TWI319987B - Bioadhesive progressive hydration tablets - Google Patents

Description

1319987 A7 B7 五、發明説明（1 ) 發明所屬之技術領域 本申請案件係美國專利申請案09/596,073之連續案，該案於2〇0〇 年6月16日提出申請，其為另一美國〇9/379,31〇之連續系案，該案於 1999年8月23日提出申請，該案之申請專利部份係於1998年87月25 曰提出申請之臨時案。 本發明係有關一種具有生體可黏性、生體浸蝕性，用於擴展及 控制活性成份釋出之組成，更進一步來說，本發明有關一種漸進水 化錠劑，可黏於體腔壁上使活性成份持續釋出，而且不須經過代謝 作用、或因潮濕、酵素或酸鹼值效應之初期分解才產生活性成份。 先前技術 藥物或其他製藥產品傳統都是以不同劑型經口服、鼻喷液或注 射等方式投與，對於需要長時間且穩定供應活性成份至血液之病人 而言’這些給藥方法已經被證明沒有效用。特別困難之處是病人在 睡眠時間所需要之劑量，曾經使用的方式有連續靜脈注射 (’’IV”）、緩慢溶解藥丸以及栓劑或經皮貼劑。然而’靜脈注射的 不方便及不舒服、口服之活性成份由於消化道分解作用或肝臟一級 代I謝（first-pass hepatic metabolism )而缩短效程，及許多產品無法舒 適地以合適之劑量或控制之濃度經皮投藥，這些都證明前述之方法 無法令人滿意》 以前曾有人嘗試達到業界需求而發展經黏膜投與活性成份之產 品’例如：某些活性成份藉由經過體腔壁例如口腔或***，寸以很 快地進入血液中，而不會有肝臟一級代謝（first-passhepatic degradation )的問題》通常活性成份經過黏膜表面投與可與生體可 黏性配方一起使用，然而有一個特殊的領域曾有人嘗試但迄今仍失 敗的是：為達到業界需求而發農一種可用於持續釋出的生體可黏性 4 138355-9809l8.doc 本纸張尺度逋用中國國家標準(CNS) A4規格(210X297公爱) 1319987 A7 B7 五、發明説明（2 ) 錠劑，同時在活性成份真正釋出前沒有分解的問題。 『持續釋出』（’’sustained release”）一般指的是一段時間内單一 劑量給藥後連續或一陣陣釋出一種活性成份，使得用於病人之活性 成份在病人體内的濃度於一段時間内通常都可以維持在某個固定的 量。如同以往的經驗，為了克服某一段時間内活性成份釋出的情 - 況，其中用於病人之活性成份在病人體内的濃度（生體可用率 [bioavailability])於治療某個案時可能會變動但可預先決定。 已知的持續釋出的生體可黏性錠劑可分類為兩類：（1)含有水 溶性的破鏈物（carbomers)的旋劑，及（2)含有水不溶性聚合物 (polymers )的鍵劑。此二類錠劑已被證明在許多製劑中無法令人 滿意’例如，許多專業人員曾經嘗試用水溶性碳鏈物如carbomer 934P 或 CARBOPOL™ 974 樹脂（為 B.F. Goodrich，Cleveland，Ohio 公司 之商品）配方出一種恰當的持續釋出的生體可黏性錠劑，但是這些 狡劑只能黏附在體腔壁一段短時間，譬如6小時或更短，而且這些 錠劑很容易從體腔内移除，因此口服此種藥劑的病人還會有窒息的 .危險。更甚者，這些先前製出的旋劑本質上很快會吸溼受潮，因此 可能提早將活性成份暴露出來以致受潮濕或病人體内環境如不潔的 口腔或***腔内細菌酵素的影響而分解。 同樣地’由水不溶性聚合物如聚碳親合物（p〇lyCarb〇phil )組成 . 的錠劑已被證明在許多應用上並不適合，舉例來說，雖然聚碳親合 物能長時間黏附在體腔壁上’但是這樣的錠劑不能立刻黏附，使它 們用在某些治療像睡眠時之口腔投與活性成份變得不切實際。更甚 者，此種錠劑通常不夠軟’無法提供舒適感及使人無感覺，或是提 供免於吸入旋劑的安全性。 再進一步舉例來說，前述的任一種錠劑用於治療許多情況都不 適合’如同先前所提，有許多醫學狀況由於各種理由需要能持續及 138355-980918.doc · 5 · 本纸乐尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1319987 A7 _B7 五、發明説明（3~) ' /或有控制地釋出活性成份，其中如減輕活性成份之肝臟一級代謝 的影響，或因潮濕、酸鹼值影響、或酵素作用而使活性成份提早分 解、或獲得合適的生體可黏性錠劑所帶來的舒適及方便。這些醫學 狀況包括，但並不限於舉例所提的，需要一種活性成份的治療，活 性成份可能是’但並不限於舉例所提的，醣蛋白（glycoprotein )、 蛋白質（protein )、性荷爾蒙（sexhorm〇ne )、抗荷爾蒙 (anti-hormone )、硝酸鹽類（nitrate )、乙型擬交感神經劑 (beta-agonist )、乙型抗交感神經劑（beta-antagonist )、鴉片鹼類 (opioid )、鴻片驗拮抗劑類（opioid-antagonist )、抗抑费劑 (antidepressant)、3-氫氧基-3-甲基戊二醯輔臃A還原酵素抑制劑 (HMG CoA [3-hydroxy-3-methylglutaryl Coenzyme A] inhibitor )、抗組織 胺（antihistamine )、腎臟升壓素轉換酶抑制劑（Ace [angiotensin converting enzyme] inhibitor )及（或）***素（prostagiandin )。因 此迄今醫界會要求病人接受更侵襲性且較不合適的給藥技術或方法 如同前述。 為了勾勒醫界的需求，以性腺官能不足男性為例，男性的性腺 官能不足（hypogonadism )的特徵是内生睪丸脂酮的製造不足或缺 乏，睪丸脂酮異常的低血中濃度會使男性處於『男性停歇』 (Andropause )的危險，其中男性還處於心血管病（cardiovascular disease )、阿滋海默氏症（Alzheimer’s disease )及骨質疏鬆症 (osteoporosis )的較大危險中' 睪丸脂酮傳統用於治療男性的官能不足，然而為達最大效果， 治療必須能有完整的生理睪丸脂酮取代作用，再進一步說，這樣的 治療必須能提供整晚持續的睪丸脂酮血中濃度，更理想的是在午夜 能出現高峰濃度。睪丸脂酮經皮貼布只能典型地產生低於生理血中 濃度，因此不能完全解除症狀。同樣地，前面提過之口服鍵劑也是 138355-980918.doc -6- 本紙張尺度適用中固留家標準(CNS) A4規格(210 X 297公釐) 1319987 A7 _____ B7 五、發明説明（4 ) 無法有效或實際地持續提供睪丸脂酮的濃度。 睪丸脂酮這個荷爾蒙就像其他許多藥物，包含許多其他蛋白質 和聽蛋白，會發生相當向的一級代謝。按照這個情形，口服或*** 鍵劑若無法將内部物質長時間保持在乾燥狀態就無法防止溶解及吞 嚥，或溶解並很快將活性成份經由黏臈吸收。更進一步依照專業技 術之判斷，旋劑若不能很快地吸附於目標區或能變成可移動，則對 於必須夜間投藥之治療如睪丸脂明治療將毫不實際。 活性成份如睪丸脂酮也可能發生未預期之代謝作用，舉例來 說，5α·還原酵素（5a-reductase )將睪丸脂酮轉化成5α_二氫睪丸 脂酮（5a-dihydrotestosterone; [DHT])，該物質可能引起不良反應，如 掉髮及***障礙（prostate disorder )。同樣地，5α-還原酵素也可 能將其他活性物質像黃體素代謝掉。 睪丸脂酮口服或不經腸道投藥原本都具有快速排出性質，因此 已經發展各種睪丸脂酮配方來遏止這個問題，這些配方包括經皮製 劑（含或不含潤滑劑）、皮下植入小錠、注射式生體可分解微小朦 囊配方以及加強荷爾蒙舌下吸收之複合體》在這些劑型中，用於陰 囊之睪丸脂酮經皮系統及其他皮膚貼劑可能是最廣為試驗的了。在 最適當的情形下，它們達到整天都接近荷爾蒙生理型態之濃度，並 且提供不經腸道治療的另一選擇。 然而，陰囊製劑引起血中二氫睪丸脂酮不均衡的增加，其濃度 達到睪丸脂酮濃度約30至40%，可能是因為5α-還原酵素在陰囊皮 膚有很高的濃度。其他皮膚貼劑也依樣產生高血中濃度的二氫睪丸 脂酮。像這樣血中二氫睪丸脂酮增加的現象也曾被報告過，在特別 長效作用之腸道外·治療投與睪丸脂酮輯類testosterone buciclate及口服 睪丸脂闕酿類一睪丸脂銅Η--烧酸鹽（testosterone undecanoate )都發 生過 〇【教科書 Williams Textbook of endocrino丨ogy，9th ED., W.B. Saunders 138355-980918.doc 本纸浪尺度適用中國固家標準(CNS) A4規格(210 X 297公釐) 1319987 A7 B71319987 A7 B7 V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) Technical Field of the Invention The present application is a continuation of U.S. Patent Application Serial No. 09/596,073, filed on June 16, 2000, which is another U.S. 〇9/379, 31〇 The continuation case was filed on August 23, 1999. The patent application part of the case was filed on August 25, 1998. The present invention relates to a composition having bioviscosity and bioerodibility for expanding and controlling the release of active ingredients. Further, the present invention relates to a progressive hydrating tablet which can be adhered to a body cavity wall. The active ingredient is continuously released and the active ingredient is produced without metabolic or initial decomposition by moisture, enzyme or pH effects. Prior art drugs or other pharmaceutical products have traditionally been administered by oral, nasal spray or injection in different dosage forms. For patients who need long-term and stable supply of active ingredients to the blood, these methods have proven to be absent. utility. A particular difficulty is the dose required by the patient during sleep, which has been used in continuous intravenous (''IV'), slow-dissolving pills, and suppositories or transdermal patches. However, 'intravenous inconvenience and discomfort Oral active ingredients shorten the course of action due to digestive tract decomposition or first-pass hepatic metabolism, and many products cannot be comfortably administered transdermally at a suitable dose or controlled concentration. The method is unsatisfactory. Previous attempts have been made to meet the needs of the industry to develop products that deliver active ingredients via mucosa. For example, certain active ingredients enter the blood quickly through the wall of the body cavity, such as the mouth or vagina. Without the problem of first-passhepatic degradation, usually the active ingredient is applied to the bioadhesive formula through the mucosal surface. However, there is a special field that has been tried but has failed so far. : To achieve the needs of the industry, a kind of bio-viscosity that can be used for continuous release is 4 138355-9809l8. Doc This paper scale adopts Chinese National Standard (CNS) A4 specification (210X297 public) 1319987 A7 B7 V. Invention description (2) Lozenges, and there is no problem of decomposition before the active ingredients are actually released. (''sustained release') generally refers to the release of an active ingredient in a continuous or burst of a single dose over a period of time, so that the concentration of the active ingredient in the patient's body is usually maintained over a period of time. At a fixed amount. As in previous experience, in order to overcome the release of active ingredients over a period of time, the concentration of the active ingredient in the patient's body (bioavailability) may vary during treatment of a case. But it can be decided in advance. Known sustained release bioadhesive lozenges can be classified into two categories: (1) a blowing agent containing water-soluble carbomers, and (2) containing water-insoluble polymers (polymers). Key agent. These two types of tablets have proven to be unsatisfactory in many formulations'. For example, many professionals have tried to formulate water-soluble carbon chains such as carbomer 934P or CARBOPOLTM 974 resin (commercially available from BF Goodrich, Cleveland, Ohio). a suitable sustained release of bioadhesive lozenges, but these tinctures can only adhere to the body wall for a short period of time, such as 6 hours or less, and these tablets are easily removed from the body cavity, so Patients who take this medicine will also have suffocation. Danger. What's more, these previously produced spinners will quickly absorb moisture and moisture, so the active ingredients may be exposed early so that they may be decomposed by moisture or the environment of the patient such as the unclean oral or vaginal bacterial enzymes. . Similarly, a tablet consisting of a water-insoluble polymer such as a polycarbohydrate (p〇lyCarb〇phil) has proven to be unsuitable for many applications, for example, although the polycarbonate can adhere for a long time. On the wall of the body cavity 'but such lozenges do not adhere immediately, making them impractical for certain active treatments such as oral administration to sleep. What's more, such tablets are usually not soft enough to provide comfort and feel, or to provide safety from inhalation. Still further by way of example, any of the foregoing tablets is not suitable for use in many cases. 