TWI834984B

TWI834984B - Controlled-release oral formulation and preparation method thereof

Info

Publication number: TWI834984B
Application number: TW110128023A
Authority: TW
Inventors: 莊瑞元; 蘇育德; 呂紹全
Original assignee: 寶齡富錦生技股份有限公司
Filing date: 2021-07-30
Publication date: 2024-03-11

Abstract

An oral formulation is provided, which includes a first composition and a second composition. The first composition includes a xanthine derivative. The second composition includes a xanthine derivative and an enteric excipient. The xanthine derivative of the second composition releases less than 35% by weight within 90 minutes from in vitrodissolution, and the xanthine derivative of the second composition releases more than 50% by weight within 3 hours from in vitrodissolution. As such, the first composition may be used as an immediate release layer, and the second composition may be used as a delayed release layer to achieve a bilayer controlled-release oral formulation.

Description

控制釋放口服製劑及其製備方法Controlled release oral preparation and preparation method thereof

本發明是有關於一種口服製劑，且特別是有關於一種控制釋放口服製劑及其製備方法。The present invention relates to an oral preparation, and in particular to a controlled release oral preparation and a preparation method thereof.

咖啡因是一種黃嘌呤衍生物，且是一種可溶於水與脂質的雙極性物質，其化學結構非常像腺苷酸（adenosine）。腺甘酸是人體能量來源三磷酸腺苷（adenosine triphosphate, ATP）的骨架，也是一種神經調節劑。腺苷酸與腺苷酸化合物本身除了會降低清醒程度和警覺性外，還會降低具有刺激性的神經傳導物質濃度。咖啡因與腺苷酸因的結構相似，會與腺苷酸互相競爭接受器，因此咖啡因具有提神的效果。另一方面，咖啡因能減少運動時肌肉所產生的疼痛感，藉此達到運動抗疲勞的效果。Caffeine is a xanthine derivative and a bipolar substance soluble in water and lipids. Its chemical structure is very similar to adenosine. Adenosine is the skeleton of adenosine triphosphate (ATP), the body's energy source, and is also a neuromodulator. In addition to reducing wakefulness and alertness, adenosine and adenylate compounds themselves reduce the concentration of stimulating neurotransmitters. Caffeine has a similar structure to adenylate and competes with adenylate for receptors, so caffeine has a refreshing effect. On the other hand, caffeine can reduce the pain in muscles during exercise, thereby achieving the anti-fatigue effect of exercise.

根據報導指出，大約有74%的精英運動員在比賽前或比賽中使用咖啡因作為增補項目，尤其在耐力運動者顯示出更高的使用盛行率。咖啡因盛行的可能原因是，其取得容易、較低的副作用、以及研究指出在低劑量（＜6 mg/kg）即可達到一定的增補效果。According to reports, approximately 74% of elite athletes use caffeine as a supplement before or during competition, with endurance athletes showing a higher prevalence of use. Possible reasons for the popularity of caffeine are its easy availability, low side effects, and studies showing that certain ergogenic effects can be achieved at low doses (<6 mg/kg).

一般來說，咖啡因的吸收率在服用後的30分鐘至90分鐘內可達到最高血中濃度。因此，根據大多數的臨床試驗結果建議，使用者應在運動前30-60分鐘服用來使比賽期間獲得咖啡因的增補效果。就一般的耐力運動，如馬拉松來說，其平均完賽時間約為4.5小時。當賽前30-60分鐘使用咖啡因後，大約在比賽的3小時至3.5小時左右則進入了低於半衰期的狀態，此時也正處於比賽的高壓期或稱撞牆期。因此，為了避免撞牆期產生的疲累感，許多使用者會在賽事中後段（剩下1至2小時完賽）投入中低劑量的咖啡因（~3 mg/kg）來進行增補。Generally speaking, the absorption rate of caffeine reaches its highest blood concentration within 30 minutes to 90 minutes after taking it. Therefore, according to the results of most clinical trials, it is recommended that users should take it 30-60 minutes before exercise to obtain the boosting effect of caffeine during competition. For general endurance sports, such as marathon, the average completion time is about 4.5 hours. When caffeine is consumed 30-60 minutes before a game, it will enter a state below the half-life about 3 to 3.5 hours into the game. This is also the high-pressure period or wall-breaking period of the game. Therefore, in order to avoid the fatigue caused by hitting the wall, many users will add low to medium doses of caffeine (~3 mg/kg) in the middle and late stages of the race (with 1 to 2 hours left to finish) for supplementation.

然而，進行耐力運動期間需要多項補給品如碳水化合物能量膠、電解質、胺基酸等，於途中需要攜帶和補充咖啡因非常不便。此外，途中單一劑量的咖啡因仍需要約一小時的吸收時間，不如緩釋劑型能提供持續的咖啡因增補效果。另外，針對緩釋劑型的咖啡因，其技術為透過高分子在體內的逐步融蝕進而釋放咖啡因，但其在人體腸胃道中並沒有特定釋放區段。因此無法滿足在服用後特定時間區段內釋放達預設目標的控釋需求，以支持整個運動期間血中咖啡因濃度都維持較高狀態，從而強化運動表現。However, endurance exercise requires multiple supplements such as carbohydrate energy gels, electrolytes, amino acids, etc. It is very inconvenient to carry and replenish caffeine during the journey. In addition, a single dose of caffeine on the way still requires about an hour to be absorbed, which is not as good as the sustained-release caffeine supplement that can be provided by the sustained-release dosage form. In addition, for sustained-release caffeine, the technology is to release caffeine through the gradual erosion of polymers in the body, but there is no specific release section in the human gastrointestinal tract. Therefore, it cannot meet the demand for controlled release to reach the preset target within a specific time period after taking it, so as to support the maintenance of high blood caffeine concentration throughout the entire exercise period, thereby enhancing exercise performance.

據此，如何有效地控制釋放黃嘌呤衍生物，從而維持血中高濃度，並且滿足長時間活動中需要多次增補/提神之需求，例如在馬拉松等耐力運動進行期間，為提升表現需另外吞服咖啡因，或是長途駕車需要分神補充咖啡因的不便或干擾，為目前所欲解決之問題。Based on this, how to effectively control the release of xanthine derivatives to maintain high blood concentrations and meet the need for multiple supplements/refreshers during long-term activities. For example, during endurance sports such as marathons, additional swallows are required to improve performance. Caffeine, or the inconvenience or interference of needing to be distracted while driving long distances to replenish caffeine, is a problem that is currently being addressed.

本發明提供一種口服製劑，能夠有效地控釋黃嘌呤衍生物，使其維持血中高濃度，從而滿足長時間的增補/提神需求。舉例來說，本發明口服製劑能夠避免在耐力運動期間需另外拿取吞服咖啡因的干擾，並且在整個運動期間能夠維持咖啡因的高含量/高血中濃度。The present invention provides an oral preparation that can effectively control the release of xanthine derivatives to maintain high blood concentrations, thereby meeting long-term supplementation/refreshing needs. For example, the oral formulation of the present invention can avoid the interference of additionally taking and swallowing caffeine during endurance exercise, and can maintain high caffeine content/high blood concentration during the entire exercise period.

本發明的一種口服製劑包括第一成分以及第二成分。第一成分包括黃嘌呤衍生物。第二成分包括黃嘌呤衍生物以及腸溶賦形劑。第二成分中的黃嘌呤衍生物於體外溶離90分鐘內釋放不達35重量%，且第二成分中的黃嘌呤衍生物於體外溶離3小時內釋放達50重量%以上。An oral preparation of the present invention includes a first component and a second component. The first component includes xanthine derivatives. The second component includes xanthine derivatives and enteric excipients. The xanthine derivatives in the second component release less than 35% by weight within 90 minutes of dissolution outside the body, and the xanthine derivatives in the second component release more than 50% by weight within 3 hours of dissolution outside the body.

在本發明的一實施例中，第二成分中的黃嘌呤衍生物於體外溶離3小時內釋放達50重量%以上至70重量%以下。In one embodiment of the present invention, the xanthine derivative in the second component is released from more than 50% to less than 70% by weight within 3 hours of dissolution in vitro.

在本發明的一實施例中，第一成分中的黃嘌呤衍生物於體外溶離1小時內釋放達80重量%以上。In one embodiment of the present invention, more than 80% by weight of the xanthine derivative in the first component is released within 1 hour after dissolution in vitro.

在本發明的一實施例中，第一成分中的黃嘌呤衍生物於體外溶離90分鐘內的釋放達100重量%，而第二成分中的黃嘌呤衍生物於體外溶離8小時至12小時內的釋放達90重量%以上，且第二成分中的黃嘌呤衍生物於體外溶離12小時至18小時內的釋放達100重量%。In one embodiment of the present invention, the xanthine derivative in the first component is released to 100% by weight within 90 minutes of dissolution outside the body, and the xanthine derivative in the second component is released within 8 to 12 hours outside the body. The release rate reaches more than 90% by weight, and the xanthine derivative in the second component is released by 100% by weight within 12 hours to 18 hours after dissolution in vitro.

在本發明的一實施例中，第二成分中的黃嘌呤衍生物於體外溶離2小時內釋放不達40重量%。In one embodiment of the present invention, the xanthine derivative in the second component is released within 2 hours after dissolution in vitro, and the release rate is less than 40% by weight.

在本發明的一實施例中，所述口服製劑為口服雙層錠，其包括由第一成分組成的第一層面，以及由第二成分組成的第二層面。In one embodiment of the present invention, the oral preparation is an oral two-layer tablet, which includes a first layer composed of a first component, and a second layer composed of a second component.

在本發明的一實施例中，第一成分與所述第二成分的重量比例為1:1至1:1.2。In an embodiment of the present invention, the weight ratio of the first component to the second component is 1:1 to 1:1.2.

在本發明的一實施例中，所述腸溶賦形劑為玉米蛋白腸溶包衣。In one embodiment of the present invention, the enteric excipient is zein enteric coating.

