TWI297274B - High molecule of anther complex and the manufacture thereof - Google Patents

Description

1297274 A7 B7 五、發明説明（/ 【發明領域】 本發明係關於一種南分子複合物，尤才 茸抽取液之高分子複合物。 種混合有鹿 【發明背景】 鹿茸抽取液中含有大量的蛋白質、胜及 物貝，對人體有增強免疫力、抗衰老等功能。口 攝取此類營養保健食品最普遍亦最方便的方法，"口月疋 之營養品在腸胃中會經強酸分解，導致某些高分子或蛋白 f失去活性，且口服效用較慢。因此，若能採用非口服方 式，而直接傳送至也液中，其活性物質可完整保存 較快。 非口服方式-般係為舌下或鼻膜喷霧方式。黏膜擁有 =量的吸收潛能，具極佳之藥物吸收能力與藥物動力機 ,，且舌下與鼻膜之表面積較大，酵素活動較少，因而相 當適合藥物吸收。且噴霧方式相當方便，深受消費者直 愛。 〇 但目前所使用之舌下或鼻膜喷霧方式亦有許多缺點， 例如其表面有大量唾液或鼻洋流動，會帶走此處之藥物， 所以鹿茸抽取液可被吸收的時間甚短；同時因高分子化入 :滲透性差’不易被舌下或鼻膜吸收。而且，一般藥二 沒有包覆基材包覆之下藥效消失很快，為了能持續24至 48小時的藥效’發展-適當的包覆基材乃為必要。 (請先閲讀背面之注意事項再填寫本頁各攔) 裝 、可 線--- • n n · _頻中國國家標準 1297274 A7 B7 五、發明説明（2·) 本發明為克服以上缺點，特別研發一種新的複合物及 其製程。 在現今製程中，有不少高分子被應用於包覆基材控制 釋放領域，但大多數的高分子對於鹿茸抽取液並不適合， 原因如下： (1)鹿茸抽取液含多種高分子化合物，其須與一種具有特 殊彈性、吸附力極強之高分子形成一種微膠囊 (microencapsulates)，方能使此複合物停留於舌 下或鼻膜之時間拉長，以助鹿茸在人體之吸收。 (2 )此高分子化合物須不溶於水，而分子大小正好可以容 納鹿茸抽取物與處方中另一些化合物。 (3 )所使用之高分子必須是醫藥級，且不會造成中毒現 象。此外，最終產物須經過殺菌步驟，因此，該包覆 基材之化學性質須在滅菌狀況下，如高温高壓，仍保 持穩定狀態。 為增加該包覆基材以及鹿茸抽取液中之複雜高分子 之滲透性，需要溶於一種具有特別水溶性與油溶性雙重效 果之溶劑。此外，為避免酵素將鹿茸抽取液中之活性因子 降解，亦須將酵素活性降至最低；因此，應將一種適用於 鹿茸抽取液之酵素抑制劑加入本複合物中。 發明人爰因於此，本於積極發明之精神，亟思一種可 以解决上述問題之「特殊鹿茸高分子複合物及其製程」， 幾經研究實驗終至完成此項嘉惠世人之發明。 祕狀糊测娜-----— nnpQdp (請先閲讀背面之注意事項再填寫本頁各欄) 裝 -----訂-------- 1297274 ， A7 B7 五、發明説明（ 【發明概述】 本發明之主要目的係在提供一種特殊鹿算高分子複合 物’不經腸胃吸收’同時使鹿算中之活性成分可被人體最 有效地吸收，以及持續地釋放。 本發明之另一目的係在提供一種特殊鹿茸高分子複合 物之製造方法，俾能使鹿茸中的活性物質有效包覆於高分 子基材中以形成複合物。 為達成上述之目的，本發明「鹿茸高分子複合物之製 備方法」，包含：製備包覆基材，係將β_環糊精（β_ cyclodextrin)、高酯類、蛋白酶抑制劑與有機溶劑以 特疋比例混合，並將該包覆基材加入水中，於室溫下慢速 授拌1 8至3 6小時，加入鹿茸抽取液，於室溫下慢速授拌 18至24小時；於代下靜置24至48小時，待沉澱析 出；以及過濾取出沉澱物。 本發明亦相關於一種鹿茸高分子複合物，其係由特定 比例之β -環糊精（β-cyclodextrin)、高酯類、蛋白酶 抑制劑與有機溶劑所形成之包覆基材，與鹿茸抽取物混合 而製得。 由於本發明構造新穎，能提供產業上利用，且確有增 進功效，故依法申請發明專利。 【發明詳細敘述】 ^長夕^】中國國家標準（CNS) A4規格（210X297公47 (請先閲讀背面之注意事項再填寫本頁各欄) 裝 -----訂------ 1·線. 1297274 A7 B7 五、發明説明（ψ ) - 甘2月之目的係在於提供一種特殊鹿茸高分子複合物 二1迨方法。忒鹿茸高分子複合物，包含以特定比例之 β衣糊精、兩S旨類、蛋白酶抑制劑與有機溶劑所形成之包 覆基以及鹿茸抽取物。其包覆基材各成分之比例較佳 為β &糊精·咼酯類··蛋白酶抑制劑：有機溶劑之比例為 1.〇.〇1.〇.〇2:0.45份重至1:〇.2 0:0.1 8:0.5 5份 重，而該包覆基材與該鹿茸抽取物之比例較佳為j : I 5 至L 2 · 7重里比。所使用之任一材料皆為醫藥級試劑。 名同自曰類較佳為由具丨2至丨8個碳之醇類與具8至丨8個碳之 羧酸類反應而得；該蛋白酶抑制劑較佳為黏膜蛋白酶抑制 劑；該有機溶劑較佳為丙二醇。 該鹿茸高分子複合物之製造方法如下：將上述比例之 β-環糊精、高酯類、蛋白酶抑制劑與有機溶劑混合，做為 包覆基材之材料，其適用之較佳例亦如上述；加入純水， 該混合物與純水之比例較佳為丨：3重量比，於室溫下慢 速攪拌1 8至3 6小時，形成包覆基材之懸浮液。於該懸浮 液中加入如上述比例之鹿茸抽取物，於室溫下用慢速攪拌 約1 8至2 4小時，形成微膠囊。該混合物於4 π靜置2 4 至4 8小時，待沉澱生成。將上述之沉澱物過濾出，其過 濾方法不限，並以清水清洗再過濾，如此重複多次，得最 終 >儿氣物。该、;儿殿物再加入3倍純水中，在均質授拌機 (homomixer)中攪拌約15-20分鐘，待完全混合後，所 得產物經完全殺菌’製成喷霧式成品；或可將該產物喷霧 乾燥成粉末，用於長期保存，需要時再加入水製成喷霧試 7 本&張尺度適用中國國家標準（CNS) A4規格(210X297公釐) --- ' 002944 (請先閲讀背面之注意事項再填寫本頁各欄) # 裝 -----訂--------^ 1297274 A71297274 A7 B7 V. INSTRUCTION DESCRIPTION OF THE INVENTION (/ [Field of the Invention] The present invention relates to a south molecular complex, a polymer compound of a special velvet extract. The seed is mixed with a deer. [Background of the Invention] The antler extract contains a large amount of protein. It wins immunity and anti-aging functions to the human body. The most common and convenient method for ingesting such nutritious health foods is that the nutrients in the stomach will be decomposed by strong acid in the stomach. Some polymers or proteins f are inactive and have a slow oral effect. Therefore, if they can be directly delivered to the liquid by non-oral means, the active substance can be stored completely faster. Lower or nasal spray method. Mucosa has the potential to absorb, has excellent drug absorption capacity and drug power machine, and the surface area of the sublingual and nasal membrane is larger, and the enzyme activity is less, so it is quite suitable for drug absorption. The spray method is quite convenient and is deeply loved by consumers. However, the sublingual or nasal spray method currently used has many disadvantages, such as a large amount of saliva on its surface. The flow of the nose will