_40B021 ^_ 五、發明説明（i.) 本發明係關於一種延遲幽門通過以控制活性物質於胃 腸道釋放的系統’其係利用一個藥囊，當其和胃液接觸時 會膨脹，以延緩通過幽門，以達到控制活性物質於胃腸道 釋放的系統。上述所說之藥囊係包埋在一種以單層膜或多 層膜所製成的聚合物外殼内，内含一種遇到胃液就會產生 氣體的成分，且此成分不會和活性物質作用。而此聚合物 外殼部分地或全部地由一種活性物質包含層組成，而其内 之活性物質和一種延緩釋放活性物質之材料，製成多種微 粒’或製成外覆此種延緩活性物質釋放之活性物質微粒。 所謂胃保持系統，係利用增加體積，使其可以於胃中 停留一段較長之時間。 經濟部智慧財產局員工消費合作社印製 '裝---.---订 (請先W讀背面之注意事項再填窝本貫) 這樣的系統於US 4,2〇7,890及DE 44 19818的例子t 被描述過。其係以一種調控之方式，使得藥囊内之活性物 質於一定的時間内溶解並且釋放至周園。而利用藥囊内含 有適當之產生氣體物質（例如碳酸氫鈉）或其他混合物， 當其與胃液中之鹽酸作用後會釋放氣體，例如二氧化碳， 以達成增加體積。而此藥囊係以薄膜製成，使其外殼膨脹 ’達到一定的大小，防止其通過十二指腸。 當胃液進入藥囊，活性物質同時被釋放出來。活性物 質釋放之特性可以經由其存在的型式而被調控，例如以微 膠囊或經由膜的特性來調控。當活性物質進入藥囊内的胃 液中，接著以擴散之方式通過膜，進而進入胃中，其可被 胃粘膜或小腸所吸收。如同曾被描述之系統，其於胃中可 保持一段長的時間，超過24小時。 國篆縣：（CNS )人4胁（210X297公釐）— -4 - 408021* A7 ____B7_ 五、發明説明（2.) 以技術上考量，此系統之缺點係將活性物質放入藥囊 的過程相當複雜。在填充後藥囊需精確地封住，且其過程 會發生一種技術上的大失誤。 將活性物質以粉末狀或微膠囊型態用精確且符合高品 質製藥產品的要求，係特別地有問題。 另一種缺點係，其必須用滚動，壓縮或其他適當之方 法將藥囊成為一種大致圓形橫切面之結構，以利將其裝入 病人可呑食之膠囊内；然而’以目前之科技水準所填充之 藥囊’其係一種不規則之橫切兩。因此，在製造過程中不 可測之力量’如滾動、擠壓等’皆可造成藥囊或微膠囊内 之活性物質受損，以致不能達到其設定之效果。 一種在運作上可能之缺點係來自於，當一方面有足夠 的胃液進入藥囊内側，且另一方面活性物質由藥囊壁擴散 至胃内時’此系統才會被活化起來。這樣會造成食用膠囊 與開始吸收之間產生延遲，其係很難控制且不被期望之結 果。 此外’不被期望之作用可能在活性化氣體產生物質時 ’發生於氣體產生物質及活性物質之間，其以相當高之濃 度存在於藥囊内》 以目前科技更進一步之缺黏係，將活性物質包埋至藥 囊膜内會有許多問題產生，例如：接合缝隙的熱壓力，封 口縫隙品質的下降，低載量的藥囊膜，此外，不夠有效地 控制活性物質釋放之速度，因為必須使藥囊膜極具親水性 ’以利其有效快速地吸收胃液。 本紙張適财卵家縣（CNS ) Α_(⑴以加公兼） -5- (請先閲讀背面之注f項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製- 經濟部智慧財產局員工消費合作社印製 _ 408021 37 五、發明説明（3.) 基於上述所描述目前之科技，本發明之目的在提供一 種胃保持活性物質包含層藥囊系統，其在胃液中具有膨脹 的能力’因而延遲通過幽門。以技術的觀點上，其提供一 個容易且方便之方法，且相當程度地改善控制活性物質釋 放之特性’其無需引發第一次胃液經由藥囊膜，擴教至藥 囊内側’且第二次活性物質由藥囊内側擴散至藥囊外團， 而其必須將藥囊膜調整至極具親水性。 現行之胃保持系統，其基本準則，係利用膨脹以增加 系統之體積，達到一定的大小，防止其通過十二指腸。 然而’根據本發明和其系統相反之活性物質不是填充 於胃保持系統藥囊中，而係直接讓其藥囊壁裝載活性物質 ’以此種方式活性物質可從藥囊壁擴散至胃中β 其可藉由裝入適當之聚合物薄膜達成上述之功能，例 如聚氨基鉀酸酯或類似適當之薄膜，其經由製成薄膜時直 接形成藥囊壁。例如，製造含有活性物質之聚合物或含覆 被於一種適當之小網上的活性物質，最後將完成之薄膜， 由小網上拿下來’而其覆被方式之溶劑及加熱軟化之覆被 方式係有選擇性的。亦可於製作藥囊之前或之後將一種或 多種覆被物，覆被至形成藥棠壁之薄膜上。 以此種製成藥囊壁薄膜或覆被藥囊壁之方法取代填充 方式，得到一種非常平且橫切面非常規則之藥囊。且上述 藥囊或活性物質可能受損之問題因而解決，係當藥囊裝入 一種填充膠囊内所造成之變形。因為此藥囊可以滾動或一 種適當之方法，改變其形狀β 本纸張尺度遄用中國國家標準（CpS ) Α4规格（210X297公釐） -6- ----1.-----— ^--------tr---^----1.1 (請先閲请背面之注^^項再填寫本頁) A7 B7 408021 五、發明説明（4.) 進一步更受喜用之具體方法係，活性物質利用覆被於 製成之藥囊膜外或藥囊膜外本身而塗抹至藥囊外區域，以 致於活性物質存在藥囊外層或有限之區域内。 另一種更受喜用之具體方法係覆被物也可塗抹至藥囊 内侧’而此藥囊係由一種具有穿孔，可讓活性物質擴散至 胃中之合適薄膜所構成。 以這種方式覆被，有利於快速、精準地塗抹，且花費 很低，特別是在一些連續劑量而非間歇劑量之例子中。 根據此發明之胃保持系統，藥囊包含一種多層膜，而 此系統中之一層或多層膜’含有不同濃度之活性物質，以 可調控之方式，釋放活性物質。 藥囊可以部分地’例如在某一側，其沒有裝入或塗抹 活性物質，係由一種親水性膜所構成。 為了避免調整藥囊膜親水性時，可能引起之缺點，本 發明也提供另一種藥囊膜穿孔之方法，其可具體地達成調 整之功能性，且沒有已知方法之問題產生，藉由穿孔，以 一種控制内部氣體產生之方式，而使藥囊快速地膨脹。 而這些微小的穿孔，提供進一步的好處，即係減低在 系統製造過程中，任何過大之壓力，且不會造成藥囊外殼 進一步之傷害。 活性物質包含層之外層，可以如同在經皮膚治療之系 統中常用之方法，由一層或多層儲存層所形成，而活性物 質經由控制從儲存層中釋放出來。 然而，它們可以類似多層藥片或扁片，也具有含不同 ^^)八4规格（210><297公釐） _ 7' —---------於—^-----訂—^—.—产'~ (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 4080S1 ^ 五、發明説明（5.) 濃度之活性物質之擦落層，且於一系列之時間内溶解》 在一種特別受喜用之具體方法中，擦落層内含活性物 質微膠囊，其外層則可抵抗胃液，而活性物質在離開胃部 後，例如在膽汁或其他消化分泌物影響下，才被釋放出來 。因此可避免經由胃液所引起的變質。 多種不同層之組合係可以想像，例如一種額外含有活 性物質包含層之擦落層，和一種内侧含有儲存層以釋放活 性物質的固體層，所形成之組合。 根據本發明，其氣體產生的措施係位於藥囊内侧》 在一種較受喜用之具體方法中，氣體產生措施係由一 種類似扁片或有彈性爲平藥片之平板所構成。 在另一種受喜用之具體方法中，氣體產生措施係被覆 被至藥囊内側。 在另一種特殊之具體方法中，氣體產生物質的釋放可 以被控制，其在接近一種被期望的時間結束時，突然產生 一種過大之壓力，使得藥囊暴開來。 經濟部智慧財產局貝工消费合作社印製 I--------袭 J—----ir (請先閲讀背面之注意事項再填寫本頁) 在本發明之一種具體方法中，藥囊之兩侧被一種黏著 方式黏在一起，其結合力會在設計之某一段時間結束時溶 解，以致於藥囊之兩側不再結合一起，而藥囊因此溶解。 