'As mentioned previously, there are many medical conditions that need to be sustainable for various reasons and 138355-980918.doc · 5 · The paper scale applies to China National Standard (CNS) A4 Specification (210 X 297 mm) 1319987 A7 _B7 V. Description of Invention (3~) ' / or controlled release of active ingredients, such as reducing the effects of liver-level metabolism of active ingredients, or Moist, pH-sensitive, or enzymatic action to allow early decomposition of the active ingredient or to obtain the comfort and convenience of a suitable bioadhesive lozenge. These medical conditions include, but are not limited to, those exemplified by the need for treatment with an active ingredient, which may be 'but not limited to the examples, glycoproteins, proteins, sex hormones (sexhorm) 〇ne ), anti-hormone, nitrate, beta-agonist, beta-antagonist, opioid, Opioid-antagonist, antidepressant, 3-hydroxy-3-methylpentadienyl hydrazine A reductase inhibitor (HMG CoA [3-hydroxy-3- Methylglutaryl Coenzyme A] inhibitor, antihistamine, Ace [angiotensin converting enzyme] inhibitor and/or prostagiandin. Therefore, the medical community has so far required patients to receive more aggressive and less suitable drug delivery techniques or methods as described above. In order to outline the needs of the medical community, male hypogonadism is characterized by insufficient or lack of production of endogenous testosterone, and abnormal low blood concentration of testosterone may cause men to be present. The danger of "Andropause", in which men are still at greater risk of cardiovascular disease, Alzheimer's disease, and osteoporosis. In the treatment of male dysfunction, however, in order to achieve maximum effect, the treatment must be able to have a complete physiological testosterone replacement. Further, such treatment must be able to provide a continuous concentration of testosterone in the blood, which is more desirable. It is the peak concentration that can occur at midnight. The percutaneous patch of the testosterone can only typically produce a lower concentration than the physiological blood, so the symptoms cannot be completely relieved. Similarly, the oral bond mentioned above is also 138355-980918.doc -6- This paper scale is applicable to the retention standard (CNS) A4 specification (210 X 297 mm) 1319987 A7 _____ B7 V. Invention description (4 The concentration of the testosterone cannot be effectively or practically continued. This hormone is like many other drugs, including many other proteins and hearing proteins, which can cause considerable first-order metabolism. According to this situation, if the oral or vaginal agent cannot keep the internal substance in a dry state for a long time, it cannot prevent dissolution and swallowing, or dissolve and quickly absorb the active ingredient through the adhesive. Further, according to the judgment of the professional technique, if the rotatory agent is not quickly adsorbed to the target area or can be made movable, it is not practical for the treatment which must be administered at night, such as sputum. Undesirable metabolism may also occur with active ingredients such as testosterone. For example, 5α-reductase converts testosterone to 5α-dihydrotestosterone ([DHT]) This substance may cause adverse reactions such as hair loss and prostate disorder. Similarly, 5α-reductase may also metabolize other active substances like lutein. Oral or parenteral administration of saponin has a rapid excretion property, so various formulas have been developed to curb this problem. These formulations include transdermal preparations (with or without lubricant) and subcutaneous implantation of small ingots. Injectable biodegradable microcapsule formulations and complexes that enhance the absorption of hormones under the tongue. Among these dosage forms, the percutaneous dermal vesicles for the scrotum and other skin patches are probably the most widely tested. In the most appropriate case, they reach concentrations close to the hormonal physiology throughout the day and provide an alternative to parenteral treatment. However, the scrotal preparation causes an unbalanced increase in dihydropyrone in the blood, which reaches a concentration of about 30 to 40% of the testosterone, probably because of the high concentration of 5α-reductase in the scrotal skin. Other skin patches also produce high blood concentrations of dihydroanthraquinone. Such an increase in the blood of dihydroanthraquinone has also been reported, in the special long-acting extra-intestinal treatment, the testosterone buciclate and the oral sputum saponin - Testosterone undecanoate has occurred [Textbook Williams Textbook of endocrino丨ogy, 9th ED., WB Saunders 138355-980918.doc This paper wave scale applies China National Standard (CNS) A4 specification (210 X 297 PCT) 1319987 A7 B7

五、發明説明（5 ) 還原酵素V. Description of invention (5) Reductase

Company, ρ·853】。因此本發明有利地避免活性成份被5α_ 代謝可能引起之副作用。 更進一步依照專業技術之判斷，本發明之持續釋出、士秘 王镫可黏 性錠劑之優點並不限於男性性腺功能低下之治療。舉例來說，病 在各種不同情形下長需要持續釋出荷爾蒙之治療，此外其他藥物像 類固醇用於治療氣喘，需要在夜晚睡眠時間有治療所需之高峰;農 度，因此就專業技術來判斷，必然存在著一種需求就是發展—種生 體可黏性的持續釋出錠劑來克服前述之需要，包括，但不僅限於 釋出有效治療數量的活性成份’而後者可能因潮濕、酵素作用、 酸鹼值效應而代謝或分解，這些如蛋白質、醣蛋白、性荷爾蒙、^ 荷爾蒙劑、硝酸鹽類、乙型擬交感神經劑、乙型抗交感神經劑、& 片鹼類、鴉片鹼拮抗劑類、抗抑鬱劑、3-氫氧基-3-甲基戊二酿辅 臃A還原酵素抑制劑、抗組織胺、腎臟升壓素轉換晦抑制劑、及/ 或***素。 舉例來說，投與治療藥劑如特卜他靈（terbutaline )(特另彳是在^ 睡覺時間投藥），以一種依照本發明之持續釋出之生體可黏性旋劑 的方式，其優點為此種給藥提供可控制的、長時間的釋出，來幫助 防止血中特卜他靈濃度過高。這對一些治療藥劑如特卜他靈之類， 血中濃度過高會產生不良副作用者，特別有用。 發明内容 本發明符合前述之業界需求，因此本發明之目標係提供—種生 體可黏性錠劑可以立刻黏附或幾乎立刻黏附於體腔内目標組織區， 並且通常在治療期間都維持黏附狀態。為符合此觀點，本發明提供 一種生體可黏性錠劑能在口腔甲黏附且釋出活性成份長達十八小時 138355-980918.doc 本纸蒗尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1319987 A7 B7 五、發明説明（6 ) 或以上。與本發明另一相關之方面，本發明提供一種生體可黏性錠 劑能在***腔中黏附且釋出活性成份長達七十二小時或以上。 本發明之另一個目標係提供一種生體可黏性錠劑可以漸進地水 化，藉此方式該錠劑内部中心核保持免於潮濕及周圍環境的干擾， 為符合此觀點，本發明提供一種生體可黏性錠劑適合用於黏膜或其 他體腔以持續釋出活性成份，即使活性成份含有蛋白質或醣蛋白或 其他對代謝作用或因酵素、酸鹼值、或潮濕引起之分解作用特別敏 感之治療藥物。 本發明之另一個相關目標係提供一種生體可黏性錠劑具有因錠 劑配方產生之可控制及持續的釋出性質，其中活性成份只是經過一 段長時間藉著錠劑内部活性成份乾燥貯存區之漸進水化作用逐漸地 作成生體可用形式。 本發明另一個目標係提供一種生體可黏性錠劑，可作成果凍樣 及/或吞嚥來協助保護病人免於因口服而窒息，特別是正在接受治 療的睡眠中病人。 本發明還有一個目標是提供製造符合前述本發明目標之生體可 黏性錠劑之方法，為符合本發明之觀點，提供一種生體可黏性錠劑 之製造方法，其中活性成份對早期代謝及/或分解作用具有抗力， 則於第一階段或第二階段（製造顆粒時）加入。與本發明另一相關 之方面，本發明提供一種生體可黏性錠劑之製造方法，其中活性成 份易於早期代謝及/或分解，則於第二階段（製造打錠混合物時） 顆粒乾燥及過篩後加入。當然還有其他考量或因素會影響何階段加 入特殊活性成份最恰當之選擇。 本發明還有其他目標，係提供使用此處所說之生體可黏性錠劑 之方法。為符合本發明之觀點，提供一種使用方法，投與男性病人 生體可黏性錠劑而持續釋出睪丸脂酮。與本發明另一相關之方面， 138355-980918.doc -9- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)Company, ρ·853]. The present invention therefore advantageously avoids the side effects that may be caused by the metabolism of the active ingredient by 5α_. Further, in accordance with the judgment of the prior art, the advantages of the sustained release of the present invention and the visceral lozenge of the priest are not limited to the treatment of male hypogonadism. For example, the disease requires long-term release of hormones in a variety of different situations. In addition, other drugs like steroids are used to treat asthma, and they need to have the peak of treatment at nighttime sleep time. The degree of farming is therefore judged by professional techniques. There must be a need to develop a continuous release lozenge that is viscous to overcome the aforementioned needs, including, but not limited to, the release of a therapeutically effective amount of active ingredient' which may be due to moisture, enzyme action, Metabolism or decomposition by acid-base effects such as proteins, glycoproteins, sex hormones, hormones, nitrates, type B sympathomimetic agents, type B antisympathetic agents, & flavonoids, opiate antagonism Agents, antidepressants, 3-hydroxy-3-methylpentane auxiliaries A reductase inhibitors, antihistamines, renal vasopressin conversion sputum inhibitors, and/or prostaglandins. For example, administration of a therapeutic agent such as terbutaline (especially at the time of sleep), in the form of a sustained release of the bioadhesive agent according to the present invention, the advantages thereof Controlled, long-term release is provided for this administration to help prevent excessive concentrations of terbutaline in the blood. This is especially useful for some therapeutic agents such as terbutaline, where excessive blood levels can cause adverse side effects. SUMMARY OF THE INVENTION The present invention meets the aforementioned industry needs, and it is therefore an object of the present invention to provide a bioadhesive tablet that adheres immediately or almost immediately to a target tissue region within a body cavity and generally maintains an adherent state during treatment. In order to comply with this viewpoint, the present invention provides a bioadhesive tablet which can adhere to the oral cavity and release the active ingredient for up to 18 hours. 