TW200840587A - Molecular dispersions of drospirenone - Google Patents
Molecular dispersions of drospirenone Download PDFInfo
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Abstract
Description
200840587 九、發明說明: 【發明所屬之技術領域】 本發明係關於醫筚續 δ ^ 桌調配科學領域,特定言之係關於改良 親月曰性化a物(例如類固醇 _ & k 刀子,特疋5之係關於屈螺_) 之溶解度與生物利用产 ) v ^ 法。本發明之特定調配技術係 關於k供为子分散形式之屈螺,之總原則。 【先前技術】 未經調配之屈螺酮在胃腸道中不能充分吸收,部分原因 為其在水中較差之溶解度及在其水中較低之溶解速度。此 外/螺酮在酸性環境中具有較差之化學穩定性,該等酸 性環境包括在胃之胃液中所提供之條件。事實上,在接觸 PH值約U之鹽酸溶液3Q分鐘内,幾乎鳩之屈螺酮降解為 其在治療學上不旋異構體。其結果為建議使用腸溶衣。吾 人假設處於類固醇分子自然狀態之屈螺酮應在胃腸道(gi 道)之上半部中吸收,例如自胃黏膜及/或十二指腸黏膜吸 收’其要求屈螺酮應完全溶解於〇1道之開始端。 吾人已發現當提供微粉化形式之屈螺酮時,其體外溶解 度較高。舉例而言如在溶解測試開始後3〇分鐘,至少7〇% 之屈螺_已溶解。然而,微粉化技術要求特殊設備、成本 較高且可能不易操作。 此可能需要該等包括微粉化形式之屈螺酮調配物之替代 調配物。 製備具有與液體、半固體或固體賦形劑混合之活性組份 的百樂組合物之不同調配技術已為吾人所熟知。然而,該 132010.doc 200840587 等技術之目的僅在於製備與賦形劑均勻分散之活性物質精 細顆粒而不是製備與賦形劑以分子級別分散之活性化a 物。此外,該等調配技術並不包含製備一組合物之方法, 其中初始關鍵步驟中之活性化合物在載劑中溶解,然後續 載劑組成最終組合物或其至少一部分。200840587 IX. INSTRUCTIONS: [Technical field to which the invention pertains] The present invention relates to the field of δ ^ table allocation science, and in particular to the improvement of pro-involution a substance (for example, steroid _ & k knife, special疋5 is related to the solubility and bioavailability of snail _) v ^ method. The particular formulation technique of the present invention is based on the general principle that k is provided as a sub-dispersed form of snail. [Prior Art] Unblended drospirenone is not sufficiently absorbed in the gastrointestinal tract, in part because of its poor solubility in water and its low dissolution rate in its water. In addition, the snail/ketone has poor chemical stability in an acidic environment including the conditions provided in the gastric juice of the stomach. In fact, within 3Q minutes of exposure to a hydrochloric acid solution having a pH of about U, almost spirulina degraded into its therapeutically non-rotating isomer. As a result, it is recommended to use an enteric coating. We hypothesize that drospirenone, which is in the natural state of steroid molecules, should be absorbed in the upper half of the gastrointestinal tract (eg, gi), for example, from the gastric mucosa and/or duodenal mucosa, which requires that drospirenone should be completely dissolved in 〇1 The beginning. We have found that when the micronized form of drospirenone is provided, its solubility in vitro is higher. For example, as long as 3 minutes after the start of the dissolution test, at least 7% of the snails have dissolved. However, micronization technology requires special equipment, is costly and may not be easy to operate. This may require alternative formulations of such drospirenone formulations including micronized forms. Different formulation techniques for preparing a Baile composition having an active ingredient in admixture with a liquid, semi-solid or solid excipient are well known. However, the technique of the technique of 132010.doc 200840587 and the like is only to prepare fine particles of the active material uniformly dispersed with the excipient, instead of preparing the activated a substance dispersed at the molecular level with the excipient. Moreover, such formulation techniques do not include a method of preparing a composition in which the active compound in the initial critical step is dissolved in a carrier and then the resuscending agent constitutes the final composition or at least a portion thereof.
WO 0245693描述適於無論是需要掩蔽味道或期望破壞 包衣時所應用的活性物質劑型。該等劑型包含在基質中均 勻分散或溶解之活性物質,該基質係選自由石蠟、脂肪醇 類、三酸甘油酯、偏甘油酯類及脂肪酸酯類組成之群。 US 5,789,442係關於與習知之例如液體、半液體、固體 有機或無機載劑之賦形劑混合的活性化合物調配物,該調 配物用於以非經腸方式或經腸方式投予。 US 5,569,652係關於藉由將媒劑及稀釋劑與活性化合物 一起加工之活性化合物調配物。 US 5,656,622係關於雌二醇之新型衍生物,其與屈螺嗣 聯合用作勝囊或旋劑。 EP 1 260 225係關於包含雌激素之組合物。 WO 2004/041289描述藉由使用習知流化床技術所製備之 醫藥鍵劑製劑中的屈螺_。 WO 2004/0222G65係關於包含睪固酮衍生物及視情況之 黃體酮之組合物(提及屈螺⑷,其中該藥物為—水性或一 油性懸浮液。 ”他技術仍建礅使用微粉化形式之活性化合物以藉由實 現該活性化合物在水中之快速溶解而改良生物利用度。、 132010.doc 200840587 WO 01/52857提及包含屈螺酮之組合物,因為在將屈螺 酮喷至惰性載劑上之前將其溶解於諸如甲醇或乙酸乙酯之 適當溶劑中。 儘管先前之成果已經對以經口形式投予之屈螺酮的生物 利用度產生某些改良,但該等成果並沒有消除在發生藥物 及收之别屈螺酮在胃腸道流體中的初始溶解步驟。 【發明内容】 現提供一種醫藥組合物,其包含至少一種呈分子分散形 式之類固醇藥物,例如黃體激素(例如屈螺酮、黃體酮、 依普利酮(eplerenone)、依託孕烯(et〇n〇gestrel))及/或雌激 素(雌醇及其s曰類)。也就是說該組合物包含一類固醇藥 物,較佳為屈螺酮,該藥物在組合物中以非微粒形式存 在。就以分子分散形式存在而言,希望該藥物以溶解狀態 存在於賦形劑中。當在劑量單位崩解時即刻發生溶解,則 口亥刀子刀政藥物將會非常迅速地釋放。在一其中藥物為分 子分散形式的醫藥組合物中,崩解時間實際上為該藥物釋 速率决疋步驟,其意谓著本發明能夠顯著改良生物利 用度。 該等組合物車交佳作為固n、半固體或液體形式提供,所 有形式較佳又適於以經口方式投予且較佳與胃液接觸且然 後自胃腸道吸收。吾人已發現此等組合物具有較高生物利 用度二良好化學穩定性及體外之迅速溶解釋放且能夠在不 要求高成本設備或安全設施之條件下生產。 本發明不僅針對醫藥組合物,而且亦針對該等組合物之 132010.doc 200840587 製備方法及用途。 本發明之組合物係藉由一包含以下步驟之方法提供: a) 提供屈螺酮及一或多種載劑;且 ^ · b) 將該屈螺酮完全溶解於該或該等載劑中;及 c) 視情況,乾燥步驟b)中所獲得之混合物。 吾人已發現包含分子分散形式之屈螺肩之醫藥組 不關於製造方法、物理或化學穩定性、體外溶解性处 腸細胞之體外渗透性及體内生物利用度之優良效能。、、、° 在第一態樣中,本發明提供—種包含分子分散於醫藥風 上可接文之載劑中的屈螺綱之組合物。換士之予 =在:藥學可接受之載劑中包含溶解开:式之㈣= 、口 ‘,、、論該組合物為固體、半固體或液體形式 ===同特徵為屈螺鲷以分子級別溶解於醫 又之载劑中且具有溶解之屈 之性質。一般而“… 貝而非s知屈螺鲖溶液 叙而&,X射線繞射分析或用其他諸如 微技術、電子顯微技術或溶解等適當方 = 溶解1在= 解形式,即分子分散形式存在時, 特徵:久:早位發生崩解時即刻發生。因此劑型之共同 、為田比較劑型之崩解時間與溶解時η 士 分析方法相關之誤差範圍内同時發生。、”,會在與 溶=二Τ涵蓋一種在醫藥學可接受之載劑中包含 體或液體开^ 組合物’無論該組合物為固體、半固 別溶解於醫;二組合物之共同特徵為屈螺,以分子級 、商枭學可接受之裁劑由 中且/、有溶解之屈螺酮性質 J32010.doc 200840587 而非習知屈螺酮溶液之性質。 本發明之組合物有利地顯示屈螺網在體外之快速溶解。 ‘ 錢速溶解定義為組合物中至少7〇%之屈螺酮在體外溶解 性測試開始之後30分鐘溶解,特定言之,至少8〇重量%之 屈螺酮在體外溶解性測試開始之後2〇分鐘時溶解,更佳為 至少85重量%之屈螺嗣在體外溶解性測試開始之後η分鐘 時溶解。使们7。(:之_ ml水作為溶解介f且使用 • XXVm葉片裝置2作為溶解測試裝置進行測試,在5(M〇〇 rpm例如50或75 rpm條件下操作該裝置。 如上文所提及,藉由使用微粉化藥物可實現較高之生物 利用度。但該技術具有某些缺點,因為微粉化藥物在生產 過程中有絮結之趨勢且其操作人員易於受到來自該微粉化 樂物之粉塵之影響。本發明之生產方法可避免該等缺點’ =將導料少數目之生產步驟、製造過程中粉塵形成之減 少、、較〶級狀容積、較高級別之環境及職業安全、製造 •:本之減少、經改良之混合均句性及經改良之劑量均句 本發明之組合物較佳為固體、半固體或液體形式。 根據本發明之固體組合物可稱作固溶體。 根據本發明之半固體及液體組合物意謂定義呈溶解形式 =屈_溶液’其中該溶劑具有確㈣組合物是否為半固 體或液體組合物之黏度及/或熔點。 半 術語”分子分散"或”分子分散劑"係用於描述任何固體、 固體及液體系統’其中將組份A(例如屈螺酮)以分子級 132〇1〇·ς|〇〇 200840587 別刀政於另一組份B(例如溶劑或聚合物)中,以致於不能 用X射線繞射分析法偵測到結晶形態之組份A,亦不能用 何、、員微技術偵測出微粒形式之組份A,無論其為結晶形 態或非結晶形態。就術語”分子分散劑”而言,應理解為將 屈螺明溶解於組份B中而不管組份B之性質。也就是說, 術語”分子分散”可與術語”分子溶解”互換。WO 0245693 describes active dosage forms suitable for use, whether it is necessary to mask the taste or to destroy the coating. These dosage forms comprise an active material which is uniformly dispersed or dissolved in a matrix selected from the group consisting of paraffin waxes, fatty alcohols, triglycerides, partial glycerides and fatty acid esters. U. US 5,569,652 relates to active compound formulations which are processed by the use of vehicles and diluents together with active compounds. US 5,656,622 is a novel derivative of estradiol which is used in combination with snail to act as a sac or a squirt. EP 1 260 225 relates to compositions comprising estrogen. WO 2004/041289 describes snails in pharmaceutical drug formulations prepared by the use of conventional fluidized bed techniques. WO 2004/0222 G65 relates to a composition comprising a testosterone derivative and optionally a progesterone (referring to snail (4), wherein the drug is an aqueous or an oily suspension." His technique is still active in micronized form. The compound improves the bioavailability by effecting rapid dissolution of the active compound in water. 132010.doc 200840587 WO 01/52857 mentions a composition comprising drospirenone because the drospirenone is sprayed onto an inert carrier. It has previously been dissolved in a suitable solvent such as methanol or ethyl acetate. Although previous results have produced some improvements in the bioavailability of drospirenone administered orally, these results have not been eliminated. The present invention provides a pharmaceutical composition comprising at least one steroid drug in a molecularly dispersed form, such as a luteinizing hormone (eg, drospirenone, Progesterone, eplerenone, etprenene (et〇n〇gestrel) and/or estrogen (estritol and its scorpion). The drug comprises a steroid drug, preferably drospirenone, which is present in the composition in a non-particulate form. In the presence of a molecularly dispersed form, it is desirable that the drug be present in the vehicle in a dissolved state. When the unit disintegrates immediately, the drug will be released very rapidly. In a pharmaceutical composition in which the drug is in a molecularly dispersed form, the disintegration time is actually the step of the drug release rate. It means that the present invention can significantly improve bioavailability. The compositions are preferably provided as solid, semi-solid or liquid forms, all of which are preferably suitable for oral administration and preferably in contact with gastric juice. And then absorbed from the gastrointestinal tract. We have found that these compositions have high bioavailability, good chemical stability and rapid dissolution in vitro and can be produced without the need for costly equipment or safety equipment. 132010.doc 200840587 Preparation methods and uses for pharmaceutical compositions, and also for such compositions. The compositions of the present invention are The method comprising the steps of: a) providing drospirenone and one or more carriers; and b) completely dissolving the drospirenone in the or the carrier; and c) drying step b as appropriate The mixture obtained in the above. We have found that the pharmaceutical group containing the molecularly dispersed form of the snail shoulder does not have excellent manufacturing methods, physical or chemical stability, in vitro permeability of intestinal cells in vitro, and in vivo bioavailability. Efficacy.,,, ° In the first aspect, the present invention provides a composition comprising a snail comprising a molecule dispersed in a carrier of the medicinal wind. The carrier contains a dissolution solution: (4) = , mouth ', ,, the composition is a solid, semi-solid or liquid form === the same characteristic is that the snail is dissolved in the carrier at the molecular level. And has the property of dissolution. Generally, "...before, instead of s knowing the solution of snail solution, X-ray diffraction analysis or other appropriate means such as microtechnology, electron microscopy or dissolution = dissolution 1 in = solution form, ie molecular dispersion When the form exists, the characteristic: long: occurs immediately when the early disintegration occurs. Therefore, the common disintegration time of the dosage form and the disintegration time of the comparative formulation of the field occur simultaneously with the error range associated with the η analysis method at the time of dissolution. And a solution comprising a body or a liquid composition in a pharmaceutically acceptable carrier, whether the composition is solid or semisolid, and the common feature of the composition is snail, Molecular grade, commercially available extracts have properties of medium and/or dissolved drospirenone properties J32010.doc 200840587 rather than conventional drospirenone solutions. The compositions of the present invention advantageously exhibit rapid dissolution of the snail web in vitro. 'Money speed dissolution is defined as at least 7% drospirenone in the composition dissolves 30 minutes after the onset of the in vitro solubility test, in particular, at least 8% by weight of drospirenone after the in vitro solubility test is started 2 〇 Dissolved in minutes, more preferably at least 85% by weight of snails are dissolved at η minutes after the onset of the in vitro solubility test. Let us 7. (: _ ml water is used as the dissolution medium and the XXVm blade device 2 is used as a dissolution test device for testing, and the device is operated at 5 〇〇 rpm, for example 50 or 75 rpm. As mentioned above, Higher bioavailability can be achieved with micronized drugs. However, this technique has certain disadvantages because micronized drugs have a tendency to flocculate during production and their operators are susceptible to dust from the micronized music. The production method of the present invention can avoid such disadvantages' = a small number of production steps of the guide material, a reduction in the formation of dust during the manufacturing process, a higher level of volume, a higher level of environment and occupational safety, manufacturing: The composition of the present invention is preferably in a solid, semi-solid or liquid form. The solid composition according to the present invention may be referred to as a solid solution. The semi-solid and liquid compositions are meant to be defined as dissolved form = 屈 solution - wherein the solvent has the viscosity and/or melting point of whether the composition is a semi-solid or liquid composition. "Molecular dispersion" or "molecular dispersant" is used to describe any solid, solid and liquid system 'where component A (eg drospirenone) is at the molecular level 132〇1〇·ς|〇〇200840587 In another component B (such as a solvent or a polymer), it is impossible to detect component A of the crystalline form by X-ray diffraction analysis, and it is impossible to detect the particle form by using micro-technology. Component A, whether crystalline or amorphous, is understood to mean that the term "molecular dispersant" is dissolved in component B regardless of the nature of component B. The term "molecular dispersion" is interchangeable with the term "molecular dissolution".
