TWI538678B - 含亞硒酸鹽化合物之醫藥組成物的用途 - Google Patents
含亞硒酸鹽化合物之醫藥組成物的用途 Download PDFInfo
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Description
本發明係關於一種醫藥組成物，包含具有亞硒酸鹽之化合物。
女性子宮頸之發炎及/或退化性病變而致之健康問題日益增加。據希臘醫師George Papanicolaou的研究，子宮頸抹片(又稱帕氏抹片；papanicolaou smear)之分期係依據"慕尼黑第二命名法(Munich nomenclature II)"而定義。其中，帕氏抹片第I分期(PAPI)表示正常結果，第II分期(PAPII)表示輕微發炎及/或退化性病變，第III分期(PAPIII)表示無法判定的細胞影像，亟待確認，第IIID分期(PAPIIID)表示化生不良(dysplasia)，第IV分期(PAPIV)表示嚴重的癌症初期，而第V分期(PAPV)則表示惡性腫瘤。而按帕氏抹片第IIID及第IV分期化生不良的形態又可進一步以細胞學區分為輕度子宮頸上皮內贅瘤(cervical intraepithelial neoplasia)化生不良(即CIN1)、中度子宮頸上皮內贅瘤化生不良(即CIN2)及重度子宮頸上皮內贅瘤化生不良(即CIN3)。此外，在英美地區另有以"貝氏分期法(Bethesda classification)"作為診斷的依據，係與CIN1之化生不良(即帕氏抹片第IIID分期)、CIN2之化生不良(即帕氏抹片第IIID分期)及CIN3之化生不良(即帕氏抹片第IV分期)相似。在此情況下，輕度子宮頸鱗狀上皮內病變(low-grade squamous intraepithelial lesion;LSIL)相當於慕尼黑第二命名法定義之CIN1，而高度細胞病變或高度子宮頸鱗狀上皮內病變(high-grade squamous intraepithelial lesion;LSIL)則相當於世界衛生組織定義之CIN2及CIN3。
一般而言，由輕度化生不良(即PAPIIID、CIN1或LSIL)在一年內恢復至正常(PAPI及II)的平均趨勢為15%。然而，近期內由輕度化生不良(即PAPIIID、CIN1或LSIL)衍生至高度化生不良之機率為每年7%，其中0.74%之高度化生不良更進一步發展為子宮癌。
現行國際婦科指導方針對於子宮頸上皮內贅瘤(CIN)及子宮頸微小癌(microcarcinomas of cervix uteri)之治療係依據細胞病變的位置及嚴重度，及患部組織表面的損害程度，利用手術刀切除，以雷射或環型電切術(loop electrosurgical excision procedure;LEEP)清除，而其他組織學治療法或非侵入性的治療法則尚未開發。
發炎組織經常伴隨著由局部性活性氧(reactive oxygen species;ROS)、自由基(radicals)及過氧化物(peroxides)增加所導致之電化學反應。此時，體內的免疫系統則會作用，釋出大量內源性及外源性的抗氧化物(antioxidants)，以對抗氧化性的發炎物質。在此情況下，許多科學研究及專利，如PCT第2001/093910號及第2003/047604號專利案，均致力於研發具有抗發炎及抗病毒功效之抗氧化合物。
本發明之主要目的係提供一種用以治療子宮頸發炎、異常增生及/或癌症之新興手段。
為達到前述發明目的，本發明所運用之技術手段包含有：一種醫藥組成物，包含具有亞硒酸鹽之化合物及醫藥上可接受之酸類，該酸類係選自檸檬酸、乙酸、蘋果酸、碳酸、硫酸、硝酸、氫氯酸、果酸、或其混合物，該醫藥組成物係用以治療子宮頸炎、異常增生及/或癌症。
本發明之醫藥組成物，其特徵在於該醫藥組成物係適用於局部給藥、黏膜給藥及陰道內給藥。
本發明之醫藥組成物，其特徵在於該醫藥組成物包含一凝膠劑。
本發明之醫藥組成物，其特徵在於該醫藥組成物包含一水凝膠劑，特別係纖維素衍生物。
本發明之醫藥組成物，其特徵在於該醫藥組成物包含一水凝膠劑，係選自羧甲基纖維素、羥丙基纖維素、甲基纖維素及羥乙基纖維素，特別係羥乙基纖維素。
本發明之醫藥組成物，其特徵在於該醫藥組成物係呈膠體狀且包含高度分散的二氧化矽，該二氧化矽係為一懸浮載體及/或一吸收劑。
本發明之醫藥組成物，其特徵在於該醫藥組成物具有小於7.0之酸鹼值，較佳係小於5.0，特別係4.0至2.5。
本發明之醫藥組成物，其特徵在於該醫藥組成物係成溶液狀、乳狀、軟膏狀或海綿狀(棉塞)。
本發明之醫藥組成物，其特徵在於該醫藥組成物另包含添加物及/或活性化合物，特別係緩衝基質、染劑、穩定劑、媒介基質或其組合。
本發明之醫藥組成物，其特徵在於該醫藥組成物包含抗生素、抗病毒劑、抗黴菌劑、止痛劑、抗發炎劑或其組合。