take away the medicine here, so the antler extract can be absorbed for a short time; at the same time, due to the high polymerization: poor permeability is not easily absorbed by the sublingual or nasal membrane. Moreover, the general medicine is not included. The effect of coating under the coating of the substrate disappears very quickly. In order to last for 24 to 48 hours, it is necessary to develop the appropriate substrate. (Please read the notes on the back and fill in the pages.) ) Installation and cable--- • nn · _ frequency Chinese national standard 1297274 A7 B7 V. Invention description (2·) The present invention overcomes the above disadvantages, and specially develops a new composite and its process. In the current process, Many polymers have been used in the controlled release of coated substrates, but most of the polymers are not suitable for antler extracts. The reasons are as follows: (1) The antler extract contains a variety of polymer compounds, which must be The elastic and highly adsorbing polymer forms a microencapsulates to allow the composite to stay under the tongue or the nasal membrane for a long time to assist the absorption of the antler in the human body. (2) The polymer compound It must be insoluble in water, and the molecular size is just enough to accommodate the antler extract and other compounds in the prescription. (3) The polymer used must be of pharmaceutical grade and will not cause poisoning. In addition, the final product must undergo a sterilization step. Therefore, the chemical properties of the coated substrate must be kept stable under sterilization conditions, such as high temperature and high pressure. In order to increase the permeability of the coated substrate and the complex polymer in the antler extract, it is necessary to dissolve in one A solvent that is particularly water-soluble and oil-soluble. In addition, enzyme activity must be minimized in order to prevent the enzyme from degrading the active factors in the velvet extract; therefore, an enzyme inhibitor suitable for antler extract should be added. In this composite, the inventor, due to this, is in the spirit of active invention, thinking about a "special antler polymer complex and its process" that can solve the above problems. After several research experiments, the company will complete the project. Invention.秘状糊测娜------ nnpQdp (Please read the notes on the back and fill in the columns on this page) Pack-------------- 1297274, A7 B7 V. Invention (Invention Summary) The main object of the present invention is to provide a special deer computing polymer compound 'intestinal absorption' while allowing the active ingredient in the deer to be most effectively absorbed by the human body, and continuously released. Another object of the present invention is to provide a method for producing a special antler polymer composite, which can effectively coat an active substance in velvet antler in a polymer substrate to form a composite. To achieve the above object, the present invention "deer antler" A method for preparing a polymer composite, comprising: preparing a coated substrate by mixing β-cyclodextrin (β_cyclodextrin), a high ester, a protease inhibitor, and an organic solvent in a specific ratio, and coating the coating The substrate is added to water, and the mixture is slowly stirred at room temperature for 18 to 36 hours, and the antler extract is added, and the mixture is slowly stirred at room temperature for 18 to 24 hours; it is allowed to stand for 24 to 48 hours under the passage to be precipitated. Precipitating; and filtering out the precipitate. The invention also Corresponding to a antler polymer complex, which is a coated substrate formed by a specific ratio of β-cyclodextrin, a high ester, a