'術5吾"固體分散劑”係指一種狀態,在該狀態中,屈螺酮 為大體上非微粒形式且其分散於聚合物基質中。該狀態亦 稱作固,合冑。或者’屈螺酮為結晶形態且其分散於聚合 基貝中以致於該等結晶如此精細以致於不能用X射線繞 μ刀析去偵,則到該等結晶。如本文所用,術語,,大體上非 微粒形式”係指一種狀態,在該狀態中,超過9〇 為非微粒形式。 、,或者’可使用顯微技術研究諸如結晶及非結晶顆粒之微 粒,質之不存在。如本文所用,術語”大體上非微粒形式" 系扎種狀態’在該狀態中,當使用顯微裝置分析時,超 過90°/〇之屈螺酮為非微粒形式。 術-固浴體”係用於描述任何固體系統,其中—組份以 分子級別分散於另一組分中。 在特疋形式中’固溶體之特徵為具有分子分散於一溶劑 之屈螺酮(或其他活性成分),該溶劑吸附於能吸附該溶 :丨同時又保持固態之固體载劑上。也就是說,屈螺綱完全 ::於存在於載劑表面之溶劑中。藉由在溶劑中完全溶解 屈螺酮且然後藉由添力”及附該溶劑之固體載劑將該溶劑轉 132〇1〇:(J〇q -11- 200840587 :成口體’同日寸保持溶解形式之屈螺_,從而形成該等固 洛體。據稱固溶體含有分子分散於組合物中之屈螺酮,更 ’、體口之合有分子分散於溶劑中之屈螺綱。 術語”溶液”係用於描述任何半固體及液體系統,其中— 組份以分子級別分散於另一組分中。 因此’吾人應理解本發明之組合物包含非微粒形式之屈 ”酮例如其中屈螺_不是以微粉化顆粒形式或奈米尺寸 fe圍内之顆粒形式存在於該組合物中。因此術語"分子分 政基本上不包括其中將非常精細之屈螺酮顆粒(例如微粉 化顆粒或奈米尺寸之顆粒)與醫藥學可接受之成份或载; 進行幹法混合之組合物或其中最終組合物仍包含顆粒形式 之屈螺網之組合物。 術語”超飽和溶液"係用於描述一種溶液,該溶液含有濃 度向於在室溫下所測定之飽和濃度之藥物。也就是說,儘 &屈螺酮含里較南,用粉末x射線繞射分析亦不能偵測到 任何結晶形態藥物。預期超飽和溶液基本上熱力學不穩 疋,其將導致溶液飽和及藥物再結晶。 術語”安定超飽和溶液”係用於描述一種超飽和溶液,其 中用X射線繞射分析偵測不到任何再結晶藥物。舉例而 口 ’猎由添加結晶抑制劑能實現安定作用。 術語”微乳液”係用於描述稍微不透明、乳白色、透明戋 大體上透明之膠態分散劑,當使其組份與水性介質接觸時 該分散劑自發或大體上自發形成。微乳液熱力學上穩定且 含有小滴或液體,,納米尺寸顆粒,其具有小於約2 μιη平均 132010.doc -12- 200840587 直徑。-般而言’併入微乳液之親脂性藥物在所提及之小 • 滴或液體”納米"尺寸顆粒中以溶解形式存在。 術語"微乳液預濃縮物”係指一種組合物,其按1:1至 1:10,例如1:10在水性介質(例如在水中)稀釋或經口投予 後在胃液中自發形成一微乳液。 在本I明之一實例中,該組合物呈液體形式。因此, 該組合物包含一醫藥學上可接受之溶劑,該溶劑在室溫下 Φ 為液體及/或具有低於4〇它之熔點。此等溶劑可選自下文h) 至U)所示之清單。 在另一實施例中,醫藥學上可接受之溶劑在室溫下為一 半固體及/或具有低於4(TC之熔點。該等溶劑可選自下文… 至U)所示之清單。 一般而言,用於本發明之液體或半固體組合物中且其在 室溫下為液體或半固體之溶劑包括(但不限於)··乙醇、異 丙醇、甘油、丙二醇、transcutol®(二乙二醇單乙醚)、多 ⑩ 元醇類、彳争檬酸酯類、單酸甘油酯類、二酸甘油酯類、植 物油類、植物性脂肪類、部分合成之三酸甘油酯類(例如 中鏈三酸甘油酯(MCT),諸如miglyo®)、合成之三酸甘油 酯類、諸如Imwitor®之甘油脂肪酸酯之混合物、脂肪醇 類、脂肪醇醚類、脂肪酸類、脂肪酸酯類、蠟類、石壤、 純水及其混合物。此外,可使用界面活性劑及共溶劑。 為習此項技術者承認,若干上文所提及之溶劑溶點取決 於例如烴鏈之長度及取代度。因此,熟習此項技術者能夠 易於選擇適當溶劑以產生液體或半固體組合物。 132010.doc -13· 200840587 該等溶劑較佳係選自包含乙醇、丙二醇、部分合成之三 • 酸甘油酯或植物油之群。 . 多元醇類之實例一般為甘油、丙二醇、山梨糖醇、甘露 糖醇、肌醇、異戊四醇、麥芽糖醇、乳糖醇。 柃棣酸酯類之實例一般為檸檬酸三丁酯、檸檬酸三乙酯、 乙l 檬酉夂一 丁酉曰(aCetyl_tributylcitrat)、硬脂酸檸檬酸甘 油酉旨。 φ 單酸甘油酯類之實例一般為甘油單硬脂酸酯、甘油單棕櫚 酸酯、甘油單油酸酯、甘油單亞油酸酯。 一 甘油自曰類之實例一般為二山蝓酸甘油酯、二硬脂酸甘 油SI。 植物油類之實例一般為撖欖油、花生油、蓖麻油。 脂肪類之實例一般為豬油。 合成及部分合成之三酸甘油酯類實例一般為中性油、 softisan®、witepsol(g)、supp〇cire⑧。 • 甘油脂肪酸醋類之實例一般為甘油單辛酸酯、十二酸甘油 酉旨、辛酸/癸酸甘油酯、硬脂酸甘油酯。 脂肪醇之實例一般為辛醇、癸醇、十二醇、十四醇、十六 醇、十八醇、油醇、亞油醇、蓖麻醇。 脂肪醇醚之實例一般為油酸油酯、棕櫚酸十六醇酯、油酸 乙酯。 脂肪酸類之實例一般為癸酸、辛酸、十二烷酸、棕櫚酸、 十六院酸、十八烷酸、油酸、亞油酸。 脂肪酸酯類之實例一般為十二烷酸酯、辛酸酯、癸酸酯、 132010.doc -14- 200840587 硬脂酸酯。 - 纖類之實例一般為白蜂躐、蜂堪。 . 適當之界面活性劑包括(但不限於): a) 印填脂 b) 環氧乙烷及環氧丙烷之嵌段共聚物例如Pluronic®及 Poloxamer® 級 c) 甘油自旨及聚氧乙稀甘油1旨及其混合物例如Gelucire®、 Labrafil® 及 Labrasol® 級 ^ d)丙二醇醋例如 Lauroglycol®及 Capryol®級 e) 嚴糖脂肪酸酯例如811(^0€31613® f) 山梨糖醇脂肪酸酯及聚氧乙烯山梨糖醇脂肪酸酯及其混 合物例如Span㊣及Tween®級 g) 聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚及聚氧乙烯單 酸、二酸及三酸甘油醋、及其混合物例如Cremophor® 級。 ^ 在本發明目前感興趣之實施例中,本發明之液體或半固 體組合物包含如下之溶劑: h) 中鏈三酸甘油酯 i) 蓖麻油 j) Imwitor® 308(甘油單辛酸酉旨)'Surgical 5" "solid dispersant" refers to a state in which drospirenone is in a substantially non-particulate form and is dispersed in a polymer matrix. This state is also referred to as solid, enthalpy. The drospirenone is in a crystalline form and is dispersed in the polymeric basal such that the crystallization is so fine that it cannot be resolved by X-rays, and then to the crystallization. As used herein, the term, substantially "Particulate form" means a state in which more than 9 Å is in a non-particulate form. , or alternatively, microscopic techniques such as crystallization and non-crystalline particles can be used to study the absence of mass. As used herein, the term "substantially non-particulate form" is used in this state, and when analyzed using a microscopic device, drospirenone in excess of 90°/〇 is in a non-particulate form. "Used to describe any solid system in which - components are dispersed in another component at the molecular level. In the special form, the solid solution is characterized by having drospirenone (or other active ingredient) having a molecule dispersed in a solvent which is adsorbed on a solid carrier capable of adsorbing the solution while remaining solid. That is, the snail is completely :: in the solvent present on the surface of the carrier. The solvent is transferred to 132〇1〇 by completely dissolving the drospirenone in the solvent and then by adding the force and the solid carrier attached to the solvent: (J〇q -11-200840587: the mouthpiece is kept at the same time) The solid form of the snails is dissolved in the form of the snails, and the solid solution is said to contain drospirenone in which the molecules are dispersed in the composition, and the phlegm of the body is dispersed in a solvent. The term "solution" is used to describe any semi-solid and liquid system in which - the component is dispersed in the other component on a molecular level. Thus, 'we understand that the composition of the present invention comprises a non-particulate form of a ketone such as The snails are not present in the composition in the form of micronized particles or in the form of particles within the nanometer range. Thus the term "molecular partitioning does not substantially include particles of drospirenone which are very fine (e.g., micronized) Particles or nano-sized particles) and pharmaceutically acceptable ingredients or carriers; compositions for dry mixing or compositions in which the final composition still comprises snails in the form of granules. The term "supersaturated solution" Used for drawing A solution containing a concentration of a drug to a saturation concentration determined at room temperature. That is, the powder is not detected by powder x-ray diffraction analysis. Crystalline form of the drug. It is expected that the supersaturated solution is substantially thermodynamically unstable, which will lead to solution saturation and drug recrystallization. The term "stabilized supersaturated solution" is used to describe a supersaturated solution in which X-ray diffraction analysis is used to detect Less than any recrystallization drug. For example, the addition of a crystallization inhibitor can achieve stability. The term "microemulsion" is used to describe a colloidal dispersant that is slightly opaque, milky white, transparent and substantially transparent, when The dispersant spontaneously or substantially spontaneously forms upon contact with the aqueous medium. The microemulsion is thermodynamically stable and contains droplets or liquids, nanosized particles having an average diameter of less than about 2 μηη 132010.doc -12-200840587. In general, 'lipophilic drugs incorporated into microemulsions are present in dissolved form in the small droplets or liquids" nanosized "size particles mentioned. The term "microemulsion preconcentrate" refers to a composition that spontaneously forms a microscopic formation in gastric juice after dilution or oral administration in an aqueous medium (e.g., in water) at a ratio of 1:1 to 1:10, such as 1:10. In one embodiment of the invention, the composition is in liquid form. Thus, the composition comprises a pharmaceutically acceptable solvent which is Φ liquid at room temperature and/or has less than 4 Å. The melting point. These solvents may be selected from the list shown in the following h) to U). In another embodiment, the pharmaceutically acceptable solvent is half solid at room temperature and/or has less than 4 (TC) The melting point. The solvents may be selected from the list shown below... to U). In general, the solvent used in the liquid or semi-solid composition of the present invention and which is liquid or semi-solid at room temperature includes ( But not limited to) · ethanol, isopropanol, glycerol, propylene glycol, transcutol® (diethylene glycol monoethyl ether), more than 10 alcohols, citric acid esters, monoglycerides, diglycerides Classes, vegetable oils, vegetable fats, partially synthesized triglycerides (eg Chain triglycerides (MCT), such as miglyo®), synthetic triglycerides, mixtures of glycerol fatty acid esters such as Imwitor®, fatty alcohols, fatty alcohol ethers, fatty acids, fatty acid esters, waxes Classes, stone soil, pure water and mixtures thereof. In addition, surfactants and cosolvents can be used. It is recognized by those skilled in the art that a number of solvent melting points mentioned above depend, for example, on the length and degree of substitution of the hydrocarbon chain. Thus, those skilled in the art will be able to readily select a suitable solvent to produce a liquid or semi-solid composition. 