138355-980918.doc The paper size is applicable to the Chinese National Standard (CNS) A4 specification ( 210X297 mm) 1319987 A7 B7 V. Description of invention (6) or above. In another aspect related to the present invention, the present invention provides a bioadhesive tablet which can adhere to the vaginal cavity and release the active ingredient for up to 72 hours or more. Another object of the present invention is to provide a bioadhesive tablet which can be gradually hydrated, whereby the inner core of the tablet is kept free from moisture and the surrounding environment. To meet this viewpoint, the present invention provides a Bio-adhesive tablets are suitable for use in mucous membranes or other body cavities to continuously release active ingredients, even if the active ingredient contains protein or glycoprotein or other substances that are particularly sensitive to metabolism or decomposition due to enzymes, pH, or moisture. Therapeutic drugs. Another related object of the present invention is to provide a bioadhesive tablet having a controlled and sustained release property resulting from a tablet formulation wherein the active ingredient is only dried over a long period of time by the active ingredient of the tablet. The progressive hydration of the zone is gradually becoming a form of bioavailability. Another object of the present invention is to provide a bioadhesive lozenge which can be used as a frozen sample and/or swallowed to help protect a patient from suffocation by oral administration, particularly in a sleeping patient undergoing treatment. Still another object of the present invention is to provide a method for producing a bioadhesive tablet in accordance with the above-described object of the present invention, and to provide a method for producing a bioadhesive tablet in accordance with the present invention, wherein the active ingredient is early Metabolism and/or decomposition has resistance and is added in the first or second stage (when the granule is produced). In another aspect related to the present invention, the present invention provides a method for producing a bioadhesive tablet, wherein the active ingredient is easy to be metabolized and/or decomposed early, and in the second stage (when the ingot mixture is produced), the particles are dried and Add after sieving. Of course, there are other considerations or factors that influence the most appropriate choice of the stage to add a particular active ingredient. Still another object of the present invention is to provide a method of using the bioadhesive tablet as described herein. In order to comply with the present invention, a method of use is provided for administering a human viscous lozenge to a male patient and continuously releasing the testosterone. Another aspect related to the present invention, 138355-980918.doc -9- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

裝Loading

線 1319987 A7 _B7_ 五、發明説明（7 ) 提供一種使用方法，投與女性病人生體可黏性錠劑而持續釋出一種 荷爾蒙如睪丸脂酮。 實施方式 本發明之發明者已發現，非常出人意料地，本發明的這些及其 他目標都可藉由製造及使用含有一種活性成份的錠劑來達到，這些 . 成份有水溶性聚合物（例如：碳鏈物carbomer974P或934P、（或 CARBOPOL™974P )及水不溶性聚碳親合物（例如：NOVEON®， • 由 B.F. Goodrich Specialty Polymers of Cleveland，0H 公司供應），較理想 的是經基丙基曱基纖維素（hydroxypropylmethyl cellulose或HPMC )、 乳聽（lactose )、玉米观粉（cornstarch)及其他標準疑劑成偷如硬 脂酸鎮（magnesium stearate )及滑石粉（talc ) 〇 本發明之生體可黏性漸進水化錠劑可以和任何適當之活性成份 一起使用，也可以用於遞送治療量的活性成份給在一段連續時間需 要控制給藥速率的病人。本發明之錠劑也可以配合錠劑之預定治療 用途來製成任何適當之形狀及任何適當之大小。 本發明之錠劑可以包含任何適當數量之活性成份，本發明之適 當數量之活性成份可從很小的量到大約50%或更多，就一般業界之 認知，“很小的量”表示活性成份的量相對於破劑是不成比例的 ' 小，例如··只有幾微克活性成份經由重達一百毫克以上之鍵劑遞 , 送。另一業界會認知的技術是以任何比例出現之任何數量的活性成 份都在本發明之範圍内。 依照本發明之鍵劑，其平衡包含水溶性聚合物及水不溶性·交錯 連接之多叛基聚合物（polycarboxylic polymer )，同時本發明典型之 錠劑最好有大約1%到75%重量比之水溶性聚合物以及大約〇5%到 10%重量比之水不溶***錯連接多羧基聚合物，這樣典盤之錠劑最 好包括大約5%到50%的纖維素，本發明之錠劑最好也含有大約 138355-980918.doc .10. L本紙張尺度^•用中0國家料(CNS) A4規格(21GX297公釐） ' 1319987 A7 B7 0.5%到25%重量比之澱粉，這些理想的錠劑也可以有大約1%到 50%重量比之乳醣。 還有，本發明之理想錠劑也可以包含有大約001%到2%重量 比之硅石（silica)及/或最多0.5%重量比之滑石粉：及/或最多 2,5%重量比之硬脂酸鎂。 因此業界可以了解鍵劑的成份可以有變化來配合特殊的目的， 例如’本發明之發明者已發現’出人意料地，一個增加（減少）漸 進水化錠劑水化時間的方法就是減少（増加）乳醣與/或殿粉的數 量以及增加（減少）水溶性聚合物的數量。或者，錠劑的密度可以 改變而影響水化時間。 適合用於本發明之活性成份包括任何活性成份或任何需要持續 或控制釋出的成份；任何活性成份或任何需要長時間避免因潮濕、 酸鹼值、或酵素而早期分解的成份；任何需要避免病人—級肝臟代 謝的活性成份。適合用於本發明之活性成份的例子包括，但不是僅 限於：⑴醣蛋白，如渡泡刺激素（follicle-stimulating hormone;FSH)、黃體化激素（luteinizingh〇rmone;LH )、人類絨毛膜 性腺激素（human chorionic gonadotropin;HCG )、甲狀腺激素 ( thyroid-stimulating hormone;TSH )、及同類物；（2)蛋白質，如性腺 激素釋出荷爾蒙（GnRH)(促進劑及拮抗劑）、催產素 (oxytocin )同質物、生長抑制素（somatostatin )同質物、組織胞 漿素原活化劑（tissue plasminogen activator;TPA )、生長激素釋出荷爾 蒙（growth hormone releasing hormone;GHRH )、親皮質素釋出荷'爾蒙 同質物（corticotropin-releasing hormone analogs;CRH analogs )、及同類 物；（3)性荷爾蒙，如雌二網（estradiol )、睪丸脂酮 (testosterone )、黃體素（progesterone )' 及同類物；（4)抗荷爾 蒙劑，如塔摩西吩（tamoxifen )、米啡普司通（mifepristone )'及 138355-980918.doc -11 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Line 1319987 A7 _B7_ V. INSTRUCTION DESCRIPTION (7) A method of use is provided for administering a viscous lozenge to a female patient and continuously releasing a hormone such as saponin. The inventors of the present invention have found that, surprisingly, these and other objects of the present invention can be attained by the manufacture and use of a tablet containing an active ingredient, such as a water-soluble polymer (e.g., carbon). Chain carbomer974P or 934P, (or CARBOPOLTM 974P) and water-insoluble polycarbohydrate (eg NOVEON®, • supplied by BF Goodrich Specialty Polymers of Cleveland, 0H), preferably propyl sulfhydryl Cellulose (hydroxypropylmethyl cellulose or HPMC), lactose, cornstarch and other standard suspects such as magnesium stearate and talc (talc) The viscous progressive hydrating lozenge can be used with any suitable active ingredient, and can also be used to deliver a therapeutic amount of the active ingredient to a patient in need of a controlled rate of administration over a continuous period of time. The lozenge of the present invention may also be formulated with a lozenge. The predetermined therapeutic use is to be made into any suitable shape and any suitable size. The lozenge of the present invention may comprise any suitable The amount of the active ingredient, the appropriate amount of the active ingredient of the present invention can be from a small amount to about 50% or more. As is generally recognized in the industry, a "small amount" means that the amount of the active ingredient is not comparable to the amount of the agent. The ratio of 'small, for example, only a few micrograms of active ingredient is delivered via a key agent weighing more than one hundred milligrams. Another technique that the industry will recognize is that any amount of active ingredient present in any ratio is in the present invention. In the range of the bonding agent according to the present invention, the balance comprises a water-soluble polymer and a water-insoluble and interlaced polycarboxylic polymer, and the typical tablet of the present invention preferably has about 1% to 75%. The weight ratio of the water-soluble polymer and about 5% to 10% by weight of the water-insoluble interlaced polycarboxy polymer, such that the tablet preferably comprises about 5% to 50% cellulose, the ingot of the present invention The agent preferably also contains about 138355-980918.doc.10. L paper size ^•Used in the country 0 (CNS) A4 specification (21GX297 mm) ' 1319987 A7 B7 0.5% to 25% by weight of starch, these The ideal lozenge can also There is about 1% to 50% by weight of lactose. Also, the preferred tablet of the present invention may also comprise from about 001% to about 2% by weight of silica and/or up to 0.5% by weight of talc. : and / or up to 2,5% by weight of