protease inhibitor and an organic solvent, and is mixed with a antler extract. Since the invention has novel construction, can provide industrial utilization, and has improved efficiency, it applies for invention patent according to law. [Detailed Description of the Invention] ^Chang Xi ^ Chinese National Standard (CNS) A4 Specification (210X297 public 47 ( Please read the notes on the back and fill in the fields on this page. Pack-----Book ------ 1· Line. 1297274 A7 B7 V. Invention Description (ψ) - The purpose of Gan 2 is to provide A special compound for antler anterior polymer compound. The velvet antler polymer complex comprises a coating base formed by a certain proportion of β clothing dextrin, two S-types, a protease inhibitor and an organic solvent, and a antler extract. The ratio of the components of the coated substrate is preferably β & dextrin· oxime ester·· protease inhibitor: the ratio of the organic solvent is 1. 〇.〇1.〇.〇2: 0.45 parts to 1 :〇.2 0:0.1 8:0.5 5 parts by weight, and the coated substrate and the antler pumping The ratio of the substance is preferably j: I 5 to L 2 · 7 by weight. Any of the materials used are pharmaceutical grade reagents. The same type of self-quinone is preferably an alcohol having from 丨2 to 丨8 carbons. It is obtained by reacting with a carboxylic acid having 8 to 8 carbons; the protease inhibitor is preferably a mucosal protease inhibitor; and the organic solvent is preferably propylene glycol. The antler polymer compound is produced by the following method: Β-cyclodextrin, high esters, protease inhibitors are mixed with an organic solvent as a material for coating a substrate, and preferred examples thereof are as described above; when pure water is added, the ratio of the mixture to pure water is preferably For the 丨: 3 weight ratio, the mixture was slowly stirred at room temperature for 18 to 36 hours to form a suspension of the coated substrate. To the suspension, a velvet antler extract of the above ratio was added, and the mixture was stirred at a slow temperature for about 18 to 24 hours at room temperature to form microcapsules. The mixture was allowed to stand at 4 π for 24 to 48 hours to be precipitated. The above precipitate is filtered out, and the filtration method is not limited, and it is washed with water and then filtered, and this is repeated a plurality of times to obtain the final > The children's house is then added to 3 times pure water and stirred in a homomixer for about 15-20 minutes. After complete mixing, the obtained product is completely sterilized to make a spray-type finished product; Spray the product into a powder for long-term storage, add water when needed to make a spray test. 7 & Please read the notes on the back and fill in the fields on this page. #装-----订--------^ 1297274 A7

劑。封包過程全程須為無菌狀態 鼻膜或舌下傳輸之喷霧式包裝。 該封包方式較佳為適合 【較佳具體實施例】 為能讓f審查委員能更瞭解本發明之技術内容，特 舉-較佳具體實施例與藥物動力學研究實驗說明如下。 本範例所使用之各化合物皆為醫藥級。將以下各種化 合物依下列重量置入一不鏽鋼混合槽中： 化合物 重量（公斤重） β-環糊精 6. 18 二級丁基-3 -戊酯 0.916 黏液蛋白酶抑制劑 0. 124 丙二醇 2.78 總量 10. 00 請 先 閲 讀 背 之 注 意 事 項 再 填 寫 本 頁 各 欄 裝 訂 將以上混合物加入3 0公斤重蒸餾水，此時總重量為 40公斤重；以慢速攪拌約18至36小時，形成包覆基材之 懸浮液。於該懸浮液中加入5 · 5公斤之鹿茸抽取物，於室 溫下用慢速攪拌約1 8至2 4小時，形成微膠囊。該混合物 於4 °C靜置2 4至4 8小時，待沉澱生成。將上述之沉澱物以 紗布過濾出，並以清水清洗再過濾，如此重複3次。此時 可得最終沉澱物約1 8公斤，將該沉澱物加入5 5公斤純水 中，在均質授拌機（homomixer)中擾拌約15分鐘，待完 8 ΪΗ家標準（CNS) A4規格（210X297公Θ 1297274 A7 B7 五、發明説明（名） 72 96 120 144 0 0 0 0 17 3 0 0 80 56 32 4 81 52 27 5 77 53 25 2 28 9 0 0 由以上結果可知，第2組與第4組的持續釋放效果最 好 (2)人體中（//?-f/fo)鹿茸抽取物複合物之釋放研究 以下實驗之控制組如上所述，惟鹿茸抽取物複合物包 裝於喷霧式瓶中，使用時係喷至受試者舌下部分，控制組 則以口服方式。 以未包覆本發明高分子複合物之鹿茸抽取液膠囊作為 控制組，並以下列各比例配製本發明鹿茸抽取物複合物， 其亦包入與控制組相同之膠囊中。 組別 第1組 第2組 第3組 第4組 第5組 鹿茸抽取液重量比 1 1 1 1 1 β-環糊精重量比 1 1. 52. 0 2. 7 3. 5 (請先閲讀背面之注意事項再填寫本頁各欄) -裝 -----訂--------· 11 本紙m尺度適用中國國家標準（CNS) Α4規格（210X297公董）002948 1297274 A7 B7 五、發明説明（11 ) 〜 效果，進而保護鹿茸抽取物中的活性物質；且此混合物相 當穩定’不會引起包覆基材之變化。 