在本發明的一實施例中，當第二成分的重量比例為100%時，玉米蛋白腸溶包衣的重量比例為第二成分的5.5%至10%。In an embodiment of the present invention, when the weight proportion of the second component is 100%, the weight proportion of the zein enteric coating is 5.5% to 10% of the second component.

在本發明的一實施例中，口服製劑中所述黃嘌呤衍生物的總重量為50mg至400mg。In one embodiment of the present invention, the total weight of the xanthine derivative in the oral preparation is 50 mg to 400 mg.

在本發明的一實施例中，黃嘌呤衍生物於所述第一成分中的重量為25mg至200mg。In an embodiment of the present invention, the weight of the xanthine derivative in the first component is 25 mg to 200 mg.

在本發明的一實施例中，黃嘌呤衍生物於所述第二成分中的重量為25mg至200mg。In one embodiment of the present invention, the weight of the xanthine derivative in the second component is 25 mg to 200 mg.

在本發明的一實施例中，第一成分更包括綠茶素、聚乙烯吡咯烷酮、微晶纖維素、交聯聚乙烯吡咯烷酮、硬脂酸鎂以及二氧化矽，且所述綠茶素包括所述黃嘌呤衍生物。In an embodiment of the present invention, the first component further includes green tea pigment, polyvinylpyrrolidone, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, magnesium stearate and silicon dioxide, and the green tea pigment includes the yellow tea pigment. Purine derivatives.

在本發明的一實施例中，第二成分更包括綠茶素、聚乙烯吡咯烷酮、微晶纖維素、中鏈三酸甘油酯、硬脂酸鎂、二氧化矽以及膜衣145K290001（Nutrafinish ® Dietary Supplement Coating 145K290001 Clear (NSC)），且所述綠茶素包括所述黃嘌呤衍生物。In one embodiment of the present invention, the second component further includes green tea pigment, polyvinylpyrrolidone, microcrystalline cellulose, medium chain triglyceride, magnesium stearate, silicon dioxide and film coating 145K290001 (Nutrafinish ® Dietary Supplement Coating 145K290001 Clear (NSC)), and the green tea pigment includes the xanthine derivative.

在本發明的一實施例中，所述口服製劑在服用後90分鐘內會達到所述黃嘌呤衍生物的最高血中濃度。In one embodiment of the present invention, the oral preparation reaches the highest blood concentration of the xanthine derivative within 90 minutes after taking it.

本發明的一種口服製劑的製備方法，包括: 將所述第一成分的粉體與所述第二成分的粉體形成雙層錠。The preparation method of an oral preparation of the present invention includes: forming the powder of the first component and the powder of the second component into a double-layer tablet.

在本發明的一實施例中，第二成分的粉體的製備包括以下步驟。提供包括腸溶賦形劑的包覆液。提供綠茶素，所述綠茶素包括黃嘌呤衍生物。將綠茶素以包覆液進行噴霧造粒以包覆至增重5%至15%的範圍。In an embodiment of the present invention, the preparation of the powder of the second component includes the following steps. A coating solution including enteric excipients is provided. Green tea pigments including xanthine derivatives are provided. The green tea element is sprayed and granulated with a coating solution to coat it to a weight gain ranging from 5% to 15%.

在本發明的一實施例中，所述的製備方法，更包括: 在噴霧造粒後，進行烘乾及過篩以形成第二成分的粉體。In one embodiment of the present invention, the preparation method further includes: after spray granulation, drying and sieving to form the powder of the second component.

在本發明的一實施例中，第一成分的粉體的製備包括以下步驟。提供綠茶素，所述綠茶素包括黃嘌呤衍生物。將聚乙烯吡咯烷酮的酒***溶液加入至包括綠茶素的粉體中，並進行造粒後，進行烘乾及過篩以形成第一成分的粉體。In an embodiment of the present invention, the preparation of the powder of the first component includes the following steps. Green tea pigments including xanthine derivatives are provided. The alcohol aqueous solution of polyvinylpyrrolidone is added to the powder including green tea pigment, and after granulation, it is dried and sieved to form the powder of the first component.

本發明的一種口服製劑的使用方法，包括: 於進行耐力運動前30分鐘至60分鐘內服用所述口服製劑，且所述口服製劑的服用劑量為3mg/kg至6mg/kg。A method of using an oral preparation of the present invention includes: taking the oral preparation within 30 minutes to 60 minutes before endurance exercise, and the dosage of the oral preparation is 3 mg/kg to 6 mg/kg.

基於上述，本發明實施例透過使用具有第一成分以及第二成分的口服製劑，能夠於服用後初期快速釋放第一成分，提供前期的咖啡因補充，並且於後段控制釋放第二成分的咖啡因。據此，本發明的雙層釋放控制口服製劑能夠有效地控制釋放黃嘌呤衍生物(如咖啡因)，使其維持血中高濃度，從而滿足長時間的增補/提神需求。舉例來說，本發明口服製劑能夠避免在耐力運動期間需另外拿取吞服咖啡因的干擾，並且透過控制釋放的第二成分可延長在整個運動期間能夠維持咖啡因的高含量/高血中濃度的時間。此外，本發明口服製劑也能夠避免長途駕車時需要分神補充咖啡因的不便或干擾。Based on the above, by using an oral preparation with a first component and a second component, embodiments of the present invention can quickly release the first component in the early stage after taking it, provide early caffeine supplementation, and control the release of the second component of caffeine in the later stage. . Accordingly, the double-layer controlled release oral preparation of the present invention can effectively control the release of xanthine derivatives (such as caffeine) to maintain high blood concentrations, thereby meeting long-term supplementation/refreshing needs. For example, the oral formulation of the present invention can avoid the interference of additionally taking and swallowing caffeine during endurance exercise, and can maintain high caffeine levels/high blood levels during the entire exercise period through the controlled release of the second component. concentration time. In addition, the oral preparation of the present invention can also avoid the inconvenience or interference of distracting caffeine supplementation during long-distance driving.

圖1是依照本發明實施例中的口服製劑的示意圖。參考圖1，本發明實施例的口服製劑100例如是由第一成分組成的第一層面102，以及由第二成分組成的第二層面104所構成的。舉例來說，第一層面102包括第一成分的粉體102A，而第二層面104包括第二成分的粉體104A。在一些實施例中，口服製劑100的製備方法包括將第一成分的粉體102A與第二成分的粉體104A以雙層打錠機打成雙層錠來形成所述口服製劑100。雖然圖1的口服製劑100是以口服雙層錠的劑型來做為範例，但本發明不限於此。Figure 1 is a schematic diagram of an oral preparation according to an embodiment of the present invention. Referring to FIG. 1 , the oral preparation 100 according to the embodiment of the present invention is composed of a first layer 102 composed of a first component, and a second layer 104 composed of a second component. For example, the first layer 102 includes powder 102A of a first component, and the second layer 104 includes powder 104A of a second component. In some embodiments, the preparation method of the oral preparation 100 includes beating the powder 102A of the first component and the powder 104A of the second component into a double-layer tablet using a double-layer tableting machine to form the oral preparation 100 . Although the oral preparation 100 in FIG. 1 is an oral double-layered tablet as an example, the present invention is not limited thereto.

在一些其他實施例中，口服製劑100也可以包括其它種類的劑型及製備方法。在一實施例中，口服製劑100的製備包括將第一成分的粉體102A與第二成分的粉體104A個別造粒後，以微粒（pellets）形式充填於膠囊。在一實施例中，口服製劑100的製備包括將第一成分的粉體102A與第二成分的粉體104A個別造粒後，以微粒（pellets）形式充填於小袋（sachet）。在另一實施例中，口服製劑100的製備包括將第一成分的粉體102A與第二成分的粉體104A個別打錠後，以微錠（micro-tablets/ mini-tablets）形式充填於膠囊。在又一實施例中，口服製劑100的製備包括將第一成分的粉體102A與所述第二成分的粉體104A個別打錠後，以微錠（micro-tablets/ mini-tablets）形式充填於小袋（sachet）。In some other embodiments, the oral formulation 100 may also include other types of dosage forms and preparation methods. In one embodiment, preparation of the oral preparation 100 includes separately granulating the powder 102A of the first component and the powder 104A of the second component, and then filling the capsules in the form of pellets. In one embodiment, preparation of the oral preparation 100 includes separately granulating the first component powder 102A and the second component powder 104A, and then filling the sachet in the form of pellets. In another embodiment, the preparation of the oral preparation 100 includes separately tableting the powder 102A of the first component and the powder 104A of the second component, and filling the capsules in the form of micro-tablets/mini-tablets. . In yet another embodiment, the preparation of the oral preparation 100 includes separately tableting the powder 102A of the first component and the powder 104A of the second component, and then filling them in the form of micro-tablets/mini-tablets. In a sachet.

由上述的說明可以得知的是，本發明的口服製劑100並不以雙層錠的劑型為限。舉例來說，只要口服製劑100包括第一成分的粉體102A做為速放（immediate release）的層面與第二成分的粉體104A做為控釋（controlled release）的層面，即可對口服製劑100的劑型做出適當的調整。在一實施例中，第二成分的粉體104A做為延遲釋放(delayed release)的層面。以下將對第一成分/第一成分的粉體102A與第二成分/第二成分的粉體104A做出進一步說明。It can be understood from the above description that the oral preparation 100 of the present invention is not limited to the dosage form of a double-layer tablet. For example, as long as the oral preparation 100 includes the powder 102A of the first component as an immediate release layer and the powder 104A of the second component as a controlled release layer, the oral preparation can be 100 dosage forms to make appropriate adjustments. In one embodiment, the powder 104A of the second component serves as a delayed release layer. The first component/powder 102A of the first component and the second component/powder 104A of the second component will be further described below.