在另一種具體方法中，藥囊之上下兩側係由類似經皮 膚治療系統中之儲存層所構成，且用已知之穿孔技術穿孔 。在此，其穿孔係可由雷射光或高壓液體噴射(“hydrojels) ，以一種可使胃液進入至藥囊内侧使其迅速膨脹之方式生 成孔洞。 本紙張尺度逋用中國國家梯率(CNS ) A4规格（210X2$公釐） 408021 A7 B7 五、發明説明（6·) 這樣之藥囊系統係，類似用於經皮膚治療系統中之藥 囊系統以同樣之製作方法所製成，例如於US 3 598 122 (Zaffaroni)，於 w〇 94/26346 (Becher)中所描述之取代方 法，或於US 5 066 494 (Becher)所用之方法。在這些文 =中所插述沒有黏著狀方法中，藥囊至少有—侧必須係 覜水性或穿孔》 -裝 ---.----tr f請先»讀背面之注意事項再填寫本頁) 趣濟部智慧財產局員工消費合作钍印製· 用中围阐家標準(CNS ) A4规格（210X29^公釐_40B021 ^ _ 5. Description of the invention (i.) The present invention relates to a system that delays the passage of pylorus to control the release of active substances in the gastrointestinal tract. It uses a medicine pouch that swells when it comes in contact with gastric juice to delay passage through the pylorus. In order to achieve a system to control the release of active substances in the gastrointestinal tract. The aforementioned sachet is embedded in a polymer shell made of a single-layer film or a multi-layer film, and contains a component that generates gas when it encounters gastric juice, and this component does not interact with the active substance. The polymer shell is partially or wholly composed of an active material containing layer, and the active material inside and a material that delays the release of the active material are made into a variety of microparticles, or are made to cover the delayed release of the active material. Active substance particles. The so-called gastric retention system is to increase the volume so that it can stay in the stomach for a longer period of time. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ---.--- Order (please read the notes on the back before filling in the original text) Such a system is used in US 4,207,890 and DE 44 19818 Example t has been described. It is in a regulated way that the active substance in the medicine pouch is dissolved and released to Zhouyuan within a certain period of time. The use of a pouch containing an appropriate gas-generating substance (such as sodium bicarbonate) or other mixture will release gas, such as carbon dioxide, when it interacts with hydrochloric acid in gastric juice to achieve an increase in volume. This pouch is made of a thin film, which swells its casing to a certain size, preventing it from passing through the duodenum. When gastric fluid enters the pouch, the active substance is released simultaneously. The release characteristics of the active substance can be regulated by the type in which it is present, for example, by microcapsules or by membrane characteristics. When the active substance enters the gastric juice in the pouch, it then diffuses through the membrane and then into the stomach, which can be absorbed by the gastric mucosa or the small intestine. As with the previously described system, it remains in the stomach for a long time, over 24 hours. Guoxian County: (CNS) 4 threats (210X297 mm)--4-408021 * A7 ____B7_ V. Description of the invention (2.) In terms of technical considerations, the disadvantage of this system is the process of putting the active substance into the medicine pouch Quite complicated. After filling, the pouch needs to be accurately sealed, and a large technical error occurs in the process. The use of