與習知技藝相較，不論是傳統上所使用之口服，或僅 將鹿茸抽取物製成粉末或溶液，以舌下或鼻膜吸收，皆益 法如本發明，可完整維持鹿茸中之活性物質；本發明所製 備之產物更加強其於黏膜上之停留時間與渗透性，增加直 生物可利用率，同時可維持鹿茸中活性物質之釋放速率 綜上所陳，本發明無論就目的、手段及功效，在在均 顯示其迥異於習知技術之特徵，為「特殊鹿茸高分子複合 物及其製程」之-大突破，懇請貴審查委員明察，早日 賜准專利，俾嘉惠社會，實感德便。惟應注意的是，上述 諸多實施例僅係為了便於說明而舉例❿已，本發明所主張 之權利範圍自應以申請專利範圍所述為準，而非僅限於上' 述實施例。 002951 裝---------訂--------^^画 (請先閲讀背面之注意事項再填寫本頁各欄) 14 92年9月30日修正頁 申請曰期 91. β. 7 案 號 91112442 類 別 A %s (以上各攔由本局填註） A4 C4 年/月 修正補充 熾靖委員明示，本案修IL後是否變更原實質内容 ••••1···1'·.. ^ 1/4 p f ;ι"^ίί 、,; .n';?/s:.itTi::;-;^ 翁|專利説明書 發明 一、h丨名私 新型 中 文 特殊鹿茸高分子複合物及其製造方法 英 文 High molecule of antler complex and the manufacture thereof 姓 名 徐孝陵、陳思如 發明 創作> 國 籍 住、居所 姓 名 (名稱） 美國 美國91765加州鑽石崗，徽鷹脊路3392號 美國91765加州鑽石崗#266，金色春街23441號 國 籍 住、居所 (事務所） 代表人 姓 名Agent. The entire packaging process must be sterile, nasal spray or sublingual spray. Preferably, the method of encapsulation is suitable for the preferred embodiment. In order to enable the review panel to better understand the technical contents of the present invention, the preferred embodiment and the pharmacokinetic study are described below. Each of the compounds used in this example is of pharmaceutical grade. The following various compounds were placed in a stainless steel mixing tank with the following weight: Compound weight (kg weight) β-cyclodextrin 6. 18 Secondary butyl-3-pentyl ester 0.916 Mucin protease inhibitor 0. 124 Propylene glycol 2.78 Total 10. 00 Please read the precautions of the back and then fill in the fields on each page. Add the above mixture to 30 kg of double distilled water, the total weight is 40 kg; stir at a slow speed for about 18 to 36 hours to form a coating base. Suspension of material. To the suspension, 5 · 5 kg of velvet antler extract was added and stirred at room temperature for about 18 to 24 hours at a slow temperature to form microcapsules. The mixture was allowed to stand at 4 ° C for 24 to 48 hours to be precipitated. The above precipitate was filtered off with gauze, washed with water and filtered, and this was repeated three times. At this point, about 18 kg of the final precipitate can be obtained. The precipitate is added to 55 kg of pure water and disturbed in a homomixer for about 15 minutes. After 8 standard (CNS) A4 specifications are completed. (210X297) 1297274 A7 B7 V. Invention description (name) 72 96 120 144 0 0 0 0 17 3 0 0 80 56 32 4 81 52 27 5 77 53 25 2 28 9 0 0 From the above results, the second group The sustained release effect with group 4 is best. (2) Release of antler extract complex in human body (//?-f/fo) The control group of the following experiment is as described above, but the antler extract complex is packaged in a spray. In the mist bottle, it is sprayed to the sublingual part of the subject during use, and the control group is taken orally. The velvet extract capsule which is not coated with the polymer complex of the present invention is used as a control group, and is prepared in the following proportions. Invented the antler extract complex, which is also included in the same capsule as the control group. Group 1 group 2 group 3 group 4 group 5 group 5 antler extract weight ratio 1 1 1 1 1 β-cyclodext Fine weight ratio 1 1. 52. 0 2. 7 3. 5 (Please read the notes on the back and fill in the fields on this page) - Pack-----Book-- ------· 11 This paper is applicable to China National Standard (CNS) on the m scale. Α4 Specification (210X297 Gongdong) 002948 1297274 A7 B7 V. Invention Description (11) ~ Effect, and thus protect the active substance in the antler extract; This mixture is quite stable 'will not cause changes in the coated substrate. Compared to conventional techniques, whether it is traditionally used orally, or only the antler extract is made into a powder or solution, absorbed by the