本發明之醫藥組成物，其特徵在於該醫藥組成物係用於治療PAP值大於等於PAPIII及/或CIN值大於等於CIN1之子宮頸細胞變異。
本發明之醫藥組成物，其特徵在於該醫藥組成物係用於治療PAPIV及PAPIIID之子宮頸發炎。
本發明之醫藥組成物，其特徵在於該醫藥組成物係治療子宮頸癌。
為了讓本發明之上述和其他目的、特徵和優點能更明確被了解，下文將特舉本發明較佳實施例，並配合所附圖式，作詳細說明如下。
本發明係關於一種醫藥組成物，包含具有亞硒酸鹽之化合物及醫藥上可接受之酸類，該酸類係選自檸檬酸、乙酸、蘋果酸、碳酸、硫酸、硝酸、氫氯酸、果酸(如蘋果酸、檸檬酸、酒十酸、草酸、及丁烯二酸，特別係檸檬酸)或其混合物，該醫藥組成物係用以治療子宮頸炎，異常增生及/或癌症。
本發明係改良前述PCT專利案(PCT第2001/093910號及第2003/047604號專利案)之缺點，提供一種可穩定應用於抗氧化之含硒製劑，可在細胞內發揮良好的功效，即使係針對子宮頸癌初期所引起之細胞病變，如化性不良及惡性腫瘤。本發明可適用於改善人類乳突病毒(Human Papillomavirus;HPV)引發及非由HPV引發的子宮頸異常。藉此，本發明之含硒製劑具有高度的實用性。通常婦科疾病之給藥係與HPV之檢測結果息息相關，而本發明不僅可針對HPV感染而引發之疾病具有療效，對非由HPV引發的子宮異常(如子宮頸炎、化生不良及惡性腫瘤)也同樣有效。再者，本發明之手段並非針對特異性的病源，而是可用以改善由各種可能病源而導致之子宮頸炎、化生不良及惡性腫瘤。
本發明係於無機硒水溶液中，加入酸類，即可獲得具有高度抗氧化物性質之組成物。本發明之組成物係製作成溶液狀、膠狀、乳狀、懸浮液狀或軟膏狀等。該組成物之療效則可依據本發明所示之方法加以驗證，藉由前述之酸類，提升其抗氧化的特性，至少係暫時地提升。在此性質下，擬於特定患部使用該組成物時，可藉著其抗氧化性可被提升之性質，而不易被其它溶液或體液所稀釋，如在靜脈內投藥的情況容易被血液稀釋，而利用口服投藥則容易被胃及腸內的物質所稀釋)。
本發明組成物較佳係利用局部給藥、黏膜給藥及陰道內給藥之方式進行外部施藥(如局部或口服)，以及直接於黏膜施藥。而適用於局部給藥、黏膜給藥及陰道內給藥之一般配方，為該技術領域具有通常知識者所熟知，且已於相關藥典中詳細記載，故不再贅述。
本發明之組成物可另包含適合之組份及/或醫藥上可相容之輔劑，以維持該含硒組成物及酸類。本發明之組成物較佳包含1至500毫克(mg)之硒，更佳為10至100毫克，特別係每100克之組成物含30至70毫克之硒。本發明之組成物所含之硒較佳係為亞硒酸鈉(sodium selenite)，該亞硒酸鈉一般係呈五水化合物(pentahydrate)之形式，且在40℃之環境下可釋出水。
本發明之組成物較佳係包含總量為1毫克至10克(g)之一種(或多種)酸類，更佳為10毫克至5克之酸類，特別係每100克之組成物含100毫克至1克之酸類(此時，所添加之酸類係呈固態)。另一方面，該酸類也可以液態形式添加，如以水配製成水溶液。而該水、水溶液或包含其他組份之溶液，其加入之總量約為0至99克，較佳係50至99克，特別係每100克之組成物加入80至98克。
本發明較佳實施例之組成物係呈膠體。該組成物較佳係包含一凝膠劑(gel-forming agent)，可以係無機或有機的水凝膠劑。特別適用之凝膠劑為纖維素衍生物(cellulose derivatives)，如羧甲基纖維素(carboxymethyl cellulose)、甲基纖維素(methyl cellulose)、羥丙基纖維素(hydroxypropyl cellulose)，特別係羥乙基纖維素(hydroxyethyl cellulose)。該凝膠劑，特別係羥乙基纖維素，之使用量較佳係為總濃度之0.1克至30克，更佳為0.5克至5克，特別係每100克之組成物含1克至3克。
該膠體組成物更佳係另包含二氧化矽(silicon dioxide)，特別為高度分散的二氧化矽，如PCT專利第WO 2001/85852 A1號專利案所示，係作為一懸浮載體及/或一吸收劑。且該二氧化矽之使用量較佳為100毫克至50克，更佳為500毫克至10克，特別係每100克之組成物使用1克至5克之二氧化矽。
本發明組成物的酸鹼值(pH value)較佳係小於7.0，更佳係小於5.0，特別係介於4.0至2.5之間。
本發明之組成物較佳係呈溶液狀、乳狀、軟膏狀或海綿狀(棉塞)，以便包含其它添加物及/或活性成分，特別係緩衝基質(buffer substances)、染劑(dyes)、穩定劑(stabilisers)、防腐劑(preservatives)、媒介基質(carrier substances)或其組合。該些基質之較佳範例如麥芽糊精(maltodextrin)、調料(flavourings)，如檸檬調料(lemon flavouring)、薄荷油(peppermint oil)、山梨酸鉀(potassium sorbate)及苯甲酸鈉(sodium benzoate)等，其中該苯甲酸鈉係作為防腐劑。