magnesium stearate. Therefore, the industry can understand that the composition of the key agent can be changed to match special purposes, such as 'the inventors of the present invention have found that 'unexpectedly, one increase ( The method of reducing the hydration time of the progressive hydrating tablet is to reduce the amount of lactose and/or powder and increase (reduce) the amount of water-soluble polymer. Alternatively, the density of the lozenge can be varied to affect the hydration time. Suitable active ingredients for use in the present invention include any active ingredient or any ingredient which requires sustained or controlled release; any active ingredient or any ingredient which requires long periods of time to avoid decomposition by moisture, pH, or enzyme; any need to avoid Patient-grade active component of liver metabolism. Examples of active ingredients suitable for use in the present invention include, but are not limited to: (1) glycoproteins such as follicle-stimulating hormone (FSH), luteinizing h〇rmone (LH), human chorionic gonads Human chorionic gonadotropin (HCG), thyroid-stimulating hormone (TSH), and congeners; (2) proteins such as gonadotropin-releasing hormones (GnRH) (accelerators and antagonists), oxytocin (oxytocin) Congenitor, somatostatin homologue, tissue plasminogen activator (TPA), growth hormone releasing hormone (GHRH), pro-cortisol release hormone Corticotropin-releasing hormone analogs (CRH analogs), and congeners; (3) sex hormones, such as estradiol, testosterone, progesterone' and congeners; (4) Anti-hormonal agents, such as tamoxifen, mifepristone, and 138355-980918.doc -11 - paper ruler Applicable Chinese National Standard (CNS) A4 size (210 X 297 mm)

裝 訂Binding

k- 1319987 A7 _____B7___ 五、發明説明（9 ) 同類物；（5)确酸鹽類，如确化甘油（nitroglycerin )、類山梨醇酐 (isosorbide )、赤蘚醇四确酸醋（erythrityl tetranitrate )、季戍四醇 四硝酸醋（pentaerythritol tetranitrate )、及同類物；（6)乙型擬交感 神經劑，如特卜他靈（terbutaline )、阿卜特羅（albuterol )、派卜 特羅（pirbuterol )、拍佗特羅（bitoterol )、力托地靈（ritodrine )、 . 及同類物；（7)乙型抗交感神經劑，如普羅潘諾羅 (propranolol )、鎮羅謹羅（metoprolol ) '、那多羅（nadolol )、天 諾羅（尽tenolol)、剔莫羅（timolol )、愛司莫羅（esmolol )、品多 羅（pindolol )、：阿赛普托羅（acebutolol )、啦培特羅（labetalol)、 及同類物；（8)***驗類，如嗎啡（morphine )、氫化嗎啡 (hydromorphone )、氧化嗎( oxymorphone )、可待因 (codeine )、氫化可待因（hydrocodone )、氧化可待因 (oxycodone) 、( leverophanol ) 、( levallorphan )、 (buprenorphine )、吩坦尼（fentanyl )、那卜吩（nabuphine )、卜 佗吩（butophanol )、潘他若新（pentazocine )、及同類物；（9)鴉 片驗拮抗劑類，如那囉克松（naloxone )、那鎮吩（nalmefene )、 及同類物；（10)抗抑營劑，如二苯環庚丙胺（amitriptyline )、阿摩 沙（amoxapine )、翔;。希胺（desipramine )、吟塞坪（doxepin )、伊 米胺（imipramine )、嗎囉提（maprotilen )、異二苯環庚丙胺 - (nortriptyline )、三二苯環庚丙胺（protripyline )、三伊米胺 (trimipramine )、芙塞濘（fluoxetine )、臂若儅（trazodone )、及 同類物；（11)3-氫氧基-3-甲基戊二醯輔酶A還原酵素抑制劑，如 洛華停（lovastatin )、湄華停（mevastatin )、芯華停 (simvastatin) '普華停（pravastatin )、阿佗華停（atorvastatin )、 及同類物；（12)抗組織胺，如洛啦搨玎（loratadine)、縮蘋果酸氣 菲安明（chlorpheniramine maleate )、縮韻果酸漠菲安明 138355-980918.doc -12- 本紙浪尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1319987 五、發明説明（K- 1319987 A7 _____B7___ V. Description of invention (9) congeners; (5) acid salts such as nitroglycerin, isosorbide, erythrityl tetranitrate , pentaerythritol tetranitrate, and congeners; (6) type B sympathomimetic agents, such as terbutaline, albuterol, pirbuterol ), taking bitoterol, ritodrine, and congeners; (7) anti-sympathetic agents such as propranolol, metoprolol , nadolol, tenolo (tenolol), timomol, esmolol, pindolol, acebutolol, pepe (labetalol, and congeners; (8) opioids such as morphine, hydromorphone, oxymorphone, codeine, hydrocodone, Oxycodone, (Leverophanol) (levallorphan), (buprenorphine), fentanyl, nabuphine, butophanol, pentazocine, and congeners; (9) opioid antagonists, Such as naloxone, nalmefene, and congeners; (10) anti-hibising agents, such as amitriptyline, amoxapine, xiang; Desiperamine, doxepin, imipramine, maprotilen, nortriptyline, protripyline, triterpenoid Trimipramine, fluoxetine, trazodone, and congeners; (11) 3-hydroxy-3-methylpentadiazine Coenzyme A reductase inhibitors, such as Luohua Lomastatin, mevastatin, simvastatin 'pravastatin', atorvastatin, and congeners; (12) antihistamines, such as lolattop (loratadine), chlorpheniramine maleate, phlegm acid Philippine Philippine 138355-980918.doc -12- This paper wave scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1319987 V. Description of invention (

iL (brompheniramine maleate ) 〜 —本·*τ 明（diphenhydramine )、氨茶 鹼二苯安明（dimenhydrinate )、卡賓安明（—e )、普美 苯塞井（Pr〇methaZine)、三此啦氨（tripdannamine )、及同類物； (13)腎臟升壓素轉換晦抑制劑，如開立爾（邮㈣）' 那立爾 (—Η1 > '力心立爾（1〜卜及同類物；㈣*** 素，如>曰姿妥（miS〇prostol )、及同類物。就一般專業之認知，本 發明可以結合相當多種不同的活性成份用於治療廣泛範園的情況。本發明也提供-種藥劑學組成，其包含：一個有效數量之活性 成伤可被5α·還原酵素代謝；_種水不溶性、具吸水膨脹性之交 錯連接的多縣聚合物；及_種水溶性聚合物^在此所稱之“組 成”是配方用來遞送所稱的活性成份通過—個似動物的黏膜表面 送到該動物的血液中。 本發明更進-步提供一種遞送方法，即遞送會被&還原酵素 代謝的活性成份到-個哺乳動物體内的方法，其包含藉著一種漸進 水化之生體可點性組錢過—個魏動物的㈣表面來投與所說的 活性成份。 此外，本發明提供-種組成，用於遞送一種會被5α還原酵素 作謝的活成伤到—個哺乳動物的血液中，其包含：—種水不溶 性、交錯連接的多縣聚合物；及—種水溶性聚合物 。在此所稱之 組成7CS&方用來遞送所稱之活性成份藉著通過該哺乳動物的黏 膜表面的方式來遞送。 此外，本發明提供一個生體可黏性漸進水化藥劑組成，其包 含.個有效數量之睪丸脂辆（testosterone )、一個水不溶性、吸 水膨脹、父錯連接的多羧基聚合物，其中所稱之組成是配方用來遞 送所稱之畢丸脂嗣經過一個哺乳動物的黏膜表面到該動物之血流 中。 138355-980918.doc 本紙張尺度適用中國國家標準(CNS) A4規格(21〇 χ 297公釐)iL (brompheniramine maleate ) ~ - * * * τ (diphenhydramine), aminophylline diphenhydramine (dimenhydrinate), carbene (-e), pumeimethine well (Pr〇methaZine), three ammonia (tripdannamine), and congeners; (13) renal vasopressin conversion sputum inhibitors, such as Kai Lier (mail (four)) 'Nalil (-Η1 > '力心立尔 (1~ Bu and similar; (4) Prostaglandins, such as >miS〇prostol, and congeners. As far as the general professional is concerned, the present invention can be combined with a wide variety of different active ingredients for the treatment of a wide range of conditions. The present invention also provides - a pharmaceutic composition comprising: an effective amount of active wounds that can be metabolized by 5α·reductase; _ a water-insoluble, water-swellable multi-counter polymer; and a water-soluble polymer This term "composition" is a formulation used to deliver a so-called active ingredient to the blood of an animal through an animal-like mucosal surface. The present invention further provides a method of delivery, i.e., delivery will be & Reactive enzyme metabolism active ingredient - a method in a mammal comprising administering the active ingredient to a surface of a Wei animal by means of a progressively hydrating body. Further, the invention provides a composition For the delivery of a lively wounded mammalian blood that is tolerated by 5α-reducing enzymes, which comprises: a water-insoluble, staggered multi-county polymer; and a water-soluble polymer. The so-called composition 7CS & is used to deliver the claimed active ingredient by means of the mucosal surface of the mammal. Further, the present invention provides a bioadhesive progressive hydration agent composition comprising. An effective amount of testosterone, a water-insoluble, water-swellable, parent-linked polycarboxy polymer, wherein the composition is a formulation used to deliver the so-called Pycnogenol through a mammalian mucosa The surface is in the bloodstream of the animal. 138355-980918.doc This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇χ 297 mm)

裝 訂Binding

