TW201642864A - 利伯西利(ribociclib)錠劑 - Google Patents
利伯西利(ribociclib)錠劑 Download PDFInfo
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- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 229950003687 ribociclib Drugs 0.000 title claims abstract description 7
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- 239000007937 lozenge Substances 0.000 claims description 45
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 19
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- 238000005259 measurement Methods 0.000 claims 1
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
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- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K9/2004—Excipients; Inactive ingredients
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Abstract
本發明係關於包含利伯西利(ribociclib)或其鹽類的口服錠劑。本發明之一個實施例係關於具有高的載藥量與立即釋放曲線之利伯西利錠劑。本發明之一個實施例係關於利伯西利之經塗覆錠劑。本發明之另一實施例係關於利伯西利之經塗覆錠劑,其中塗料為先進的防潮塗料(例如,Opadry® amb II塗料,其中該塗料係以PVA為基礎)。
Description
本發明係關於利伯西利(ribociclib)及/或其醫藥上可接受之鹽的錠劑調配物,以及使用其進行治療之方法。
式(I)之化合物
已知為利伯西利。其化學名稱為7-環戊基-N,N-二甲基-2-{[5-(哌嗪-1-基)吡啶-2-基]胺基}-7H-吡咯并[2,3-d]嘧啶-6-甲醯胺且其合成具體描述於WO 2010/020675 A1之實例74中。
利伯西利之丁二酸鹽由式(II)描述:
且描述於WO2012/064805中。
利伯西利及其醫藥上可接受之鹽具有有價值的藥理學特性且可例如(1)用作週期素依賴性激酶(尤其選自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6及CDK9之週期素依賴性激酶)之抑制劑;及(2)用作肝糖合成酶激酶-3(GSK-3)之調節劑及/或抑制劑。
利伯西利亦已知在代碼名稱LEE011下。
本發明係關於利伯西利,包括其鹽及/或溶劑合物之口服調配物。本發明之一個實施例係關於具有高的載藥量與立即釋放曲線之利伯西利的錠劑調配物。本發明之一個實施例係關於利伯西利之經塗覆錠劑調配物。本發明之另一實施例係關於利伯西利之經塗覆錠劑調配物,其中該塗料為先進的防潮塗料(例如,Opadry® amb II塗料,其中該塗料係以PVA為基礎)。
參考下文所描述之隨附圖式來說明本發明。
圖1A及1B描繪製備利伯西利錠劑之方法流程圖。未經塗覆錠劑係根據步驟1-8製備。經塗覆錠劑係根據步驟1-9製備。
圖2展示以Opadry®(基於標準HPMC)及以Opadry® amb II(基於PVA之先進防潮(AMB)塗料)製備之錠劑的影像。
圖3展示經以標準Opadry®及Opadry® amb II塗覆之利伯西利錠劑的動態氣相吸附(DVS)資料。
圖4展示藉由100rpm之旋轉籃及在37℃下具有不同pH值之溶解介質所獲得的經Opadry® amb II塗覆之利伯西利(LEE011)錠劑之溶解曲線。
本發明係關於一種利伯西利或其醫藥上可接受之鹽的固體口服錠劑劑型。該調配物具有極好之加工效能及高穩定性。
本發明之錠劑具有立即釋放曲線。在處於標準溶解測試下45分鐘後,此等錠劑釋放至少75%(Q)(其中Q係指由USP第<711>章定義之接受準則)之活性劑。在實施例中,當使用100rpm之旋轉籃,且在37℃下以900ml之HCl pH 1作為溶解介質時,在45分鐘後錠劑釋放至少75%之活性劑。在另一實施例中,當使用100rpm之旋轉籃,且在37℃下以900ml之HCl pH 2作為溶解介質時,在45分鐘後錠劑釋放至少75%之活性劑。在另一實施例中,當使用100rpm之旋轉籃,且在37℃下以900ml之乙酸鹽緩衝液pH 4.5作為溶解介質時,在45分鐘後錠劑釋放至少75%之活性劑。在另一實施例中,當在37℃下使用100rpm之旋轉籃,且以900ml之磷酸鹽緩衝液pH 6.8作為溶解介質時,在45分鐘後錠劑釋放至少75%之活性劑。