該活性成分之較佳範例如抗生素、抗病毒劑、抗黴菌劑、止痛劑、抗發炎劑或其組合。
經試驗證實，本發明之組成物可有效治療PAP值大於等於PAPIII及/或CIN值大於等於CIN1之子宮頸細胞病變。特別係用以治療PAP值為PAPIII及PAPIIID之子宮頸炎。
此外，本發明之組成物也可適用於子宮頸癌之治療。
本發明之遠層目標係為提供一種可治療子宮頸發炎、化生不良及/或癌症之方法，該方法係將適當劑量之該組成物投藥於前述病症之患者。較佳之劑量為每100克之膠體組成物包含0.005至0.1克亞硒酸鈉五水化合物，特別係每100克之膠體組成物包含0.01至0.1克。
本發明組成物之詳細應用如下方實施例所示，為其應用並不以此例為限：
第一實施例：製備酸化之亞硒酸鈉膠體(acidulated sodium selenite gel)
每100克之酸化之亞硒酸鈉膠體係由以下配方所配製：
第二實施例：治療子宮頸化生不良
設計：多中心試驗性研究(multi-centre pilot study)
遴選標準：年齡大於19歲，PAP值大於PAPIII，小於PAPIV
實施：
陰道內之使用，一旦診斷為PAP值大於PAPIII，小於PAPIV，則投藥超過90天，每天投藥5毫升的亞硒酸鈉膠體。若遇經期則暫停投藥。投藥90日後進行檢查。
結果：
31名患者，27名(87.1%)具有反應，4名(12.9%)不具有反應。
n.d.：未測定
n.a.：未獲得
neg.：陰性
pos.：陽性
由該酸化之亞硒酸鈉膠體在兩名病患上之反應顯示，本發明之膠體組成物可有效治療子宮頸化生不良。
第四實施例：使用酸化之亞硒酸鈉膠體治療38歲的子宮頸鱗狀細胞癌患者(該酸化亞硒酸鈉膠體之製備如第一實施例所示)
該名患者係於1975年12月31日出生，姓名縮寫為IG，因其子宮頸化生不良之情況(PAP值為PAPIV，CIN3)，而在2008年5月29日至2008年6月2日之間於澳洲公立診所(Public Austrian clinic)接受錐型切除術及子宮頸刮除術。所分離之組織經組織學檢驗而判定為侵入性子宮頸鱗狀細胞癌，且該原位癌係屬早期階段(FIGO分期第FIGO IB1期)。其後由該澳洲診所之婦科部門確認此結果。
由電腦斷層掃描(computer tomography;CT)、磁共振造影(magnetic resonance imaging;MRI)及聲像圖檢查(sonography)結果均顯示清楚的惡性腫瘤，範圍約10至12公厘，位於子宮頸內側且延伸至子宮峽，但尚未發生淋巴性移轉。因該腫瘤發生的位置不適用於子宮保留手術，該擴及於子宮峽之腫瘤建議以極端的手術進行切除，如Wertheim PIVER II切除術。儘管在分秒必爭的壓力下，該名患者仍選擇以本發明之組成物進行治療，此治療結果可能得以保留子宮。在接受該酸化亞硒酸鈉膠體4個月的治療之後，婦科、放射科及組織學監控結果均顯示該名患者的腫瘤明顯減小且發炎狀況也獲得改善。再經2個月的治療之後，患者的腫瘤完全消失且組織抹片結果顯示其發炎程度為PAPII+。
雖然本發明已利用上述較佳實施例揭示，然其並非用以限定本發明，任何熟習此技藝者在不脫離本發明之精神和範圍之內，相對上述實施例進行各種更動與修改仍屬本發明所保護之技術範疇，因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。
Claims (3)
- 一種包含一含亞硒酸鹽化合物及一醫藥上可接受之酸類的醫藥組成物之用途，係用以製備治療PAP值≧PAPIII及/或CIN值≧CIN1之子宮頸細胞變異的藥物，其中，該酸類係選自檸檬酸、乙酸、蘋果酸、碳酸、硫酸、硝酸、氫氯酸、果酸、或其混合物。
- 一種包含一含亞硒酸鹽化合物及一醫藥上可接受之酸類的醫藥組成物之用途，係用以製備治療PAPIII及PAPIIID期之子宮頸發炎的藥物，其中，該酸類係選自檸檬酸、乙酸、蘋果酸、碳酸、硫酸、硝酸、氫氯酸、果酸、或其混合物。
- 如申請專利範圍第1或2項所述之包含該含亞硒酸鹽化合物及該醫藥上可接受之酸類的醫藥組成物之用途，其中，該醫藥組成物係以局部給藥、黏膜給藥或陰道內給藥的方式投予一所需個體。
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| GB2323030A (en) | 1997-03-12 | 1998-09-16 | Essential Nutrition Ltd | Dietary supplements for immunocompromised patients |