k 1319987 A7 B7 五、發明説明（11 ) 此外，本發明提供一個生體可黏性漸進水化藥劑組成，其包 含：一個有效數量之特卜他靈（terbutaline )、一個水不溶性、吸水 膨脹、交錯連接的多羧基聚合物、及一個水溶性之聚合物，其中所 稱之組成是配方用來遞送所稱之特卜他靈經過一個哺乳動物的黏膜 表面到該動物之血流中。 . 此外，本發明提供一個方法，經由一個生體可黏性漸進水化藥 劑組成通過一個哺乳動物黏膜表面，用來遞送一個有效數量的睪丸 ' 脂酮到該哺乳動物之血流中，其包含：所稱之睪丸脂酮、一個水不 溶性、吸水膨脹、交錯連接的多羧基聚合物、及一個水溶性之聚合 物。 此外，本發明提供一個方法，經由一個生體可黏性漸進水化藥 劑組成通過一個哺乳動物黏膜表面，用來遞送一個有效數量的特卜 他靈到該哺乳動物之血流中，其包含：所稱之特卜他靈、一個水不 溶性、吸水膨脹、交錯連接的多羧基聚合物、及一個水溶性之聚合 物。 理想的情況是，本發明之組成是制式配方，經由哺乳動物的陰 道腔、口腔、鼻腔或直腸腔遞送所稱之活性成份。 有關本發明前述及其他方面之觀點，參考圖式及具體描述將會 更清楚。 . 圖1描述本發明一個理想的具體呈現，圖1之第1幅顯示：在 錠劑投與之前，所有的活性成份都在乾燥狀態，因此未受到潮濕、 酸鹼值、酵素或其他化學物質的不利作用，它也不適合吸收（或生 體可用）。圖1之第2至第6幅顯示：殘留的活性成份隨時間經過 仍維持乾燥狀態，此乾燥狀態如同一個貯藏所可防止受水及環境影 響，而可持續地及有控制地釋出活性成份，這樣的遞送系統非常適 合於遞送蛋白質、醣蛋白及其他必須防止代謝之藥物、或長時間給 138355-980918.doc - 14- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1319987 A7 B7 五、發明説明（12 ) 藥時會因酵素、酸鹼值或潮濕導致分解之藥物。 一個理想的具體模式是：當以口服方式使用時，生體可黏性錠 劑的漸進水化作用可以保護病人，錠劑可移動因為變的果凍狀地， 而且較重，因此較不可能在氣管中流動而危及呼吸。這使得本項具 體模式特別適合用於必須在半夜達到尖峰濃度的藥物，例如：治療 . 氣喘之荷爾蒙類像睪丸脂酮或類固醇（steroids )。依據本發明，若 配方作為口服錠劑，其水化最好能以小時（也就是12至24小時）為 ' 單位，或若配方作為***使用，其水化甚至以天計算。一般專業之 認知，最初專業之生體可黏性錠劑並不能保護活性成份免受潮濕、 酸鹼值、或未消毒之口腔、***管内細菌製造之酵素的影響。 再者，依循本申請案件之指導，可被一般業界接受之認知，製 造之錠劑可以訂定大小、形狀及劑量以符合特殊治療需要，舉例來 說：在圖1所描述之口腔生體可黏性錠劑為了病人舒適，只製作成 9毫米直徑，.但卻能每天遞送7毫克的睪丸脂酮，達到完全生理濃 度。相反地，先前業界認可之經皮貼劑只能每天遞送5毫克，換句 話說，其量低於生理濃度。 一個目前較理想的製造生體可黏性錠劑的方法以圖示方式於圖 2呈現，該理想方法包含三個步驟，將描述於下： . 1、 第一步驟：製作顆粒。 羥基丙基曱基纖維素15000 (= HPMC15000 )和玉米澱粉及乳 醣混合，如果一種活性成份對潮濕不敏感，則加入該活性成份。上 述之混合物以5的水溶液濕潤後，揉製再做成顆粒。 將顆粒置於中溫烘箱中（低於50°C )烘乾至水分含量2.5%以 下。 乾燥的顆粒再以網眼1000微米（μηι )之不鏽鋼篩網震動過篩 138355-980918.doc - 15- 本紙浪尺度適用中國國家標準(CNS) Α4規格(210X297公釐） 1319987 A7 B7 五、發明説明（13 ) 成細粉。 2、 竿二舟珑：製作打錠之混合物。 滑石粉、二氧化矽、硬脂酸鎂及活性成份（如果該成份對潮渴 敏感）加在一起，以孔徑500微米之篩子過篩，然後倒入一個自動 . 搖落之混合器中。 將第一步驟之顆粒加進來，接著加入聚碳親合物 (polycarbophil )、破鍵物（carbomer )、及乳酷，混合直到均句。 3、 竿s步驟：打錠。 將打錠之混合物用旋轉式打錠機壓製成錠劑，打錠機裝置之詞 孔上側為9毫米之平面’下側為弧長9毫米之弧形，兩側都有斜角 邊緣。將完成之錠劑清除粉末，然後包裝。 如同圖2所示，一種活性成份如果對潮濕不敏感，最好在製作 顆粒時加入；然而替代性方法是活性成份可在第二步驟也就是等顆 粒已乾燥及過篩後才加入。另外也如同一般業界熟知的技術，這個 第二個方法特別適合對潮濕敏感的活性成份。 在一個目前比較理想的製造過程中，活性成份應避免受到潮済 影響較為適宜。溼的顆粒是用乳畴、玉米澱粉和經基丙基甲基纖^維 • 素製成’而睪丸脂酮、聚碳親合物、碳鏈物974P、滑石粉及硬月旨 酸鎮則在最後壓鍵時加入〇 再者，如同一般業界熟知的技術，依循本申請之指導，構成錢 劑的原料可以改變，使錠劑所需之特質能充分發揮。舉例來說，本 發明已發現逐漸減少乳醣和玉米澱粉的量，並且逐漸増加碳鏈物 974P的量，則鼓劑水化的時間會逐漸增加。依此，適用於特殊治療 (例如：特定的活性成份、特定的劑量、特定的遞送時間）的錄;劑 138355-980918.doc - 16- 本紙浪尺度適用中國圉家標準(CNS) A4規格(210X297公釐) 1319987 A7 B7 五、發明説明（14 ) 也能夠製造。 本發明所稱以上這些及其他的觀念可以由下面所舉的實例更清 楚的呈現。 實例1:睪丸脂酮錠劑 以下為一種配方（配方第八項，批號#00029906)的實例，設計 用於男性可完全取代生理睪丸脂酮。 成 份 含量 重量比％ 睪丸脂酮 30.000毫克 24.0% 羥基丙基甲基纖維素 (HPMC ) 26.250毫克 21.0%. 玉米澱粉 22.500毫克 18.0% 乳醣水合物. 30.125毫克 24.1% 石圭石 1.250毫克 1.0% 聚礙親合物（Noveon ) 3.125毫克 2.5% 碳鏈物 974P 9.375毫克 7.5% 滑石粉 1.500毫克 1.2% 硬脂酸鎂 0.875毫克 0.7% 如上之配方在試管中作溶解試驗有持續釋出的結果，當以女性 為試驗對象時，如上之配方也能在12小時或更久的時間持續且可控 制的釋出睪丸脂酮。 如上之配方也提供在所稱之哺乳動物血液中睪丸脂酮與5α-二 氫睪丸脂酮（DHT)之濃度約為12比1之比例。此種血中濃度比被 預期較理想的是10比1或更大一些。 個別單獨的成份都是在工業界的供應商所熟知且隨時可供應 的。 HPMC 或經基丙基曱基纖維素（hydroxypropylmethylcellulose )是 138355-980918.doc -17- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1319987 A7 B7 五、發明説明（15 ) 一種膨脹分散劑，其在工業界熟知之替選物包括其他吸水會膨脹的 纖維素和聚合物。 玉米澱粉是一種填料和黏合劑，其替代物在工業界已為人熟 知0 乳糖（lactose )是一種填料，其替代物在工業界已為人熟知。 . 硅石或二氧化硅之作用如同懸浮劑和增稠劑，其替代物在工業 界已為人熟知。 ' 滑石粉和硬脂酸鎂是潤滑粉末，一般用於壓製錠劑的製造，其 替代物在工業界已為人熟知。 碳鏈物934P和974P (或CARBOPOL 974P )是水溶性的聚合 物，此聚合物可提供最初始的生體可黏性，其替代物在工業界已為 人熟知，包括如其他水溶性聚合物。 聚碳親合物是一種水不溶性聚合物，並且可提供較大的生體可 黏性，其替代物包括如其他水不溶性、吸水膨脹的生體可黏性的聚 合物。 表一描述依據本發明設計之九種不同的生體可黏性錠劑之配 方。活性成份，睪丸脂酮，是固定的，為30.0毫克（24%重量）， 因此改變其他非活性成份之比例，其效果就可以加以研究。 " 然後研究各配方中睪丸脂酮的溶解速率。表二描述由第一配方 - (批號#0069904 )選出之六種錠劑之睪丸脂酮的溶解速率；表三描 述由第三配方（批號#0049904 )選出之六種錠劑之睪丸脂酮的溶解 速率；表四描述由第五配方（批號#0029904 )選出之六種錠劑之睪 丸脂酮的溶解速率；表五描述由第六配方（批號#0019904 )選出之 六種錠劑之睪丸脂酮的溶解速率。 各個溶解速率數據再劃成曲線圖，顯示每小時睪丸脂酮釋出的 百分比。圖3描述第一配方之睪丸脂酮釋出速率（參看表二）；圖 138355-980918.doc -18- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1319987 A7 . B7 五、發明説明（16 ) 4描述第三配方之睪丸脂酮釋出速率（參看表三）；圖5描述第五 配方之睪丸脂酮釋出速率（參看表四）；圖6描述第六配方之睪丸 脂酮釋出速率（參看表五）。 138355-980918.doc - 19- 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1319987 A7 B7 五、發明説明（17 ) 配方九 00039906 Λ3 棚 24.00 21.00 18.00 26.60 〇 2.50 5.00 0.70 100.00 30.000 26.250 22.500 33.250 〇 1〇 (N 3.125 6.250 〇 »η 0.875 125.000 配方八 00029906 •1 24.00 21.00 18.00 24.10 〇 2.50 7.50 0.70 100.00 30.000 26.250 22.500 30.125 1.250 3.125 9.375 〇 0.875 125.000 配方七 _ ! 00019906 1_ Ί&1 24.00 21.00 18.00 22.10 〇 2.50 10.00 0.70 0.70 100.00 30.000 26.250 27.625 1.250 3.125 12.500 1 _1 0.875 0.875 125.000 i 配方六 1_:_ 0019904 彡申1 麵 24.00 21.00 18.00 19.60 〇 «Μ 2.50 12.50 0.70 0.70 100.00 毫克 30.000 26.250 22.500 24.500 1.250 3.125 15.625 0.875 0.875 125.000 配方五 0029904 £ ^ ΦΙ 如1 24.00 21.00 18.00 17.10 § 2.50 15.00 0.70 0.70 100.00 30.000 26.250 22.500 21.375 (N 3.125 18.750 0.875 0.875 125.000 配方四 0039904 JJ 彡ΦΙ 24.00 22.00 14.00 15.10 〇 2.50 20.00 0.70 0.70 100.00 30.000 27.500 17.500 18.875 1.250 3.125 25.000 0.875 0.875 125.000 配方三 0049904 Jmj Wi 24.00 23.00 10.00 13.10 〇 2.50 25.00 0.70 0.70 100.00 30.000 28.750 12.500 16.375 3.125 31.250 0.875 0.875 125.000 配方二 0059904 £ ^ «W 锏 24.00 6.00 11.10 〇 2.50 30.00 0.70 0.70 100.001 30.000 30.000 7.500 13.875 1.250 3.125 | 37.500 0.875 0.875 125.000 1 1 配方一 0069904 ^ Μ Μ 24.00 25.00 2.00 9.10 〇 2.50 35.00 0.70 0.70 100.00 30.000 31.250 2.500 11.375 1.250 3.125 43.750 0.875 0.875 125.000 批號# I睪丸脂酮| 5*1 玉米澱粉 I乳醣水合物 硅石（二氧 化硅） 聚碳親合物 (Noveon) 者CLc 滑石粉 硬脂酸錤 總重量 138355-980918.doc 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) -20· 1319987 A7 B7 五 明説 明發 隸09墩令# <諱赵盔喪蕻呦收：鲥铋遂钱 (丨柃tos) S66900 :餚莫k 1319987 A7 B7 V. INSTRUCTION DESCRIPTION (11) Further, the present invention provides a bioadhesive progressive hydration agent composition comprising: an effective amount of terbutaline, a water insoluble, water swellable, A cross-linked polycarboxy polymer, and a water soluble polymer, wherein the composition is a formulation used to deliver the so-called terbutaline to the bloodstream of the animal through the mucosal surface of a mammal. Furthermore, the present invention provides a method for delivering an effective amount of testosterone 'lipid ketone into the bloodstream of the mammal via a mammalian mucosal surface via a bioadhesive progressive hydrating agent, which comprises : The so-called saponin, a water-insoluble, water-swellable, interlaced polycarboxy polymer, and a water-soluble polymer. Furthermore, the present invention provides a method for delivering an effective amount of terbutaline to the bloodstream of a mammal via a mammalian mucosal surface via a bioadhesive progressive hydrating agent comprising: It is called terbutaline, a water-insoluble, water-swellable, interlaced polycarboxy polymer, and a water-soluble polymer. Ideally, the compositions of the present invention are formulated to deliver the claimed active ingredient via the vaginal, buccal, nasal or rectal cavity of a mammal. The above and other aspects of the present invention will be apparent from the following description and drawings. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts an ideal embodiment of the present invention. The first panel of Figure 1 shows that all active ingredients are in a dry state prior to administration of the tablet, and thus are not exposed to moisture, pH, enzymes or other chemicals. The adverse effect, it is also not suitable for absorption (or biologically available). Figures 2 to 6 of Figure 1 show that the remaining active ingredient remains dry over time, which is like a store to prevent water and environmental influences, and to release the active ingredient in a sustainable and controlled manner. Such a delivery system is well suited for the delivery of proteins, glycoproteins and other drugs that must be prevented from metabolism, or for a long time to 138355-980918.doc - 14- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 1319987 A7 B7 V. INSTRUCTIONS (12) Drugs that are broken down by enzymes, pH or moisture. An ideal specific mode is that when used orally, the progressive hydration of the bioadhesive lozenge protects the patient, and the lozenge can move because it becomes jelly-like and heavier, so it is less likely Flowing in the trachea jeopardizes breathing. This makes this specific mode particularly suitable for drugs that must reach peak concentrations in the middle of the night, for example: treatment. Asthma like hormones such as steroids or steroids. According to the present invention, if the formulation is used as an oral lozenge, the hydration is preferably in units of hours (i.e., 12 to 24 hours), or if the formulation is used as a vagina, the hydration is even calculated in days. It is generally recognized that the original professional viscous lozenges do not protect the active ingredients from moist, pH-based or unsterilized oral, vaginal bacteria-derived enzymes. Furthermore, in accordance with the guidance of the case of the present application, it can be accepted by the general industry that the manufactured tablets can be sized, shaped and dosed to meet specific therapeutic needs. For example, the oral body described in Figure 1 can be used. For the comfort of the patient, the viscous tablet is only made to a diameter of 9 mm, but it can deliver 7 mg of testosterone per day to a full physiological concentration. Conversely, previously approved transdermal patches can only deliver 5 mg per day, in other words, below physiological concentrations. A currently preferred method of making a bioadhesive lozenge is presented graphically in Figure 2, which comprises three steps, which will be described below: 1. First step: Making the granules. Hydroxypropyl decyl cellulose 15000 (= HPMC15000) is mixed with corn starch and lactose, and if an active ingredient is not sensitive to moisture, the active ingredient is added. After the above mixture was wetted with an aqueous solution of 5, it was made into granules by tanning. The granules were placed in a medium temperature oven (less than 50 ° C) and dried to a moisture content of 2.5% or less. The dried granules are then shaken with a mesh of 1000 micron (μηι) stainless steel screen. 