the active substance in powder or microcapsule form accurately and meets the requirements of high-quality pharmaceutical products is particularly problematic. Another disadvantage is that it must be rolled, compressed or other appropriate methods to make the capsule into a generally circular cross-sectional structure to facilitate its filling into a patient's swallowable capsule; however, 'at the current technological level The filled pouch 'is an irregular cross-cutting two. Therefore, unpredictable forces 'such as rolling, squeezing, etc.' in the manufacturing process can cause damage to the active substance in the medicine capsule or microcapsule, so that the set effect cannot be achieved. One possible disadvantage in operation comes from the fact that when there is enough gastric fluid to enter the inside of the pouch, and the active substance diffuses from the wall of the pouch into the stomach, the system is activated. This can cause a delay between the consumption of the capsule and the start of absorption, which can be a difficult to control and undesired result. In addition, the "unexpected effect may occur when the gas-generating substance is activated" between the gas-generating substance and the active substance, and it exists in the drug pouch at a relatively high concentration. There are many problems that occur when the active substance is embedded in the sachet membrane, such as: the thermal pressure of the joint gap, the deterioration of the quality of the sealing gap, the low-capacity sachet membrane, and in addition, the rate of active substance release is not effectively controlled because The sachet membrane must be made extremely hydrophilic to facilitate its effective and rapid absorption of gastric juice. This paper is suitable for wealth in the county (CNS) Α_ (⑴ 加加加) -5- (Please read the note f on the back before filling out this page) Order printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumer cooperative-Wisdom of the Ministry of Economic Affairs Printed by the Consumer Affairs Cooperative of the Property Bureau _ 408021 37 V. Description of the invention (3.) Based on the current technology described above, the purpose of the present invention is to provide a gastric retaining active substance containing layer drug pouch system, which has a swollen Ability 'thus delays passage through the pylorus. From a technical point of view, it provides an easy and convenient method, and considerably improves the characteristics of controlling the release of the active substance 'it does not need to cause the first gastric juice to pass through the sachet membrane to expand to the inside of the sachet' and the second time The active substance diffuses from the inside of the sachet to the outer mass of the sachet, and the sachet membrane must be adjusted to be extremely hydrophilic. The basic principle of the current gastric retention system is to use inflation to increase the volume of the system to a certain size and prevent it from passing through the duodenum. However, 'the active substance opposite to the system according to the present invention is not filled in the pouch of the gastric retention system, but the drug substance is directly loaded on the