍包含端點,除非另外明確定義。說明書引用的所有出版內容的整體經引用併入本文。Furthermore, ranges stated in the specification include the endpoints unless expressly defined otherwise. All publications cited in the specification are incorporated by reference in their entirety.
之後以下述實施例詳述本發明。然而這些實施例僅用於說明目的而非侷限本發明的範疇。 [實施例] The present invention will be described in detail below with reference to the following examples. However, these examples are for illustrative purposes only and do not limit the scope of the invention. [Example]
1. 評估標準1. Evaluation criteria
(1)裝置資訊(1)Device information
採用的裝置資訊如下。The device information used is as follows.
HPLC: Shimadzu HPLC/型號為NO.L20204908166 CDHPLC: Shimadzu HPLC/model NO.L20204908166 CD
Zeta粒徑分析儀: Malvern Zeta粒徑分析儀NS/型號為NO.MAL1045766Zeta particle size analyzer: Malvern Zeta particle size analyzer NS/model NO.MAL1045766
滲透壓計: Fiske Model 210微滲透壓計/型號為NO.1402195DOsmometer: Fiske Model 210 micro osmometer/model NO.1402195D
pH計: Mettler Toledo pH計/型號為NO.DLCCCL0411CpH meter: Mettler Toledo pH meter/model NO.DLCCCL0411C
(2)-1 分析條件(2)-1 Analysis conditions
以下數分析條件分析組成物1、2、8、9、10、及12。Compositions 1, 2, 8, 9, 10, and 12 were analyzed under the following numerical analysis conditions.
① HPLC分析條件① HPLC analysis conditions
依據活性藥學成分化合物,可在下述條件下進行分析。Depending on the active pharmaceutical ingredient compound, analysis can be performed under the following conditions.
A. 化合物1aA. Compound 1a
管柱:Shiseido C18 4.6 x 150 nm,5 μmColumn: Shiseido C18 4.6 x 150 nm, 5 μm
溫度(°C): 40Temperature (°C): 40
移動相:等位沖提(乙腈:去離子水:三氟乙酸=40:60:0.05)Mobile phase: isobaric elution (acetonitrile: deionized water: trifluoroacetic acid = 40:60:0.05)
流速(mL/min): 1.0Flow rate (mL/min): 1.0
注入體積(μl): 20Injection volume (μl): 20
波長(nm): 240Wavelength (nm): 240
滯留時間(min): 5.0Residence time (min): 5.0
B. 化合物1bB. Compound 1b
管柱:Shiseido C18 4.6 x 150 nm,5 μmColumn: Shiseido C18 4.6 x 150 nm, 5 μm
溫度(°C): 40Temperature (°C): 40
移動相:等位沖提(乙腈:去離子水:三氟乙酸=40:60:0.05)Mobile phase: isobaric elution (acetonitrile: deionized water: trifluoroacetic acid = 40:60:0.05)
流速(mL/min): 1.0Flow rate (mL/min): 1.0
注入體積(μl): 20Injection volume (μl): 20
波長(nm): 240Wavelength (nm): 240
滯留時間(min): 4.1Residence time (min): 4.1
C. 化合物1cC. Compound 1c
管柱:Shiseido C18 4.6 x 150 nm,5 μmColumn: Shiseido C18 4.6 x 150 nm, 5 μm
溫度(°C): 40Temperature (°C): 40
移動相:等位沖提(乙腈:去離子水:三氟乙酸=25:75:0.05)Mobile phase: isobaric elution (acetonitrile: deionized water: trifluoroacetic acid = 25:75:0.05)
流速(mL/min): 1.0Flow rate (mL/min): 1.0
注入體積(μl): 20Injection volume (μl): 20
波長(nm): 240Wavelength (nm): 240
滯留時間(min): 4.6Residence time (min): 4.6
②製備庫存溶液②Prepare stock solution
秤取25 mg的樣品並將其加入100 mL的定量瓶。製備稀釋溶劑(去離子水:甲醇=2:8),並將約50 mL的稀釋溶劑加入定量瓶並渦旋10分鐘以溶解樣品。將額外稀釋溶劑加入定量瓶以準確對準100 mL的標線(濃度:250 μg/mL)。Weigh 25 mg of sample and add it to a 100 mL quantitative flask. Prepare a diluting solvent (deionized water: methanol = 2:8), and add approximately 50 mL of the diluting solvent to the quantitative flask and vortex for 10 minutes to dissolve the sample. Add additional dilution solvent to the volumetric flask to accurately align with the 100 mL mark (concentration: 250 μg/mL).
③ 製備標準溶液③ Prepare standard solution
以乙腈或去離子水與甲醇的混合溶液(去離子水:甲醇=2:8)稀釋庫存溶液之後,以移動相進行2倍至10倍的最終稀釋,並以0 μg/mL至50 μg/mL的濃度進行分析。After diluting the stock solution with acetonitrile or a mixed solution of deionized water and methanol (deionized water:methanol=2:8), perform a final dilution of 2 to 10 times with the mobile phase, and dilute it with 0 μg/mL to 50 μg/mL. The concentration in mL was analyzed.
④製備樣本④Preparing samples
以乙腈或去離子水與甲醇的混合溶液(去離子水:甲醇=2:8)稀釋樣品之後,以移動相進行2倍至10倍的最終稀釋,並以0 μg/mL至50 μg/mL的濃度進行分析。After diluting the sample with acetonitrile or a mixed solution of deionized water and methanol (deionized water:methanol=2:8), perform a final dilution of 2 to 10 times with the mobile phase, and dilute it with 0 μg/mL to 50 μg/mL. concentration was analyzed.
(2)-2 分析條件(2)-2 Analysis conditions
依據下述分析條件分析組成物3、4、5、6、7、及11。Compositions 3, 4, 5, 6, 7, and 11 were analyzed according to the following analysis conditions.