在本發明實施例中，第一成分/第一成分的粉體102A可以至少包括綠茶素、聚乙烯吡咯烷酮（Polyvinylpyrrolidone）、微晶纖維素（Microcrystalline Cellulose）、交聯聚乙烯吡咯烷酮（Crospovidone）、硬脂酸鎂（Magnesium Stearate）以及二氧化矽。綠茶素可以包括黃嘌呤衍生物（或是咖啡因）。在一些實施例中，微晶纖維素可以由乳糖或是玉米澱粉替代。交聯聚乙烯吡咯烷酮可以由羧甲基澱粉鈉（Sodium Carboxymethyl Starch）、交聯羧甲基纖維素鈉（Croscarmellose Sodium）、羥丙基纖維素（Hydroxypropyl Cellulose）、預糊化澱粉（pregelatinized starch）替代。In the embodiment of the present invention, the first component/first component powder 102A may include at least green tea, polyvinylpyrrolidone (Polyvinylpyrrolidone), microcrystalline cellulose (Microcrystalline Cellulose), cross-linked polyvinylpyrrolidone (Crospovidone), hard Magnesium Stearate and silicon dioxide. Green tea pigments can include xanthine derivatives (or caffeine). In some embodiments, microcrystalline cellulose can be replaced by lactose or corn starch. Cross-linked polyvinylpyrrolidone can be replaced by Sodium Carboxymethyl Starch, Croscarmellose Sodium, Hydroxypropyl Cellulose, and pregelatinized starch. .

在一實施例中，第一成分的粉體102A的製備可以包括以下的步驟，但並不以此為限。首先提供綠茶素，所述綠茶素包括黃嘌呤衍生物。將綠茶素、微晶纖維素以及交聯聚乙烯吡咯烷酮過篩整粒後混合均勻放入快速混合造粒機中。接著，將聚乙烯吡咯烷酮的酒***溶液加入至上述包括所述綠茶素的粉體中，並以造粒機進行造粒後，進行烘乾及過篩整粒。接著，再加入交聯聚乙烯吡咯烷酮、微晶纖維素以及二氧化矽混合均勻後以形成第一成分的粉體102A。據此，所獲得的第一成分的粉體102A可用於形成上述不同劑型的口服製劑100。In one embodiment, the preparation of the first component powder 102A may include the following steps, but is not limited thereto. First, green tea pigments including xanthine derivatives are provided. Sieve the green tea pigment, microcrystalline cellulose and cross-linked polyvinylpyrrolidone into granules, mix them evenly and put them into a rapid mixing granulator. Next, the alcohol aqueous solution of polyvinylpyrrolidone is added to the above-mentioned powder including the green tea pigment, and is granulated using a granulator, followed by drying and sieving to granulate. Next, cross-linked polyvinylpyrrolidone, microcrystalline cellulose and silica are added and mixed evenly to form the first component powder 102A. Accordingly, the obtained powder 102A of the first component can be used to form the above-mentioned oral preparations 100 of different dosage forms.

在本發明實施例中，第二成分/第二成分的粉體104A可以包括綠茶素、腸溶賦形劑、聚乙烯吡咯烷酮、微晶纖維素、中鏈三酸甘油酯（medium chain triglycerides）、硬脂酸鎂、二氧化矽以及膜衣145K290001（Nutrafinish ® Dietary Supplement Coating 145K290001 Clear (NSC)）。綠茶素可以包括黃嘌呤衍生物（或是咖啡因）。膜衣145K290001為羥丙基甲基纖維素（Hydroxypropyl Methyl Cellulose）、甘油三乙酸酯（Triacetin）以及滑石粉（Talc）的混合物。腸溶賦形劑可以為玉米蛋白（Zein）腸溶包衣。In an embodiment of the present invention, the second component/second component powder 104A may include green tea, enteric excipients, polyvinylpyrrolidone, microcrystalline cellulose, medium chain triglycerides, Magnesium stearate, silica and film coating 145K290001 (Nutrafinish ® Dietary Supplement Coating 145K290001 Clear (NSC)). Green tea pigments can include xanthine derivatives (or caffeine). Film coating 145K290001 is a mixture of Hydroxypropyl Methyl Cellulose, Triacetin and Talc. The enteric excipient can be zein enteric coating.

在一些實施例中，微晶纖維素可以由乳糖或是玉米澱粉替代。中鏈三酸甘油酯可以由甘油（Glycerol）、聚乙二醇（PEG）、礦物油（Mineral Oil）或是脂肪酸（Fatty Acid）替代。此外，在一些實施例中，腸溶賦形劑除了玉米蛋白腸溶包衣外，也可以是丙烯酸乙酯/甲基丙烯酸共聚物（Ethyl Acrylate/methacrylic Acid Copolymer）、醋酸羥丙基甲基纖維素琥珀酸酯（Hydroxypropyl Methylcellulose Acetate Succinate）、鄰苯二甲酸乙酸纖維素（Cellulose Acetate Phthalate）或是羥丙基甲基纖維素鄰苯二甲酸酯（Hydroxypropyl Methylcellulose Phthalate）等，或其混合物。In some embodiments, microcrystalline cellulose can be replaced by lactose or corn starch. Medium chain triglycerides can be replaced by glycerol (Glycerol), polyethylene glycol (PEG), mineral oil (Mineral Oil) or fatty acid (Fatty Acid). In addition, in some embodiments, in addition to zein enteric coating, the enteric excipients can also be ethyl acrylate/methacrylic acid copolymer (Ethyl Acrylate/methacrylic Acid Copolymer), hydroxypropyl methyl fiber acetate Hydroxypropyl Methylcellulose Acetate Succinate, Cellulose Acetate Phthalate or Hydroxypropyl Methylcellulose Phthalate, etc., or mixtures thereof.

在一實施例中，第二成分的粉體104A的製備可以包括以下的步驟，但並不以此為限。首先，秤取適量的酒***溶液，將中鏈三酸甘油酯邊攪拌邊加入後，再將做為腸溶賦形劑的玉米蛋白與膜衣145K290001混合後緩緩加入酒***溶液中，使其完全溶解分散得到包覆液。接著，提供綠茶素，所述綠茶素包括黃嘌呤衍生物。將綠茶素以所述包覆液進行噴霧造粒以包覆至增重5%至15%的範圍後，進行烘乾及過篩整粒。再來，加入微晶纖維素、聚乙烯吡咯烷酮、硬脂酸鎂以及二氧化矽混合均勻後以形成第二成分的粉體104A。據此，所獲得的第二成分的粉體104A可用於形成上述不同劑型的口服製劑100。In one embodiment, the preparation of the second component powder 104A may include the following steps, but is not limited thereto. First, weigh an appropriate amount of alcohol aqueous solution, add medium chain triglyceride while stirring, then mix zein as an enteric excipient with film coating 145K290001 and slowly add it to the alcohol aqueous solution to make it completely Dissolve and disperse to obtain coating liquid. Next, green tea pigments including xanthine derivatives are provided. The green tea element is sprayed and granulated with the coating liquid to coat it to a weight gain range of 5% to 15%, and then dried and sieved to granulate. Next, microcrystalline cellulose, polyvinylpyrrolidone, magnesium stearate and silica are added and mixed evenly to form the second component powder 104A. Accordingly, the obtained powder 104A of the second component can be used to form the above-mentioned oral preparations 100 of different dosage forms.

在本發明實施例中，於口服製劑100中的黃嘌呤衍生物（咖啡因）的總重量為50mg至400mg。舉例來說，黃嘌呤衍生物於第一成分中的重量為25mg至200mg，且黃嘌呤衍生物於第二成分中的重量為25mg至200mg。在一些實施例中，口服製劑100中的第一成分與第二成分的重量比例為1:1至1:1.2。另外，當第二成分的重量比例為100%時，做為腸溶賦形劑的玉米蛋白腸溶包衣的重量比例為第二成分的5.5%至10%。當所述玉米蛋白腸溶包衣的重量比例是控制在上述範圍時，能夠達到較理想的控制釋放效果，尤其是利用腸溶物質包覆達到前段減少釋放，而在到達腸道後再行釋放的效果。In the embodiment of the present invention, the total weight of the xanthine derivative (caffeine) in the oral preparation 100 is 50 mg to 400 mg. For example, the weight of the xanthine derivative in the first component is 25 mg to 200 mg, and the weight of the xanthine derivative in the second component is 25 mg to 200 mg. In some embodiments, the weight ratio of the first ingredient to the second ingredient in the oral formulation 100 is from 1:1 to 1:1.2. In addition, when the weight proportion of the second component is 100%, the weight proportion of the zein enteric coating used as the enteric excipient is 5.5% to 10% of the second component. When the weight ratio of the zein enteric coating is controlled within the above range, a more ideal controlled release effect can be achieved, especially when the enteric substance coating is used to reduce the release in the early stage and then release after reaching the intestinal tract. Effect.

在本發明的口服製劑100中，第一成分中的黃嘌呤衍生物於體外溶離1小時內釋放會達80重量%以上。第一成分中的黃嘌呤衍生物於體外溶離90分鐘內釋放達100重量%。此外，第二成分中的黃嘌呤衍生物於體外溶離90分鐘內釋放不達35重量%，且第二成分中的黃嘌呤衍生物於體外溶離3小時內釋放達50重量%以上。在一些實施例中，第二成分中的黃嘌呤衍生物於體外溶離3小時內釋放達50重量%以上至70重量%以下。另外，第二成分中的黃嘌呤衍生物於體外溶離2小時內釋放不達40重量%，而第二成分中的黃嘌呤衍生物於體外溶離8小時至12小時內的釋放達90重量%以上，且第二成分中的黃嘌呤衍生物於體外溶離12小時至18小時內的釋放達100重量%。據此，本發明的口服製劑100中，第一成分（第一成分的粉體102A）可以做為速放層，而第二成分（第二成分的粉體104A）可以做為控釋層，來達成初期快速釋放以及控制至後段釋放（或稱延遲釋放）的雙層釋放控制的口服製劑100。In the oral preparation 100 of the present invention, more than 80% by weight of the xanthine derivative in the first component is released within 1 hour after dissolution in vitro. The xanthine derivative in the first component is released up to 100% by weight within 90 minutes of dissolution in vitro. In addition, the xanthine derivatives in the second component are released by less than 35% by weight within 90 minutes of dissolution in vitro, and the xanthine derivatives in the second component are released by more than 50% by weight within 3 hours of dissolution in vitro. In some embodiments, the xanthine derivative in the second component is released from more than 50% to less than 70% by weight within 3 hours of dissolution in vitro. In addition, the xanthine derivatives in the second component are released less than 40% by weight within 2 hours of dissolution in vitro, while the release of the xanthine derivatives in the second component is more than 90% by weight within 8 hours to 12 hours of dissolution in vitro. , and the xanthine derivative in the second component is released by 100% by weight within 12 hours to 18 hours after dissolution in vitro. Accordingly, in the oral preparation 100 of the present invention, the first component (the powder 102A of the first component) can be used as a rapid release layer, and the second component (the powder 104A of the second component) can be used as a controlled release layer. A dual-layer controlled release oral preparation 100 is used to achieve initial rapid release and control to later release (or delayed release).