wall of the pouch'. In this way, the active substance can diffuse from the wall of the pouch to the stomach β It can achieve the above-mentioned functions by loading an appropriate polymer film, such as polyurethane or similar suitable film, which directly forms the wall of the capsule when it is made into a film. For example, manufacture a polymer containing an active substance or an active substance coated on a suitable small net, and finally remove the finished film from the small net 'and the coating method of the solvent and heat-softened coating The approach is selective. It is also possible to coat one or more coatings on the film forming the wall of the medicine tang before or after making the medicine capsule. In this way, the method of making the sachet wall film or covering the sachet wall is used instead of the filling method to obtain a sachet with a very flat and regular cross section. In addition, the problem that the sachet or the active substance may be damaged is solved, and the deformation is caused when the sachet is filled in a filled capsule. Because the sachet can be rolled or an appropriate method to change its shape β This paper size uses the Chinese National Standard (CpS) A4 specification (210X297 mm) -6- ---- 1 .-----— ^ -------- tr --- ^ ---- 1.1 (Please read the note on the back ^^ before filling in this page) A7 B7 408021 5. Description of the invention (4.) The specific method used is that the active substance is applied to the area outside the sachet by coating the outside of the sachet membrane or the sachet membrane itself, so that the active substance exists in the outer layer or a limited area of the sachet. Another more preferred method is that the covering can also be applied to the inside of the pouch ', and this pouch is made of a suitable film with perforation to allow the active substance to diffuse into the stomach. Coating in this way facilitates fast, precise application and is very low cost, especially in the case of continuous rather than intermittent doses. According to the gastric retaining system of the present invention, the sachet contains a multi-layer film, and one or more layers of the system 'contain different concentrations of the active substance in a controlled manner to release the active substance. The sachet can be partially'for example on one side, which is not filled or coated with an active substance, and is composed of a hydrophilic film. In order to avoid the disadvantages that may be caused when adjusting the hydrophilicity of the sachet membrane, the present invention also provides another method for perforating the sachet membrane, which can specifically achieve the functionality of the adjustment, and there is no problem with the known method. In a way to control the internal gas production, the medicine pouch is rapidly expanded. And these tiny perforations provide a further benefit, which is to reduce any excessive pressure during the system manufacturing process without causing further damage to the pouch shell. The active substance comprises an outer layer, which can be formed from one or more storage layers as is commonly used in transdermal systems, and the active substance is controlled to be released from the storage layer. However, they can be similar to multi-layered tablets or flat tablets, and also have different specifications containing ^^) 8-4 (210 > < 297mm) _ 7 '—--------- Yu-^ ---- -订 — ^ —.