① HPLC分析條件① HPLC analysis conditions
10分鐘的分析時間內的HPLC分析條件如下:The HPLC analysis conditions within the 10-minute analysis time are as follows:
管柱: Shiseido C18 4.6 x 150 nm,5 μmColumn: Shiseido C18 4.6 x 150 nm, 5 μm
溫度 (°C): 40Temperature (°C): 40
移動相:等位沖提(乙腈:去離子水:三氟乙酸=33:67:0.05)Mobile phase: isobaric elution (acetonitrile: deionized water: trifluoroacetic acid = 33:67:0.05)
流速(mL/min): 1.0Flow rate (mL/min): 1.0
注入體積(μl): 20Injection volume (μl): 20
波長(nm): 240Wavelength (nm): 240
滯留時間(min): 8.7Residence time (min): 8.7
②製備庫存溶液②Prepare stock solution
秤取10 mg的樣品並將其加入10 mL的定量瓶。製備稀釋溶劑(去離子水:甲醇=2:8),並將約5 mL的稀釋溶劑加入定量瓶並渦旋10分鐘以溶解樣品。將額外稀釋溶劑加入定量瓶以準確對準10 mL的標線(濃度:1.0 mg/mL)。Weigh 10 mg of sample and add it to a 10 mL quantitative flask. Prepare a diluting solvent (deionized water: methanol = 2:8), and add approximately 5 mL of the diluting solvent to the quantitative flask and vortex for 10 minutes to dissolve the sample. Add additional dilution solvent to the quantitative flask to accurately align with the 10 mL mark (concentration: 1.0 mg/mL).
③製備標準溶液③Prepare standard solution
以去離子水與乙腈的混合溶液(去離子水:乙腈=67:33,含0.05%的三氟乙酸)稀釋庫存溶液,並以100 μg/mL的濃度進行分析。The stock solution was diluted with a mixed solution of deionized water and acetonitrile (deionized water:acetonitrile = 67:33, containing 0.05% trifluoroacetic acid) and analyzed at a concentration of 100 μg/mL.
④製備樣本④Preparing samples
以移動相稀釋樣品,並以100 μg/mL的濃度進行分析。Samples were diluted in mobile phase and analyzed at a concentration of 100 μg/mL.
⑤雜質計算⑤ Impurity calculation
每一相對滯留時間(RRT)的雜質以相對於比較所用的主要成分的%表示。主要成分的訊號峰以外的所有訊號峰均視作雜質,且非每一訊號峰的面積都分配權重因子。Impurities for each relative retention time (RRT) are expressed as % relative to the major component used for comparison. All signal peaks other than the signal peak of the main component are considered impurities, and not every signal peak area is assigned a weighting factor.
(3)物理化學特性評估(3) Assessment of physical and chemical properties
①量:依據前述HPLC條件量測每一配方中的量。①Amount: Measure the amount in each formula according to the aforementioned HPLC conditions.
②滲透壓:依據凝固點下降理論量測滲透壓。② Osmotic pressure: Measure osmotic pressure based on the freezing point depression theory.
③粒徑:將每一樣品置於管中,並以Zeta粒徑分析儀NS設備量測其粒徑。③Particle size: Place each sample in a tube and measure its particle size with Zeta Particle Size Analyzer NS equipment.
④ pH: 以pH計量測每一配方的pH值。④ pH: Measure the pH value of each formula with a pH meter.
(4)評估60˚C下的穩定性(4) Evaluate stability at 60˚C
為了短時間評估藥物的化學穩定性,將樣品儲存於60˚C下的烘箱中至少3天,並評估其外觀、pH、與量。To evaluate the chemical stability of the drug over a short period of time, the samples were stored in an oven at 60˚C for at least 3 days and their appearance, pH, and quantity were evaluated.
(5)評估離心/冷凍-解凍條件下的穩定性(5) Evaluate stability under centrifugation/freeze-thaw conditions
評估具有確保的化學穩定性的配方,其於短時間的物理穩定性(如沉澱、凝聚、異物形成、或類似特性)如下。Formulations with guaranteed chemical stability were evaluated for physical stability over short periods of time (such as precipitation, aggregation, foreign body formation, or similar properties) as follows.
①離心:以13,000 rpm離心5分鐘後,由Zeta粒徑分析儀評估粒徑。① Centrifugation: After centrifugation at 13,000 rpm for 5 minutes, the particle size is evaluated by Zeta particle size analyzer.
②冷凍-解凍:以4小時的間隔重複冷凍-解凍製程5次之後,由Zeta粒徑分析儀量測粒徑。②Freezing-thawing: After repeating the freezing-thawing process 5 times at 4-hour intervals, measure the particle size with a Zeta particle size analyzer.
(6) 評估LDPE材料的相容性(6) Evaluate the compatibility of LDPE materials
將藥物填入LDPE滴眼液容器,並評估藥物在惡劣條件(60˚C)下的外觀、量、雜質、粒徑、pH、滲透壓、與不溶性異物。Fill the drug into the LDPE eye drop container, and evaluate the drug's appearance, amount, impurities, particle size, pH, osmotic pressure, and insoluble foreign matter under harsh conditions (60˚C).
(7)評估項目(7)Assessment items
測試各自的評估標準如表1所示。The respective evaluation criteria for the tests are shown in Table 1.
測試各自的評估標準Test their respective assessment criteria
表1
2. 製備滴眼液配方(組成物2至12)2. Preparation of eye drop formula (compositions 2 to 12)
1) 含增稠劑 (組成物6及11)1) Contains thickener (compositions 6 and 11)
(1) 製備溶液A (藥物溶液)(1) Prepare solution A (drug solution)
A. 在將磁棒置於玻璃閃爍瓶中,並將6 mL的無菌水加入後,以水浴加熱玻璃閃爍瓶至60˚C。A. Place the magnetic rod in the glass scintillation vial and add 6 mL of sterile water, then heat the glass scintillation vial to 60˚C in a water bath.