在本發明實施例中，黃嘌呤衍生物的體外溶離的數據是可以用於模擬/對照其體內溶離的結果。在一些實施例中，體外溶離的測試方法為使用攪拌槳裝置（即USP apparatus II）在每分50轉速至75轉速及37±0.5°C的溫度下進行試驗。受試的口服製劑是在至少三個足以模擬胃腸道（pH值之範圍應於1.2至6.8之間）之緩衝液中進行。舉例來說，在進行總試驗時間為4小時的溶離試驗時，是於0-1小時的時段於pHH 1.2的緩衝液中，於1-2小時的時段置換到pHH 4.5的緩衝液中，以及於2-4小時的時段置換到pH 6.8的緩衝液中進行試驗。更具體地，pH 1.2的緩衝液是用於模擬胃液（gastric fluid）環境，pH4.5的緩衝液是用於模擬十二指腸液（duodenal fluid）環境，且pH 6.8的緩衝液是用於模擬腸液（intestinal fluid）環境。於試驗中，是在開始溶離後的30分鐘、60分鐘、90分鐘、120分鐘、150分鐘、180分鐘和240分鐘收集溶液，並透過對照組（standard）計算其溶離的比例。In the embodiments of the present invention, the in vitro dissolution data of xanthine derivatives can be used to simulate/control the results of its in vivo dissolution. In some embodiments, the test method for in vitro dissolution is to use a stirring paddle device (i.e., USP apparatus II) to perform the test at 50 to 75 rpm and a temperature of 37±0.5°C. Oral formulations are tested in at least three buffers sufficient to simulate the gastrointestinal tract (pH range should be between 1.2 and 6.8). For example, when performing a dissolution test with a total test time of 4 hours, the solution is in a pHH 1.2 buffer during the 0-1 hour period, and is replaced into a pHH 4.5 buffer during the 1-2 hour period, and The test was carried out by exchanging to pH 6.8 buffer over a period of 2-4 hours. More specifically, the buffer at pH 1.2 is used to simulate a gastric fluid environment, the buffer at pH 4.5 is used to simulate a duodenal fluid environment, and the buffer at pH 6.8 is used to simulate intestinal fluid ( intestinal fluid) environment. In the experiment, solutions were collected at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes and 240 minutes after the start of dissolution, and the proportion of dissolution was calculated through the control group (standard).

在本發明一些實施例中，口服製劑100在服用後90分鐘內會達到黃嘌呤衍生物（咖啡因）的最高血中濃度。當口服製劑100是做為耐力運動的增補劑時，其使用方法為在進行耐力運動前30分鐘至60分鐘內服用口服製劑100，且所述口服製劑100的服用劑量以服用者的體重計算時，為3mg/kg（每公斤3毫克）至6mg/kg。服用本發明口服製劑100後，能夠避免在耐力運動期間需另外拿取吞服咖啡因的干擾，並且透過控制釋放的第二成分的使用，能夠維持咖啡因的高含量/高血中濃度至少6小時至8小時的時間。In some embodiments of the present invention, the oral formulation 100 reaches the highest blood concentration of the xanthine derivative (caffeine) within 90 minutes after administration. When the oral preparation 100 is used as a supplement for endurance exercise, the method of use is to take the oral preparation 100 within 30 minutes to 60 minutes before the endurance exercise, and the dosage of the oral preparation 100 is calculated based on the body weight of the user. , 3 mg/kg (3 mg per kilogram) to 6 mg/kg. After taking the oral preparation 100 of the present invention, the interference of having to take and swallow caffeine during endurance exercise can be avoided, and through the use of the second component of controlled release, the high content/blood concentration of caffeine can be maintained at least 6 hours to 8 hours.

在一些實施例中，做為耐力運動的選手，可於比賽前30分鐘的時間服用本發明口服製劑100。舉例來說，若是選手的體重為60公斤時，則是服用約180 mg至360 mg的口服製劑100。此外，口服製劑100中第一成分與所述第二成分的重量比例約為1:1至1:1.2。在服用口服製劑100後的1小時至2小時內，由於口服製劑100的第一成分（速放層）已釋放超過80重量%以上的黃嘌呤衍生物（咖啡因），因此，使用者可於耐力運動前期（開始至2小時）維持黃嘌呤衍生物的高血中濃度，以提供增補效果。In some embodiments, endurance sports athletes can take the oral formulation 100 of the present invention 30 minutes before competition. For example, if a player weighs 60 kg, he or she will take approximately 180 mg to 360 mg of oral preparation 100. In addition, the weight ratio of the first component to the second component in the oral formulation 100 is approximately 1:1 to 1:1.2. Within 1 hour to 2 hours after taking the oral preparation 100, since the first component (quick release layer) of the oral preparation 100 has released more than 80% by weight of the xanthine derivative (caffeine), the user can Maintain high blood concentrations of xanthine derivatives during the early stages of endurance exercise (up to 2 hours from the start) to provide a supplemental effect.

在耐力運動的後期，如服用口服製劑100後的2小時至4.5小時內，由於第一成分已全部釋放而進入了半衰期，因此，第一成分的黃嘌呤衍生物（咖啡因）的血中濃度會慢慢降低。相較之下，口服製劑100的第二成分（控釋層）在運動前期時，如服用後90分鐘的時間內，其黃嘌呤衍生物（咖啡因）釋放不達35重量%，而在服用3小時內才會釋放達50重量%以上至70重量%以下。因此，第二成分（控釋層）能夠於耐力運動的後期（2小時至4.5小時）提高並維持黃嘌呤衍生物（咖啡因）的高血中濃度，並給予耐力運動選手第二劑的咖啡因促進（caffeine boost）效果。In the later stages of endurance exercise, such as within 2 hours to 4.5 hours after taking the oral preparation 100, since the first component has been fully released and entered the half-life, therefore, the blood concentration of the xanthine derivative (caffeine) of the first component will slowly decrease. In comparison, the xanthine derivative (caffeine) of the second component (controlled release layer) of the oral preparation 100 does not release up to 35% by weight during the pre-exercise period, such as within 90 minutes after taking it. It will take more than 50% by weight and less than 70% by weight to be released within 3 hours. Therefore, the second component (controlled release layer) can increase and maintain high blood concentrations of xanthine derivatives (caffeine) in the later stages of endurance exercise (2 hours to 4.5 hours), and give endurance athletes a second dose of coffee. Because of the caffeine boost effect.

據此，耐力運動選手於整個耐力運動期間都能維持黃嘌呤衍生物（咖啡因）的高血中濃度，並促進/支持其運動相關表現。此外，由於第二成分中的黃嘌呤衍生物（咖啡因）是於服用12小時至18小時內才會釋放達100重量%，因此，即使在結束耐力運動後，在咖啡因持續釋放的期間，也可繼續延長並維持其增補/提神的效果。 實驗例 Accordingly, endurance athletes can maintain high blood concentrations of xanthine derivatives (caffeine) throughout endurance exercise and promote/support their exercise-related performance. In addition, since the xanthine derivative (caffeine) in the second component is only released to 100% by weight within 12 hours to 18 hours after taking it, even after the end of endurance exercise, during the period of continuous release of caffeine, It can also continue to prolong and maintain its tonic/refreshing effects. Experimental example

為了證明本發明的口服製劑100與傳統的基質型（matrix type）長效釋放劑型的體外溶離釋放的效果差異，是以下述實施例來進行詳細說明。以下，將先對第一成分的粉體102A、第二成分的粉體104A與傳統基質型的長效釋放粉體的製備進行說明。 第一成分的粉體的製備例 In order to prove the difference in the in vitro dissolution release effect between the oral preparation 100 of the present invention and the traditional matrix type long-acting release dosage form, the following examples will be described in detail. Hereinafter, the preparation of the first component powder 102A, the second component powder 104A and the traditional matrix-type long-acting release powder will be described. Preparation example of powder of first component

圖2是依照本發明實施例的第一成分粉體的製備流程圖。圖2中所使用的各種材料是以表1所記載的製備例A1~製備例A5中的含量進行調配。Figure 2 is a flow chart for preparing the first component powder according to an embodiment of the present invention. Various materials used in Figure 2 are prepared according to the contents in Preparation Examples A1 to A5 described in Table 1.