138355-980918.doc - 15- This paper wave scale is applicable to China National Standard (CNS) Α4 specification (210X297 mm) 1319987 A7 B7 V. Invention Description (13) into a fine powder. 2. 竿二舟珑: Make a mixture of ingots. Add talc, cerium oxide, magnesium stearate and active ingredients (if the ingredient is sensitive to thirst), sieve through a 500 μm sieve, and pour into an automatic shaker. The particles of the first step are added, followed by the addition of polycarbophil, carbomer, and milk, and mixed until the same sentence. 3, 竿 s steps: ingots. The mixture of the ingots was pressed into a tablet by a rotary tableting machine. The upper side of the hole was 9 mm in the plane of the spindle. The lower side was curved with an arc length of 9 mm, and both sides had beveled edges. The finished tablet is cleared of powder and then packaged. As shown in Figure 2, an active ingredient, if it is not sensitive to moisture, is preferably added during the preparation of the granules; however, an alternative method is that the active ingredient can be added after the second step, i.e., after the granules have been dried and sieved. Also, as is well known in the art, this second method is particularly suitable for moisture sensitive active ingredients. In an currently desirable manufacturing process, the active ingredient should be protected from tidal effects. Wet granules are made from dairy domains, corn starch and propyl methacrylate. While saponin, polycarbohydrate, carbon chain 974P, talc and hard acid are used. In the final press of the key, the enthalpy is added. As is well known in the art, the raw materials constituting the money can be changed according to the guidance of the present application, so that the desired properties of the tablet can be fully utilized. For example, the present inventors have discovered that the amount of lactose and corn starch is gradually reduced, and the amount of carbon chain 974P is gradually added, and the time for hydration of the drum is gradually increased. Accordingly, it is applicable to special treatments (eg, specific active ingredients, specific doses, specific delivery times); 138355-980918.doc - 16- This paper wave scale applies to China National Standard (CNS) A4 specifications ( 210X297 mm) 1319987 A7 B7 V. Invention description (14) can also be manufactured. These and other concepts referred to in the present invention can be more clearly presented by the examples set forth below. Example 1: Saponin Tablets The following is an example of a formulation (Formulation 8th, Lot #00029906) designed to completely replace physiological steroids in men. Ingredient content by weight% 睪 脂 脂 3 3 30.000 mg 24.0% Hydroxypropyl methylcellulose (HPMC) 26.250 mg 21.0%. Corn starch 22.500 mg 18.0% Lactose hydrate. 30.125 mg 24.1% Shi Guishi 1.250 mg 1.0% Poly Nuveon 3.125 mg 2.5% carbon chain 974P 9.375 mg 7.5% talc 1.500 mg 1.2% Magnesium stearate 0.875 mg 0.7% The above formulation has a sustained release in a test tube. When a female is used as a test subject, the above formulation can also continuously and controlfully release the testosterone in 12 hours or longer. The above formulation also provides a concentration of about 2 to 1 in the so-called mammalian blood of the testosterone and 5?-dihydroquinone (DHT). This blood concentration ratio is expected to be 10 to 1 or greater. Individual individual ingredients are well known and readily available from suppliers in the industry. HPMC or hydroxypropylmethylcellulose is 138355-980918.doc -17- This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1319987 A7 B7 V. Invention description (15) An intumescent dispersant, which is well known in the industry, includes other water-swellable celluloses and polymers. Corn starch is a filler and binder, and its replacement is well known in the industry. 0 Lactose is a filler and its alternatives are well known in the industry. Silica or silica acts like a suspending agent and a thickener, and alternatives are well known in the industry. 'Task powder and magnesium stearate are lubricating powders and are generally used in the manufacture of pressed tablets. Alternatives are well known in the industry. Carbon chains 934P and 974P (or CARBOPOL 974P) are water soluble polymers that provide the most initial bioadhesive properties, and alternatives are well known in the industry, including, for example, other water soluble polymers. . The polycarbonate is a water insoluble polymer and provides greater bioadhesiveness, and alternatives include, for example, other water insoluble, water swellable, bioadhesive polymers. Table 1 describes the formulation of nine different bioadhesive tablets designed in accordance with the present invention. The active ingredient, the testosterone, is fixed at 30.0 mg (24% by weight), so the effect of changing the ratio of other inactive ingredients can be studied. " Then study the dissolution rate of the testosterone in each formulation. Table 2 describes the dissolution rates of the six lozenges selected from the first formulation - (batch #0069904); Table 3 describes the six lozenges selected from the third formulation (batch #0049904). Dissolution rate; Table 4 describes the dissolution rates of the six lozenges selected from the fifth formulation (batch #0029904); Table 5 describes the six lozenges selected from the sixth formulation (batch #0019904) The rate of dissolution of the ketone. Each dissolution rate data is then plotted as a graph showing the percentage of release of the saponin per hour. Figure 3 depicts the release rate of the testosterone in the first formulation (see Table 2); Figure 138355-980918.doc -18- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1319987 A7 . B7 V. INSTRUCTION DESCRIPTION (16) 4 describes the release rate of the testosterone in the third formulation (see Table 3); Figure 5 depicts the release rate of the testosterone in the fifth formulation (see Table 4); Figure 6 depicts the sixth formulation After the release rate of the peptide ketone (see Table 5). 138355-980918.doc - 19- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1319987 A7 B7 V. Invention description (17) Formula 900039906 Λ3 Shed 24.00 21.00 18.00 26.60 〇2.50 5.00 0.70 100.00 30.000 26.250 22.500 33.250 〇1〇(N 3.125 6.250 〇»η 0.875 125.000 Formula VIII2929906 •1 24.00 21.00 18.00 24.10 〇2.50 7.50 0.70 100.00 30.000 26.250 22.500 30.125 1.250 3.125 9.375 〇0.875 125.000 Formula 7 _ ! 00019906 1_ Ί&1 24.00 21.00 18.00 22.10 〇2.50 10.00 0.70 0.70 100.00 30.000 26.250 27.625 1.250 3.125 12.500 1 _1 0.875 0.875 125.000 i Formulation 6 1:: 0019904 彡申1面 24.00 21.00 18.00 19.60 〇«Μ 2.50 12.50 0.70 0.70 100.00 mg 30.000 26.250 22.500 24.500 1.250 3.125 15.625 0.875 0.875 125.000 Formulation 500029904 £ ^ ΦΙ 如1 24.00 21.00 18.00 17.10 § 2.50 15.00 0.70 0.70 100.00 30.000 26.250 22.500 21.375 (N 3.125 18.750 0.875 0.875 125.000 Formulation 4039394 JJ 彡ΦΙ 24.00 22.00 14.00 15.10 〇2.50 20.00 0.70 0.70 10 0.00 30.000 27.500 17.500 18.875 1.250 3.125 25.000 0.875 0.875 125.000 Formula 3049904 Jmj Wi 24.00 23.00 10.00 13.10 〇 2.50 25.00 0.70 0.70 100.00 30.000 28.750 12.500 16.375 3.125 31.250 0.875 0.875 125.000 Formula 2 0059904 £ ^ «W 锏24.00 6.00 11.10 〇2.50 30.00 0.70 0.70 100.001 30.000 30.000 7.500 13.875 1.250 3.125 | 37.500 0.875 0.875 125.000 1 1 Formulation 1 0699904 ^ Μ Μ 24.00 25.00 2.00 9.10 〇 2.50 35.00 0.70 0.70 100.00 30.000 31.250 2.500 11.375 1.250 3.125 43.750 0.875 0.875 125.000 Lot # I 睪 脂 酮 | 1 Corn starch I lactose hydrate silica (silica) Polycarbonate (Noveon) CLc talcum powder stearic acid 錤 total weight 138355-980918.doc This paper scale applies to China National Standard (CNS) A4 specifications (210X 297 mm) -20· 1319987 A7 B7 Wu Ming Explain the hair of the 09 Pier Order # < 讳 Zhao Helmet Funeral: Money (丨柃tos) S66900: Dish