B. 依據每一組成物所用的組成表所示的量,將增溶劑與增稠劑以外的賦形劑(如緩衝劑、等滲劑、抗氧化劑、或類似物)加入步驟A的溶液,接著在60˚C的溫度下以300 rpm攪拌30分鐘。此處僅將各組成物的組成表中記載的緩衝劑的的一半量添加到步驟A的溶液中,並將另一半添加到(2)製備溶液B中的步驟B的溶液。B. Add excipients other than solubilizers and thickeners (such as buffers, isotonic agents, antioxidants, or the like) to the solution in step A according to the amounts shown in the composition table for each composition, Then stir at 300 rpm for 30 minutes at 60˚C. Here, only half the amount of the buffer described in the composition table of each composition is added to the solution in Step A, and the other half is added to the solution in Step B in (2) Preparing Solution B.
C.依據每一組成物的組成表,以黏度移液器將增溶劑滴入步驟B的溶液,接著以水浴加熱到60˚C,並以300 rpm攪拌90分鐘。C. According to the composition table of each component, use a viscosity pipette to drop the solubilizer into the solution in step B, then heat it to 60˚C in a water bath, and stir at 300 rpm for 90 minutes.
D. 依據每一組成物的組成表的量添加活性藥學成分(即式1a、1b、或1c的化合物)至步驟C的溶液,接著在60˚C的水浴溫度下以400 rpm攪拌180分鐘。D. Add the active pharmaceutical ingredient (i.e., the compound of formula 1a, 1b, or 1c) to the solution in step C according to the amount in the composition table of each composition, and then stir at 400 rpm at a water bath temperature of 60˚C for 180 minutes.
(2)製備溶液B (增稠劑溶液)(2) Prepare solution B (thickener solution)
A. 在將磁棒置於玻璃閃爍瓶中,並將6 mL的無菌水加入後,以水浴加熱玻璃閃爍瓶至60˚C。A. Place the magnetic rod in the glass scintillation vial and add 6 mL of sterile water, then heat the glass scintillation vial to 60˚C in a water bath.
B. 將每一組成物在組成表中所述的緩衝劑的一半量加入步驟A的溶液,接著維持在60˚C的水浴下以300 rpm攪拌30分鐘。B. Add half the amount of the buffer described in the composition table for each composition to the solution in step A, and then stir at 300 rpm in a water bath at 60˚C for 30 minutes.
C. 將每一組成物在組成表中的增稠劑添加至步驟B的溶液,接著維持在60˚C的水浴下以300 rpm攪拌5分鐘,並在室溫下經由多重渦旋器充分攪拌溶解。C. Add the thickener of each composition in the composition table to the solution in step B, then maintain it in a water bath at 60˚C and stir at 300 rpm for 5 minutes, and stir thoroughly through a multi-vortexer at room temperature. Dissolve.
(3)混合與無菌過濾溶液A及B(3) Mix and sterile filter solutions A and B
A.混合5 mL的溶液A與5 mL的溶液B,並在室溫下採用多重渦旋器充分攪拌大於或等於2小時。A. Mix 5 mL of solution A and 5 mL of solution B, and stir thoroughly using a multi-vortexer at room temperature for greater than or equal to 2 hours.
B.接著滴入1N HCl與1 N NaOH,使溶液的pH值達到約7.0。B. Then drop in 1N HCl and 1N NaOH to bring the pH value of the solution to about 7.0.
C.在乾淨工作台中,以注射器吸取步驟B的溶液,其緩慢通過由0.20 μm的混合纖維素酯(MCE)材料所組成的注射器過濾器,並將其分裝至高壓滅菌的小瓶中儲存。C. On a clean workbench, use a syringe to draw the solution from step B, slowly pass it through a syringe filter composed of 0.20 μm mixed cellulose ester (MCE) material, and dispense it into autoclaved vials for storage.
2)不含增稠劑(組成物2至5與組成物7至10)2) No thickener (compositions 2 to 5 and compositions 7 to 10)
A.將磁棒放入玻璃閃爍瓶中,添加10 mL的無菌水後,以水浴加熱玻璃閃爍瓶至60°C。A. Place the magnetic rod into the glass scintillation vial, add 10 mL of sterile water, and heat the glass scintillation vial to 60°C in a water bath.
B.依據每一組成物在組成表中的組成量,添加增溶劑以外的賦形劑(如緩衝劑、等滲劑、抗氧化劑、與類似物)至步驟A的溶液中,接著在60˚C的溫度下以300rpm攪拌30分鐘。B. According to the amount of each component in the composition table, add excipients other than solubilizers (such as buffers, isotonic agents, antioxidants, and the like) to the solution in step A, and then incubate at 60˚ Stir at 300 rpm for 30 minutes at a temperature of C.
C.依照各組成物的組成表,以黏度移液器將增溶劑滴入步驟B的溶液,接著以水浴加熱至60˚C並以300 rpm攪拌90分鐘。C. According to the composition table of each component, use a viscosity pipette to drop the solubilizer into the solution in step B, then heat it to 60˚C in a water bath and stir at 300 rpm for 90 minutes.
D.依照各組成物的組成表,將藥學活性成分(即式1a、1b或1c的化合物)加入步驟C的溶液,接著維持在60˚C的水浴下以400 rpm攪拌180分鐘。。D. According to the composition table of each composition, add the pharmaceutically active ingredient (ie, the compound of formula 1a, 1b or 1c) to the solution in step C, and then maintain it in a water bath at 60˚C and stir at 400 rpm for 180 minutes. .
E.接著滴入1N HCl與1N NaOH以調整溶液的pH至約7.0。E. Then drop in 1N HCl and 1N NaOH to adjust the pH of the solution to about 7.0.