表1: 第一成分的粉體的處方表第一成分製備例A1 製備例A2 製備例A3 製備例A4 製備例A5 　物質名稱比例(%) 比例(%) 比例(%) 比例(%) 比例(%) 1 酒***溶液 95% - - - - - 2 綠茶素 78.13% 78.13% 83.33% 83.33% 83.33% 3 微晶纖維素 7.18% 7.18% 7.97% 7.97% 7.97% 4 交聯聚乙烯吡咯烷酮 10.00% 10.00% 4.00% 4.00% 4.00% 5 聚乙烯吡咯烷酮 3.00% 3.00% 3.00% 3.00% 3.00% 6 硬脂酸鎂 1.50% 1.50% 1.50% 1.50% 1.50% 7 二氧化矽 0.20% 0.20% 0.20% 0.20% 0.20% 　　 100.00% (320mg) 100.00% (320mg) 100.00% (300mg) 100.00% (300mg) 100.00% (300mg) Table 1: Recipe list of the first ingredient powder first ingredient Preparation Example A1 Preparation Example A2 Preparation Example A3 Preparation Example A4 Preparation Example A5 Substance name Proportion(%) Proportion(%) Proportion(%) Proportion(%) Proportion(%) 1 Alcohol aqueous solution 95% - - - - - 2 green tea pigment 78.13% 78.13% 83.33% 83.33% 83.33% 3 microcrystalline cellulose 7.18% 7.18% 7.97% 7.97% 7.97% 4 Cross-linked polyvinylpyrrolidone 10.00% 10.00% 4.00% 4.00% 4.00% 5 Polyvinylpyrrolidone 3.00% 3.00% 3.00% 3.00% 3.00% 6 Magnesium stearate 1.50% 1.50% 1.50% 1.50% 1.50% 7 Silicon dioxide 0.20% 0.20% 0.20% 0.20% 0.20% 100.00% (320mg) 100.00% (320mg) 100.00% (300mg) 100.00% (300mg) 100.00% (300mg)

參考圖2的步驟A10以及表1，首先，是將綠茶素、微晶纖維素以及交聯聚乙烯吡咯烷酮進行混合調配。接著，如步驟A12進行過篩整粒後，是於步驟A14將上述成分混合均勻後再放入快速混合造粒機中。再來，如步驟A16，將聚乙烯吡咯烷酮加入至酒***溶液 95%中，並於步驟A18中將其攪拌至完全溶解。接著，參考步驟A20，是將於步驟A18所得到的液體加入到步驟A14的粉體中，並以快速混合造粒機進行濕法造粒。於濕法造粒完成後，是於步驟A22進行烘乾處理，以及於步驟A24進行過篩整粒。再來，於步驟A26中，是將交聯聚乙烯吡咯烷酮、硬脂酸鎂以及二氧化矽以表1所記載的含量進行調配，並於步驟A28進行過篩處理。接著，於步驟A30，在將步驟A28所得到粉體與步驟A24所得到粉體進行混合。據此，可於步驟A32中得到第一成分的粉體。 第二成分的粉體的製備例 Referring to step A10 in Figure 2 and Table 1, first, green tea element, microcrystalline cellulose and cross-linked polyvinylpyrrolidone are mixed and prepared. Next, after sieving and granulating as in step A12, the above ingredients are mixed evenly in step A14 and then put into a rapid mixing granulator. Next, as in step A16, add polyvinylpyrrolidone to the 95% alcohol aqueous solution, and stir it until it is completely dissolved in step A18. Next, referring to step A20, the liquid obtained in step A18 is added to the powder in step A14, and wet granulation is performed using a rapid mixing granulator. After the wet granulation is completed, drying is performed in step A22, and sieving and granulation are performed in step A24. Next, in step A26, cross-linked polyvinylpyrrolidone, magnesium stearate and silicon dioxide are prepared at the contents listed in Table 1, and then sieved in step A28. Next, in step A30, the powder obtained in step A28 and the powder obtained in step A24 are mixed. Accordingly, the powder of the first component can be obtained in step A32. Preparation example of the second component powder

圖3是依照本發明實施例的第二成分粉體的製備流程圖。圖3中所使用的各種材料是以表2所記載的製備例B1~製備例B4中的含量進行調配。Figure 3 is a flow chart for preparing the second component powder according to an embodiment of the present invention. Various materials used in Figure 3 are prepared according to the contents in Preparation Examples B1 to B4 described in Table 2.

表2: 第二成分的粉體的處方表第二成分製備例B1 (Ex 1) 製備例B2 (Ex 2) 製備例B3 (Ex 3) 製備例B4 (Ex 4) 　物質名稱比例(%) 比例(%) 比例(%) 比例(%) 1 酒***溶液 95% - - - - 2 淨化水 - - - - 3 綠茶素 71.43% 71.43% 71.43% 71.43% 4 微晶纖維素 16.00% 13.14% 22.64% 19.43% 5 玉米蛋白腸溶包衣 8.00% 10.00% 3.00% 5.50% 6 中鏈三酸甘油酯 1.64% 2.14% 0.64% 1.07% 7 膜衣145K290001 1.07% 1.43% 0.43% 0.71% 8 聚乙烯吡咯烷酮 0.36% 0.36% 0.36% 0.36% 9 硬脂酸鎂 1.00% 1.00% 1.00% 1.00% 10 二氧化矽 0.50% 0.50% 0.50% 0.50% 　　 100.00% (350mg) 100.00% (350mg) 100.00% (350mg) 100.00% (350mg) Table 2: Recipe list for the powder of the second component second component Preparation Example B1 (Ex 1) Preparation Example B2 (Ex 2) Preparation Example B3 (Ex 3) Preparation Example B4 (Ex 4) Substance name Proportion(%) Proportion(%) Proportion(%) Proportion(%) 1 Alcohol aqueous solution 95% - - - - 2 Purify water - - - - 3 green tea pigment 71.43% 71.43% 71.43% 71.43% 4 microcrystalline cellulose 16.00% 13.14% 22.64% 19.43% 5 Zein enteric coating 8.00% 10.00% 3.00% 5.50% 6 medium chain triglycerides 1.64% 2.14% 0.64% 1.07% 7 Film coating 145K290001 1.07% 1.43% 0.43% 0.71% 8 Polyvinylpyrrolidone 0.36% 0.36% 0.36% 0.36% 9 Magnesium stearate 1.00% 1.00% 1.00% 1.00% 10 Silicon dioxide 0.50% 0.50% 0.50% 0.50% 100.00% (350mg) 100.00% (350mg) 100.00% (350mg) 100.00% (350mg)

參考圖3的步驟B10以及表2，是將淨化水與酒精混合調配成酒***溶液。接著，於步驟B12提供中鏈三酸甘油酯，並且於步驟B14將中鏈三酸甘油酯邊攪拌邊加入酒***溶液中進行混合。接著，參考步驟B16，將玉米蛋白腸溶包衣與膜衣145K290001混合後，是於步驟B18將其緩緩加入上述酒***溶液中進行混合。於步驟B20中，是將加入酒***溶液中的成分攪拌至完全溶解分散以形成包覆液。在得到包覆液後，是於步驟22提供綠茶素，並且於步驟B24中將步驟B20的包覆液對綠茶素進行噴霧造粒。於步驟B24中，是以元成流動造粒床(型號FBDD-2)進行噴霧造粒，且其參數如表3所示。Referring to step B10 in Figure 3 and Table 2, purified water and alcohol are mixed to prepare an alcohol aqueous solution. Next, in step B12, medium-chain triglyceride is provided, and in step B14, the medium-chain triglyceride is added to the aqueous alcohol solution while stirring for mixing. Next, referring to step B16, after mixing the zein enteric coating and film coating 145K290001, in step B18, slowly add them to the above-mentioned alcohol aqueous solution for mixing. In step B20, the ingredients added to the alcohol aqueous solution are stirred until they are completely dissolved and dispersed to form a coating liquid. After obtaining the coating liquid, green tea element is provided in step 22, and in step B24, the green tea element is sprayed and granulated with the coating liquid of step B20. In step B24, the Yuancheng fluid granulation bed (model FBDD-2) is used for spray granulation, and its parameters are shown in Table 3.

表3: 噴霧造粒參數入風(℃) 出風(℃) 品溫(℃) 排風(%) 流速(rpm) 振動(sec/sec) 風車(rpm) 管徑(Ø) 45~60 32~42 31~38 100 5~25 5 / 55 1500~2500 6 Table 3: Spray granulation parameters Incoming air(℃) Outlet air(℃) Product temperature(℃) Exhaust air(%) Flow rate(rpm) Vibration(sec/sec) Windmill(rpm) Pipe diameter(Ø) 45~60 32~42 31~38 100 5~25 5/55 1500~2500 6

在噴霧造粒後，是於步驟B26進行烘乾處理，以及於步驟B28進行過篩整粒。再來，於步驟B30中，是將微晶纖維素、聚乙烯吡咯烷酮、硬脂酸鎂以及二氧化矽以表2所記載的含量進行調配，並於步驟B32進行過篩處理。接著，於步驟B34，在將步驟B28所得到粉體與步驟B32所得到粉體進行混合。據此，可於步驟B36中得到第二成分的粉體。 傳統長效釋放粉體的製備例 After spray granulation, drying is performed in step B26, and sieving and granulation are performed in step B28. Next, in step B30, microcrystalline cellulose, polyvinylpyrrolidone, magnesium stearate and silicon dioxide are prepared at the contents listed in Table 2, and then sieved in step B32. Next, in step B34, the powder obtained in step B28 and the powder obtained in step B32 are mixed. Accordingly, the powder of the second component can be obtained in step B36. Preparation example of traditional long-lasting release powder

圖4是依照本發明比較例的長效釋放粉體的製備流程圖。圖4所使用的各種材料是以表4所記載的製備例C5中的含量進行調配。Figure 4 is a flow chart for the preparation of long-lasting release powder according to a comparative example of the present invention. The various materials used in Figure 4 were prepared at the contents in Preparation Example C5 described in Table 4.