釋出〈小時〉 24 83.6 88.5 84.9 88.3 87.4 86.6 86.6 釋出〈小時〉 8 16.0 18.0 17.9 17.0 18.3 17.4 釋出〈小時〉 6 10.6 11.7 卜 11.2 10.9 12.4 11.4 釋出〈小時〉 4 卜 〇\ VO Ο 00 釋出〈小時〉 2 Os 1—Η 卜 Ϊ-Η 〇 oi ι&gt; Τ-Η Ον CN 〇\ 釋出〈小時〉 I 卜 〇 VO 〇 卜 〇 ο 卜 Ο 卜 Ο Γ- ο 釋出〈小時〉 0 〇 〇 〇 〇 〇 〇 ο ο ο ο Ο ο ρ ο 樣本 (Ν m 寸 1平均值I _138355-980918.doc_-21 - 本纸張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 1319987 A7 B7 ' 五 (3-^tog) S66 寸 00 :餚莫 釋出〈小時〉 24 83.6 82.2 83.4 82.7 83.0 85.6 83.4 釋出〈小時〉 8 16.5 16.9 18.0 16.7 16.7 16.8 16.9 釋出〈小時〉 6 10.6 10.5 oo 1—H 10.8 10.6 | 11.0 10.9 釋出〈小時〉 4 v〇 寸 卜 v〇 in 卜 釋出〈小時〉 2 rn Η rn 寸 rn On (N Os 寸 Os (N 寸 rn 釋出〈小時〉 1 Q\ Ο r-H &lt;N ON 〇 〇 〇 釋出〈小時〉 0 Ο Ο ρ ο p o 〇 〇 o o p o p o 樣本 CN m 寸 Ό 1平均值1 _138355-980918.doc_-22- 本纸張尺度逋用中國國家標準(CNS) A4規格(210X 297公釐） 1319987 A7 B7 五、發明説明（2〇 ) 諱09墩令#*隸游袅喪莪命耶：鲥域遂效 (?拎2晒) 寸066SO :絜4 釋出〈小時〉 24 80.3 87.5 75.2 82.4 83.2 86.6 82.5 釋出〈小時〉 8 16.3 17.8 17.7 18.6 19.5 18.8 00 釋出〈小時〉 6 ί 10.8 OO 12.3 12.4 12.9 12.2 cs 釋出〈小時〉 4 OS in 卜 vd os VO 00 Os vd Os VO 釋出〈小時〉 2 CN (N 寸 cs m CN CN CN &lt;N 寸 CN 釋出〈小時〉 1 On 〇 as o o o 〇\ o σ\ o ON o OS o 釋出〈小時〉 0 〇 o o o o o o o o o o o o o 樣本 CN m 寸 1平均值1 _i38355-980918.doc_ 本纸蒗尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1319987 A7 B7 五、發明説明（) 隸09墩令# *隸驾盔喫鉍呦收：瞓铋逖钱18.d (权柃齧) S66S0 :餚奚8091 -9 5 5 ^1383 釋出〈小時〉 24 71.7 ο 74.6 68.6 74.0 70.3 72.0 釋出〈小時〉 8 16.1 14.1 15.8 15.0 14.6 cn Τ&quot;Η 14.8 釋出〈小時〉 6 Η 卜 Os 11.3 10.4 〇\ On On 10.3 釋出〈小時〉 4 C\ Ο wS 寸 \ό On — Ο) — 寸 uS 釋出〈小時〉 2 r-H oi Ο CN ΓΟ CN ο CN 00 00 Ο (Ν 釋出〈小時〉 1 CN οο ο 〇\ Ο &lt;J\ Ο 00 c&gt; as ο ο 釋出〈小時〉 0 ο ci ο ο ο ο Ο d ο ο ο ο ο ο 樣本 CN m 寸 1平均值ι 本纸蒗尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1319987 A7 B7 五、發明説明（22 ) 如同圖式及表所顯示，減少乳醣及玉米澱粉的量，增加水溶 性聚合物的量，則鍵劑水化的時間會逐漸增加。配方一 ( 0069904 )及其他同類物具有高量之碳鏈物974P與低量之乳醣及 玉米澱粉，可能是最適合用於須投藥數日之***給藥製劑。在第 一實例中，給與上述之配方八（0029906 )，其乳醣及玉米澱粉為 高量而碳鏈物974P為低量，此配方可能用作只需12小時給藥即足 夠之口腔給藥之製劑較好。 實例2 :睪丸脂玥錠劑（30毫克） 以下為一種配方的實例，設計作為睪丸脂酮補充治療： 成 份 含量 重量比％ 睪丸脂酮 30.000毫克 21.4% 羥基丙基曱基纖維素 (HPMC ) 26.250毫克 18.8% 玉米澱粉 22.500毫克 16.1% 乳醣 45.125毫克 32.2% 石圭石 1.250毫克 0.9% 聚碳親合物（Noveon ) 3.125毫克 2.2% 碳鏈物974P 9.375毫克 6.7% 滑石粉 1.500毫克 1.1% 硬脂酸鎂 0.875毫克 0.6% 實例3 :睪丸脂酮錠劑（6毫克） 以下為一種配方的實例，設計作為睪丸脂酮補充治療： 成 份 含量 重量比％ 睪丸脂酮 6.000毫克 6.0% 138355-980918.doc -25- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X297公釐） 1319987 A7 B7 五、發明説明（23 ) 羥基丙基甲基纖維素 (HPMC ) 5.250毫克 5.3% 玉米澱粉 4.500毫克 4.5% 乳醣 78.970毫克 79.0% 石圭石 0.700毫克 0.7% 聚碳親合物（Noveon ) 2.230毫克 2.2% 碳鏈物974P 1.000毫克 1.0% 滑石粉 0.850毫克 0.9% 硬脂酸鎂 0.500毫克 0.5% 實例4 :睪丸脂酮錠剤（3毫克） 以下為一種配方的實例，設計作為睪丸脂酮補充治療： 成 份 含量 重量比％ 睪丸脂酮 3.000毫克 3.0% 羥基丙基曱基纖維素 (HPMC ) 2.625毫克 2.6% 玉米澱粉 2.250毫克 2.3% 乳醣 86.845毫克 86.8% 石圭石 0.700毫克 0.7% 聚瑞親合物（Noveon ) 2.230毫克 2.2% 碳鏈物974P 1.000毫克 1.0% 滑石粉 0.850毫克 0.9% 硬脂酸鎂 0.500毫克 0.5% 實例5 :特卜他靈錠劑（4毫克） 以下為一種特卜他靈配方的實例，設計此配方係提供特卜他 靈投與後的治療利益： 成 份 含量 重量比％ 特卜他靈 4.000毫克 4.4% 羥基丙基曱基纖維素 18.760毫克 20.8% 138355-980918.doc - 26- 本纸蒗尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) 1319987 A7 B7 五、發明説明（24 ) (HPMC ) 玉米澱粉 16.070毫克 17.9% 乳醣 39.640毫克 44.0% 石圭石 0.900毫克 1.0% 聚碳親合物（Noveon ) 2.235毫克 2.5% 碳鏈物974P 6.700毫克 7.4% 滑石粉 1.070毫克 1.2% 硬脂酸鎂 0.625毫克 0.7% 實例6 :特卜他靈錠劑（2毫克） 以下為一種特卜他靈配方的實例，設計此配方係提供特卜他 靈投與後的治療利益： 成 份 含量 重量比％ 特卜他靈 2.000毫克 2.2% 羥基丙基甲基纖維素 (HPMC ) 18.760毫克 20.8% 玉米澱粉 16.070毫克 17.9% 乳醣 41.640毫克 46.3% 石全石 0.900毫克 1.0% 聚碳親合物（Noveon ) 2.235毫克 2.5% 碳鏈物974P 6.700毫克 7.4% 滑石粉 1.070毫克 1.2% 硬脂酸鎂 0.625毫克 0.7% 如一般業界之認知，以上之實例或理論的具體化表現並不侷 限於此，本發明可應用到各種錠劑，其組成包含任何活性成份， 以及任何錠劑原料的併用。更進一步，亦如一般業界之認知，本 發明嘗試涵蓋前面所述之錠劑的製造方法及臨床治療用法。 -27- 138355-980918.doc 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1319987 A7 __B7 _ 五、發明説明（25 ) 本發明已如上所描述者’這些專業技術可能以多種形式改 變’但不會脫離本發明之精神及範圍卻是很明顯的.這些改變也 包括在本發明申請專利之範圍内。 於本詳細說明書内所提到的全部發表内容及專利或應用是合 併在一起的，如同每一個詳細說明和分別併入一樣。 圖式簡單說明 圖1係描述本發明之生體可黏性旋劑漸進水化情形之照片。 圖2係描述本發明製造生體可黏性錠劑之最理想方法之流程。 圖3係描述第一配方之睪丸脂網釋出速率（參看表_)。 圖4係描述第三配方之睪丸脂酮釋出速率（參看表=)。 圖5係描述第五配方之睪丸脂輞釋出速率（參看表四）。 圖6係描述第六配方之睪丸脂酮釋出速率（參看表五） _^38355-980918(替換本).doc -28- 本紙張尺度通用中國國家標準(CNS) A4规格(210X 29·7公釐）Release <hour> 24 83.6 88.5 84.9 88.3 87.4 86.6 86.6 Release <hour> 8 16.0 18.0 17.9 17.0 18.3 17.4 Release <hour> 6 10.6 11.7 Bu 11.2 10.9 12.4 11.4 Release <hour> 4 Buddhism \ VO Ο 00 Release <hour> 2 Os 1—Η卜Ϊ-Η 〇oi ι&gt; Τ-Η Ον CN 〇\ Release <hour> I 〇 〇 〇 〇 〇 Ο 〈 0 〇〇〇〇〇〇ο ο ο ο Ο ο ρ ο Sample (Ν m 1 1 average I _138355-980918.doc_-21 - This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 13)7 A7 B7 'five (3-^tog) S66 inch 00: dish release (hour) 24 83.6 82.2 83.4 82.7 83.0 85.6 83.4 release <hour> 8 16.5 16.9 18.0 16.7 16.7 16.8 16.9 Release <hour 〉 6 10.6 10.5 oo 1—H 10.8 10.6 | 11.0 10.9 Release <hour> 4 v〇 inch 卜 v〇in 卜 release <hour> 2 rn Η rn inch rn On (N Os inch Os (N inch rn release) <hour> 1 Q\ Ο rH &lt;N ON 〇〇〇 release <hour> 0 Ο Ο ρ ο po 〇〇oopo Po sample CN m inch Ό 1 average 1 _138355-980918.doc_-22- This paper scale adopts Chinese National Standard (CNS) A4 specification (210X 297 mm) 1319987 A7 B7 V. Invention description (2〇) 讳09 Ding Ling #* Li Yu 袅 莪 耶 耶 鲥 : : :: 鲥 晒 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 066 24 24 24 24 24 24 24 24 24 24 24 24 18.6 19.5 18.8 00 Release <hour> 6 ί 10.8 OO 12.3 12.4 12.9 12.2 cs Release <hour> 4 OS in Bud os VO 00 Os vd Os VO Release <hour> 2 CN (N inch cs m CN CN CN &lt;N inch CN release <hour> 1 On 〇as ooo 〇\ o σ\ o ON o OS o Release <hour> 0 〇ooooooooooooo Sample CN m inch 1 average 1 _i38355-980918.doc_ Paper size Applicable to China National Standard (CNS) A4 Specification (210 x 297 mm) 1319987 A7 B7 V. Invention Description () Lieutenant 09 Pier Order # *Driver 铋呦 铋呦 瞓铋逖 瞓铋逖 瞓铋逖 瞓铋逖 瞓铋逖 瞓铋逖 瞓铋逖 瞓铋逖 瞓铋逖 瞓铋逖 瞓铋逖 瞓铋逖 18 18 18 S66S0 :Food 奚8091 -9 5 5 ^1383 Release <hour> 24 71.7 ο 74.6 68.6 74.0 70.3 72.0 Release <hour> 8 16.1 14.1 15.8 15.0 14.6 cn Τ&quot;Η 14.8 Release <hour> 6 Η Ob Os 11.3 10.4 〇\ On On 10.3 Release <hour> 4 C\ Ο wS inch \ό On — Ο) — inch uS release <hour> 2 rH Oi Ο CN ΓΟ CN ο CN 00 00 Ο (Ν Release <hour> 1 CN οο ο 〇 Ο Ο &lt;J\ Ο 00 c&gt; as ο ο Release <hour> 0 ο ci ο ο ο ο Ο d ο ο ο ο ο ο Sample CN m 1 1 average ι This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 1319987 A7 B7 V. Invention description (22) As shown in the figure and table, By reducing the amount of lactose and corn starch and increasing the amount of water-soluble polymer, the time for hydration of the bond will gradually increase. Formulation 1 (0069904) and other concomitants have a high amount of carbon chain 974P and low amounts of lactose and corn starch, which may be the most suitable vaginal administration for several days. In the first example, the above formula VIII (0029906) is given, wherein the lactose and corn starch are high and the carbon chain 974P is low. This formulation may be used as an oral cavity for only 12 hours of administration. The preparation of the medicine is better. Example 2: 睪 玥 玥 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 30 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Mg 18.8% Corn starch 22.500 mg 16.1% Lactose 45.125 mg 32.2% Shi Guishi 1.250 mg 0.9% Polycarbohydrate (Noveon) 3.125 mg 2.2% Carbon chain 974P 9.375 mg 6.7% Talc 1.500 mg 1.1% Stearyl Magnesium Oxide 0.875 mg 0.6% Example 3: Saponin Tablets (6 mg) The following is an example of a formulation designed to be used as a supplement for the treatment of saponin: Ingredient content by weight % 睪 脂 脂 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 138 138 138 138 138 138 138 138 138 138 138 138 138 138 138 -25- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X297 mm) 1319987 A7 B7 V. Description of invention (23) Hydroxypropyl methylcellulose (HPMC) 5.250 mg 5.3% Corn starch 4.500 mg 4.5% lactose 78.970 mg 79.0% shigui stone 0.700 mg 0.7% polycarbohydrate (Noveon) 2.230 mg 2.2% carbon chain 974P 1.000 mg 1.0% slippery Stone powder 0.850 mg 0.9% Magnesium stearate 0.500 mg 0.5% Example 4: saponin saponin (3 mg) The following is an example of a formula designed to be used as a supplement for the treatment of saponin: Ingredient content by weight % 睪 脂 脂 3.0 3.00 mg 3.0 % hydroxypropyl decyl cellulose (HPMC) 2.625 mg 2.6% corn starch 2.250 mg 2.3% lactose 86.845 mg 86.8% shigui stone 0.700 mg 0.7% poly ruthenium complex (Noveon) 2.230 mg 2.2% carbon chain 974P 1.000 mg 