F.在乾淨工作台中,以注射器吸取步驟E的溶液,其緩慢通過由0.20 μm的混合纖維素酯(MCE)材料所組成的注射器過濾器,並將其分裝至高壓滅菌的小瓶中儲存。F. On a clean workbench, use a syringe to draw the solution from step E, slowly pass it through a syringe filter composed of 0.20 μm mixed cellulose ester (MCE) material, and dispense it into autoclaved vials for storage.
3. 製備與評估組成物1至113. Preparation and Evaluation of Compositions 1 to 11
1) 製備組成物1與每一界面活性劑的溶解度評估1) Preparation of composition 1 and solubility evaluation of each surfactant
(1)製備10 mM的磷酸鹽緩衝溶液(1) Prepare 10 mM phosphate buffer solution
秤取1.549 g的Na 2HPO 4·7H 2O與0.659 g的NaH 2PO 4·2H 2O並添加至1 L的蒸餾水,且由磁力攪拌器攪拌4小時。 1.549 g of Na 2 HPO 4 ·7H 2 O and 0.659 g of NaH 2 PO 4 ·2H 2 O were weighed and added to 1 L of distilled water, and stirred by a magnetic stirrer for 4 hours.
滴入1N NaOH與1N HCl以調整pH至7.0。1N NaOH and 1N HCl were added dropwise to adjust the pH to 7.0.
(2)製備組成物1 (組成物1A至1E)並評估每一界面活性劑的溶解度(2) Prepare Composition 1 (Compositions 1A to 1E) and evaluate the solubility of each surfactant
改變界面活性劑的成分,以製備含有式1a的化合物(磷酸鹽緩衝的鹽水中的溶解度為34.1 μg/mL)的組成物。可依據表2中的界面活性劑的量製備組成物,並評估其溶解度。The composition of the surfactant was varied to prepare a composition containing the compound of formula 1a (solubility in phosphate buffered saline 34.1 μg/mL). Compositions can be prepared based on the amounts of surfactants in Table 2 and their solubility can be evaluated.
詳細而言,將5 mL的磷酸鹽緩衝鹽水加入20 mL的閃爍瓶,並將Tween 80的界面活性劑溶解其中(濃度為1 %,組成物1A)。此外,取5 mL之前製備的10 mM的磷酸鹽緩衝溶液加入20 mL的閃爍瓶,並分別添加Tween 80、聚乙二醇40-硬脂酸酯、Kolliphor EL、與Tween 80 + Kolliphor (濃度分別為4 %、7 %、5 %、4 % + 5 %,組成物1B至1E)。此處將過量的式1a的化合物滴入每個樣品,並以多重渦旋器攪拌大於或等於6小時。當pH改變時,滴加1N NaOH/HCl以再次將pH調整至約7.0。Specifically, 5 mL of phosphate buffered saline was added to a 20 mL scintillation vial, and the surfactant of Tween 80 was dissolved in it (concentration: 1%, composition 1A). In addition, add 5 mL of the previously prepared 10 mM phosphate buffer solution to a 20 mL scintillation vial, and add Tween 80, polyethylene glycol 40-stearate, Kolliphor EL, and Tween 80 + Kolliphor (concentrations respectively). 4%, 7%, 5%, 4% + 5%, compositions 1B to 1E). Here, an excess of the compound of formula 1a is added dropwise to each sample and stirred with a multivortexer for greater than or equal to 6 hours. When the pH changes, add IN NaOH/HCl dropwise to adjust the pH to approximately 7.0 again.
在冷藏與室溫條件下保存樣品12小時以上。接著將1 mL的每一樣品1mL加入電解拋光管中,並以13,000 rpm離心5分鐘。取離心後的澄清上清液, 以稀釋溶劑(乙腈/去離子水+甲醇/移動相)稀釋,且校正曲線濃度為0 μg/mL至50 μg/mL。接著將結果置入HPLC小瓶中並進行HPLC分析(n=2)。Store samples under refrigeration and room temperature for more than 12 hours. Then 1 mL of each sample was added to the electropolishing tubes and centrifuged at 13,000 rpm for 5 min. Take the clarified supernatant after centrifugation and dilute it with the diluting solvent (acetonitrile/deionized water + methanol/mobile phase), and the calibration curve concentration is 0 μg/mL to 50 μg/mL. The results were then placed into HPLC vials and analyzed by HPLC (n=2).
接著評估含有每一界面活性劑的組成物的溶解度,其結果如表2所示。The solubility of the composition containing each surfactant was then evaluated, and the results are shown in Table 2.
溶解度評估的結果Results of solubility assessment
表2
如表2所示,確認採用界面活性劑(即聚山梨酯80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油(Kolliphor EL)、或上述之組合)可改善式1a的化合物的溶解度。此外,總結表4的量,採用聚山梨酯80、聚乙二醇40-硬脂酸酯、聚氧乙烯-35蓖麻油(Kolliphor EL)作為界面活性劑時,可減少外觀變化而改善物理化學穩定性。As shown in Table 2, it is confirmed that the use of surfactants (i.e., polysorbate 80, polyethylene glycol 40-stearate, polyoxyethylene-35 castor oil (Kolliphor EL), or a combination of the above) can improve formula 1a the solubility of the compound. In addition, summarizing the amounts in Table 4, polysorbate 80, polyethylene glycol 40-stearate, and polyoxyethylene-35 castor oil (Kolliphor EL) can be used as surfactants to reduce changes in appearance and improve physical chemistry. Stability.