表4: 長效釋放粉體的處方表長效釋放粉體製備例C5 (Ex 5) 物質名稱比例(%) 1 酒***溶液 95% - 2 淨化水 - 3 綠茶素 71.43% 4 微晶纖維素 16.07% 5 玉米蛋白腸溶包衣 10.00% 6 中鏈三酸甘油酯 0.00% 7 膜衣145K290001 0.00% 8 聚乙烯吡咯烷酮 1.00% 9 硬脂酸鎂 1.00% 10 二氧化矽 0.50% 100.00% (350mg) Table 4: Prescription list for long-lasting release powder long lasting release powder Preparation Example C5 (Ex 5) Substance name Proportion(%) 1 Alcohol aqueous solution 95% - 2 Purify water - 3 green tea pigment 71.43% 4 microcrystalline cellulose 16.07% 5 Zein enteric coating 10.00% 6 medium chain triglycerides 0.00% 7 Film coating 145K290001 0.00% 8 Polyvinylpyrrolidone 1.00% 9 Magnesium stearate 1.00% 10 Silicon dioxide 0.50% 100.00% (350mg)

參考圖4的步驟C10以及表4，是將綠茶素、微晶纖維素以及玉米蛋白腸溶包衣混合。接著，如步驟C12進行過篩整粒後，是於步驟C14將上述成分混合均勻後再放入快速混合造粒機中。再來，於步驟C16以及步驟C18提供聚乙烯吡咯烷酮與酒***溶液95%。並且，於步驟C20將聚乙烯吡咯烷酮加入至酒***溶液95%中進行混合並攪拌至完全溶解。於步驟C22提供玉米蛋白腸溶包衣，接著於步驟C24將其加入至上述酒***溶液中進行混合使其懸浮分散。參考步驟C26，是將步驟C24所得到的液體加入上述步驟C14的粉體中，並以快速混合造粒機進行濕式造粒。在濕式造粒後，是於步驟C28進行烘乾處理，以及於步驟C30進行過篩整粒。再來，於步驟C32中，是將硬脂酸鎂以及二氧化矽以表4所記載的含量進行調配，並於步驟C34進行過篩處理。接著，於步驟C36，在將步驟C30所得到粉體與步驟C34所得到粉體進行混合。據此，可於步驟C38中得到傳統的長效釋放粉體。 體外溶離試驗 I Referring to step C10 of Figure 4 and Table 4, green tea element, microcrystalline cellulose and zein enteric coating are mixed. Next, after sieving and granulating in step C12, the above ingredients are mixed evenly in step C14 and then put into a rapid mixing granulator. Next, a 95% aqueous solution of polyvinylpyrrolidone and alcohol is provided in steps C16 and C18. Furthermore, in step C20, polyvinylpyrrolidone is added to the 95% alcohol aqueous solution, mixed and stirred until completely dissolved. In step C22, zein enteric coating is provided, and then in step C24, it is added to the above-mentioned alcohol aqueous solution and mixed to cause suspension and dispersion. Referring to step C26, the liquid obtained in step C24 is added to the powder in step C14, and wet granulation is performed with a rapid mixing granulator. After wet granulation, drying is performed in step C28, and sieving and granulation are performed in step C30. Next, in step C32, magnesium stearate and silicon dioxide are prepared at the contents listed in Table 4, and then sieved in step C34. Next, in step C36, the powder obtained in step C30 and the powder obtained in step C34 are mixed. Accordingly, traditional long-lasting release powder can be obtained in step C38. In vitro dissolution test I

為了確認本發明的第二成分（製備例B1~B4）與傳統的長效釋放粉體（製備例C5）的咖啡因釋放效果差異，是以下列的方式進行體外溶離試驗。In order to confirm the difference in caffeine release effects between the second component of the present invention (Preparation Examples B1 to B4) and the traditional long-lasting release powder (Preparation Example C5), an in vitro dissolution test was conducted in the following manner.

在本實驗例的體外溶離試驗中，是使用攪拌槳裝置（即USP apparatus II）在每分50轉速及37±0.5°C的溫度下進行試驗。本發明的第二成分（製備例B1~B4）與傳統的長效釋放粉體（製備例C5）是於0-1小時的時段於pHH 1.2的模擬胃液中，於1-2小時的時段於pHH 4.5的模擬十二指腸液中，以及於2-4小時的時段於pH 6.8的模擬腸液中進行試驗。其中，是在不同的時間點（30分、60分、90分、120分、150分、180分以及240分）下提取一定含量的溶液來進行黃嘌呤衍生物的濃度計算。其中，是使用紫外線可見光分光光譜儀(UV/VIS)來進行濃度分析，並透過對照組（standard）計算並確認其溶離的比例。試驗結果如圖5以及表5所示。In the in vitro dissolution test of this experimental example, a stirring paddle device (i.e. USP apparatus II) was used to conduct the test at 50 rpm and a temperature of 37±0.5°C. The second component of the present invention (Preparation Examples B1 to B4) and the traditional long-acting release powder (Preparation Example C5) are placed in simulated gastric juice of pHH 1.2 during a period of 0-1 hour, and in a period of 1-2 hours. Tests were conducted in simulated duodenal fluid at pH 4.5, and in simulated intestinal fluid at pH 6.8 over a period of 2-4 hours. Among them, a certain amount of solution was extracted at different time points (30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes and 240 minutes) to calculate the concentration of xanthine derivatives. Among them, an ultraviolet-visible spectrometer (UV/VIS) is used to conduct concentration analysis, and the dissolution ratio is calculated and confirmed through the control group (standard). The test results are shown in Figure 5 and Table 5.

表5: 第二成分(控釋層)與比較例的體外溶離表時間(分) 製備例B1 (Ex 1) 製備例B2 (Ex 2) 製備例B3 (Ex 3) 製備例B4 (Ex 4) 製備例C5 (Ex 5) pH 1.2 0 0.0% 0.0% 0.0% 0.0% 0.0% 30 8.7% 8.5% 17.4% 17.0% 21.6% 60 14.1% 12.6% 38.1% 25.9% 33.0% pH 4.5 90 18.2% 15.4% 46.4% 30.7% 40.4% 120 23.5% 17.9% 52.9% 35.8% 46.0% pH 6.8 150 48.1% 44.1% 57.7% 50.1% 50.6% 180 52.3% 50.1% 62.2% 55.2% 54.5% 240 64.3% 59.8% 69.3% 61.5% 60.7% Table 5: In vitro dissolution table of the second component (controlled release layer) and comparative examples time (minutes) Preparation Example B1 (Ex 1) Preparation Example B2 (Ex 2) Preparation Example B3 (Ex 3) Preparation Example B4 (Ex 4) Preparation Example C5 (Ex 5) pH 1.2 0 0.0% 0.0% 0.0% 0.0% 0.0% 30 8.7% 8.5% 17.4% 17.0% 21.6% 60 14.1% 12.6% 38.1% 25.9% 33.0% pH 4.5 90 18.2% 15.4% 46.4% 30.7% 40.4% 120 23.5% 17.9% 52.9% 35.8% 46.0% pH 6.8 150 48.1% 44.1% 57.7% 50.1% 50.6% 180 52.3% 50.1% 62.2% 55.2% 54.5% 240 64.3% 59.8% 69.3% 61.5% 60.7%

圖5是依照本發明實施例的第二成分與比較例的體外溶離曲線圖。參考圖5以及表5，可以得知，製備例B1（Ex1）以及製備例B2（Ex2）具有較佳的控制釋放效果。在體外溶離2小時內其黃嘌呤衍生物（咖啡因）的釋放不達30重量%，且僅分別為23.5重量%以及17.9重量%。並且，製備例B1（Ex1）以及製備例B2（Ex2）的黃嘌呤衍生物（咖啡因）在2.5小時後才會分別釋放達48.1重量%以及44.1重量%。因此，製備例B1（Ex1）以及製備例B2（Ex2）所製備的第二成分可於2小時後才開始有明顯的黃嘌呤衍生物（咖啡因）促進效果，能夠於進入腸道環境（pH 6.8）後才進行控制釋放。據此，所製備的第二成分能夠有效於服用的後期補充並維持黃嘌呤衍生物的血中高濃度。Figure 5 is an in vitro dissolution curve diagram of the second component according to the embodiment of the present invention and the comparative example. Referring to Figure 5 and Table 5, it can be seen that Preparation Example B1 (Ex1) and Preparation Example B2 (Ex2) have better controlled release effects. Within 2 hours of dissolution in vitro, the release of xanthine derivatives (caffeine) did not reach 30% by weight, and were only 23.5% by weight and 17.9% by weight respectively. Moreover, the xanthine derivatives (caffeine) of Preparation Example B1 (Ex1) and Preparation Example B2 (Ex2) will be released up to 48.1% by weight and 44.1% by weight respectively after 2.5 hours. Therefore, the second component prepared in Preparation Example B1 (Ex1) and Preparation Example B2 (Ex2) can start to have an obvious xanthine derivative (caffeine) promoting effect after 2 hours, and can enter the intestinal environment (pH 6.8) before performing controlled release. Accordingly, the prepared second component can effectively supplement and maintain high blood concentrations of xanthine derivatives in the later stages of administration.

參考製備例B4（Ex4），其也具有可接受的控制釋放效果。如圖5以及表5所示，製備例B4的成分，在體外溶離90分鐘內其黃嘌呤衍生物（咖啡因）的釋放不達35重量%，且在體外溶離2小時內其黃嘌呤衍生物（咖啡因）的釋放不達40重量%。因此，製備例B4的第二成分也能夠控制為在服用後期（2小時後）再延遲釋放，以利於補充並維持黃嘌呤衍生物的血中高濃度。如上述表2所示，製備例B1、B2與B4的玉米蛋白腸溶包衣的重量比例是控制在第二成分的5.5重量%至10重量%的範圍內，因此，可達到本發明的控制釋放效果。Referring to Preparation Example B4 (Ex4), it also has acceptable controlled release effect. As shown in Figure 5 and Table 5, the component of Preparation Example B4 has a xanthine derivative (caffeine) release of less than 35% by weight within 90 minutes of in vitro dissolution, and its xanthine derivatives (caffeine) have not been released within 2 hours of in vitro dissolution. (Caffeine) release is less than 40% by weight. Therefore, the second component of Preparation Example B4 can also be controlled to be released in a delayed manner at the later stage of administration (after 2 hours) to facilitate supplementation and maintenance of high blood concentrations of xanthine derivatives. As shown in Table 2 above, the weight ratio of the zein enteric coating in Preparation Examples B1, B2 and B4 is controlled in the range of 5.5% by weight to 10% by weight of the second component. Therefore, the control of the present invention can be achieved. Release effect.