本發明之錠劑可經塗覆或未經塗覆。
當以核心錠劑之利伯西利丁二酸鹽的w/w百分比來進行量測時,本發明之錠劑具有至少40%、45%、50%、55%或60%之高載藥量。
當以核心錠劑之利伯西利游離鹼的w/w百分比來進行量測時,本發明之錠劑具有至少32%、40%、44%、47%或52%之高載藥量。
利伯西利丁二酸鹽之重量比(w/w)為核心錠劑之至少40%。在一個實施例中,利伯西利丁二酸鹽之重量比(w/w)為核心錠劑之至少
50%。在另一實施例中,利伯西利丁二酸鹽之重量比(w/w)為核心錠劑之至少55%。在另一實施例中,利伯西利丁二酸鹽之重量比(w/w)為核心錠劑之約55%至65%。在另一實施例中,利伯西利丁二酸鹽之重量比(w/w)為核心錠劑之約60%。
當就利伯西利游離鹼而言來進行量測時,利伯西利之重量比(w/w)為核心錠劑之至少32%。在一個實施例中,利伯西利之重量比(w/w)為核心錠劑之至少40%。在另一實施例中,利伯西利之重量比(w/w)為核心錠劑之至少44%。在另一實施例中,利伯西利之重量比(w/w)為核心錠劑之約44%至52%。在另一實施例中,利伯西利之重量比(w/w)為核心錠劑之約47%。
核心錠劑亦稱作「錠劑核心」。
在未經塗覆錠劑中,錠劑核心為整個錠劑。在經塗覆錠劑中,錠劑核心為錠劑排除塗料之部分。
根據本發明之錠劑調配物可含有常用於醫藥調配物中之醫藥學上可接受的賦形劑,尤其例如用於口服投藥之賦形劑,如填充劑、黏合劑、崩解劑及潤滑劑。
填充劑例如可為單獨或其組合形式之纖維素、甘露醇、磷酸二鈣、乳糖、微晶纖維素。
黏合劑例如可為單獨或其組合形式之羥丙基纖維素、聚乙烯吡咯啶酮。
崩解劑例如可為單獨或其組合形式之交聯聚乙烯吡咯啶酮、交聯羧甲基纖維素鈉、低取代羥丙基纖維素、羥基乙酸澱粉鈉。
潤滑劑例如可為單獨或其組合形式之硬脂酸鎂、硬脂酸、滑石、二氧化矽、硬脂醯反丁烯二酸鈉。
舉例而言,圖1A及1B展示製備利伯西利錠劑之方法流程圖。未經塗覆錠劑係根據步驟1-8製備。經塗覆錠劑係根據步驟1-9製備。
在一個實施例中,核心利伯西利錠劑具有內相及外相,該內相包含利伯西利或其鹽。
塗料材料:
本發明之利伯西利錠劑為立即釋放之錠劑且可經任何立即釋放之塗料材料塗覆。舉例而言,塗料材料可為Opadry®、Opadry® 200、Opadry® amb II、Opadry® fxTM、Opadry® II、Opalux®或其混合物。Opadry®、Opadry® 200、Opadry® amb II、Opadry® fxTM、Opadry® II及Opalux®皆可購自Colorcon,Inc。
在一個實施例中,塗料材料為Opadry®。Opadry®為HPMC(羥丙基甲基纖維素)塗料材料且具有下列組成:HPMC(Pharmacoat 603)71.4%、聚乙二醇7.15%、滑石7.15%及氧化鐵14.3%。
在另一實施例中,塗料材料為Opadry® amb II。Opadry® amb II係以PVA(聚乙烯醇)為基礎之塗料材料且具有下列組成:聚乙烯醇45.52%、氧化鐵32%、滑石20%、卵磷脂(大豆)2%及三仙膠0.48%。
當利伯西利錠劑經以Opadry® amb II塗覆時,該錠劑會顯示經改良之外觀且基本上沒有開裂的缺陷。
本發明在以下實例中進一步描述。下列非限制性實例係說明本發明且不視為限制所附申請專利範圍之範疇。
下表1詳述未經塗覆之50mg及200mg利伯西利錠劑的組成。此等錠劑係根據方法流程圖(圖1A-1B)之步驟1-8製備。
1 鹽因子為1.272。原料藥量在含量為99.5%時增加,且微晶纖維素含量相對應減少。
2 植物來源
下表2詳述未經塗覆之100mg、150mg及300mg利伯西利錠劑的組成。此等錠劑係根據方法流程圖(圖1A-1B)之步驟1-8製備。
1 鹽因子為1.272。原料藥量在含量為99.5%時增加,且微晶纖維素含量相對應減少。
2 植物來源
下表3詳述經膜衣塗覆之50mg及200mg利伯西利錠劑的組成。此等錠劑係根據方法流程圖(圖1A-1B)之步驟1-9製備。塗覆材料為Opadry® amb II,其為市售的且係以PVA為基礎之先進防潮(AMB)塗料。
1 鹽因子為1.272。原料藥量在含量為99.5%時增加,且微晶纖維素含量相對應減少。
2 植物來源
3 製備過量塗料以補償塗覆過程期間之損耗
4 該塗料預混物為市售產品
5 在加工期間移除
下表4詳述經膜衣塗覆之100mg、150mg及300mg利伯西利錠劑的組成。此等錠劑係根據方法流程圖(圖1A-1B)之步驟1-9製備。塗料材料為Opadry® amb II,其為市售的且係以PVA為基礎之先進防潮(AMB)塗料。
1 鹽因子為1.272。原料藥量在含量為99.5%時增加,且微晶纖維素含量相對應減少。
2 植物來源
3 製備過量塗料以補償塗覆過程期間之損耗
4 塗料預混物為市售產品
5 在加工期間移除