— 产 '~ (Please read the notes on the back before filling this page) 4080S1 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ V. Description of the invention (5.) Concentration of active substances Layer, and dissolve within a series of time. In a particularly preferred method, the microspheres containing the active substance are rubbed off, and the outer layer is resistant to gastric juice, and the active substance leaves the stomach, such as in It is released under the influence of bile or other digestive secretions. Therefore, deterioration caused by gastric juice can be avoided. A combination of a plurality of different layers is conceivable, for example, a combination of an eraser layer additionally containing an active material-containing layer and a solid layer containing a storage layer inside to release the active material. According to the present invention, the gas-generating measure is located inside the medicine pouch. In a preferred method, the gas-generating measure is composed of a flat tablet or a flat tablet with elasticity and flatness. In another preferred method, the gas generating measures are applied to the inside of the pouch. In another specific and specific method, the release of gas-generating substances can be controlled, and at the end of a desired time, an excessive pressure is suddenly generated, causing the medicine capsule to burst out. Printed by I ----- I J ----- ir from the Intellectual Property Bureau of the Intellectual Property Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) In a specific method of the present invention, The two sides of the medicine pouch are glued together by an adhesive method, and the binding force will dissolve at the end of a certain period of design, so that the two sides of the medicine pouch are no longer combined together, and the medicine pouch is dissolved. In another specific method, the upper and lower sides of the pouch are composed of a storage layer similar to a transdermal therapeutic system, and are perforated using known perforation techniques. Here, the perforation system can be formed by laser light or high-pressure liquid jet ("hydrojels") in a way that allows gastric fluid to enter the inside of the pouch and expand rapidly. This paper uses China National Slope (CNS) A4 Specifications (210X2 $ mm) 408021 A7 B7 5. Description of the invention (6 ·) Such a sachet system is similar to a sachet system used in a transdermal therapeutic system and is made in the same way, such as in US 3 598 122 (Zaffaroni), the substitution method described in WO 94/26346 (Becher), or the method used in US 5 066 494 (Becher). In the methods described in these articles, there is no adhesive-like method. The bag must have at least-the side must be overlooking water or perforation "-pack ---.---- tr f Please read the precautions on the back before filling out this page) Printed by the consumer cooperation of the Intellectual Property Bureau of the Ministry of Interest Using Zhongwei Standard (CNS) A4 (210X29 ^ mm)