2)製備組成物2並評估每一界面活性劑的相容性2) Prepare composition 2 and evaluate the compatibility of each surfactant
(1)製備組成物2 (組成物2A至2D)(1) Preparation of composition 2 (compositions 2A to 2D)
改變界面活性劑的成分以製備含有式1a的化合物的組成物,如表3所示。就細節而言,可依據前述2. 製備滴眼液配方的段落所述的方法製備組成物。製備滴眼液配方。可考量表2中各界面活性劑的溶解度,設定各組成物的活性藥學成分量(mg)。The composition of the surfactant was changed to prepare a composition containing the compound of formula 1a, as shown in Table 3. In terms of details, the composition can be prepared according to the method described in the aforementioned paragraph 2. Preparing the Eye Drop Formula. Prepare eye drop formulation. The solubility of each surfactant in Table 2 can be considered to set the active pharmaceutical ingredient amount (mg) of each composition.
界面活性劑篩選研究的組成表(1)Composition table for surfactant screening study (1)
表3
(2)相容性評估的結果(2) Results of compatibility assessment
評估含有每一界面活性劑的組成物的相容性,其結果如表4所示。確認組成物2A至2C合適,因其外觀澄清透明。確認組成物2D合適,因其具有均勻的牛奶狀外觀(見表1)。在組成物2A、2B、及2C中,可確保式1a的化合物相容性。The compatibility of the compositions containing each surfactant was evaluated, and the results are shown in Table 4. Compositions 2A to 2C were confirmed to be suitable because of their clear and transparent appearance. Composition 2D was confirmed to be suitable as it had a uniform milky appearance (see Table 1). In compositions 2A, 2B, and 2C, the compatibility of the compound of formula 1a can be ensured.
相容性評估的結果Results of compatibility assessment
表4
如表4所適,組成物2D採用聚山梨酯80與聚氧乙烯-35蓖麻油的組合作為界面活性劑,其確認為外觀不合適(因顏色變化)。As shown in Table 4, Composition 2D used a combination of polysorbate 80 and polyoxyethylene-35 castor oil as the surfactant, which was confirmed to have an inappropriate appearance (due to color change).
綜上所述,確認採用聚山梨酯80、聚乙二醇40-硬脂酸酯、或聚氧乙烯-35蓖麻油(Kolliphor EL)作為界面活性劑(如組成物2A、2B、及2C),可確保式1a的化合物的相容性。In summary, it is confirmed that polysorbate 80, polyethylene glycol 40-stearate, or polyoxyethylene-35 castor oil (Kolliphor EL) is used as the surfactant (such as compositions 2A, 2B, and 2C) , ensuring the compatibility of the compound of formula 1a.
3)製備組成物3並評估每一界面活性劑的相容性3) Prepare composition 3 and evaluate the compatibility of each surfactant
(1)製備組成物3 (組成物3A至3C)(1) Preparation of composition 3 (compositions 3A to 3C)
採用相同濃度但不同組成的界面活性劑製備含有式1a的化合物的組成物,如表5所示。Compositions containing the compound of formula 1a were prepared using surfactants of the same concentration but different compositions, as shown in Table 5.
界面活性劑篩選研究組成表(2)Composition table for surfactant screening research (2)
表5
(2) 相容性評估的結果(2) Results of compatibility assessment
接著評估含有每一界面活性劑的組成物的相容性,且結果如表6所示。The compatibility of the compositions containing each surfactant was then evaluated, and the results are shown in Table 6.
相容性評估的結果(在60˚C下儲存10天之後)Results of compatibility assessment (after 10 days of storage at 60˚C)
表6
如表6所示,採用Tween 80作為界面活性劑的組成物3B的pH值改變。此外,採用聚乙二醇40-硬脂酸酯作為界面活性劑的組成物3C外觀產生異物,且pH值改變。採用Kollinphor ELP作為界面活性劑的組成物3A的外觀、量、與pH值均合適。As shown in Table 6, the pH value of composition 3B using Tween 80 as the surfactant changed. In addition, composition 3C using polyethylene glycol 40-stearate as the surfactant produced foreign matter in appearance and changed the pH value. The appearance, amount, and pH value of composition 3A using Kollinphor ELP as the surfactant were all suitable.
(3)雜質評估結果(3) Impurity evaluation results
評估含有每一界面活性劑的組成物中的雜質,其結果如表7所示。The impurities in the compositions containing each surfactant were evaluated and the results are shown in Table 7.
雜質評估結果(60˚C下10天)Impurity evaluation results (10 days at 60˚C)
表7
評估惡劣條件下含有每一界面活性劑的組成物的穩定性,並總結外觀、量、pH值、與雜質的評估結果,確認採用Kolliphor ELP作為界面活性劑的組成物具有最佳相容性。Evaluate the stability of the composition containing each surfactant under harsh conditions, and summarize the evaluation results of appearance, amount, pH value, and impurities to confirm that the composition using Kolliphor ELP as the surfactant has the best compatibility.
4)製備組成物4並評估每一緩衝劑的相容性4) Prepare composition 4 and evaluate the compatibility of each buffer
(1)製備組成物4 (組成物4A至4D)(1) Preparation of composition 4 (compositions 4A to 4D)
改變緩衝劑的組成以製備含有式1a的化合物的組成物,如表8所示。可設定每一緩衝劑的量以進行評估比較,其中pH為7.0,藥物濃度為2.5 mg/mL,且緩衝劑濃度為10 mM。The composition of the buffer was changed to prepare a composition containing the compound of Formula 1a, as shown in Table 8. The amount of each buffer can be set for evaluation comparison where the pH is 7.0, the drug concentration is 2.5 mg/mL, and the buffer concentration is 10 mM.
緩衝劑篩選研究組成表Buffer screening study composition table
表8
(2) 相容性評估結果(2) Compatibility evaluation results
在60˚C的條件下儲存10天之後,評估每一緩衝劑所用的組成相容性,其結果如表9所示。After 10 days of storage at 60˚C, the composition compatibility of each buffer was evaluated and the results are shown in Table 9.
表9
如表9所示,可確認組成物的外觀與類似性質合適,不論緩衝劑的種類為何。特別是使用檸檬酸作為緩衝劑的組成物4D的pH變化明顯降低。As shown in Table 9, it was confirmed that the appearance and similar properties of the composition were suitable regardless of the type of buffer. In particular, the pH change of composition 4D using citric acid as a buffer was significantly reduced.