132010.doc -13· 200840587 Preferably, the solvents are selected from the group consisting of ethanol, propylene glycol, partially synthesized triglycerides or vegetable oils. Examples of the polyhydric alcohols are generally glycerin, propylene glycol, sorbitol, mannitol, inositol, pentaerythritol, maltitol, lactitol. Examples of the phthalic acid esters are generally tributyl citrate, triethyl citrate, aCetyl_tributylcitrat, and citric acid citrate. Examples of φ monoglycerides are typically glyceryl monostearate, glycerol monopalmitate, glycerol monooleate, glycerol monolinoleate. An example of a glycerin self-oxime is generally glyceryl dibehenate and glycerol distearate. Examples of vegetable oils are generally eucalyptus oil, peanut oil, and castor oil. Examples of fats are generally lard. Examples of synthetic and partially synthesized triglycerides are generally neutral oil, softisan®, witepsol(g), supp〇cire8. • Examples of glycerin fatty acid vinegars are generally glycerol monocaprylate, glyceryl dodecanoate, caprylic/capric glyceride, glyceryl stearate. Examples of fatty alcohols are generally octanol, decyl alcohol, dodecanol, tetradecanol, hexadecanol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, ricinoleol. Examples of fatty alcohol ethers are generally oleic acid oleate, cetyl palmitate, and ethyl oleate. Examples of fatty acids are generally capric acid, caprylic acid, dodecanoic acid, palmitic acid, hexadecanolic acid, octadecanoic acid, oleic acid, and linoleic acid. Examples of fatty acid esters are typically dodecanoate, caprylate, phthalate, 132010.doc -14-200840587 stearate. - Examples of fiber types are generally white bee stings and bee stings. Suitable surfactants include, but are not limited to: a) printing grease b) block copolymers of ethylene oxide and propylene oxide such as Pluronic® and Poloxamer® grade c) glycerol and polyoxyethylene Glycerin 1 and its mixtures such as Gelucire®, Labrafil® and Labrasol® grades d) Propylene glycol vinegars such as Lauroglycol® and Capryol® grade e) Severe sugar fatty acid esters such as 811 (^0 € 31613® f) sorbitol fatty acids Esters and polyoxyethylene sorbitol fatty acid esters and mixtures thereof such as Span and Tween® grade g) polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers and polyoxyethylene monoacids, diacids and triglycerides And mixtures thereof such as Cremophor® grade. In an embodiment of the present invention of the present invention, the liquid or semi-solid composition of the present invention comprises the following solvents: h) medium chain triglyceride i) castor oil j) Imwitor® 308 (glycerol monooctanoate)
k) Cremophor⑧EL l) Cremophor⑧RH 40(聚氧乙烯-40-甘油-羥基硬脂酸酯) m) 聚乙二醇400 n) transcutol® P(二乙二醇單乙趟) 132010.doc -15- 200840587 〇)檸檬酸三乙酉旨 ρ) 7重量%之甘油與93重量%之聚乙二醇4〇〇之混合物 q) 50重量%iImwitor 308與50重量%之聚乙二醇4〇〇之混合 物 r) 50重量。/❶之蓖麻油與50重量d/❾之檸檬酸三丁酯之混合物 s) 50重量%之蓖麻油與50重量。/。之聚乙二醇4〇〇之混合物 t) 75重量%2lmwitor® 742與25重量%之聚乙二醇400之混 合物 1〇75重量%之Imwitor⑧742、15重量0/〇之聚乙二醇400與10 重量%乙醇之混合物,或h)至u)任何溶劑之混合物。 因此,在本發明之某些實施例中,至少一種醫藥學上可 接受之載劑係選自由中鏈三酸甘油酯、蓖麻油、甘油單辛 酸酉旨(Imwitor® 308)、辛酸/癸酸甘油酷(Imwitor 742®)、 聚氧乙稀-3 5-甘油-三蓖麻油酸_((1^111〇卩11〇1:£1^)、聚氧 乙烯-40-甘油-羥基硬脂酸酯(Cremophor® RH 40)、聚乙二 醇400、二乙二醇單乙醚(transcutol® P)、檸檬酸三乙酯及 其混合物組成之群。特定言之,為甘油與聚乙二醇400之 混合物、甘油單辛酸酯(Imwitor® 308)與聚乙二醇400之混 合物、蓖麻油與檸檬酸三丁酯之混合物、蓖麻油與聚乙二 醇400之混合物、辛酸/癸酸甘油酯(Imwitor® 742)與聚乙 二醇400之混合物、辛酸/癸酸甘油酯(Imwitor® 742)及聚 乙二醇400與乙醇之混合物。 在2 g此等液體或半固體組合物中屈螺酮之量一般在1 mg 至30 mg範圍内,較佳為8 mg。 132010.doc •16- 200840587 可將所有忒等液體組合物裝入膠囊,例如裝入軟明膠膠 囊中。 在本發明之其他實施例中,該組合物呈微乳液預濃縮物 形式。此等實施例-般包含如上文所提及之液體及半固體 溶劑,但可另外包含至少一種乳化劑。 本發明之適當乳化劑係關於聚氧乙烯_35_甘油-三蓖麻油 酸酉《(Cremophor® EL)、聚氧乙烯“Ο-甘油-羥基硬脂酸酯 (Cremophor® RH40)、聚氧乙烯4〇〇_單蓖麻油酸酯、聚氧 乙稀脂肪酸甘油酯(Gelueire⑧、Labrafil®、Labras〇1⑧)及 其匕。可將該乳化劑與適當之共乳化劑及/或共溶劑混 白,例如一乙一醇單乙_ (Transcut〇l⑧p)、甘油單辛酸酉旨 (Imwitor® 308)及丙二醇酯(Lauroglycol®、Capryol®)。 在本發明之另外其他實施例中,該組合物呈固體形式。 在其中一實施例中,該組合物包含醫藥學上可接受之載 劑’該載劑在室温下為固體形式及/或具有高於4〇 〇c之溶 點,例如在40-80°C範圍内。作為適當固體載劑可提及固 體聚乙二醇(例如聚乙二醇6000)、植物油及脂肪、部分合 成之二酸甘油S旨、合成之二酸甘油自旨、諸如Imwitor®之甘 油脂肪酸酯之混合物、單酸、二酸與三酸甘油醋之混合 物、聚氧伸乙基甘油脂肪酸醋(例如Gelucire®)、脂肪酸 類、脂肪酸酯類、蠟類、石蠟或其混合物。 在其中某些實施例中,分子分散劑包含基本上均勻分散 於包含一混合物之基質中的屈螺酮,該混合物包含至少一 種脂肪醇及至少一種固體石蠟。在其他實施例中,該基質 132010.doc 200840587 包含至少一種三酸甘油酯及至少一種固體石蠟或至少一種 偏甘油知及至少一種固體石壌或至少一種脂肪酸醋及至少 . 一種固體石蠟。在此等製劑中,包含微球體之製劑為較 佳。 在本發明另一形式之固體組合物中,醫藥學上可接受之 載劑為聚合物。該聚合物較佳為包含游離親水性基團之親 水性聚合物,例如在側鏈中具有官能基之聚合物,如具有 φ ’轉離親水性s能基’諸如缓基、δ旨基、經基、胺基、酸胺 基、έ基或確基。 Τ /谷於水之親水性聚合物之典型實例包括(但不限於): 聚乙烯吡咯啶酮(Povidone⑧、Kollidon⑧)、聚醋酸乙烯 酯、聚乙烯醇、聚乙烯醇鄰苯二甲酸酯、聚乙二醇 (PEG)、聚氧化乙烯、明膠、卡波姆、甲基丙烯 酸共聚物、銨基曱基丙烯酸酯共聚物、纖維素、羧甲基纖 維素、甲基纖維素、經乙基纖維素、㈣基甲基纖維素 • (HPMC)、經丙基纖維素(HPC)、鄰苯二甲酸醋酸纖維素及 ’坐丙基甲基纖維素鄰苯二甲酸酯或其共聚物或混合物。 該親水性聚合物亦可為非水溶性聚合物,其包括(但不 限於交聯聚烯吼_、經基乙酸激粉納及交聯緩甲纖維 素。 该聚合物較佳係選自包含聚乙烯料咬酮刪⑧、 K〇lHd〇_及聚乙二醇(PEG)之群’且尤其較佳為聚乙歸 ㈣咬酮。當使用非水溶性聚合物時,其較佳為交聯聚烯 σ比酮。 1320I0.doc -18 - 200840587 所有前述聚合物在此項技術中已為吾人所熟知。 ,聚乙烯吡咯啶酮係1-乙烯基_2_吡咯啶酮之聚合物。市售 .之承合物為Povidone或Kollidon,其具有約2,000至約 1,5 00,〇〇〇範圍内之平均分子量。所使用之聚乙烯吡咯啶酮 一般具有約7,〇〇〇至約54,000範圍内之平均分子量,較佳係 在約28,0〇〇至約54,000範圍内。 交聯聚烯吡酮係N-乙浠基-2·吡咯啶酮之非水溶性合成 • 之交聯均聚物。該交聯聚烯吡_ 一般具有約2〇 μπι至約25〇 μπι之顆粒尺寸,且其較佳為約5〇 μιη至約25〇 例如參 見科利當(Kollidon),由B ASF生產用於醫藥工業之聚乙烯 吡咯啶酮)。 屈螺酮相對於聚合物之比例較佳為約丨:丨至約丨:丨,更 佳為約1:2至約1:20,且其最佳為約1:5至約1:1〇。 當藉由在一有機溶劑或有機溶劑之混合物中溶解屈螺酮 及聚合物以製備本發明之分子分散劑時,適當之有機溶劑 • 包括(但不限於)二氣甲烷、甲醇、乙醇、異丙醇、丙酮、 四氫呋喃或其混合物。 可藉由習知手段移除溶劑:例如在一遮罩下蒸發該溶 背J使用雙轉5支乾*呆裔或噴霧乾燥器或超臨界流體萃取方 法。 吾人應瞭解亦可將本組合物應用於除屈螺酮外之其他藥 物分子及應用於兩種或兩種以上類型之藥物分子的組合。 因此,本發明之組合物亦包含任何親脂性且在25它水中具 有差溶解性之化合物。一般而言,化合物在25t水中具^ 132010.doc -19- 200840587k) Cremophor8EL l) Cremophor8RH 40 (polyoxyethylene-40-glycerol-hydroxystearate) m) polyethylene glycol 400 n) transcutol® P (diethylene glycol monoethyl hydrazine) 132010.doc -15- 200840587 〇) citric acid triethyl hydrazine ρ) a mixture of 7% by weight of glycerin and 93% by weight of polyethylene glycol 4 q q) a mixture of 50% by weight of iImwitor 308 and 50% by weight of polyethylene glycol 4 r ) 50 weight. / Mixture of castor oil with 50 weight d/❾ of tributyl citrate s) 50% by weight of castor oil with 50% by weight. /. a mixture of polyethylene glycol 4 t t) 75 wt% 2 lmwitor® 742 and 25% by weight of polyethylene glycol 400 mixture 1 〇 75% by weight of Imwitor 8742, 15 weight 0 / 〇 polyethylene glycol 400 and a mixture of 10% by weight ethanol, or a mixture of h) to u) any solvent. Accordingly, in certain embodiments of the invention, the at least one pharmaceutically acceptable carrier is selected from the group consisting of medium chain triglycerides, castor oil, glycerol monocaprylate (Imwitor® 308), caprylic/capric acid Glycerol Cool (Imwitor 742®), Polyoxyethylene-3 5-Glycerol-Triricinoleic Acid _((1^111〇卩11〇1:£1^), Polyoxyethylene-40-glycerol-hydroxystearate a group of esters (Cremophor® RH 40), polyethylene glycol 400, diethylene glycol monoethyl ether (transcutol® P), triethyl citrate and mixtures thereof. In particular, glycerol and polyethylene glycol a mixture of 400, a mixture of glycerol monocaprylate (Imwitor® 308) and polyethylene glycol 400, a mixture of castor oil and tributyl citrate, a mixture of castor oil and polyethylene glycol 400, octanoic acid/capric acid glycerol Mixture of ester (Imwitor® 742) with polyethylene glycol 400, octanoic acid/capric acid glyceride (Imwitor® 742) and a mixture of polyethylene glycol 400 and ethanol. Included in 2 g of these liquid or semi-solid compositions The amount of snail is generally in the range of 1 mg to 30 mg, preferably 8 mg. 132010.doc •16- 200840587 All liquids such as hydrazine can be used. The capsule is enclosed, for example, in a soft gelatin capsule. In other embodiments of the invention, the composition is in the form of a microemulsion preconcentrate. These examples generally comprise a liquid and a half as mentioned above. a solid solvent, but may additionally comprise at least one emulsifier. Suitable emulsifiers for the present invention are related to polyoxyethylene _35_glycerol-sodium ruthenium oleate (Cremophor® EL), polyoxyethylene "Ο-glycerol-hydroxyl hard" Acid ester (Cremophor® RH40), polyoxyethylene 4〇〇_monoricinoleate, polyoxyethylene fatty acid glyceride (Gelueire8, Labrafil®, Labras〇18) and its hydrazine. The co-emulsifier and/or the co-solvent are mixed, such as monoethyl ketone (Transcut® 18p), glycerol monocaprylate (Imwitor® 308) and propylene glycol ester (Lauroglycol®, Capryol®). In still other embodiments, the composition is in solid form. In one embodiment, the composition comprises a pharmaceutically acceptable carrier, the carrier being in solid form at room temperature and/or having a higher than 4 〇溶c melting point, for example at 40-80 ° C As a suitable solid carrier, mention may be made of solid polyethylene glycol (for example polyethylene glycol 