sublingual or nasal membrane The method of the present invention can completely maintain the active substance in the velvet antler; the product prepared by the invention further enhances the residence time and permeability on the mucosa, increases the availability of the direct bio-availability, and maintains the active substance in the antler The release rate of the present invention is comprehensive, and the present invention shows that it is different from the conventional technology in terms of purpose, means and efficacy, and is a breakthrough in the "special antler polymer compound and its process". The reviewer clearly observed that the patent was granted as soon as possible, and the company was in a good sense. However, it should be noted that the above-mentioned various embodiments are merely for convenience of explanation, and the present invention claims The scope of the rights is subject to the scope of the patent application, and is not limited to the above described examples. 002951 装---------订--------^^画 (please first Read the notes on the back and fill in the fields on this page. 14 September 30, 1992 Revision page application period 91. β. 7 Case number 91112442 Category A %s (The above are filled by this Council) A4 C4 year/month The amendment added to the blazing committee member to express whether the original substance was changed after the revision of the case.••••1···1'·.. ^ 1/4 pf ;ι"^ίί ,,; .n';?/s: .itTi::;-;^ Weng|Patent specification invention one, h丨 name new Chinese special antler polymer complex and its manufacturing method English High molecule of antler complex and the manufacture thereof Name Xu Xiaoling, Chen Siru invention creation > Nationality residence, residence name (name) United States United States 91765 California Diamond Hill, Huiying Ridge Road 3392, United States 91765 California Diamond Hill #266, Golden Spring Street 23441 Nationality residence, residence (office) Representative name

本紙張尺度適用中國國家標準（CNS ) A4現格（210X297公釐） I I I裝 訂 線 1297274 A7 B7 五、發明説明（G )This paper scale applies to China National Standard (CNS) A4 (210X297 mm) I I I binding line 1297274 A7 B7 V. Invention description (G)

全混合後’以瞬間加熱機加熱至2 1 2 T，2分鐘；急速冷 卻後’裝入以酒精消毒過之玻璃瓶中，該玻璃瓶上附有噴 霧產生器。封包過程全程為無菌狀態。 樂物動力 _學..研究貫驗（Pharmaco-kinetics study") 本實驗係比較本發明之配方及其服用方法，與傳統鹿 茸抽取液服用方法之效果，尤其在人體吸收與持續釋放方 面作一詳細比較。傳統之鹿茸抽取液係作成粉狀，包入膠 囊中，以口服方式投藥。而本發明則將鹿茸抽取液複合物 以瓶裝喷霧方式輸送。 類胰島素生長因子IGF(Insulin-like Growth Factor)為鹿茸抽取液中最重要的成分之一且含量固定； 因此我們以IGF之含量作為鹿茸抽取物中活性物質含量之 代表。實驗中所有鹿茸抽取液來自同一批原料，以方便比 較各組之差異。 (1)試管内試驗（/77決定複合物與鹿茸抽取物之 比例 以未包覆本發明高分子複合物之鹿茸抽取液膠囊作為 控制組，並以下列各比例配製本發明鹿茸抽取物複合物， 其亦包入與控制組相同之膠囊中。 組別 鹿茸抽取液重量比β -環糊精重量比 第1組 1 ， 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公爱） (請先閲讀背面之注意事項再填寫本頁各欄) ---------訂 i 参After full mixing, it was heated to 2 1 2 T by an instant heating machine for 2 minutes; after rapid cooling, it was placed in an alcohol-sterilized glass bottle with a spray generator attached thereto. The entire process of the packaging process is sterile. Pharmaco-kinetics study" This experiment compares the formulation of the present invention and its administration method with the effect of the traditional antler extract taking method, especially in the absorption and sustained release of the human body. Detailed comparison. The traditional antler extract is made into a powder, encapsulated in a capsule, and administered orally. In the present invention, the antler extract compound is delivered in a bottle spray manner. Insulin-like growth factor (IGF) is one of the most important components in the antler extract and its content is fixed. Therefore, we use the content of IGF as the representative of the active substance content in the antler extract. All the antler extracts from the experiment were from the same batch of raw