(3)雜質評估結果(3) Impurity evaluation results
每種緩衝劑對組成物中的雜質評估結果,如表10所示。The results of the evaluation of impurities in the composition for each buffer are shown in Table 10.
雜質評估結果(在60°C下10天)Impurity assessment results (10 days at 60°C)
表10
如表10所示,採用檸檬酸作為緩衝劑的組成物(4D)中,產生的雜質明顯減少。As shown in Table 10, in the composition (4D) using citric acid as the buffering agent, the impurities produced were significantly reduced.
評估每一緩衝劑對組成物在惡劣條件下的穩定性。總結外觀、量、pH、粒徑、與雜質的評估結果,確認採用檸檬酸作為緩衝劑的組成物具有最好的相容性。Each buffer was evaluated for its stability under harsh conditions. Summarizing the evaluation results of appearance, quantity, pH, particle size, and impurities, it was confirmed that the composition using citric acid as the buffer agent has the best compatibility.
5)製備組成物並評估每一等滲劑的相容性5) Prepare the composition and evaluate the compatibility of each isotonic agent
(1) 製備組成物5 (組成物5A至5F)(1) Preparation of composition 5 (compositions 5A to 5F)
改變等滲劑的成分以製備含有式1a的化合物的組成物,如表11所示。將pH固定在7.0、將藥物濃度固定在2.5 mg/mL、以及採用10 mM的磷酸鹽緩衝溶液以進行比較評估。The composition of the isotonic agent was changed to prepare a composition containing the compound of formula 1a, as shown in Table 11. The pH was fixed at 7.0, the drug concentration was fixed at 2.5 mg/mL, and a phosphate buffer solution of 10 mM was used for comparative evaluation.
等滲劑篩選研究的組成表Composition table for isotonic agent screening studies
表11
(2)相容性評估的結果(2) Results of compatibility assessment
在60˚C的條件下儲存10天之後,評估含有每一等滲劑的組成物的相容性,其結果如表12所示。After 10 days of storage at 60˚C, the compatibility of the compositions containing each isotonicity agent was evaluated and the results are shown in Table 12.
表12
如表12所示,確認不論等滲劑的種類為何,組成物的外觀、粒徑、或類似性質都合適。具體而言,採用NaCl作為等滲劑的化合物5A中,明顯降低pH變化。As shown in Table 12, it was confirmed that the appearance, particle size, or similar properties of the composition were suitable regardless of the type of isotonic agent. Specifically, in compound 5A using NaCl as the isotonic agent, the pH change was significantly reduced.
(3)雜質評估的結果(3) Results of impurity assessment
評估含有每一等腎劑的組成物中的雜質,其結果如表13所示。The impurities in the compositions containing each renal agent were evaluated and the results are shown in Table 13.
雜質評估結果(60˚C下10天)Impurity evaluation results (10 days at 60˚C)
表13
如表13所示,在採用NaCl作為等滲劑的組成物5A中,雜質產生的量明顯減少。As shown in Table 13, in the composition 5A using NaCl as the isotonic agent, the amount of impurities generated is significantly reduced.
可評估惡劣條件下含有每一等滲劑的組成物的穩定性,藉由總結外觀、量、pH、粒徑、與雜質的評估結果,可確認採用NaCl作為等滲劑的組成物具有最佳相容性。The stability of the composition containing each isotonic agent can be evaluated under harsh conditions. By summarizing the evaluation results of appearance, amount, pH, particle size, and impurities, it can be confirmed that the composition using NaCl as the isotonic agent has the best compatibility.
6)製備組成物6並評估每一增稠劑的相容性6) Prepare composition 6 and evaluate the compatibility of each thickener
(1)製備組成物6 (組成物6A至6F)(1) Preparation of composition 6 (compositions 6A to 6F)
改變增稠劑的成分以製備含有式1a的化合物的組成物,如表14所示。將pH固定在7.0、將藥物濃度固定在2.5 mg/mL、以及採用10 mM的磷酸鹽緩衝溶液以進行比較評估。The composition of the thickener was changed to prepare a composition containing the compound of Formula 1a, as shown in Table 14. The pH was fixed at 7.0, the drug concentration was fixed at 2.5 mg/mL, and a phosphate buffer solution of 10 mM was used for comparative evaluation.
增稠劑篩選研究的組成表Composition table for thickener screening studies
表14
上表中所用的增稠劑如下:聚乙烯醇(GOHSENOL EG-30P, Mitsubishi Chemical)、羥丙基甲基纖維素(HPMC,Pharmacoat 606,Shin-Etsu)、羧甲基纖維素鈉(Na.CMC)、羥乙基纖維素(Natrosol 250L Pharm, Ashland)、與 and聚乙烯吡咯烷酮(PVP,Kollidon 25,BASF)。The thickeners used in the above table are as follows: polyvinyl alcohol (GOHSENOL EG-30P, Mitsubishi Chemical), hydroxypropyl methylcellulose (HPMC, Pharmacoat 606, Shin-Etsu), sodium carboxymethylcellulose (Na. CMC), hydroxyethylcellulose (Natrosol 250L Pharm, Ashland), and polyvinylpyrrolidone (PVP, Kollidon 25, BASF).
(2)相容性評估的結果(2) Results of compatibility assessment
在60˚C的條件下儲存10天之後,評估含有每一增稠劑的組成物的相容性,如表15所示。After 10 days of storage at 60˚C, the compatibility of the compositions containing each thickener was evaluated as shown in Table 15.