相較之下，參考製備例B3（Ex3），做為腸溶賦形劑的玉米蛋白腸溶包衣的重量比例為所述第二成分的3重量%時（如表2所示)，其無法有效地達到控制釋放效果。如圖5所示，製備例B3的成分在體外溶離90分鐘內其黃嘌呤衍生物（咖啡因）的釋放已超過40重量%，且與傳統的長效釋放粉體劑型（製備例C5）的溶離曲線類似。因此，製備例B3的第二成分無法有效地達到於特定時段的控制釋放效果。In comparison, referring to Preparation Example B3 (Ex3), when the weight ratio of zein enteric coating as an enteric excipient is 3% by weight of the second component (as shown in Table 2), the The controlled release effect cannot be effectively achieved. As shown in Figure 5, the release of xanthine derivatives (caffeine) of the ingredients in Preparation Example B3 has exceeded 40% by weight within 90 minutes of in vitro dissolution, and is different from the traditional long-acting release powder dosage form (Preparation Example C5). The dissolution curves are similar. Therefore, the second component of Preparation Example B3 cannot effectively achieve the controlled release effect within a specific period of time.

為了進一步確認本發明的腸溶造粒與傳統的基質型混合造粒的差異，是將製備例B2（Ex2）與製備例C5（Ex5）的試驗結果單獨的進行比較。圖6是依照本發明的腸溶造粒（Ex2）與傳統的基質型混合造粒（Ex5）的體外溶離曲線比較圖。製備例B2（Ex2）與製備例C5（Ex5）具有相同的玉米蛋白腸溶包衣與綠茶素的比例（皆為10重量%與71.43重量%）。然而，製備例B2是以腸溶造粒（enteric granulation）的方式（圖3步驟）進行製備，而製備例C5則是以基質型混合造粒（matrix mixing）的方式（圖4步驟）進行製備，兩者的製備方式有很大的不同。In order to further confirm the difference between the enteric granulation of the present invention and the traditional matrix-type mixed granulation, the test results of Preparation Example B2 (Ex2) and Preparation Example C5 (Ex5) were individually compared. Figure 6 is a comparison chart of the in vitro dissolution curves of enteric granulation (Ex2) according to the present invention and traditional matrix-type mixed granulation (Ex5). Preparation Example B2 (Ex2) and Preparation Example C5 (Ex5) have the same ratios of zein enteric coating and green tea pigment (both 10% by weight and 71.43% by weight). However, Preparation Example B2 was prepared by enteric granulation (step 3), while Preparation Example C5 was prepared by matrix mixing (step 4). , the preparation methods of the two are very different.

參考圖6，可以得知的是，即使是使用相同重量比例的玉米蛋白來進行造粒，若不是以本發明的腸溶造粒（enteric granulation）的步驟製備的粉體，則無法有效達成控制釋放的效果。如圖6所示，製備例C5在體外溶離90分鐘內黃嘌呤衍生物（咖啡因）的釋放已達40重量%，屬於持續釋放的劑型。相較之下，本發明的製備例B2在體外溶離2小時內黃嘌呤衍生物（咖啡因）的釋放未達20重量%，且在體外溶離150分內黃嘌呤衍生物（咖啡因）的釋放可以達到46重量%，能夠明顯達到在控制下而延遲釋放的效果。 體外溶離試驗 II Referring to Figure 6, it can be known that even if the same weight ratio of zein is used for granulation, if the powder is not prepared by the enteric granulation step of the present invention, control cannot be effectively achieved. Release effect. As shown in Figure 6, the release of xanthine derivatives (caffeine) in Preparation Example C5 has reached 40% by weight within 90 minutes of in vitro dissolution, which is a sustained-release dosage form. In comparison, the release of xanthine derivatives (caffeine) in Preparation Example B2 of the present invention did not reach 20% by weight within 2 hours of in vitro dissolution, and the release of xanthine derivatives (caffeine) within 150 minutes of in vitro dissolution was It can reach 46% by weight, which can obviously achieve the effect of delayed release under control. In vitro dissolution test II

為了確認本發明的第一成分具有快速釋放的效果，是使用製備例A1的第一成分來進行體外溶離試驗。另外，為了確認本發明口服製劑100的溶離效果，是以製備例A1的第一成分配合製備例B1的第二成分（A1+B1），以及製備例A2的第一成分配合製備例B2的第二成分（A2+B2）來形成雙層錠的口服製劑，並進行體外溶離試驗。體外溶離試驗的步驟與「體外溶離試驗I」中所提到的類似，因此不再予以贅述。差別在於，於口服製劑（雙層錠）的溶離試驗中，是持續溶液的提取至1440分（24小時）。試驗結果如圖7以及圖8所示。In order to confirm that the first component of the present invention has a rapid release effect, the first component of Preparation Example A1 was used to conduct an in vitro dissolution test. In addition, in order to confirm the dissolution effect of the oral preparation 100 of the present invention, the first component of Preparation Example A1 was mixed with the second component (A1+B1) of Preparation Example B1, and the first component of Preparation Example A2 was mixed with the second component of Preparation Example B2. Two components (A2+B2) were used to form a double-layered tablet oral preparation, and an in vitro dissolution test was performed. The steps of the in vitro dissolution test are similar to those mentioned in "In vitro dissolution test I", so they will not be described again. The difference is that in the dissolution test of oral preparations (double-layer tablets), the extraction of the solution is continued until 1440 minutes (24 hours). The test results are shown in Figures 7 and 8.

圖7是依照本發明實施例第一成分（速放層）的體外溶離曲線圖。參考圖7，可以得知的是，由本發明製備例A1所製備而得的第一成分具有明顯的快速釋放效果。如圖7的試驗結果所示，在體外溶離60分鐘內黃嘌呤衍生物（咖啡因）的釋放已達80%以上，且在體外溶離90分鐘內黃嘌呤衍生物（咖啡因）的釋放已達100%。據此，本發明的第一成分能夠有效地於服用後前期（2小時內）快速釋放黃嘌呤衍生物，維持其血中高濃度，並提供增補效果。Figure 7 is an in vitro dissolution curve diagram of the first component (rapid release layer) according to an embodiment of the present invention. Referring to Figure 7, it can be seen that the first component prepared by Preparation Example A1 of the present invention has an obvious rapid release effect. As shown in the test results in Figure 7, the release of xanthine derivatives (caffeine) has reached more than 80% within 60 minutes of in vitro dissolution, and the release of xanthine derivatives (caffeine) has reached 90 minutes of in vitro dissolution. 100%. Accordingly, the first component of the present invention can effectively release the xanthine derivative quickly in the early stage (within 2 hours) after taking it, maintain its high concentration in the blood, and provide a supplementing effect.

圖8是依照本發明實施例口服製劑的體外溶離曲線圖。參考圖8，不論是由製備例A1配合製備例B1所形成的口服雙層錠或是由製備例A2配合製備例B2所形成的口服雙層錠都可以在體外溶離90分鐘內達到黃嘌呤衍生物（咖啡因）的50%以上的釋放。亦即，口服雙層錠中的第一成分已經全部釋放，而第二成分則是緩慢的控制釋放。另外，於體外溶離90分鐘至720分鐘（12小時）的時間內，黃嘌呤衍生物（咖啡因）的釋放會增加至90%以上，並於體外溶離12小時至18小時內的釋放達100重量%。據此，透過第一成分的快速釋放與第二成分的控制釋放，本發明的雙層釋放控制口服製劑能夠有效地控制釋放黃嘌呤衍生物(如咖啡因)，使其維持血中高濃度，從而滿足長時間的增補/提神需求。Figure 8 is an in vitro dissolution curve diagram of an oral preparation according to an embodiment of the present invention. Referring to Figure 8, both the oral double-layer tablet formed by Preparation Example A1 and Preparation Example B1 or the oral double-layer tablet formed by Preparation Example A2 and Preparation Example B2 can achieve xanthine derivatization within 90 minutes of in vitro dissolution. More than 50% of the substance (caffeine) is released. That is, the first component of the oral double-layer tablet has been fully released, while the second component is released slowly and controlled. In addition, the release of xanthine derivatives (caffeine) will increase to more than 90% within 90 minutes to 720 minutes (12 hours) of in vitro dissolution, and the release of xanthine derivatives (caffeine) will reach 100 wt. within 12 hours to 18 hours of in vitro dissolution. %. Accordingly, through the rapid release of the first component and the controlled release of the second component, the double-layer controlled release oral preparation of the present invention can effectively control the release of xanthine derivatives (such as caffeine) to maintain high blood concentrations, thereby Satisfies long term energizing/refreshing needs.

綜上所述，本發明實施例使用具有第一成分以及第二成分的口服製劑，且第二成分具有由腸溶造粒方式製備的腸溶賦形劑。因此，本發明的口服製劑能夠於服用後初期快速釋放第一成分，提供前期的咖啡因補充，並且於後段控制釋放第二成分的咖啡因。由於第二成分具有食用腸溶材質，因此，能夠於鹼性腸道環境下逐步溶解，造就了第二段釋放的結果。據此，本發明的雙層釋放控制口服製劑能夠有效地控制釋放黃嘌呤衍生物(如咖啡因)，使其維持血中高濃度，從而滿足長時間的增補/提神需求。舉例來說，本發明的雙層釋放控制口服製劑能夠滿足長時間活動中需要多次增補/提神之需求，例如在馬拉松等耐力運動進行期間，為提升表現需另外吞服咖啡因，或是長途駕車需要分神補充咖啡因的不便或干擾，並且透過控制釋放的第二成分能夠在整個運動期間都維持咖啡因的高含量/高血中濃度，並且於運動後也能夠持續提供增補/提神效果。To sum up, embodiments of the present invention use an oral preparation having a first component and a second component, and the second component has an enteric excipient prepared by enteric granulation. Therefore, the oral preparation of the present invention can quickly release the first component in the early stage after taking it, provide early caffeine supplementation, and control the release of the second component of caffeine in the later stage. Since the second component has an edible enteric-coated material, it can gradually dissolve in an alkaline intestinal environment, creating a second-stage release effect. Accordingly, the double-layer release controlled oral preparation of the present invention can effectively control the release of xanthine derivatives (such as caffeine) to maintain high blood concentrations, thereby meeting long-term supplementation/refreshing needs. For example, the double-layer controlled release oral preparation of the present invention can meet the need for multiple supplements/refreshers during long-term activities. For example, during endurance sports such as marathons, caffeine needs to be swallowed to improve performance, or during long-distance running. Driving requires distraction to supplement the inconvenience or interference of caffeine, and through the controlled release of the second component, the high content/blood concentration of caffeine can be maintained throughout the exercise period, and it can also continue to provide a tonic/refreshing effect after exercise. .