materials to facilitate comparison of the differences between the groups. (1) In-tube test (/77 determines the ratio of the complex to the antler extract), the antler extract capsule which is not coated with the polymer complex of the present invention is used as a control group, and the antler extract complex of the present invention is prepared in the following proportions. It is also included in the same capsule as the control group. The weight ratio of the antler extract is β-cyclodextrin weight ratio group 1 , the paper scale is applicable to the Chinese National Standard (CNS) Α 4 specification (210X297 public) Please read the notes on the back and fill in the fields on this page. ---------Book i

1297274 ________B7 五、發明説明（7 ) 第2組 1 第3組 1 C請先閲讀背面之注意事項再填窝本頁各襴} 第4組 1 第5組 1 上述鹿茸抽取物係為同一批成品取樣，其中IGF含量 為150 mg。IGF係以IRMA (RADZM公司製造）進行化學 定里。其餘各成分如實施例1所述。 將上述鹿茸抽取物複合物分別置入試管中，其内含有 10毫升PBS緩衝溶液，並以攪拌裝置持續攪拌。24小時 後，將試管中所有溶液移入另一試管中進行IGF含量分 析，該實驗樣品再放入另一新的1〇毫升PBS緩衝溶液。如 此每2 4小時測量一次，直至1 4 4小時為止。結果如下表i 所示： 表1 時間 ⑻ IGF含量 (mg) - 控制組 第1組 第2組 第3組 第4組 第5組 0 150 150 150 150 150 150 24 35 75 135 129 123 98 48 12 54 114 107 109 73 10 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 1297274 五、發明説明（q) A7 B71297274 ________B7 V. INSTRUCTIONS (7) Group 2 1 Group 3 1 C Please read the notes on the back and refill the pages on this page. Group 4 1 Group 5 1 The above antler extracts are the same batch of finished products. Sampling with an IGF content of 150 mg. IGF is chemically prepared by IRMA (manufactured by RADZM). The remaining ingredients are as described in Example 1. The above antler extract complexes were separately placed in a test tube containing 10 ml of a PBS buffer solution and continuously stirred with a stirring device. After 24 hours, all of the solution in the test tube was transferred to another test tube for IGF content analysis, and the test sample was again placed in another new 1 ml PBS buffer solution. This is measured every 24 hours until 144 hours. The results are shown in Table i below: Table 1 Time (8) IGF content (mg) - Control group Group 1 Group 2 Group 3 Group 4 Group 5 0 150 150 150 150 150 150 24 35 75 135 129 123 98 48 12 54 114 107 109 73 10 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1297274 V. Invention description (q) A7 B7

修正鶴 上述鹿茸抽取物係為同一批成品取樣’其中IG F含量 為150 mg。IGF係以IRMA (RADZM公司製造）進行化學 定量。其餘各成分如實施例1所述。 受試者分別以口服方式服用控制組，以及將第1組至 第5組以噴入舌下方式投藥。每組6人，男女各佔一半，共 2 8組參與試驗。受試者每2 4小時抽血一次，將血漿抽出 測試其内IGF含量；總共144小時。結果如下表2，該數據 為平均值，除標有*號者外，其餘皆有ρ = 0· 05之統計學顯 著性。 表2 ~ IGF 含量 (h) (mg) 控制組 第1組 第2組 第3組 第4組 第5組 0 150 150 150 150 150 150 24 23 105 127 132 130 112 48 0 8 3 109 115 117 87 72 0 50 81 87 89 62 96 0 17* 52* 59 58 24 120 0 0 29 33 37 3 144 0 0 3 5 9 0 *這些組別未達到統計學顯著性（p> 0 0 5 )。Modified Crane The above antler extracts were sampled for the same batch of finished products, where the IG F content was 150 mg. IGF was chemically quantified by IRMA (manufactured by RADZM). The remaining ingredients are as described in Example 1. The subjects were administered the control group orally, and the first to fifth groups were administered by sublingual injection. Each group of 6 people, half of men and women, a total of 28 groups participated in the trial. Subjects were bled once every 24 hours and plasma was withdrawn to test for IGF content; a total of 144 hours. The results are shown in Table 2 below. The data is the average value. Except for the number marked with *, the others have statistical significance of ρ = 0.05. Table 2 ~ IGF Content (h) (mg) Control Group Group 1 Group 2 Group 3 Group 4 Group 5 0 150 150 150 150 150 150 24 23 105 127 132 130 112 48 0 8 3 109 115 117 87 72 0 50 81 87 89 62 96 0 17* 52* 59 58 24 120 0 0 29 33 37 3 144 0 0 3 5 9 0 *These groups did not reach statistical significance (p> 0 0 5 ).