表15
如表15所示,確認組成物6A至6D合適。具體而言,採用羥丙基甲基纖維素(HPMC)作為增稠劑的組成物6C或採用羧甲基纖維素鈉(Na.CMC)作為增稠劑的化合物6D具有較佳穩定性。As shown in Table 15, it was confirmed that compositions 6A to 6D were suitable. Specifically, composition 6C using hydroxypropyl methylcellulose (HPMC) as the thickener or compound 6D using sodium carboxymethylcellulose (Na.CMC) as the thickener has better stability.
7)製備組成物7並評估每一抗氧化劑的相容性7) Prepare composition 7 and evaluate the compatibility of each antioxidant
(1)製備組成物7 (組成物7A及7B)(1) Preparation of composition 7 (compositions 7A and 7B)
改變抗氧化劑的成分以製備含有式1a的化合物的組成物,如表16所示。將pH固定在7.0、將藥物濃度固定在2.5 mg/mL、以及採用10 mM的磷酸鹽緩衝溶液以進行比較評估。The composition of the antioxidant was changed to prepare a composition containing the compound of Formula 1a, as shown in Table 16. The pH was fixed at 7.0, the drug concentration was fixed at 2.5 mg/mL, and a phosphate buffer solution of 10 mM was used for comparative evaluation.
抗氧化劑篩選研究的組成表Composition table for antioxidant screening studies
表16
(2)相容性評估的結果(60˚C下儲存10天之後)(2) Results of compatibility evaluation (after 10 days of storage at 60˚C)
表17
如表17所示,不含抗氧化劑的組成物7A可明顯減少pH的變化。As shown in Table 17, composition 7A without antioxidants can significantly reduce pH changes.
(3) 雜質評估結果(3) Impurity assessment results
評估含有每一抗氧化劑的組成物中的雜質,其結果如表18所示。The impurities in the compositions containing each antioxidant were evaluated and the results are shown in Table 18.
雜質評估的結果(60˚C下10天)Results of impurity assessment (10 days at 60˚C)
表18
如表18所示,不含抗氧化劑的組成物7A可明顯減少雜質產生。As shown in Table 18, composition 7A without antioxidants can significantly reduce the generation of impurities.
評估惡劣條件下含有每一緩衝劑的組成物的穩定性,總結外觀、量、pH、粒徑、與雜質的評估結果,可確認不含抗氧化劑的組成物具有最佳相容性。Evaluate the stability of the composition containing each buffer under harsh conditions, and summarize the evaluation results of appearance, amount, pH, particle size, and impurities to confirm that the composition without antioxidants has the best compatibility.
8)製備組成物8 (組成物8A及8B)與穩定性評估(1)8) Preparation of composition 8 (compositions 8A and 8B) and stability evaluation (1)
(1)製備組成物8 (組成物8A及8B)(1) Preparation of composition 8 (compositions 8A and 8B)
製備式1a及1b的化合物以用於含有表19所示的組成物的滴眼液,並評估其於多種條件下的物理化學穩定性。The compounds of Formula 1a and 1b were prepared for use in eye drops containing the composition shown in Table 19, and their physicochemical stability under various conditions was evaluated.
表19
(2) 冷藏與60˚C下的實驗結果(2) Experimental results under refrigeration and 60˚C
對組成物8A及8B進行冷藏與60˚C下等條件的儲存測試,其結果如表20所示。Compositions 8A and 8B were subjected to storage tests under refrigeration and 60˚C conditions, and the results are shown in Table 20.
表20
如表20所示,可確認組成物在冷藏與60˚C的條件下的物理化學穩定性。As shown in Table 20, the physical and chemical stability of the composition under refrigeration and 60˚C conditions was confirmed.
(3)離心/冷凍-解凍條件下的穩定性評估結果(3) Stability evaluation results under centrifugation/freeze-thaw conditions
可對組成物8A及8B進行離心與冷凍-解凍條件下的穩定性測試,其結果如表21所示。Compositions 8A and 8B can be tested for stability under centrifugation and freeze-thaw conditions, and the results are shown in Table 21.
表21
如表21所示,可確認組成物在離心與冷凍-解凍條件下的物理化學穩定性。As shown in Table 21, the physical and chemical stability of the composition under centrifugation and freezing-thawing conditions was confirmed.
(4)過濾除菌的結果評估(4) Evaluation of results of filtration sterilization
對組成物8A及8B進行過濾除菌評估,其結果如表22所示。Compositions 8A and 8B were evaluated for filtration sterilization, and the results are shown in Table 22.
表22
總結上述的整體結果,可確認組成物8的滴眼液在60˚C下、冷藏、離心、或冷凍-解凍等條件下為物理化學穩定,且在此基礎上可用於臨床前評估所用的配方。Summarizing the above overall results, it can be confirmed that the eye drops of composition 8 are physicochemically stable at 60˚C, refrigeration, centrifugation, or freeze-thaw conditions, and on this basis, it can be used in the formulation for preclinical evaluation. .
9)製備組成物9 (組成物9A、9B、及9C)與穩定性評估(2)9) Preparation of composition 9 (compositions 9A, 9B, and 9C) and stability evaluation (2)
(1)製備組成物9 (組成物9A、9B、及9C)(1) Preparation of composition 9 (compositions 9A, 9B, and 9C)
如表23所示,製備式1a、1b、及1c的化合物以用於組成物9的滴眼液(如組成物9A (濃度:1.0 mg/mL)、組成物9B (濃度:0.05 mg/mL)、與組成物9C (濃度:0.05 mg/mL))。As shown in Table 23, compounds of formulas 1a, 1b, and 1c were prepared for eye drops of composition 9 (such as composition 9A (concentration: 1.0 mg/mL), composition 9B (concentration: 0.05 mg/mL) ), and composition 9C (concentration: 0.05 mg/mL)).
表23
(2)品質控制結果(2)Quality control results
組成物9A、9B、及9C的品質控制結果如表24所示。The quality control results of compositions 9A, 9B, and 9C are shown in Table 24.