6000), vegetable oils and fats, partially synthesized diglycerides, synthetic diglycerides, such as Imwitor®. Mixtures of glycerol fatty acid esters, monoacids, mixtures of diacids and triglycerides, polyoxyethylidene fatty acid vinegars (eg Gelucire®), fatty acids, fatty acid esters, waxes, paraffins or mixtures thereof. In some of these embodiments, the molecular dispersing agent comprises drospirenone substantially uniformly dispersed in a matrix comprising a mixture comprising at least one fatty alcohol and at least one paraffin wax. In other embodiments, the substrate 132010.doc 200840587 comprises at least one triglyceride and at least one solid paraffin or at least one partial glycerol and at least one solid dendrobium or at least one fatty acid vinegar and at least one solid paraffin wax. Among these preparations, preparations containing microspheres are preferred. In a solid composition of another form of the invention, the pharmaceutically acceptable carrier is a polymer. The polymer is preferably a hydrophilic polymer containing a free hydrophilic group, such as a polymer having a functional group in a side chain, such as having a φ 'transferred hydrophilic s energy group such as a slow group, a δ group, A benzyl group, an amine group, an acid amine group, a thiol group or a decyl group. Typical examples of 亲水/gluten-water hydrophilic polymers include, but are not limited to, polyvinylpyrrolidone (Povidone 8, Kollidon 8), polyvinyl acetate, polyvinyl alcohol, polyvinyl phthalate, Polyethylene glycol (PEG), polyethylene oxide, gelatin, carbomer, methacrylic acid copolymer, ammonium methacrylate copolymer, cellulose, carboxymethyl cellulose, methyl cellulose, ethyl Cellulose, (tetra)methylcellulose • (HPMC), propyl cellulose (HPC), cellulose acetate phthalate and 'propyl propyl methyl cellulose phthalate or copolymers thereof mixture. The hydrophilic polymer may also be a water-insoluble polymer including, but not limited to, crosslinked polyalkylene fluorene, transacetin and crosslinked stearyl cellulose. The polymer is preferably selected from the group consisting of The polyethylene bitumen is a group of 8, K〇lHd〇_ and polyethylene glycol (PEG) and is particularly preferably a poly(b) ketone. When a water-insoluble polymer is used, it is preferably a cross. Polyalkenyl ketone ketone. 1320I0.doc -18 - 200840587 All of the foregoing polymers are well known in the art. Polyvinylpyrrolidone is a polymer of 1-vinyl-2-pyrrolidinone. Commercially available as Povidone or Kollidon having an average molecular weight in the range of from about 2,000 to about 1,500, 〇〇〇. The polyvinylpyrrolidone used typically has from about 7, from about 5 to about 54,000. The average molecular weight in the range is preferably in the range of from about 28,0 Torr to about 54,000. Crosslinking of the cross-linked povidone-based N-ethyl fluoren-2-pyrrolidone The crosslinked polyethylidene typically has a particle size of from about 2 μm to about 25 μm, and is preferably about 5 μm See, for example, from about 25〇 Kollidon (Kollidon), produced by the B ASF for the polyvinyl pyrrolidone, the pharmaceutical industry). The ratio of drospirenone to polymer is preferably from about 丨: 丨 to about 丨: 丨, more preferably from about 1:2 to about 1:20, and most preferably from about 1:5 to about 1:1〇 . When the molecular dispersant of the present invention is prepared by dissolving drospirenone and a polymer in a mixture of an organic solvent or an organic solvent, suitable organic solvents include, but are not limited to, di-methane, methanol, ethanol, and Propanol, acetone, tetrahydrofuran or a mixture thereof. The solvent can be removed by conventional means: e.g., evaporation of the solution J under a mask using a double-turn 5 dry* dander or spray dryer or supercritical fluid extraction method. It is to be understood that the present compositions can also be applied to other drug molecules other than drospirenone and to combinations of two or more types of drug molecules. Accordingly, the compositions of the present invention also comprise any compound which is lipophilic and has poor solubility in water of 25. In general, the compound has a water in 25t ^ 132010.doc -19- 200840587
低於1 mg/ml之溶解度,例如低於0.5、0.1、0.05或0·01 mg/ml。該彳匕合物一般為類固醇分子及/或通常為激素/抗激 素。大範圍之其他活性醫藥成份可受益於本技術,例如阿 苯達嗤(albendazole)、胺基格魯米特(aminogluthethimide)、 胺基水楊酸(3-、4-或5-胺基水揚酸)、胺峨達隆 (amiodarone)、阿司 口米嗤(astemizole)、口米嗤硫嗓吟 (azathioprine)、苄氣丙酷胺(beclamide)、撲炎痛 (benorylate)、苯旅利多(benperidol)、苯紮貝特 (bezafibrate)、生物素、溴麥角環肽(bromocriptine)、甲石黃 酸溴麥角環肽(bromocriptine mesylate)、布美他尼 (bumetanide) 白消安(busulphan)、卡麥角林 (cabergoline)、卡馬西泮(carbamazepine)、頭孢克肪 (cefixime)、鶴去氧膽酸(chenodeoxycholic acid)、苯丁酸 氮芥(chlorambucil)、氣喧(chloroquine)、氣石黃丙脲 (chlorpropamide)、氯普嗟領(chlorprothixene)、氣嗟 _ (chlorthalidone)、肉桂苯旅嗓(cinnarizine)、西誤沙星 (cinoxacin)、氯巴占(clobazam)、氯苯吩嗓(clofazimine)、 安妥明(clofibrate)、氯石肖西泮(clonazepam)、環戊σ塞口秦 (cyclopenthiazide)、環孢菌素 A(cyclosporin Α)、胺苯石風 (dapsone)、地美環素(demeclocycline)、二氮 ^(diazoxide)、 二氟尼柳(diflunisal)、洋地黃毒苦(以名丨1:〇\丨11)、地高辛 (digoxin)、戒酒硫(disulfiram)、多潘立酮(domperidone)、 氟11辰利多(droperidol)、依諾沙星(enoxacin)、埃坡黴素 (epothilone)、乙硫異煙胺(ethionamide)、依曲替酉旨 132010.doc -20- 200840587A solubility below 1 mg/ml, such as less than 0.5, 0.1, 0.05 or 0·01 mg/ml. The chelate is typically a steroid molecule and/or is typically a hormone/anti-hormone. A wide range of other active pharmaceutical ingredients may benefit from this technology, such as albendazole, aminogluthethimide, aminosalicylic acid (3-, 4- or 5-amino sulphate) Acid), amiodarone, astemizole, azathioprine, beclamide, benorylate, benzene british ( Benperidol), bezafibrate, biotin, bromocriptine, bromocriptine mesylate, bumetanide, busulphan , cabergoline, carbamazepine, cefixime, chenodeoxycholic acid, chlorambucil, chloroquine, magnesite (chlorpropamide), chlorprothixene, chlorthalidone, cinnarizine, cinoxacin, clobazam, clofazimine, Clofibrate, chlorite shaws (clonazepam), cyclopentthiazide, cyclosporin 、, dapsone, demeclocycline, diazoxide, diflunis Diflunisal, digitalis poison (by name: 〇\丨11), digoxin, disulfiram, domperidone, droperidol, enoxa Enoxacin, epothilone, ethionamide, etretin 132010.doc -20- 200840587
(etretinate)、非洛地平(felodipine)、芬布芬(fenbufen)、非 索非那定(fexofenadine)、氟馬西尼(flumazenii)、葉酸、 呋塞米(furosemide)、格列吡嗓(glipizide)、格列喹酮 (gliquidone)、灰黃黴素(griseofulvin)、氟哌啶醇 (haloperidol)、雙氫氯噻嗪(hydrochlorothiazide)、雙氫氟 噻嗪(hydroflumethiazide)、布洛芬(ibuprofen)、伊洛前列 素(iloprost)、哚美辛(indomethacin)、異卡波肼 (isocarboxazid)、二硝酸異山梨酯(isosorbide dinitrate)、 異維甲酸(isotretinoin)、伊拉地平(isradipine)、伊曲康嗤 (itraconazole)、凱他唾侖(ketazolam)、酮康唑 (ketoconazol)、酮洛芬(ketoprofen)、蘭索拉唑 (lansoprazole)、埃塞羅寧納(liothyronine sodium)、麥角乙 脲(lisuride)、洛旅 丁胺(loperamide)、氯雷他定 (loratadine)、氯經安定(lorazepam)、洛伐他汀(lovastatin)、 甲苯達。坐(mebendazole)、美達西泮(medazepam)、甲芬那 酸(mefenamic acid)、甲萘酉昆(menadione)、美喧他嗓 (mequitazine)、曱胺蝶呤(methotrexate)、米索前列醇 (misoprostol)、嗎啡(morphine)、氯石肖柳胺(niclosamide)、 硝苯地平(nifedipine)、尼莫地平(nimodipine)、石肖基安定 (nitrazepam)、奥美拉口坐(omeprazole)、奥沙西泮(oxazepam)、 氧四環素(oxytetracycline)、泮托拉 °坐(pantoprazole)、奮乃 靜(perphenazine)、保泰松(phenylbutazone)、娘迷清 (pimozide)、ϋ弓卜朵洛爾(pindolol)、丙磺舒(probenecid)、普 羅布考(probucol)、雙經萘酸售哺 °定(pyrantel embonate)、 132010.doc -21 - 200840587(etretinate), felodipine, fenbufen, fexofenadine, flumazenii, folic acid, furosemide, glipizide ), gliquidone, griseofulvin, haloperidol, hydrochlorothiazide, hydroflumethiazide, ibuprofen, ilo Iproprost, indomethacin, isocarboxazid, isosorbide dinitrate, isotretinoin, isradipine, istraconazole Itraconazole), ketazolam, ketoconazol, ketoprofen, lansoprazole, liothyronine sodium, lisuride Loperamide, loratadine, lorazepam, lovastatin, toluene. Mebendazole, medazepam, mefenamic acid, menadione, mequitazine, methotrexate, misoprostol (misoprostol), morphine, niclosamide, nifedipine, nimodipine, nitrazepam, omeprazole, Oxacy Oxa (oxazepam), oxytetracycline, pantoprazole, perphenazine, phenylbutazone, pimozide, pindolol , probenecid, probucol, pyrantel embonate, 132010.doc -21 - 200840587