補充 斑 1297274 五、發明説明（/σ) = 由以上結果可知’仍是第2組至第4組之持續釋放效果 最好。由此可知鹿茸抽取物與包覆基材的最佳重量比介於 1 · 1 · 5至1 ·· 2 · 7。同時此比例中之鹿茸抽取物複合物遠比 傳統方式（控制組）更能達到持久釋放之效。本實驗更證明 I里本發明特殊複合物包覆之鹿茸抽取物，在體内試驗中， 該鹿茸抽取物（以IGF含量為代表）可留在人體中達6曰之 久，其功效顯著，可見Supplementary spot 1297274 V. Description of invention (/σ) = It can be seen from the above results that the sustained release effect of Groups 2 to 4 is still the best. It can be seen that the optimum weight ratio of the antler extract to the coated substrate is between 1 · 1 · 5 · 1 · · · · · 7. At the same time, the antler extract complex in this proportion is far more effective than the traditional method (control group). The experiment further proves that the antler extract coated by the special composite of the invention is in the in vivo test, the antler extract (represented by the IGF content) can be left in the human body for 6 years, and the effect is remarkable. visible

由上所述可知，本發明所製備之鹿茸高分子複合物， 係採舌下或鼻膜噴霧吸收，不經胃酸分解，可完整保存其 内所含之活性物質。發明中以環糊精做為包覆基材， β-環糊精為一種有彈性、吸附力極強，不溶於水，無毒 性，具食品安全特性之高分子化合物；此外，此高分子在 月中所使用之適當比例可恰好包覆鹿茸抽取物，並使 =:囊之尺寸為最佳化（2至10微米），不會太過鬆散而慢 鬆脫，亦不會太緊密而失去滲透性，因此可控制鹿茸抽 =物於血液中的釋放速率，使藥效可於24至48小時内持 績釋放。此外，為增進鹿茸抽取物之滲透性，本發 ::入水溶性與油溶性極佳之溶劑—丙二醇，其穩定㈣ ’且無毒性，特別適合用於鹿茸處方中。另外，舌下盘 鼻腔黏膜中的少數酵素，其抑制劑並不易找出。本發明I =2:與深入研究，發現加入適當比例之高酿類與黏It can be seen from the above that the antler polymer compound prepared by the present invention is absorbed by the sublingual or nasal membrane spray, and can completely preserve the active substance contained therein without decomposition by gastric acid. In the invention, cyclodextrin is used as a coating substrate, and β-cyclodextrin is a polymer compound which is elastic, has strong adsorption, is insoluble in water, is non-toxic, and has food safety characteristics; The appropriate ratio used in the month can just cover the antler extract and optimize the size of the capsule: 2 to 10 microns. It will not be too loose and loose, and will not be too tight to lose. Permeability, therefore, can control the release rate of antlers in the blood, so that the efficacy can be released within 24 to 48 hours. In addition, in order to improve the permeability of the antler extract, the present invention is a solvent (340) which is excellent in water solubility and oil solubility, and is stable (four)' and non-toxic, and is particularly suitable for use in antler prescriptions. In addition, a small number of enzymes in the nasal mucosa of the sublingual disc are not easily found. The present invention I = 2: and in-depth study, found that adding a suitable proportion of high brewing and sticky

訂 § 液蛋白_制劑⑴：1至1:9重量比），可具極佳的抑制§ Liquid protein_formulation (1): 1 to 1:9 weight ratio), with excellent inhibition

Claims (1)

12972741297274 申請專利範圍 1. 一種鹿茸高分子複合物之製備方法，包含下列步驟： (a) 製備包覆基材，係將卜環糊精（— cyclodextrin)、高酯類、蛋白酶抑制劑與有機 溶劑以特定比例混合，並將該包覆基材加入水 中，於室溫下慢速攪拌18至36小時； (b) 加入鹿茸抽取液，於室溫下慢速攪拌18至小 時； (C)於4°c下靜置24至48小時，待沉澱析出；以及 (d )過濾取出沉澱物。 2·如申請專利範圍第i項所述之製備方法，其中該步驟 (a)之β-環糊精：高酯類··蛋白酶抑制劑：有機溶劑 之比例為1 : 〇. 〇 i : 0 · 0 2 : 〇. 4 5份重至i : 〇 · 〇·18:0·55 份重。 · 3·如申請專利範圍第丨項所述之製備方法，其中該步驟 (a )之β -環糊精係為醫藥級。 4. 如申請專利範圍第i項所述之製備方法，其中該步驟 (a)之高酯類係由具12至18個碳之醇類與具8至18 個碳之羧酸類反應而得。 5. 如申請專利範圍第1項所述之製備方法，其中該步驟 (〇之蛋白酶抑制劑為黏液蛋白酶抑制劑 proteinase inhibitor)。 6· μ請專利範圍第1項所述之製備方法，其中該步驟 a)之有機溶劑為丙二醇（pr〇pylene glyc〇l)。 7·如申請專利範圍帛1項所述之製備方法，其中步驟⑷ (請先閲讀背面之注意事項再填寫本頁各欄) -----訂----- n ^^1 —.1 HI 線· φ I3Si7i234， 97年1月修正頁Patent Application 1. A method for preparing a antler polymer complex, comprising the following steps: (a) preparing a coated substrate by using cyclodextrin, a high ester, a protease inhibitor and an organic solvent. Mix in a specific ratio, and add the coated substrate to water and stir slowly at room temperature for 18 to 36 hours; (b) Add antler extract and slowly stir for 18 hours at room temperature; (C) at 4 Allow to stand at °c for 24 to 48 hours, to be precipitated; and (d) filter to remove the precipitate. 2. The preparation method according to item yi of the patent application, wherein the ratio of the β-cyclodextrin: high ester type protease inhibitor: organic solvent in the step (a) is 1: 〇. 〇i : 0 · 0 2 : 〇. 4 5 parts to i: 〇· 〇·18:0·55 parts by weight. 