比較經以不同塗料(Opadry®(基於標準HPMC)對比Opadry® amb II(基於PVA之先進防潮(AMB)塗料材料))塗覆之利伯西利錠劑。在Bohle塗覆機(1Kg規模)中以3g/min之噴塗速率進行塗覆。在標準Opadry®塗覆之情況下,觀察到錠劑標識橋接問題及錠劑開裂的缺陷。相比而言,在以PVA為基礎之Opadry® amb II經塗覆錠劑之情況下,並未觀察到開裂。
圖2展示以Opadry®(基於標準HPMC)及以Opadry® amb II(基於PVA之先進防潮(AMB)塗料材料)製備之錠劑的影像。
經以標準Opadry®及Opadry® amb II塗覆之利伯西利錠劑的動態氣相吸附(DVS)資料呈現於圖3中。在50mg及200mg劑量單位下,與標準Opadry®錠劑相比,經以AMB塗料(Opadry® amb II)塗覆之錠劑展示更佳效能。
在不同pH值之介質中評估經以Opadry® amb II塗覆之利伯西利錠劑的溶解曲線。裝置:離心籃,旋轉:100rpm,體積:900mL,介質:HCl pH 1、HCl pH 2、乙酸鹽緩衝液pH 4.5、磷酸鹽緩衝液pH 6.8。圖4展示在不同pH值之介質中,經以Opadry® amb II膜衣塗覆之利伯西利錠劑的溶解曲線。
下表5詳述相比於實例3,以不同塗料預混物組合的經膜衣塗覆之50mg及200mg利伯西利錠劑的組成。此等錠劑係根據方法流程圖
(圖1A-1B)之步驟1-9製備。塗料材料為Opadry® amb II,其為市售的且係以PVA為基礎之先進防潮(AMB)塗料。
1 鹽因子為1.272。原料藥量在含量為99.5%時增加,且微晶纖維素含量相對應減少。
2 植物來源
3 製備過量塗料以補償塗覆過程期間之損耗
4 塗料預混物為市售產品
5 在加工期間移除
下表6詳述相比於實例4,以不同塗料預混物組合的經膜衣塗覆之100mg、150mg及300mg利伯西利錠劑的組成。此等錠劑係根據方法流程圖(圖1A-1B)之步驟1-9製備。塗料材料為Opadry® amb II,其
為市售的且係以PVA為基礎之先進防潮(AMB)塗料。
1 鹽因子為1.272。原料藥量在含量為99.5%時增加,且微晶纖維素含量相對應減少。
2 植物來源
3 製備過量塗料以補償塗覆過程期間之損耗
4 塗料預混物為市售產品
5 在加工期間移除
Claims (26)
- 一種醫藥口服錠劑,其包含利伯西利(ribociclib)或其醫藥學上可接受之鹽。
- 如請求項1之錠劑,其包含利伯西利丁二酸鹽。
- 如請求項1之錠劑,其包含利伯西利或其鹽,其中當根據USP<711>,在37℃下以100rpm之旋轉籃及900ml pH 2或pH 4.5之溶解介質測試時,在45分鐘後該錠劑釋放至少75%之該利伯西利或其鹽。
- 如請求項1之錠劑,其在錠劑核心中包含利伯西利或其鹽,其中就利伯西利游離鹼而言進行量測,該錠劑核心包含至少32%重量比(w/w)之利伯西利。
- 如請求項4之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之至少40%。
- 如請求項5之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之至少44%。
- 如請求項6之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之約44%至52%。
- 如請求項4之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之約47%。
- 一種醫藥口服錠劑,其包含利伯西利丁二酸鹽,其中利伯西利丁二酸鹽之重量比(w/w)為錠劑核心之至少40%。
- 如請求項9之錠劑,其中利伯西利丁二酸鹽之重量比(w/w)為該錠劑核心之至少50%。
- 如請求項10之錠劑,其中利伯西利丁二酸鹽之重量比(w/w)為該錠劑核心之至少55%。
- 如請求項11之錠劑,其中利伯西利丁二酸鹽之重量比(w/w)為該錠劑核心之約55%至65%。
- 如請求項9之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之約60%。
- 一種經塗覆醫藥口服錠劑,其包含利伯西利或其醫藥上可接受之鹽,其中塗料包含聚乙烯醇(PVA)。
- 一種經塗覆醫藥口服錠劑,其包含利伯西利丁二酸鹽,其中塗料包含PVA。
- 一種經塗覆醫藥口服錠劑,其包含利伯西利或其鹽,其中當根據USP<711>,在37℃下以100rpm之旋轉籃及900ml pH 2或pH 4.5之溶解介質測試時,在45分鐘後該錠劑釋放至少75%之該利伯西利或其鹽,且其中塗料包含PVA。
- 一種經塗覆醫藥口服錠劑,其包含利伯西利或其鹽,其中就利伯西利游離鹼而言來進行量測,利伯西利之重量比(w/w)為錠劑核心之至少32%,且其中塗料包含PVA。
- 如請求項17之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之至少40%。
- 如請求項18之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之至少44%。