乙胺口密咬(pyrimethamine)、視黃醇(retinol)、核黃素 (riboflavin)、辛伐他汀(simvastatin)、己稀雌紛 (stilboestrol)、舒林酸(sulindac)、績胺嘴淀(sulphadiazine)、 石黃胺曱基異°惡σ坐(sulphamethoxazole)、柳氮磺胺σ比口定 (sulphasalazine)、舒必利(sulpiride)、它莫西芬(tamoxifen)、 替馬西泮(temazepam)、17塞苯咪峻(thiabendazole)、硫鳥嗓 呤(thioguanine)、生育齡(tocopherol)、甲苯石黃丁脲 (tolbutamide)、維甲酸(tretinoin)、胺苯蝶咬(triamteren)、 三σ坐侖(triazolam)、甲氧苄胺哺咬(trimethoprim)及左匹克 隆(zopiclone) 〇 如上述的,本發明之化合物一般為類固醇分子或另外為 可提及之激素: • 雄激素類,諸如睪固酮(testosterone)及其酯(庚酸睪固 酮、Η--酸睪固酮、環戊丙酸睪固酮(testosterone cypionate)、 丙酸睪固酮。 •雌激素類/抗雌激素類,諸如雌二醇及其酯(戊酸雌二 醇、庚酸雌二醇、環戊丙酸雌二醇、十一酸雌二醇)、 雌三醇(estriol)、雌酮(estrone)、共輛雌激素類、馬烯雌 酮(equilin)、乙炔雌二醇〇1:1^1171€81:1^(11〇1)、芬雌酸 (fenestrel)、美雌醇(mestranol)、尼爾雌醇(nylestriol)、 快雌&| (quinestrol)、氯米芬(clomifene)、雌激素受體α 激動劑、雌激素受體α拮抗劑、雌激素受體β激動劑、雌 激素受體β拮抗劑、雌激素受體向下調節劑。 •皮質類固酵類,諸如可的松(cortisones)及糖皮質激素 132010.doc -22- 200840587 類,例如二丙酸倍氯米松(beclomethasone dipropionate)、 倍他米松(betamethasone)、倍他米松戊酸酯、布地奈德 (budesonide)、丙酸氯倍他索(clobetasol propionate)、丁 酸氣倍他松(clobetasone butyrate)、醋酸可的松 (cortisone acetate)、地塞米松(dexamethasone)、醋酸氟 氛可的松(fludrocortisone acetate)、潑尼松龍 (prednisolone)、潑尼松(prednisone) 〇Pyrimethamine, retinol, riboflavin, simvastatin, stilboestrol, sulindac, sulindip Sulphadiazine), sulphamethoxazole, sulphasalazine, sulpiride, tamoxifen, temazepam, 17 phenylene Thiabendazole, thioguanine, tocopherol, tolbutamide, tretinoin, triamteren, triazolam, armor Trimethoprim and zopiclone As described above, the compounds of the invention are generally steroid molecules or otherwise may be mentioned: • Androgens, such as testosterone and its esters (heptanoic acid sterolone, hydrazine-acid sterolone, testosterone cypionate, propionate sterolone • estrogens/antiestrogens such as estradiol and its esters (estradiol valerate, Acid estradiol, estradiol cyclopentanoate, estradiol undecylate, estriol, estrone, co-estrogens, equilin, ethinyl Glycol 〇 1:1^1171 € 81:1^(11〇1), fenestrel, mestranol, nylestriol, fast female &| (quinestrol), Clomifen (clomifene), estrogen receptor alpha agonist, estrogen receptor alpha antagonist, estrogen receptor beta agonist, estrogen receptor beta antagonist, estrogen receptor downregulator. Types of solids, such as cortisones and glucocorticoids 132010.doc -22- 200840587, such as beclomethasone dipropionate, betamethasone, betamethasone valerate , budesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, dexamethasone, fluorinated acetate Fludrocortisone acetate, prednisolone, prednis One) 〇
•助孕素類/抗雄激素類,諸如環丙孕嗣(cyproterone)、依 託孕婦(etonogestrel)、去氧孕烯(desogestrel)、孕二烯酮 (gestodene)、左炔諾孕酮(levonorgestrel)、煥諾 _ 類 (norethisterones)、諾孕自旨(norgestimate)、炔諾酮 (norethindrone)、醋酸炔諾酮、異快諾酮(norethynodrel)、 語孕酿(norgestimate)、甲基炔講酮(11〇1^681:化1)、美屈孕 酮(medrogestone)、醋 g曼甲經孕酮(medroxyprogesterone acetate)、孕顚I (progesterone)、孕酮受體A特異性配位 體、孕酮受體B特異性配位體、中助孕素類 (mesoprogestins)、抗助孕素類、asoprisnil、asoprisnil ecamate ° •搭固酮拮抗劑類,諸如螺内酯類(spironolactones)、依普 利酮(eplerenone)、坎利酸鹽(canrenoate)、坎利酮 (canrenone)、地西利酮(dicirenone)、麥克利酸鹽 (mexrenoate)、丙利酸鹽(prorenoate)、環氧司坦(epostane)、 美螺利酮(mespirenone)、奥孕酸鹽(oxprenoate)、螺利酮 (spirorenone)、螺沙宗(spiroxasone)、丙利酮(prorenone)。 132010.doc 23· 200840587 •維生素D激素類’諸如阿法約化醇(他以丨^。1)、約化二 醇㈣cifedid)、詞化醇(論伽〇1)、鈣化三醇㈣也㈣。 應瞭解本發明之組合物可包含一種以上活性藥物,例如 兩種或兩種以上藥物之組合。舉例而言,本發明之組合物 可包含、冶療有效劑量之屈螺酮及治療有效劑量之雌激素。 醫藥調配物之形式 包含分子分散劑之la合物可視情況進—步包含—或多種• Progesterone/antiandrogen, such as cyproterone, etonogestrel, desogestrel, gestodene, levonorgestrel , norethisterones, norgestimate, norethindrone, norethisterone acetate, norethynodrel, norgestimate, methyl acetylenketone (11 〇1^681: 1), medrogestone, mederate progesterone acetate, progesterone, progesterone receptor A-specific ligand, progesterone receptor Body B-specific ligands, mesoprogestins, antiprogestins, asoprisnil, asoprisnil ecamate ° • ketone antagonists, such as spironolactones, eplerenone , canrenoate, canrenone, dicirenone, mexrenoate, prorenoate, epostane, snail Ketone (mespirenone), oxprenoate, snail Spironone, spiroxasone, prorenone. 132010.doc 23· 200840587 • Vitamin D hormones such as afaractin (he is 丨^.1), diol (four) cifedid), liquefied alcohol (on gamma 1), calcitriol (four) also (four) . It will be appreciated that the compositions of the present invention may comprise more than one active drug, such as a combination of two or more drugs. For example, the compositions of the present invention may comprise, administer an effective amount of drospirenone and a therapeutically effective amount of estrogen. The form of the pharmaceutical formulation may include a plurality of molecular dispersing agents.
另外活性成份及/或賦形劑’係選自包含崩解劑、潤滑 劑、助流劑、人造甜味劑、增積劑' 著色劑及一或多種食 用香料之群。 < 能夠以固體劑型產生包含分子分散劑之組合物。固體劑 型包含錠劑、薄膜包衣錠劑、顆粒、丸粒、九劑、膠囊及 政劑,舉例而s其包括該等劑型之任何改良釋放形式,諸 如具有延遲釋放包衣、持續釋放包衣、腸溶包衣之劑型、 即刻釋放調配物、泡騰劑型及_形式。㈣包括例 明膠膠囊、硬明膠膠囊、經丙基甲基纖維素(Hp 及角又菜膠膠囊。 ^ =某些實施例中,可將組合物進行適當調配以用於 =或舌下投予。舉例而言,在調味基劑之分子分散劑中包 =屈螺㈣π含劑形式或在明膠、請、蔗糖或阿拉 酮::性基劑中的片劑形式。亦可將聚合物膜形式之屈螺 二广體直接置於臉頰黏膜而不需任何其他處理。液體組 。物可適用於臉頰或舌下喷霧施用。 、、、 猎由此項技術中所熟知之方法可製備所有劑型。 13201〇.d〇c -24 - 200840587 -般地,屈螺酮在分子分散組合物中的量在約i至約5〇 重量。/。,較佳在約5至約50重量%範圍内;且其在諸如鍵 劑:顆粒、丸粒或散劑之醫藥劑型中的量在約〇ι至約5〇 重量%範圍内’較佳為約1〇至約5 〇重量%。意即,分子分 散組合物在醫藥劑型中的量一般在約5至⑽重量%範圍 内’較佳為約1 〇至約5 〇重量%。 賦形劑Further, the active ingredient and/or excipient' is selected from the group consisting of a disintegrant, a lubricant, a glidant, an artificial sweetener, a bulking agent' colorant, and one or more flavorants. < A composition containing a molecular dispersant can be produced in a solid dosage form. The solid dosage form comprises a troche, a film-coated lozenge, granules, pellets, nine doses, capsules, and administrations, for example, and includes any modified release form of such dosage forms, such as a delayed release coating, a sustained release coating Enteric coated dosage form, immediate release formulation, effervescent dosage form and _ form. (d) including gelatin capsules, hard gelatin capsules, propylmethylcellulose (Hp and guacamole capsules. ^ = In some embodiments, the composition may be suitably formulated for use in sublingual or sublingual administration. For example, in the molecular dispersing agent of the flavoring base, it is in the form of a tablet or a tablet in the form of a gelatin, a sucrose or an arsenone: a base. The snail snail is directly placed on the cheek mucosa without any other treatment. The liquid group can be applied to the cheek or sublingual spray application.,,, hunting, all dosage forms can be prepared by methods well known in the art. 13201〇.d〇c -24 - 200840587 Similarly, the amount of drospirenone in the molecularly dispersed composition ranges from about i to about 5 ounces by weight, preferably from about 5 to about 50% by weight. And the amount thereof in a pharmaceutical dosage form such as a granule: granule, pellet or powder is in the range of from about 10 to about 5% by weight, preferably from about 1 Torr to about 5% by weight. The amount of the dispersion composition in the pharmaceutical dosage form is generally in the range of from about 5 to 10% by weight, preferably about 1 Torr. Up to about 5% by weight. Excipients
如上所述’本發明之組合物包含除所要求之聚合物、溶 劑、界面活性劑及結晶抑制劑外之若干其他賦形劑。 適當之崩解劑係選自&交聯緩甲纖維素納(一種缓甲基 纖維素鈉之交聯聚合物)、交聯聚烯吡酮、澱粉nf、泊拉 可林(Μη)鈉或鉀及羥基乙酸澱粉鈉組成之群。孰習 此項技術者應瞭解吾人需要可壓縮之錠劑在3q分鐘内崩 解’更需要其在10分鐘内崩解,最需要其在5分鐘内崩 解;因此所使用之崩解劑較佳導致錠劑在3()分鐘内崩解, 更佳為在10分鐘内崩解,最佳為在5分鐘内崩解。 適當之潤滑劑包括滑石、硬脂酸鎮、硬脂酸約、硬脂 酸、氫化植物油及其類似物。較佳使用硬脂酸鎂。 適當之助流劑包括熱解二氧化矽、滑石及其類似物。 適當之增積劑包括木糖醇、甘露糖醇、可壓縮糖、乳 糖、磷酸鈣及微晶纖維素。 適當之人造甜味劑包括糖精、賽克拉美及阿斯巴甜。 必要時可將已知之食用香料及已知之舰。著色劑添加 至組合物中。 I32010.doc 25 200840587 製備屈螺酮分子分散劑之方法 1·藉由包含下列㈣之方法^本發明之組合物: a) 提供屈螺酮及一或多種栽劑;及 b) 將屈螺_完全溶解於-或多種載劑中;及 c) 視情況’乾燥步驟b)中所獲得之混合物。 由中’在步驟b)中溶解屈螺酮之步驟較佳藉係 由選自加熱、超音波處理、 壓之方法執行。 μ混合、授拌及/或炼融擠 乾燥步驟b所產生之混合物可包括喷霧乾燥或此項技術 中吾人已知之其他方法。 吾人應瞭解可使用上文所提及之醫藥學上可接受之載劑 及上文所提及之活性化合物執行該方法。 在實例1至6中描述用於製備微乳液預濃縮物之方法及組 合物。在確保屈螺嗣完全溶解於液體/半固體溶劑中之條 件下’例如在5(TC下使用超音波浴進行操作,藉由包含將 液體或半固體溶劑或其混合物與屈螺酮混合之方法製備微 乳液預濃縮物。舉例而言’關於液體/半固體溶劑可參見 上文’尤其為h)至u)所列之溶劑。該所得預濃縮物可含有 的屈螺酮為:自每15〇0 mg濃縮物中含i叫至每_呵濃 縮物中含! mg屈螺肩’較佳為自每咖叫濃縮物中含i 叫至每HO mg濃縮物中含i mg屈螺酮,例如每75〇叫或 25〇 mg濃縮物中含i mg屈螺酮。 視情況亦可將至少-種如上文所提及之乳化劑添加至液 體/半固體溶劑中。 132010.doc -26- 200840587 一旦將水添加至預濃縮物中,則 ^ , 則可自發形成一隨時可投 予之乳白色微乳液。所添加之水量—奴、 般為每1 g該濃縮物 添加2ml至⑽,例如每1§該遭縮物添加hm, 例如每1 g該濃縮物添加5 ml至70 mi。 該所得微乳液至少三日内不顯示任 $何/儿降或結晶且離心 作用(6_u’ H) min)亦不會產生任何沉降或結晶。 