| US5999844A (en) * | 1997-04-23 | 1999-12-07 | Accumed International, Inc. | Method and apparatus for imaging and sampling diseased tissue using autofluorescence |
| US6069152A (en) | 1997-10-07 | 2000-05-30 | Eli Lilly And Company | 5-HT4 agonists and antagonists |
| GB9722361D0 (en) | 1997-10-24 | 1997-12-17 | Pharma Nord Uk Ltd | Pharmaceutical formulation for treating liver disorders |
| IT1297080B1 (it) | 1997-11-26 | 1999-08-03 | Andrea Carnevali | Composizione per il trattamento di ustioni, eritemi solari, abrasioni, piaghe e irritazioni cutanee |
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| US6120758A (en) | 1998-07-16 | 2000-09-19 | Shaklee Corporation | Preservative system for topically applied products |
| FR2782642B1 (fr) | 1998-08-31 | 2001-12-07 | Xavier Forceville | Utilisation du selenium pour le traitement de patients atteints d'un syndrome de reponse inflammatoire systemique (sirs), et composition pour la mise en oeuvre du traitement |
| US6114348A (en) | 1999-03-10 | 2000-09-05 | Weber; Paul J. | Method of treating warts using tazarotene |
| EP1292645B8 (de) | 2000-05-10 | 2006-03-15 | NUTROPIA Ernährungsmedizinische Forschungs GmbH | Verfahren zur verringerung der oberfläche von siliziumdioxid |
| AT412758B (de) | 2000-06-05 | 2005-07-25 | Vis Vitalis Lizenz & Handels | Verwendung einer selenithältigen lösung zur behandlung viraler erkrankungen |
| AT412448B (de) | 2001-02-13 | 2005-03-25 | Vis Vitalis Lizenz & Handels | Verwendung von selenhältigen präparaten |
| AT412703B (de) * | 2001-12-04 | 2005-06-27 | Vis Vitalis Lizenz & Handels | Verwendung von selenithältigen präparaten zur topischen oder bukkalen anwendung |
| US8404272B2 (en) * | 2003-06-26 | 2013-03-26 | Poly-Med, Inc. | Fiber-reinforced composite rings for intravaginal controlled drug delivery |
-
2011
- 2011-02-16 AT ATA201/2011A patent/AT511159A1/de not_active Application Discontinuation
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2012
- 2012-02-15 TW TW101104960A patent/TWI538678B/zh active
- 2012-02-16 ES ES12707218.9T patent/ES2577150T3/es active Active