- 如請求項19之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之約44%至52%。
- 如請求項17之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之約47%。
- 一種經塗覆醫藥口服錠劑,其包含利伯西利丁二酸鹽,其中利伯西利丁二酸鹽之重量比(w/w)為錠劑核心之至少40%。
- 如請求項22之錠劑,其中利伯西利丁二酸鹽之重量比(w/w)為該 錠劑核心之至少50%。
- 如請求項23之錠劑,其中利伯西利丁二酸鹽之重量比(w/w)為該錠劑核心之至少55%。
- 如請求項24之錠劑,其中利伯西利丁二酸鹽之重量比(w/w)為該錠劑核心之約55%至65%。
- 如請求項22之錠劑,其中利伯西利之重量比(w/w)為該錠劑核心之約60%。
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PL3283058T3 (pl) * | 2015-04-16 | 2023-03-20 | Novartis Ag | Tabletka rybocyklibu |
CA3048036A1 (en) | 2018-07-02 | 2020-01-02 | Apotex Inc | Novel crystalline form of ribociclib succinate |
BR112022011851A2 (pt) | 2019-12-16 | 2022-09-06 | Lunella Biotech Inc | Terapêutica de câncer inibidor de cdk4/6 seletivo |
WO2022029798A1 (en) * | 2020-08-03 | 2022-02-10 | Natco Pharma Limited | Pharmaceutical compositions comprising ribociclib |
WO2022162122A1 (en) | 2021-01-29 | 2022-08-04 | Biotx.Ai Gmbh | Genetically verified netosis inhibitor for use in the treatment of a sars-cov2 infection |
TW202329977A (zh) | 2022-01-25 | 2023-08-01 | 瑞士商諾華公司 | 瑞博西尼藥物組成物 |
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Publication number | Priority date | Publication date | Assignee | Title |
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JPS5428812A (en) * | 1977-08-09 | 1979-03-03 | Yoshitomi Pharmaceut Ind Ltd | Preparation of coated tablet |
GB9414045D0 (en) | 1994-07-12 | 1994-08-31 | Berwind Pharma Service | Moisture barrier film coating composition, method, and coated form |
CN1097619C (zh) * | 1994-07-12 | 2003-01-01 | 伯温德药品服务公司 | 隔潮膜涂层组合物及其生产方法以及涂层制品 |
US6448323B1 (en) * | 1999-07-09 | 2002-09-10 | Bpsi Holdings, Inc. | Film coatings and film coating compositions based on polyvinyl alcohol |
JO2924B1 (en) | 2008-08-22 | 2015-09-15 | نوفارتيس ايه جي | Pyroloperimidine compounds and their uses |
US20120115878A1 (en) * | 2010-11-10 | 2012-05-10 | John Vincent Calienni | Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
US9283230B2 (en) * | 2011-02-11 | 2016-03-15 | Wista Laboratories Ltd. | Phenothiazine diaminium salts and their use |
CN108143728A (zh) * | 2012-07-13 | 2018-06-12 | Gtx公司 | 选择性雄激素受体调节剂在治疗乳癌中的用途 |