100:口服製劑 102:第一層面 102A:第一成分的粉體 104:第二層面 104A:第二成分的粉體 A10、A12、A14、A16、A18、A20、A22、A24、A26、A28、A30、A32:步驟 B10、B12、B14、B16、B18、B20、B22、B24、B26、B28、B30、B32、B34、B36:步驟 C10、C12、C14、C16、C18、C20、C22、C24、C26、C28、C30、C32、C34、C36、C38:步驟 100: Oral preparation 102:First level 102A: Powder of the first component 104:Second level 104A: Powder of the second component A10, A12, A14, A16, A18, A20, A22, A24, A26, A28, A30, A32: steps B10, B12, B14, B16, B18, B20, B22, B24, B26, B28, B30, B32, B34, B36: Steps C10, C12, C14, C16, C18, C20, C22, C24, C26, C28, C30, C32, C34, C36, C38: Steps

圖1是依照本發明實施例中的口服製劑的示意圖。圖2是依照本發明實施例的第一成分粉體的製備流程圖。圖3是依照本發明實施例的第二成分粉體的製備流程圖。圖4是依照本發明比較例的長效釋放粉體的製備流程圖。圖5是依照本發明實施例的第二成分與比較例的體外溶離曲線圖。圖6是依照本發明的腸溶造粒與傳統的基質型混合造粒的體外溶離曲線比較圖。圖7是依照本發明實施例第一成分的體外溶離曲線圖。圖8是依照本發明實施例口服製劑的體外溶離曲線圖。 Figure 1 is a schematic diagram of an oral preparation according to an embodiment of the present invention. Figure 2 is a flow chart for preparing the first component powder according to an embodiment of the present invention. Figure 3 is a flow chart for preparing the second component powder according to an embodiment of the present invention. Figure 4 is a flow chart for the preparation of long-lasting release powder according to a comparative example of the present invention. Figure 5 is an in vitro dissolution curve diagram of the second component according to the embodiment of the present invention and the comparative example. Figure 6 is a comparison chart of the in vitro dissolution curves of enteric granulation according to the present invention and traditional matrix-type mixed granulation. Figure 7 is an in vitro dissolution graph of the first component according to an embodiment of the present invention. Figure 8 is an in vitro dissolution curve diagram of an oral preparation according to an embodiment of the present invention.

B10、B12、B14、B16、B18、B20、B22、B24、B26、B28、B30、B32、B34、B36:步驟 B10, B12, B14, B16, B18, B20, B22, B24, B26, B28, B30, B32, B34, B36: Steps

Claims

一種口服製劑，包括：第一成分，其包括咖啡因，所述第一成分中的所述咖啡因於體外溶離1小時內釋放達80重量%以上；以及第二成分，其包括所述咖啡因以及腸溶賦形劑，其中所述第二成分中的所述咖啡因於體外溶離90分鐘內釋放不達35重量%，且所述第二成分中的所述咖啡因於體外溶離3小時內釋放達50重量%以上。 An oral preparation, comprising: a first component, which includes caffeine, and the caffeine in the first component releases more than 80% by weight within 1 hour of dissolution outside the body; and a second component, which includes the caffeine and enteric excipients, wherein the caffeine in the second component is released within 90 minutes of dissolution in vitro, less than 35% by weight, and the caffeine in the second component is dissociated in vitro within 3 hours The release reaches more than 50% by weight.

如請求項1所述的口服製劑，其中所述第二成分中的所述咖啡因於體外溶離3小時內釋放達50重量%以上至70重量%以下。 The oral preparation according to claim 1, wherein the caffeine in the second component is released from 50% to 70% by weight within 3 hours of dissolution in vitro.

如請求項1所述的口服製劑，其中所述第一成分中的所述咖啡因於體外溶離90分鐘內釋放達100重量%，而所述第二成分中的所述咖啡因於體外溶離8小時至12小時內的釋放達90重量%以上，且所述第二成分中的所述咖啡因於體外溶離12小時至18小時內的釋放達100重量%。 The oral preparation according to claim 1, wherein the caffeine in the first component is released in vitro to 100% by weight within 90 minutes, and the caffeine in the second component is dissolved in vitro in 8 The release rate reaches more than 90% by weight within 12 hours to 12 hours, and the release of the caffeine in the second component reaches 100% by weight within 12 hours to 18 hours after dissolution in vitro.

如請求項1所述的口服製劑，其中所述第二成分中的所述咖啡因於體外溶離2小時內釋放不達40重量%。 The oral preparation as claimed in claim 1, wherein the caffeine in the second component is released within 2 hours of dissolution in vitro and does not reach 40% by weight.

如請求項1所述的口服製劑，其中所述口服製劑為口服雙層錠，其包括由所述第一成分組成的第一層面，以及由所述第二成分組成的第二層面。 The oral preparation according to claim 1, wherein the oral preparation is an oral two-layer tablet, which includes a first layer composed of the first component, and a second layer composed of the second component.

如請求項1所述的口服製劑，其中所述第一成分與所述第二成分的重量比例為1：1至1：1.2。 The oral preparation according to claim 1, wherein the weight ratio of the first component to the second component is 1:1 to 1:1.2.

如請求項1所述的口服製劑，其中所述腸溶賦形劑為玉米蛋白腸溶包衣。 The oral preparation according to claim 1, wherein the enteric excipient is zein enteric coating.

如請求項7所述的口服製劑，其中當所述第二成分的重量比例為100%時，所述玉米蛋白腸溶包衣的重量比例為所述第二成分的5.5%至10%。 The oral preparation according to claim 7, wherein when the weight ratio of the second component is 100%, the weight ratio of the zein enteric coating is 5.5% to 10% of the second component.

如請求項1所述的口服製劑，其中所述口服製劑中所述咖啡因的總重量為50mg至400mg。 The oral preparation according to claim 1, wherein the total weight of caffeine in the oral preparation is 50 mg to 400 mg.

如請求項9所述的口服製劑，其中，所述咖啡因於所述第一成分中的重量為25mg至200mg。 The oral preparation according to claim 9, wherein the weight of the caffeine in the first component is 25 mg to 200 mg.

如請求項9所述的口服製劑，其中，所述咖啡因於所述第二成分中的重量為25mg至200mg。 The oral preparation according to claim 9, wherein the weight of the caffeine in the second component is 25 mg to 200 mg.

如請求項1所述的口服製劑，其中，所述第一成分更包括綠茶素、聚乙烯吡咯烷酮、微晶纖維素、交聯聚乙烯吡咯烷酮、硬脂酸鎂以及二氧化矽，且所述綠茶素包括所述咖啡因。 The oral preparation according to claim 1, wherein the first component further includes green tea, polyvinylpyrrolidone, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, magnesium stearate and silicon dioxide, and the green tea Vitamins include the caffeine.

如請求項1所述的口服製劑，其中，所述第二成分更包括綠茶素、聚乙烯吡咯烷酮、微晶纖維素、中鏈三酸甘油酯、硬脂酸鎂、二氧化矽以及膜衣145K290001，且所述綠茶素包括所述咖啡因。 The oral preparation according to claim 1, wherein the second component further includes green tea, polyvinylpyrrolidone, microcrystalline cellulose, medium chain triglycerides, magnesium stearate, silicon dioxide and film coating 145K290001 , and the green tea element includes the caffeine.

如請求項1所述的口服製劑，其中所述口服製劑在服用後90分鐘內會達到所述咖啡因的最高血中濃度。 The oral preparation of claim 1, wherein the oral preparation reaches the highest blood concentration of caffeine within 90 minutes after taking it.

一種如請求項1所述的口服製劑的製備方法，包括：將所述第一成分的粉體與所述第二成分的粉體形成雙層錠。 A method for preparing an oral preparation according to claim 1, comprising: forming the powder of the first component and the powder of the second component into a double-layer tablet.

如請求項15所述的製備方法，其中所述第二成分的粉體的製備包括：提供包括所述腸溶賦形劑的包覆液；提供綠茶素，所述綠茶素包括所述咖啡因；以及將所述綠茶素以所述包覆液進行噴霧造粒以包覆至增重5%至15%的範圍。 The preparation method according to claim 15, wherein the preparation of the powder of the second component includes: providing a coating liquid including the enteric excipient; providing green tea element, the green tea element including the caffeine ; And the green tea element is sprayed and granulated with the coating liquid to coat it to a weight gain range of 5% to 15%.

如請求項16所述的製備方法，更包括：在所述噴霧造粒後，進行烘乾及過篩以形成所述第二成分的粉體。 The preparation method according to claim 16, further comprising: after the spray granulation, drying and sieving to form the powder of the second component.

如請求項15所述的製備方法，其中所述第一成分的粉體的製備包括：提供綠茶素，所述綠茶素包括所述咖啡因；以及將聚乙烯吡咯烷酮的酒***溶液加入至包括所述綠茶素的粉體中，並進行造粒後，進行烘乾及過篩以形成所述第一成分的粉體。 The preparation method according to claim 15, wherein the preparation of the powder of the first component includes: providing green tea element, the green tea element includes the caffeine; and adding the alcohol aqueous solution of polyvinylpyrrolidone to the solution including the caffeine. into the powder of green tea element, and after granulation, drying and sieving are performed to form the powder of the first component.

一種如請求項1所述的口服製劑的使用方法，包括：於進行耐力運動前30分鐘至60分鐘內服用所述口服製劑，且所述口服製劑的服用劑量為3mg/kg至6mg/kg。 A method of using the oral preparation as described in claim 1, including: taking the oral preparation within 30 minutes to 60 minutes before endurance exercise, and the dosage of the oral preparation is 3 mg/kg to 6 mg/kg.