表24
如表24所示,確認組成物9 (如組成物9A、9B、及9C)對臨床前刺激測試的所有項目均合適。As shown in Table 24, it was confirmed that composition 9 (such as compositions 9A, 9B, and 9C) was suitable for all items of the preclinical stimulation test.
10)製備組成物10與穩定性評估(3)10) Preparation of composition 10 and stability evaluation (3)
(1)製備組成物10(1) Preparation of composition 10
對臨床前刺激測試而言,製備組成物10的配方(濃度:0.2 mg/mL),如表25所示。For preclinical stimulation testing, a formulation of composition 10 (concentration: 0.2 mg/mL) was prepared as shown in Table 25.
表25
(2)品質控制結果(2)Quality control results
組成物10的品質控制結果如表26所示。The quality control results of Composition 10 are shown in Table 26.
表26
如表26所示,可確認組成物10的配方對臨床前刺激測試的所有項目均合適。As shown in Table 26, it can be confirmed that the formula of composition 10 is suitable for all items of the preclinical stimulation test.
11) 製備組成物11並在加速條件下評估穩定性,並評估LDPE容器的相容性。11) Prepare composition 11 and evaluate the stability under accelerated conditions, and evaluate the compatibility of LDPE containers.
(1) 製備組成物11 (組成物11A至11C)(1) Preparation of composition 11 (compositions 11A to 11C)
製備組成物11A至11C的組成如表27所示。The compositions of the preparation compositions 11A to 11C are shown in Table 27.
表27
(2) 組成物11A的穩定性評估結果(2) Stability evaluation results of Composition 11A
組成物11A的穩定性評估與雜質評估的結果如表28至30所示。The results of the stability evaluation and impurity evaluation of Composition 11A are shown in Tables 28 to 30.
組成物11A的穩定性評估結果Stability evaluation results of composition 11A
表28
組成物11A的雜質評估結果Impurity evaluation results of composition 11A
表29
組成物11A的雜質評估結果(在惡劣條件如60˚C下10天的穩定性評估)Impurity evaluation results of Composition 11A (stability evaluation under harsh conditions such as 60˚C for 10 days)
表30
(3)組成物11B的穩定性評估結果(LDPE)(3) Stability evaluation results of composition 11B (LDPE)
組成物11B的穩定性評估與雜質評估的結果如表31及32所示。The results of the stability evaluation and impurity evaluation of Composition 11B are shown in Tables 31 and 32.
組成物11B的穩定性評估結果Stability evaluation results of composition 11B
表31
組成物11B的雜質評估結果Impurity evaluation results of composition 11B
表32
(4)組成物11C的穩定性評估結果(玻璃瓶)(4) Stability evaluation results of composition 11C (glass bottle)
組成物11C的穩定性評估與雜質評估的結果如表33及34所示。The results of the stability evaluation and impurity evaluation of composition 11C are shown in Tables 33 and 34.
組成物11C的穩定性評估結果Stability evaluation results of composition 11C
表33
組成物11C的雜質評估結果Impurity evaluation results of composition 11C
表34
如上述結果所示,可確認製備的滴眼液在LDPE容器與玻璃容器中均具有物理化學穩定性。此外,減少增稠劑量可改善滴眼液的物理化學穩定性。As shown in the above results, it was confirmed that the prepared eye drops have physical and chemical stability in both LDPE containers and glass containers. Furthermore, reducing the thickening dose improves the physicochemical stability of the eye drops.
4. 製備滴眼液配方(組成物12)與惡劣條件下的穩定性評估4. Preparation of eye drop formula (composition 12) and stability evaluation under harsh conditions
(1) 如製備組成物12的表35所示,製備式1b及1c的化合物作為組成物12的滴眼液配方(如組成物12A至12H)。(1) As shown in Table 35 for preparing composition 12, prepare the compounds of formulas 1b and 1c as eye drop formulations of composition 12 (such as compositions 12A to 12H).
組成物12的組成(組成物12A至12H)Composition of composition 12 (compositions 12A to 12H)
表35
(2) 評估惡劣條件(60˚C下)的穩定性(2) Evaluate stability under harsh conditions (at 60˚C)
惡劣條件(60˚C)下的穩定性的評估結果中,組成物12A至12D的評估結果如表36所示,而組成物12E至12H的評估結果如表37所示。Among the evaluation results of stability under harsh conditions (60˚C), the evaluation results of compositions 12A to 12D are shown in Table 36, and the evaluation results of compositions 12E to 12H are shown in Table 37.
滴眼液配方在惡劣條件下的穩定性評估結果(1):組成物12A至12D (即式1b的化合物)Stability evaluation results of eye drop formulations under harsh conditions (1): Compositions 12A to 12D (i.e. compounds of formula 1b)
表36
如此一來,可確保式1b的化合物的量、pH、與粒徑的穩定性,並特別確認組成物12C (丙二醇)的配方最穩定。In this way, the stability of the amount, pH, and particle size of the compound of formula 1b can be ensured, and the formula of composition 12C (propylene glycol) is particularly confirmed to be the most stable.
滴眼液配方(2)在惡劣條件下的穩定性評估結果:組成物12E至12H (即式1c的化合物)Stability evaluation results of eye drop formulation (2) under harsh conditions: compositions 12E to 12H (i.e. compounds of formula 1c)
表37
本技術領域中具有通常知識者應理解,在不背離本發明基本特徵的情況下,可由調整形式實現本發明。因此揭露的實施例應視作說明性而非侷限性。本發明的範疇應由申請專利範圍界定而非上述說明界定,且與範疇等位的差異應包含於本發明中。It will be understood by those of ordinary skill in the art that the present invention can be implemented in modified forms without departing from the essential characteristics of the invention. The disclosed embodiments should therefore be considered illustrative rather than limiting. The scope of the present invention should be defined by the patent application scope rather than the above description, and differences equivalent to the scope should be included in the present invention.
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