實例7描述一種製備含有經分子分 刀政屈螺酮之液體组合As noted above, the compositions of the present invention comprise several other excipients in addition to the desired polymers, solvents, surfactants, and crystallization inhibitors. Suitable disintegrants are selected from & cross-linked stearyl cellulose (a cross-linked polymer of slow methylcellulose sodium), cross-linked povidone, starch nf, posacine sodium Or a group consisting of potassium and sodium starch glycolate. Those skilled in the art should understand that we need a compressible tablet to disintegrate in 3 minutes. It is more necessary to disintegrate within 10 minutes, and it is most necessary to disintegrate within 5 minutes; therefore, the disintegrant used is more Preferably, the tablet disintegrates in 3 () minutes, more preferably disintegrates in 10 minutes, and most preferably disintegrates in 5 minutes. Suitable lubricants include talc, stearic acid, stearic acid, stearic acid, hydrogenated vegetable oils, and the like. Magnesium stearate is preferably used. Suitable glidants include pyrogenic ceria, talc, and the like. Suitable builders include xylitol, mannitol, compressible sugars, lactose, calcium phosphate and microcrystalline cellulose. Suitable artificial sweeteners include saccharin, sikaram and aspartame. Known flavorants and known ships can be used if necessary. A colorant is added to the composition. I32010.doc 25 200840587 Method for preparing drospirenone molecular dispersing agent 1. Composition according to the invention by the method comprising the following (4): a) providing drospirenone and one or more seeding agents; and b) Completely dissolved in - or a plurality of carriers; and c) a mixture obtained as in the case of 'drying step b'. The step of dissolving drospirenone in the step 'in step b) is preferably carried out by a method selected from the group consisting of heating, ultrasonic treatment, and pressing. Mixing, batching and/or smelting extrusion The mixture produced by drying step b may include spray drying or other methods known in the art. It is to be understood that the method can be carried out using the pharmaceutically acceptable carrier mentioned above and the active compounds mentioned above. Methods and compositions for preparing microemulsion preconcentrates are described in Examples 1 through 6. Under the condition of ensuring that the snail is completely dissolved in the liquid/semi-solid solvent, for example, operating at 5 (TC using an ultrasonic bath, by including a method of mixing a liquid or semi-solid solvent or a mixture thereof with drospirenone) A microemulsion preconcentrate is prepared. For example, 'for liquid/semisolid solvents, see the solvents listed above, especially h) to u). The resulting preconcentrate may contain drospirenone: from every 15 〇 0 mg concentrate containing i to each _ concentrated concentrate! The mg snail shoulders preferably contain i mg of drospirenone per gram of concentrated concentrate, for example, i mg drospirenone per 75 yoke or 25 〇mg concentrate. . It is also possible to add at least one of the emulsifiers as mentioned above to the liquid/semi-solid solvent. 132010.doc -26- 200840587 Once water is added to the preconcentrate, ^, then a ready-to-feed milky white microemulsion can be formed spontaneously. The amount of water added - slaves, is typically 2 ml to (10) per 1 g of the concentrate, for example hm is added per 1 § of the condensate, for example 5 ml to 70 mi per 1 g of the concentrate. The resulting microemulsion did not show any precipitation or crystallization and centrifugation (6_u' H) min for at least three days and did not cause any sedimentation or crystallization. Example 7 describes the preparation of a liquid combination containing molecularly divided drospirenone
物之方法及較佳組合物。藉由將—定量之㈣_在⑸代 下擾拌溶解於-溶劑巾而製得含有經分子分散屈螺納之液 體組合物,該溶劑在室溫下為液體 π狀IS且其係如上文所定義 般。屈螺_的量-般為每2 g該液體施用i叫至3〇叫較 佳為8 mg。適當溶劑之實例一般為上文所提及,尤其為如 上文h)至u)中所列之溶劑。 可將根據實例之組合物裝入膠囊中。基本上較佳將 根據實例1-6之組合物裝入硬明膠膠囊中並在填充後密封 之;且較佳將根據實例7之組合物裝入軟明膠膠囊中。 貝例8顯示本發明之液體及半固體組合物中溶劑及界面 /舌性劑之選擇並不會改變屈螺酮之溶解速度及滲透性,屈 螺酮自所有研究之調配物中快速吸收。然而,令人驚訝地 發現根據實例2之調配物提供較低降解度之屈螺酮。 實例9至13及24描述製備固溶體之方法及較佳調配物: 基本上存在兩種製備固溶體之方法。在一實施例(實例 12、13及24)中,將活性物與乾燥粉末化之聚合物或聚合 物之混合物及視情況之添加劑混合,其中該添加劑為如 132〇l〇.doc -27- 200840587 sucr_er之界面活性劑。使用單螺桿擠麼機或雙螺桿擠廢 機或類似設備在1 0至i 0 〇 r p m範圍内之旋轉速率下連續擠 壓該混合物。視情況,分別藉由加熱及冷卻控制該擠壓機 之溫度,以使該製程溫度係在例如4〇_15〇t;範圍内。在此 製权中’在最終壓力及溫度下液化整個混合物,因此將活 性物溶於聚合物巾。將該所得經再固化之漏物切為或破 碎為碎片,經研磨及過篩以作進一步加工。該所得之體外 溶解資料可參見實例25。 在另一實施例(實例10及u)中,藉由噴霧乾燥可自溶液 製備固溶體,其中該溶液包含活性物及聚合物及視情況選 用例如界面活性劑之呈溶解形式的添加劑。熟習此項技術 者瞭解喷霧乾燥條件必須適應於所用設備。將該經噴霧乾 燥產物在乾燥箱中或經由儲存於使用例如五氧化二磷之乾 燥劑的乾燥器中進一步乾燥。 如先前所提及,聚合物較佳為包含游離親水性基團之親 水性聚合物,例如側鏈具有官能基之聚合物,其中該等官 能基例如可為游離親水性官能基,如敌基、g旨基、声美 胺基、酿胺基、鹵基或續酸基。可溶於水之親水性聚合物 之典型實例包括(但不限於)··聚乙烯吡咯啶酮(P〇vid〇ne⑧、 Kollidon®)、聚醋酸乙烯酯、聚乙烯醇、聚乙烯醇鄰苯二 曱酸酯、聚乙二醇(PEG)、聚氧化乙烯、明膠、卡波姆、 曱基丙晞酸共聚物、銨基曱基丙烯酸酯共聚物、纖維素、 叛甲基纖維素、甲基纖維素、經乙基纖維素、經丙夷甲美 纖維素(HPMC)、羥丙基纖維素(HPC)、鄰苯二曱酸醋酸纖 132010.doc •28- 200840587 維素及羥丙基曱基纖維素鄰苯二甲酸酯或其共聚物或混合 物。親水性聚合物亦可為非水溶性聚合物,包括(但不限 於)·交聯聚乙烯吡咯啶酮、羥基乙酸澱粉鈉及交聯羧曱 纖維素。該聚合物較佳係選自包含聚乙烯吡咯啶酮 (Povidone⑧、Kollidon®)及聚乙二醇(PEG)之群,且尤其較 佳為聚乙烯吼咯啶酮。當使用非水溶性聚合物時,其較佳 為交聯聚烯σ比酮。Method and preferred composition. A liquid composition containing a molecularly dispersed dextrosane is obtained by dissolving - (quantitative) (4) _ in (5) generations by dissolving in a solvent towel, the solvent being liquid π-like IS at room temperature and which is as above As defined. The amount of snail _ is generally 8 mg per 2 g of the liquid applied to 3 〇. Examples of suitable solvents are generally mentioned above, especially the solvents as listed in h) to u) above. The composition according to the examples can be enclosed in a capsule. It is substantially preferred to incorporate the composition according to Examples 1-6 into a hard gelatin capsule and to seal it after filling; and preferably the composition according to Example 7 is filled into a soft gelatin capsule. Shell Example 8 shows that the choice of solvent and interface/tongue agent in the liquid and semi-solid compositions of the present invention does not alter the dissolution rate and permeability of drospirenone, which is rapidly absorbed from all of the formulations studied. However, it was surprisingly found that the formulation according to Example 2 provided a lower degree of degradation of drospirenone. Examples 9 to 13 and 24 describe a method of preparing a solid solution and a preferred formulation: There are basically two methods of preparing a solid solution. In one embodiment (Examples 12, 13 and 24), the active is mixed with a dry powdered polymer or polymer mixture and optionally an additive, such as 132〇l〇.doc -27- 200840587 Sucr_er surfactant. The mixture is continuously extruded at a rotation rate in the range of 10 to i 0 〇 r p m using a single-screw extruder or a twin-screw extruder or the like. Optionally, the temperature of the extruder is controlled by heating and cooling, respectively, such that the process temperature is within the range of, for example, 4 〇 15 Torr. In this exercise, the entire mixture is liquefied at the final pressure and temperature, so that the active material is dissolved in the polymer towel. The resulting resolidified leak is cut or broken into pieces which are ground and sieved for further processing. See Table 25 for the in vitro dissolution data obtained. In another embodiment (Examples 10 and u), a solid solution can be prepared from the solution by spray drying, wherein the solution comprises the active compound and the polymer and optionally an additive such as a surfactant in dissolved form. Those skilled in the art understand that spray drying conditions must be adapted to the equipment used. The spray dried product is further dried in a dry box or via a drier stored in a desiccant such as phosphorus pentoxide. As mentioned previously, the polymer is preferably a hydrophilic polymer comprising a free hydrophilic group, such as a polymer having a functional group in the side chain, wherein the functional groups may, for example, be free hydrophilic functional groups, such as an enradyl group. , g-based, succinyl, aramidyl, halo or a reductive acid group. Typical examples of water-soluble hydrophilic polymers include, but are not limited to, polyvinylpyrrolidone (P〇vid〇ne8, Kollidon®), polyvinyl acetate, polyvinyl alcohol, polyvinyl alcohol ortho-benzene Dicaprate, polyethylene glycol (PEG), polyethylene oxide, gelatin, carbomer, mercaptopropionic acid copolymer, ammonium thiol acrylate copolymer, cellulose, methyl cellulose, A Cellulose, ethyl cellulose, cellulose acetate (HPMC), hydroxypropyl cellulose (HPC), phthalic acid acetate 132010.doc •28- 200840587 Vitamin and hydroxypropyl Mercapto cellulose phthalate or a copolymer or mixture thereof. The hydrophilic polymer may also be a water insoluble polymer including, but not limited to, crosslinked polyvinylpyrrolidone, sodium starch glycolate, and crosslinked carboxyindole cellulose. Preferably, the polymer is selected from the group consisting of polyvinylpyrrolidone (Povidone 8, Kollidon®) and polyethylene glycol (PEG), and particularly preferably polyvinylpyrrolidone. When a water-insoluble polymer is used, it is preferably a crosslinked polyene σ specific ketone.