EP2742940B1 (en) * | 2012-12-13 | 2017-07-26 | IP Gesellschaft für Management mbH | Fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-l-aza-bicyclo-[2.2.2]octane for adminstration once daily, twice daily or thrice daily |
ES2676177T3 (es) * | 2012-12-20 | 2018-07-17 | Novartis Ag | Una combinación farmacéutica que comprende binimetinib |
CN112641787A (zh) * | 2013-03-21 | 2021-04-13 | 诺华股份有限公司 | 包含B-Raf抑制剂和第二抑制剂的组合疗法 |
EP2810644A1 (en) * | 2013-06-06 | 2014-12-10 | Ferrer Internacional, S.A. | Oral formulation for the treatment of cardiovascular diseases |
PL3283058T3 (pl) * | 2015-04-16 | 2023-03-20 | Novartis Ag | Tabletka rybocyklibu |
CN109953966A (zh) * | 2017-12-26 | 2019-07-02 | 天津耀辰实业发展有限公司 | 一种含有瑞博西尼的药物组合物及其制备方法 |
JP7347388B2 (ja) | 2020-09-25 | 2023-09-20 | 信越化学工業株式会社 | 紫外線硬化型有機変性シリコーン組成物および硬化物 |
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2016
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- 2016-04-14 AU AU2016248017A patent/AU2016248017A1/en not_active Abandoned
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- 2016-04-14 KR KR1020177029433A patent/KR20170137101A/ko not_active Application Discontinuation
- 2016-04-14 SG SG11201708084PA patent/SG11201708084PA/en unknown
- 2016-04-15 TW TW105111921A patent/TW201642864A/zh unknown
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2017
- 2017-10-01 IL IL254818A patent/IL254818A0/en unknown
- 2017-10-04 PH PH12017501820A patent/PH12017501820A1/en unknown
- 2017-10-13 CL CL2017002593A patent/CL2017002593A1/es unknown
- 2017-10-13 CO CONC2017/0010510A patent/CO2017010510A2/es unknown
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2019
- 2019-03-20 AU AU2019201929A patent/AU2019201929B2/en active Active
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2020
- 2020-08-26 US US17/003,771 patent/US20200390771A1/en not_active Abandoned
- 2020-10-06 AU AU2020250190A patent/AU2020250190A1/en not_active Abandoned
-
2022
- 2022-06-08 US US17/805,956 patent/US20230104792A1/en active Pending
- 2022-08-08 AU AU2022215155A patent/AU2022215155A1/en active Pending
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