3. The preparation method according to the invention of claim 2, wherein the β-cyclodextrin of the step (a) is a pharmaceutical grade. 4. The preparation method according to the invention of claim 1, wherein the high ester of the step (a) is obtained by reacting an alcohol having 12 to 18 carbons with a carboxylic acid having 8 to 18 carbons. 5. The preparation method according to claim 1, wherein the step (the protease inhibitor of sputum is a proteinase inhibitor). The preparation method according to the first aspect of the invention, wherein the organic solvent of the step a) is propylene glycol (pr〇pylene glyc〇l). 7. If the preparation method described in the scope of patent application 帛1, step (4) (please read the notes on the back and then fill in the columns on this page) ---------- n ^^1 —. 1 HI line · φ I3Si7i234, revised version of January 1997 六、申請專利範圍 之包覆基材與水之重量比為1 : 3。 8·如申請專利範圍第1項所述之製備方法，其中該包覆 基材與該鹿茸抽取物之重量比為1:1.5至1:2 7。 9·如申請專利範圍第1項所述之製備方法，其中該步驟 (d)更包含至少一次以清水清洗該沉澱物，並再次過濾 取沉澱物。 10·如申請專利範圍第1項所述之製備方法，其更包含 將最終沉澱物加入3倍重量純水混合，並經殺菌步 驟，以無菌方式封包。 11β如申請專利範圍第10項所述之製備方法，其中該 封包方式係為適合鼻膜或舌下傳輸之噴霧式包裝。 1一種用於鼻膜或舌下傳輸之鹿茸高分子複合物，其 係由特定比例之β-環糊精（p-cyclodextrin)、高酯 類、蛋白酶抑制劑與有機溶劑所形成之包覆基材，與 鹿茸抽取物混合而製得。 13·如申請專利範圍第12項所述之鹿茸高分子複合 物，其中該β -環糊精：高酯類：蛋白酶抑制劑：有機 溶劑之比例為1 : 〇 · 〇 1 : 〇 · 〇 2 ·· 〇 · 4 5份重至1 ··6. The weight ratio of the coated substrate to water in the patent application range is 1:3. 8. The preparation method according to claim 1, wherein the weight ratio of the coated substrate to the antler extract is 1:1.5 to 1:27. 9. The preparation method according to claim 1, wherein the step (d) further comprises washing the precipitate with water at least once and filtering the precipitate again. 10. The preparation method of claim 1, further comprising mixing the final precipitate with 3 times by weight of pure water and sterilizing the solution in a sterile manner. 11β The preparation method according to claim 10, wherein the method of packaging is a spray-type package suitable for nasal membrane or sublingual transmission. A antler polymer complex for nasal membrane or sublingual transmission, which is a coating base formed by a specific ratio of β-cyclodextrin, a high ester, a protease inhibitor and an organic solvent. Material, prepared by mixing with antler extract. 13. The antler polymer compound according to claim 12, wherein the β-cyclodextrin: high ester: protease inhibitor: organic solvent ratio is 1: 〇· 〇1 : 〇· 〇2 ·· 〇· 4 5 parts to 1 ·· I £ I I h \ I 訂 i § 〇·20 · 0·18 : 〇·55 份重。 14·如申請專利範圍第12項所述之鹿茸高分子複合 物，其中該β -環糊精係醫藥級。 15·如申請專利範圍第1 2項所述之鹿茸高分子複合 物’其中該高酯類係由具1 2至1 8個碳之醇類與具8 至1 8個碳之羧酸類反應而得。 16 本紙張尺度適用中國國家標準（CNS) Α4規格（210x297公釐） 1297274 ·· 丨戠 C8 ______J D8___ 六、申請專利範圍 16· 如申請專利範圍第12項所述之鹿茸高分子複合 物，其中該蛋白酶抑制劑為黏液蛋白酶抑制劑（Mucus proteinase inhibitor) 〇 1 7. 如申請專利範圍第1 2項所述之鹿茸高分子複合 物’其中該有機溶劑為丙二醇（Propylene glycol) 〇 18· 如申請專利範圍第12項所述之鹿茸高分子複合 物，其中該包覆基材與該鹿茸抽取物之重量比為i : 1. 5 至 1 : 2. 7。 19· 如申請專利範圍第1 2項所述之鹿茸高分子複合 物，其係經過殺菌並以無菌方式封包，該封包方式係 為喷霧式包裝。 本紙張尺度適用中國國家標準（CNS) A4規格（210x297公釐） -----------------------IT-------- 請先讀背面之注意事項再填寫本頁各欄I £ I I h \ I order i § 〇·20 · 0·18 : 〇·55 parts weight. 14. The antler polymer compound according to claim 12, wherein the β-cyclodextrin is a pharmaceutical grade. 15. The antler polymer complex as described in claim 12, wherein the high ester is reacted with an alcohol having 12 to 18 carbons and a carboxylic acid having 8 to 18 carbons. Got it. 16 The paper size is applicable to China National Standard (CNS) Α4 specification (210x297 mm) 1297274 ·· 丨戠C8 ______J D8___ VI. Patent application scope 16. The antler polymer complex described in claim 12, wherein The protease inhibitor is a Mucus proteinase inhibitor 〇1 7. The antler polymer complex described in claim 12, wherein the organic solvent is Propylene glycol 〇18· The antler polymer compound according to claim 12, wherein the weight ratio of the coated substrate to the antler extract is i: 1. 5 to 1: 2. 7. 19. The antler polymer compound as described in claim 12, which is sterilized and packaged aseptically, and is packaged in a spray package. This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) -----------------------IT-------- Please Read the notes on the back and fill in the columns on this page.