貝例14 17 4田述將固溶體併入如旋劑之經口劑型中之方 法。熟習此項技術者不難想像可將類似調配物填充至硬明 膠膠囊中。較佳調配物基本上包括如上文所提及之親水性 聚合物以促進藥物與腸液之隔離。 實例18描述—種製備聚合物薄膜中之固溶體之方法。基 本上將如上文所述之活性物及聚合物之溶液或懸浮液及= 情況之添加劑在使㈣㈣範圍内之刮刀的薄膜拉 伸機上拉:為:薄膜。將所得之薄膜在乾燥箱中加以乾燥 且切為規定的皁位县声兮# 長度该種類型組合物可經口投予(實 例20)且亦可經臉頰黏膜及舌下 、 扯供點,I卩兮t丨旦 ’、技予(實例19)。後者提 : 、㈣置可易於適應每個患者之個體需要。該所 得之體外溶解資料可參見實例26。 實例21-23描述另-種臉賴及舌下投予之方法,盆提供 直收部位的低黏度至”黏度溶液。…、 實例 實例1 1320I0.doc -29- 200840587 藉由將18.9 g Crem〇ph〇r® RH 40及 2,1 g Transcut〇1® ?及 9.0 g中鍵二酸甘油醋在50°C下混合以製備一微乳液預濃縮 物。然後,加入40 mg屈螺_且使用超音波浴在下混 合10分鐘。750 mg所得之微乳液預濃縮物含有lmg屈螺 當加入100 mL水時,自發形成乳白色微乳液。該所得微乳 液在至少三日内未顯示任何沉降或結晶。離心作用(6〇〇〇 U,10 min)不會產生任何沉降或結晶。 加入2 0 00 mL水後隨即進行相同之觀察。 實例2 根據實例1使用12〇 mg而非4〇 mg屈螺酮製備之調配物具有 相同之特性,但250 mg所得之微乳液預濃縮物含有} mg屈 螺酮。 實例3 精由將 18·9 g Cremophor® EL及 2.1 g Transcutol® P及 9·0 g 中鏈三酸甘油醋在50°C下混合以製備一微乳液預濃縮物。 然後’加入40 mg屈螺酮且使用超音波浴在5〇°c下混合j 5 分鐘。750 mg所得之微乳液預濃縮物含有! mg屈螺酮。 當加入1 00 mL水時,自發形成稍不透明之微乳液。該所得 微乳液在至少二日内未顯示任何沉降或結晶。離心作用 (6000 U,10 min)不會產生任何沉降或結晶。 加入2000 mL水後隨即進行相同之觀察。 實例4 根據實例3使用120 mg而非40 mg屈螺嗣製備之組合物具有 132010.doc •30- 200840587 相同之特性,但250 mg所得之微乳液預濃縮物含有i mg屈 螺_。 實例5 藉由將 18·9 g Cremophor® EL及 2.1 g TranScutol® Ρ&9·0 g 蓖麻油在50°C下混合以製備一微乳液預濃縮物。然後,加 入40 mg屈螺酮且使用超音波浴在5〇它下混合$分鐘。75〇 mg所得之微乳液預濃縮物含有1 mg屈螺_。 當加入100 mL水時,自發形成乳白色微乳液。所得微乳液 在至少三日内不顯示任何沉降或結晶。離心作用(6〇〇〇 u,10 min)不產生任何沉降或結晶。 加入2000 mL水後隨即進行相同之觀察。 實例6 根據實例5使用120 mg而非40 mg屈螺酮製備之調配物具有 相同之特性,但250 mg所得微乳液預濃縮物含有! mg屈螺 酉同。 實例7 藉由在25-40°C下攪拌將1 mg至30 mg範圍内(較佳為8 mg) 1之屈螺酮溶解於1,992 g任一種下列液體中而製備含有經 分子分散屈螺酮之液體組合物: h) 中鏈三酸甘油酯 i) 麻油 j) 甘油單辛酸g旨(例如Imwit〇r® 308) k) 來氣乙細_35-甘油-二說麻油酸酯(例如Cremophor® EL) l) 來氣乙細-40-甘油·經基硬脂酸酉I (Cremophor® RH 40) 132010.doc -31 - 200840587Shell Example 14 17 4 Field describes the method of incorporating a solid solution into an oral dosage form such as a rotatory agent. It is not difficult to imagine a person skilled in the art to fill a similar formulation into a hard gelatin capsule. Preferred formulations essentially comprise a hydrophilic polymer as mentioned above to promote isolation of the drug from intestinal fluid. Example 18 describes a method of preparing a solid solution in a polymer film. The solution or suspension of the active and polymer as described above and the additive of the condition are generally pulled up in a film stretcher of the doctor blade in the range of (4) (iv): a film. The obtained film is dried in a dry box and cut into a prescribed soap level. The length of the type composition can be administered orally (Example 20) and can also be applied through the cheek mucosa and under the tongue. I卩兮t丨旦', technology (example 19). The latter mentions that: (4) can be easily adapted to the individual needs of each patient. See Table 26 for the in vitro dissolution data obtained. Examples 21-23 describe another method of face-to-sublingual administration, the basin providing a low viscosity to the "viscosity solution" of the straight-receiving portion...., Example 1 1320I0.doc -29- 200840587 by 18.9 g Crem〇 Ph〇r® RH 40 and 2,1 g Transcut® 1® and 9.0 g of medium-bond diglyceride were mixed at 50 ° C to prepare a microemulsion pre-concentrate. Then, 40 mg of snail was added and used The ultrasonic bath was mixed for 10 minutes. The 750 mg of the obtained microemulsion preconcentrate contained 1 mg of snail. When 100 mL of water was added, the milky white microemulsion spontaneously formed. The obtained microemulsion did not show any sedimentation or crystallization within at least three days. The effect (6 〇〇〇U, 10 min) did not cause any sedimentation or crystallization. The same observation was carried out immediately after adding 200 00 mL of water. Example 2 Preparation according to Example 1 using 12 〇mg instead of 4 〇mg drospirenone The formulation has the same characteristics, but the 250 mg of the resulting microemulsion pre-concentrate contains } mg drospirenone. Example 3 Fine-grained 18·9 g Cremophor® EL and 2.1 g Transcutol® P and 9·0 g medium chain Triglyceride was mixed at 50 ° C to prepare a microemulsion preconcentrate. After adding '40 mg of drospirenone and mixing for 5 minutes at 5 ° C using an ultrasonic bath. 750 mg of the resulting microemulsion preconcentrate contains ! mg drospirenone. When added to 100 mL of water, spontaneous formation A slightly opaque microemulsion. The resulting microemulsion did not show any sedimentation or crystallization within at least two days. Centrifugation (6000 U, 10 min) did not cause any sedimentation or crystallization. The same observation was carried out immediately after adding 2000 mL of water. 4 The composition prepared according to Example 3 using 120 mg instead of 40 mg snail was having the same characteristics as 132010.doc • 30- 200840587, but the 250 mg of the obtained microemulsion preconcentrate contained i mg snail _. Example 5 A microemulsion preconcentrate was prepared by mixing 18·9 g of Cremophor® EL and 2.1 g of TranScutol®® & 9 g of castor oil at 50° C. Then, 40 mg of drospirenone was added and an ultrasonic bath was used. The mixture was mixed for 5 minutes under 5 。. The microemulsion pre-concentrate obtained at 75 〇mg contained 1 mg of snail. When the 100 mL of water was added, the milky white microemulsion spontaneously formed. The obtained microemulsion did not show any sedimentation for at least three days. Or crystallization. Centrifugation (6〇〇 〇u, 10 min) did not produce any sedimentation or crystallization. The same observation was carried out immediately after adding 2000 mL of water. Example 6 The formulation prepared according to Example 5 using 120 mg instead of 40 mg drospirenone had the same characteristics, but 250 The microemulsion pre-concentrate obtained in mg contains! Mg 螺 酉 酉. Example 7 Preparation of a molecularly dispersed yield by dissolving 1% to 30 mg (preferably 8 mg) of drospirenone in 1,992 g of any of the following liquids by stirring at 25-40 ° C Liquid composition of spirone: h) medium chain triglyceride i) sesame oil j) glycerol monooctanoic acid g (eg Imwit〇r® 308) k) incoming gas _35-glycerol-two sesame oleate ( For example, Cremophor® EL) l) Incompetent Ethylene-40-glycerol·Hydroxyphoric Acid I (Cremophor® RH 40) 132010.doc -31 - 200840587
m)聚乙二醇400 - n) transcutol P ^ 〇)檸檬酸三乙酯 p) 7%甘油與93%聚乙二醇400之混合物 q) 50%甘油單辛酸酯(例如Imwitor® 308)與50%聚乙二醇 400之混合物 r) 50%蓖麻油與50%檸檬酸三丁酯之混合物 s) 50%蓖麻油與50%聚乙二醇400之混合物 ® t) 75%辛酸/癸酸甘油酯(例如Imwitor® 742)與25%聚乙二 醇400之混合物 u)75%辛酸/癸酸甘油酯(例如Imwitor® 742)、15%聚乙二 醇400與10%乙醇之混合物。 在使用8 mg屈螺酮進行製備之情況下,250 mg所得之微 乳液預濃縮物含有1 mg屈螺酮。 所有該等組合物及其混合物可裝入膠囊中,例如軟明膠 膠囊。 ❿ 實例8 以聯合之體外溶解性-體外滲透性測試來研究含有根據實 例2、4、6及7之分子分散形式屈螺酮之組合物。將每250 mg屈螺酮分散於250 mL等滲緩衝鹽溶液中。1 mL所得液 體在Caco-2滲透性研究中進行120分鐘測試。Caco-2研究 之原理在如下之文獻中有詳細描述,例如Haltner E, Schmitz S? Gindorf C. In vitro Permeabilitatsuntersuchungen als Ersatz fur Tier- und Humanstudien - welche 132010.doc -32- 200840587m) polyethylene glycol 400 - n) transcutol P ^ 〇) triethyl citrate p) mixture of 7% glycerol and 93% polyethylene glycol 400 q) 50% glycerol monocaprylate (eg Imwitor® 308) Mixture with 50% polyethylene glycol 400 r) Mixture of 50% castor oil and 50% tributyl citrate s) Mixture of 50% castor oil and 50% polyethylene glycol 400® t) 75% caprylic acid/癸Mixture of glycerides (eg Imwitor® 742) with 25% polyethylene glycol 400 u) 75% caprylic/capric glyceride (eg Imwitor® 742), 15% polyethylene glycol 400 and 10% ethanol. In the case of preparation using 8 mg of drospirenone, 250 mg of the resulting microemulsion preconcentrate contained 1 mg of drospirenone. All such compositions and mixtures thereof can be enclosed in capsules, such as soft gelatin capsules.例 Example 8 A composition containing the molecularly dispersed form of drospirenone according to Examples 2, 4, 6 and 7 was studied in a combined in vitro solubility-in vitro permeability test. Each 250 mg of drospirenone was dispersed in 250 mL of isotonic buffered saline. 1 mL of the resulting liquid was tested in a Caco-2 permeability study for 120 minutes. The principles of the Caco-2 study are described in detail in the following literature, for example, Haltner E, Schmitz S? Gindorf C. In vitro Permeabilitatsuntersuchungen als Ersatz fur Tier- und Humanstudien - welche 132010.doc -32- 200840587
Voraussetzungen miissen erfullt sein? ALTEX 18(2001): 81-87; and Le Ferrec E,Chesne C,Artursson P,Brayden D, Fabre G,Gires P,Guillou F,Rousset M,Rubas W· In vitro models of the intestinal barrier: The report and recommendations of ECVAM workshop 46. ATLA Alternatives to Laboratory Animals. 29 (2001): 649-668 〇 基本上對化合物通過單層人結腸癌細胞之滲透性進行量 測。此外,關於屈螺酮轉化為其不旋異構體之腸内代謝及 化學穩定性進行研究。在37°C下,使用900 mL水作為溶解 介質且使用USP XXVIII葉片裝置2作為溶解測試裝置確定 體外溶解性,在5 0 rpm下操作該裝置。 屈螺酮自所有組合物中滲透通過人結腸細胞之表觀滲透 性經研究係在200及350 nm/s之間的範圍内,其顯示無顯 著性差異之高滲透性。然而,偵測到關於因屈螺酮之異構 化作用而降解的程度差異。在最初時(在製備組合物之 後),-在溶解之後,滲透性研究開始之前-及在最終滲透 性研究結束時(意即與結腸細胞接觸120分鐘後)量測屈螺酮 之降解(意即轉化為不旋異構體):Voraussetzungen miissen erfullt sein? ALTEX 18 (2001): 81-87; and Le Ferrec E, Chesne C, Artursson P, Brayden D, Fabre G, Gires P, Guillou F, Rousset M, Rubas W· In vitro models of the intestinal Barrier: The report and recommendations of ECVAM workshop 46. ATLA Alternatives to Laboratory Animals. 29 (2001): 649-668 〇 essentially measures the permeability of a compound through a single layer of human colon cancer cells. In addition, studies have been conducted on the intestinal metabolism and chemical stability of drospirenone converted to its atropisomer. The device was operated at 37 ° C using 900 mL of water as the dissolution medium and USP XXVIII blade device 2 as the dissolution test device to determine in vitro solubility at 50 rpm. The apparent permeability of drospirenone from all compositions through human colon cells was in the range between 200 and 350 nm/s, which showed no significant difference in high permeability. However, differences in the degree of degradation due to isomerization of drospirenone were detected. Measure the degradation of drospirenone at the beginning (after preparation of the composition), - after dissolution, before the start of the permeability study - and at the end of the final permeability study (ie after 120 minutes of contact with colon cells) That is, converted to a non-rotating isomer):