- 2012-02-16 PT PT127072189T patent/PT2675432T/pt unknown
- 2012-02-16 WO PCT/AT2012/000032 patent/WO2012109685A1/de not_active Ceased
- 2012-02-16 EP EP12707218.9A patent/EP2675432B1/de active Active
- 2012-02-16 US US14/000,133 patent/US10201566B2/en active Active
- 2012-02-16 MX MX2013009459A patent/MX342098B/es active IP Right Grant
- 2012-02-16 EA EA201691236A patent/EA033519B1/ru unknown
- 2012-02-16 AU AU2012219005A patent/AU2012219005B2/en active Active
- 2012-02-16 JP JP2013553740A patent/JP5986110B2/ja active Active
- 2012-02-16 HU HUE12707218A patent/HUE029811T2/hu unknown
- 2012-02-16 CA CA2826999A patent/CA2826999C/en active Active
- 2012-02-16 RS RS20160556A patent/RS54952B1/sr unknown
- 2012-02-16 BR BR112013020702-7A patent/BR112013020702B1/pt active IP Right Grant
- 2012-02-16 ME MEP-2016-123A patent/ME02422B/me unknown
- 2012-02-16 HR HRP20160891TT patent/HRP20160891T1/hr unknown
- 2012-02-16 CN CN201710854416.3A patent/CN107582563B/zh active Active
- 2012-02-16 AR ARP120100530A patent/AR085265A1/es unknown
- 2012-02-16 EA EA201300910A patent/EA025419B1/ru unknown
- 2012-02-16 PL PL12707218.9T patent/PL2675432T3/pl unknown
- 2012-02-16 GE GEAP201213231A patent/GEP201606590B/en unknown
- 2012-02-16 CN CN2012800083501A patent/CN103379899A/zh active Pending
- 2012-02-16 SI SI201230644A patent/SI2675432T1/sl unknown
- 2012-02-16 UA UAA201310913A patent/UA112767C2/uk unknown
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2013
- 2013-08-14 CL CL2013002353A patent/CL2013002353A1/es unknown
- 2013-08-15 IL IL227981A patent/IL227981A/en active IP Right Grant
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2016
- 2016-07-11 CY CY20161100648T patent/CY1117768T1/el unknown
- 2016-07-15 SM SM201600233T patent/SMT201600233B/it unknown
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2018
- 2018-12-19 US US16/225,263 patent/US10543228B2/en active Active
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2020
- 2020-01-09 US US16/738,797 patent/US20200206262A1/en active Pending
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