1.0% talcum powder 0.850 mg 0.9% magnesium stearate 0.500 mg 0.5% Example 5: terbutaline lozenge (4 mg) The following is an example of a formulation of terbutaline, which is designed to provide Tebta Benefits of Pilling and Post-Treatment: Ingredient content by weight % Tebhalamine 4.000 mg 4.4% Hydroxypropyl decyl cellulose 18.760 mg 20.8% 138355-980918.doc - 26- This paper size applies to Chinese national standards (CNS A4 size (21〇x 297 mm) 1319987 A7 B7 V. Description of invention (24) (HPMC) Corn starch 16.070 mg 17.9% Lactose 39.640 m 44.0% Shi Guishi 0.900 mg 1.0% Polycarbohydrate (Noveon) 2.235 mg 2.5% Carbon chain 974P 6.700 mg 7.4% Talc 1.070 mg 1.2% Magnesium stearate 0.625 mg 0.7% Example 6: Tebapamine Lozenges (2 mg) The following is an example of a formulation of terbutaline, which is designed to provide therapeutic benefit after administration of terbutaline: Ingredient content by weight % Tebbutine 2.000 mg 2.2% Hydroxypropyl group Cellulose (HPMC) 18.760 mg 20.8% Corn starch 16.070 mg 17.9% Lactose 41.640 mg 46.3% Shi Quanshi 0.900 mg 1.0% Polycarbohydrate (Noveon) 2.235 mg 2.5% Carbon chain 974P 6.700 mg 7.4% Talc Powder 1.070 mg 1.2% Magnesium stearate 0.625 mg 0.7% As is generally recognized in the industry, the specific examples of the above examples or theories are not limited thereto, and the present invention can be applied to various lozenges, the composition of which contains any active ingredient, And the combination of any tablet materials. Further, as also recognized by the general industry, the present invention attempts to cover the manufacturing method and clinical treatment usage of the above-mentioned tablet. -27- 138355-980918.doc This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1319987 A7 __B7 _ V. Invention description (25) The present invention has been described above as 'these expertise may It is obvious that the invention is not limited by the spirit and scope of the invention. These modifications are also included in the scope of the present invention. All publications and patents or applications referred to in this specification are incorporated as if each of the detailed description BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a photograph showing the progressive hydration of a bio-adhesive spinner of the present invention. Figure 2 is a flow chart depicting the most preferred method of making a bioadhesive lozenge of the present invention. Figure 3 is a graph showing the release rate of the pellets of the first formulation (see Table_). Figure 4 is a graph showing the release rate of the testosterone in the third formulation (see Table =). Figure 5 is a graph showing the release rate of the pellets of the fifth formulation (see Table 4). Figure 6 is a diagram showing the release rate of the saponin in the sixth formula (see Table 5) _^38355-980918 (replacement).doc -28- This paper scale is the common Chinese national standard (CNS) A4 specification (210X 29·7) MM)

Claims (1)

1319987六、申請專利範園 Α8 Β8 C8 D8 L 一種生體可黏性漸進水化之醫藥組成物，其包含·· 一有效量之特卜他靈（terbutaline)， 一水不溶性、吸水膨脹之交錯連接的多羧基聚合物，及 一水溶性聚合物； 其中該組成物係配方製成能將該特卜他靈經由穿過一哺乳動物 的黏膜表面傳遞到該哺乳動物的血液中。 2. 如請求項1之組成物，其中該特卜他靈係以每單位劑量組合物 約4毫克之量存在。 3. 如請求項1之組成物，其中該特卜他靈係以每單位劑量組合物 約2毫克之量存在。 4.如請求項1之組成物，其中該組合物係配方為錠劑，其可經過 口腔或***腔遞送該特卜他靈， 且該林溶性、吸水_之交錯連接的多絲聚合物為聚碳親 合物（Polycarbophil)。 5. 如請求項2之組成物，其中該組合物係配方為錠劑其可經過 口腔或***腔遞送該特卜他靈， 且該水不溶性 合物。 吸水膨脹之交錯連接的錄基聚合物為聚碳親 6_如凊求項3之組成物，其中該組合物係配方為錠劑其了纟_&lt;過 口腔或***腔遞送該特卜他靈， &quot; 且該水不溶性、吸水膨脹之交錯連接的多羧基 人札„ 表。物為聚碳親 如睛求項4、5及6中任一項之組成物，其中 138355-980918.doc 本紙張（度適財目@家料(CNS) M規格(咖〉⑽公爱)1319987 VI. Application for Patent Fan Yuan 8 Β 8 C8 D8 L A pharmaceutical composition of bio-adhesive progressive hydration, containing an effective amount of terbutaline, a water-insoluble, water-swellable interlaced a linked polycarboxy polymer, and a water soluble polymer; wherein the composition is formulated to deliver the terbutaline to the blood of the mammal via a mucosal surface of a mammal. 2. The composition of claim 1, wherein the terbutaline is present in an amount of about 4 mg per unit dose of the composition. 3. The composition of claim 1, wherein the terbutaline is present in an amount of about 2 mg per unit dose of the composition. 4. The composition of claim 1, wherein the composition is formulated as a lozenge which delivers the terbutaline through the oral cavity or vaginal cavity, and the intercalated, water-absorbent multi-filament polymer is Polycarbophil. 5. The composition of claim 2, wherein the composition is formulated as a lozenge which delivers the terbutaline through the oral cavity or vaginal cavity, and the water is insoluble. The water-swellable interlaced base polymer is a composition of a polycarbon parent, such as the composition of claim 3, wherein the composition is formulated as a tablet, and the tablet is delivered to the oral or vaginal cavity. Ling, &quot; and the water-insoluble, water-swellable, interlaced polycarboxy-character. The composition is a composition of any of items 4, 5, and 6, wherein 138355-980918.doc This paper (degree of money @家料(CNS) M specification (coffee) (10) public love) 1319987 A8 B8 C8 D8 申請專利範園 該水溶性聚合物為碳鏈物974P (Carbomer 974P)， 且該組合物更包括乳糖羥基丙基甲基纖維素（HPMC)、玉米澱 粉、滑石粉、矽石及硬脂酸鎂。 8. 9. 一種生體可黏性漸進水化之醫藥組成物之用途，其係用於製備 能將一有效量之特卜他靈經由穿過一哺乳動物的黏膜表面遞送 到該哺乳動物血液中之醫藥品，該組成物包含 該特卜他靈， 一水不溶性、吸水膨脹之交錯連接的多羧基聚合物，及 一水溶性聚合物。 如請求項8之用途，其中該特卜他靈係以每單位劑量組合物約 其中該特卜他靈係以每單位劑量組合物約 其中 4毫克之量存在。 10.如請求項8之用途 2毫克之量存在。 11 ·如請求項8之用途 該組合物係配方為錠劑，其可經過口腔或***腔遞送該特卜他 靈， 且該水不溶性、吸水膨脹之交錯連接的多羧基聚合物係聚碳親 合物， 該水溶性聚合物為碳鏈物974P， 且該組合物更包括羥基丙基曱基纖維素、玉米澱粉滑石粉 矽石及硬脂酸鎂。 12.如請求項9之用途，其中 該組合物係配方為錠劑，其可經過口腔或***腔遞送該特卜 138355-980918.doc 本纸張尺度適用中國國家標準(CNS) A4·規格(210X 297公釐） 1319987 as C8 D8 六、申請專利範園 靈， 且該水不溶性、吸水膨脹之交錯連接的多羧基聚合物係聚碳親 合物， 該水溶性聚合物為碳鏈物974P， 且該組合物更包括乳糖羥基丙基甲基纖維素、玉米澱粉、滑石 ' 粉、矽石及硬脂酸鎂。 - 13.如請求項10之用途，其中 該組合物係配方為錠劑，其可經過口腔或***腔遞送該特卜他 靈， 且該水不溶性、吸水膨脹之交錯連接的多羧基聚合物係聚碳親 合物， 該水溶性聚合物為碳鏈物974P， 且該組合物更包括乳糖羥基丙基曱基纖維素、玉米澱粉、滑石 粉、矽石及硬脂酸鎂。 138355-980918.doc 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐）1319987 A8 B8 C8 D8 Patent Application The water-soluble polymer is carbon chain 974P (Carbomer 974P), and the composition further includes lactose hydroxypropyl methylcellulose (HPMC), corn starch, talcum powder, vermiculite And magnesium stearate. 8. Use of a pharmaceutical composition of biocompatible gradual hydration for the preparation of an effective amount of terbutaline to be delivered to the mammalian blood through a mucosal surface of a mammal In the pharmaceutical composition, the composition comprises the terbutaline, a water-insoluble, water-swellable interlaced polycarboxy polymer, and a water-soluble polymer. The use of claim 8, wherein the terbutaline is present per unit dose of the composition wherein the terbutaline is present in an amount of about 4 mg per unit dose of the composition. 10. The use of claim 8 exists in the amount of 2 mg. 11. Use of claim 8 The composition is formulated as a lozenge which delivers the terbutaline via the oral cavity or vaginal cavity, and the water insoluble, water swellable interlaced polycarboxy polymer polycarbon pro The water-soluble polymer is a carbon chain 974P, and the composition further comprises hydroxypropyl decyl cellulose, corn starch talc vermiculite and magnesium stearate. 12. The use of claim 9, wherein the composition is formulated as a lozenge which can be delivered through the oral cavity or vaginal cavity. 138355-980918.doc This paper size applies to the Chinese National Standard (CNS) A4. 210X 297 mm) 1319987 as C8 D8 VI. The patented Fan Yuanling, and the water-insoluble, water-swellable interlaced polycarboxy polymer polycarbonate, the water-soluble polymer is a carbon chain 974P, And the composition further includes lactose hydroxypropyl methylcellulose, corn starch, talc' powder, vermiculite and magnesium stearate. 13. The use of claim 10, wherein the composition is formulated as a lozenge which delivers the terbutaline via the oral cavity or vaginal cavity, and the water insoluble, water swellable interlaced polycarboxy polymer system The polycarbonate is a carbon chain 974P, and the composition further comprises lactose hydroxypropyl decyl cellulose, corn starch, talc, vermiculite and magnesium stearate. 138355-980918.doc This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)