組合物 %降解之DRSP 最初 最終 差異 根據實例2 (RH40, Transcutol®,MCT) 2·0 3.1 + 1.1 根據實例4 (EL,Transcuto1®,MCT) 3.8 4.7 + 0.9 根據實例ό (EL,Transcutol®,ricirms) 4.8 5.4 + 0.6 根據實例7) (Imwitor® 308) 6.5 7.5 + 1.0 132010.doc •33- 200840587 4.9 5.7 + 0.8 4.5 5.1 + 0.6 3.4 3.9 + 0.5 7.6 7.9 + 0.3 3.8 5.3 + 1.5 5.8 6.4 + 0.6 根據實例7k (EL) 根據實例71 (RH40) 根據實例7 m (PEG 400) 根據實例 7n (Transcutol®) 根據實例7〇 (檸檬酸三乙酯) 根據實例 7q (PEG 400, Imwitor® 308) 實例9The initial difference in the composition of the % degradation of DRSP was based on Example 2 (RH40, Transcutol®, MCT) 2·0 3.1 + 1.1 according to Example 4 (EL, Transcuto1®, MCT) 3.8 4.7 + 0.9 according to the example EL (EL, Transcutol®, Ricrims) 4.8 5.4 + 0.6 according to Example 7) (Imwitor® 308) 6.5 7.5 + 1.0 132010.doc •33- 200840587 4.9 5.7 + 0.8 4.5 5.1 + 0.6 3.4 3.9 + 0.5 7.6 7.9 + 0.3 3.8 5.3 + 1.5 5.8 6.4 + 0.6 According to Example 7k (EL) according to Example 71 (RH40) according to Example 7 m (PEG 400) according to Example 7n (Transcutol®) according to Example 7 (triethyl citrate) according to Example 7q (PEG 400, Imwitor® 308) 9
藉由在約100°C下熔化所有組份並攪拌將1 11^至30 mg範圍 内置之屈螺明溶解於1·05 g白蜂蠟及2 g中鏈三酸甘油酯及 0·07 g印磷脂之混合物中而製備含有分子分散形式屈螺酮 之半固體組合物。 可將該組合物裝入軟膠囊或硬膠囊中。 實例1 0 藉由贺務乾燥製備屈螺酮之固溶體: g sucroester WE15攪; 將 1 g屈螺顯I、8 g Kollidon® K30及 1 拌刀政於300 mL純水中。將該分散液加熱至6〇它且連續攪 拌直至所有賦形劑均溶解。使用小噴霧乾燥器(Mid Spray yer)Buchi 190(入口溫度為12〇£3(:,出口溫度為8代,流 率為4 g/min)噴霧乾燥所得溶液。將該經喷霧乾燥之產物 儲存於使用五氧化二剌為乾燥劑之乾燥器中至少24h。 實例11 藉由噴霧乾燥製備屈螺鲷之固溶體: 將1 g屈螺綱、8这广祕 g乙烯吡咯啶酮-醋酸乙烯醋共聚物 (Koliidon® VA 64、β ι )及 1 g Gelucire® 44/14 攪拌分散於 3〇〇 1320I0.doc -34- 200840587 mL純水中。將分散液加熱至60°C且連續攪拌直至所有賦 形劑均溶解。使用小喷霧乾燥器Biichi 19〇(入口溫度為12〇 C,出口溫度為80°C,流率為4 g/min)喷霧乾燥所得溶 液。將經噴霧乾燥之產物儲存於使用五氧化二磷作為乾燥 劑之乾燥器中至少24 h。 實例12 藉由熔融擠壓製備屈螺酮之固溶體: 混合10%屈螺酮、50%聚乙烯吡咯啶酮及5〇%蔗糖單油酸 酯。使用單螺桿擠壓機在60t:及5〇 rpm下連續擠壓該混合 物。 實例13 藉由熔融擠壓製備屈螺酮之固溶體·· 混合30%屈螺酮、30%聚乙二醇6〇〇〇及4〇%蔗糖單油酸 酯。使用單螺桿擠壓機在6〇t&5〇 rpm下連續擠壓該混合 物。 實例14 可將根據實例10-12之組合物加工成錠劑。為達成此目 的,將300 g各自組合物與49〇 g微晶纖維素摻合,然後加 入10 g硬脂酸鎂且將該混合物再次摻合丨分鐘。將所得物 質直接製錠以產生錠劑重量為8〇 mg的錠劑。各單一錠劑 含有3 mg屈螺_。 " 實例1 5 可將根據實例UM2之組合物加工成錠劑。為達成此目 的,將3〇〇 g各自組合物與49〇 §乳糖摻合,然後加入⑺ § 132010.doc 200840587 硬脂酸鎂且將該混合物再次摻合i分鐘。將所得物質直接 製錠以產生錠劑重量為80 mg的錠劑。各單一錠劑含有3 mg屈螺酮。Dissolving the phloem shown in the range of 1 11 ^ to 30 mg in 1·05 g white beeswax and 2 g medium chain triglyceride and 0·07 g by melting all the components at about 100 ° C and stirring. A semi-solid composition containing the molecularly dispersed form of drospirenone is prepared in a mixture of phospholipids. The composition can be enclosed in a soft or hard capsule. Example 1 0 Preparation of a solid solution of drospirenone by drying: g sucroester WE15; 1 g of snail, I, 8 g of Kollidon® K30 and 1 were mixed in 300 mL of pure water. The dispersion was heated to 6 Torr and continuously stirred until all the excipients were dissolved. The resulting solution was spray dried using a small spray dryer (Mid Spray yer) Buchi 190 (inlet temperature of 12 3£3 (:, outlet temperature of 8 generations, flow rate of 4 g/min). The spray dried product Stored in a desiccator using ruthenium pentoxide as a desiccant for at least 24 h. Example 11 Preparation of solid solution of snail snail by spray drying: 1 g of snail, 8 of the snail, vinylpyrrolidone-acetic acid Ethylene vinegar copolymer (Koliidon® VA 64, β ι ) and 1 g Gelucire® 44/14 were stirred and dispersed in 3〇〇1320I0.doc -34- 200840587 mL pure water. The dispersion was heated to 60 ° C and continuously stirred. Until all the excipients were dissolved. The resulting solution was spray dried using a small spray dryer Biichi 19 (inlet temperature 12 〇 C, outlet temperature 80 ° C, flow rate 4 g / min). The product was stored in a desiccator using phosphorus pentoxide as a desiccant for at least 24 h. Example 12 Preparation of a solid solution of drospirenone by melt extrusion: mixing 10% drospirenone, 50% polyvinylpyrrolidone And 5 % sucrose monooleate. Continuously extruded at 60 t: and 5 rpm using a single screw extruder Example 13 Preparation of solid solution of drospirenone by melt extrusion · Mixing 30% drospirenone, 30% polyethylene glycol 6 〇〇〇 and 4% sucrose monooleate. Using a single screw The extruder was continuously extruded at 6 Torr & 5 rpm. Example 14 The compositions according to Examples 10-12 were processed into troches. To achieve this, 300 g of each composition was combined with 49 〇g. The microcrystalline cellulose was blended, then 10 g of magnesium stearate was added and the mixture was blended again for a few minutes. The resulting material was directly tableted to yield a tablet having a tablet weight of 8 〇 mg. Each single tablet contained 3 Mg snail _. " Example 1 5 The composition according to Example UM2 can be processed into a tablet. To achieve this, 3 〇〇g of each composition is blended with 49 〇 乳糖 lactose, and then added (7) § 132010. Doc 200840587 Magnesium stearate and the mixture was blended again for 1 minute. The resulting material was directly tableted to yield a tablet with a tablet weight of 80 mg. Each tablet contained 3 mg drospirenone.
實例16 月將根據實例10-12 日人;L 12之組合物加工成錠劑。為達成此目 的’將300 g各自組合物與_ g微晶纖維素摻合,然後加 入10 g熱解一氧化矽且將該混合物再次摻合i分鐘。將所Example 16 will be processed into a tablet according to the example 10-12 Japanese; L 12 composition. To achieve this, 300 g of each composition was blended with _g microcrystalline cellulose, then 10 g of pyrogenic cerium oxide was added and the mixture was again blended for 1 minute. Will
得物質直接製錠以產生錠劑重量為80 mg之錠劑。各單一 錠劑含有3 mg屈螺酮。 實例1 7 將1〇〇 g根據實例13之組合物與395 §微晶纖維素摻合,然 後加入5 g硬知酸鎂且將該混合物再次摻合丨分鐘。將所得 物質直接製鍵以產生錠劑重量為5〇叫之鍵劑。各單一旋 劑含有3 mg屈螺酮。 實例1 8 藉由授拌將1 §屈螺酮及1 g聚氧化乙烯-聚氧化丙烯共聚物 溶解於94 g乙醇中。將17 g經丙基纖維素及i7 g纖維素之 :末混合物均句添加至所得溶液中。使用5〇〇 _刮刀將所 付之懸汙液在適當之薄膜拉伸機上拉伸成為一薄膜。乾燥 後,獲得厚度為約18〇 μιη之帶白色的乾㈣樣薄膜。__個 單位此薄臈(意即約3 c m 2之薄片)含有i m g屈_。 實例19 可將根據實例18之組合物切為約丨至約15 cy之碎片,該 等碎片可直接投予至臉_膜,釋放G33W mg屈螺朗至 I32010.doc -36- 200840587 臉頰黏膜。 - 實例20 . 可將根據貝例18之組合物切為碎片,將該等碎片填充於硬 膠囊中用於經口施用。 實例21 用乙醇將5 g屈螺_、i g生育酚乙酸酯及$滴薄荷油製成 1000 mL且攪拌溶解。將所得溶液填充於i〇 玻璃瓶中且The material was directly tableted to yield a tablet having a tablet weight of 80 mg. Each single tablet contains 3 mg of drospirenone. Example 1 7 A composition of Example 13 was blended with 395 § microcrystalline cellulose, followed by the addition of 5 g of magnesium amicate and the mixture was blended again for a minute. The resulting material was directly bonded to give a lozenge weight of 5 nicknames. Each single vortex contains 3 mg of drospirenone. Example 1 8 1 § drospirenone and 1 g of a polyoxyethylene-polyoxypropylene copolymer were dissolved in 94 g of ethanol by mixing. A final mixture of 17 g of propylcellulose and i7 g of cellulose was added to the resulting solution. The suspended liquid which was applied was stretched into a film on a suitable film stretching machine using a 5 〇〇 doctor blade. After drying, a white (4)-like film having a thickness of about 18 Å μηη was obtained. __ Units This thin 臈 (meaning a sheet of about 3 c m 2) contains i m g 屈. Example 19 A composition according to Example 18 can be cut into pieces of about 丨 to about 15 cy, which can be directly administered to the face film, releasing G33W mg 屈罗朗 to I32010.doc -36- 200840587 cheek mucosa. - Example 20. The composition according to the shell example 18 can be cut into pieces which are filled in a hard capsule for oral administration. Example 21 5 g of snail _, i g tocopheryl acetate and $ peppermint oil were made into 1000 mL with ethanol and dissolved by stirring. The resulting solution is filled in an i〇 glass bottle and
帛果喷_覆盖。一次施用釋放含有〇·5 mg屈螺酮之mL 攀 溶液。 實例22 用乙醇將5 g屈螺酮、1 g抗壞血酸棕櫚酸酯、50 g中鏈三 酸甘油酯、300 g Cremoph〇r⑧EL&2〇 g甘油單酯製成1〇⑻ mL且攪拌溶解。將所得溶液填充於1〇 111]1玻璃瓶中且用泵 噴鳴覆盍。一次施用釋放含有〇 5 mg屈螺_之〇•丨茁^容 液。 實例23 鲁 將根據實例21及22之溶液分別作為舌下噴霧投予,例如6 次喷務釋放3 mg屈螺酮。根據實例22之調配物提供延長之 於臉頰黏膜上的滯留時間。 實例24 藉由熔融擠壓製備屈螺酮之固溶體: 混合10%屈螺闕及90%聚乙二醇6000。使用單螺桿擠麼機 在60°C及50rpm下連續擠壓該混合物。 實例25 132010.doc -37- — —200840587 在37 C下’使用900 mL水作為溶解介質且使用卿 xxvm葉片裝置2作為溶解測試裝置在體外溶解性測試中 根據實例24之調酉己斗勿,在5〇啊下操作該褒 置。調配物中含有之屈螺酮在ι〇分鐘内完全溶解。 因此’吾人瞭解在該劑型崩解時間内發生快速溶解。因 此該溶解步驟並非釋放屈_之限速步驟。吾人應瞭解, 因此屈螺财本實例中已經以,,溶解形式"存在,例如分子 分散形式’否則將不能獲得如此快速之溶解。 實例26 將根據實例18之組合物切為9cm2之碎片(含有3邮屈螺 酮)’在m:下’使用900机水作為溶解介質且使用 XXV陶片裝置2作為溶解測試裝置使該等碎片經受體外 溶解性測試,在50 rpm下操作該裝置。發現結果如下⑺ 分鐘後釋放95·嶋螺_、2G分鐘後釋放97 1%屈_且3〇 分鐘後釋放97.2%屈螺酮。Capsule spray _ cover. The mL solution containing 〇·5 mg drospirenone was released in one application. Example 22 5 g of drospirenone, 1 g of ascorbyl palmitate, 50 g of medium chain triglyceride, 300 g of Cremoph〇r8EL & 2 g g monoglyceride were made into 1 〇 (8) mL with ethanol and dissolved by stirring. The resulting solution was filled in a 1 〇 111] 1 glass vial and sprinkled with a pump. One dose of sputum containing 5 mg of snails was released. Example 23 Lu The solutions according to Examples 21 and 22 were separately administered as a sublingual spray, for example, 3 mg of drospirenone was released 6 times. The formulation according to Example 22 provides an extended residence time on the cheek mucosa. Example 24 A solid solution of drospirenone was prepared by melt extrusion: 10% snail and 90% polyethylene glycol 6000 were mixed. The mixture was continuously extruded at 60 ° C and 50 rpm using a single screw extruder. Example 25 132010.doc -37--200840587 'At 37 C' using 900 mL of water as the dissolution medium and using the Qingxvm blade device 2 as the dissolution test device in the in vitro solubility test according to Example 24 Operate the device under 5 。. The drospirenone contained in the formulation completely dissolved in ι〇 minutes. Therefore, we understand that rapid dissolution occurs during the disintegration time of the dosage form. Therefore, the dissolution step is not a step of releasing the rate limit. We should understand that, therefore, in the example of Qujing, the dissolved form "existence, such as molecularly dispersed form, would otherwise not achieve such rapid dissolution. Example 26 A composition according to Example 18 was cut into pieces of 9 cm 2 (containing 3 Mailroxone) using 900 machine water as a dissolution medium under m: and using XXV pottery device 2 as a dissolution test device to make the pieces Subject to in vitro solubility testing, the device was operated at 50 rpm. The results were found to be as follows (7) minutes after release of 95. snail _, after 2G minutes, release 97 1% _ and after 3 〇 minutes, 97.2% drospirenone was released.
132010.doc 38-132010.doc 38-
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