12527581252758
五、發明說明（ 本發明係關於一種製造含費洛狄平（felodipine) 口服 持，丨生釋放藥物的製造方法，尤其係指一種可使費洛狄平 在長時間緩緩釋出，以便減少忘記服藥的可能性並能控制 夜間至清晨這段時間疾病的發作之含費洛狄平口服持續性 釋放藥物的製造方法。 古費洛狄平為鈣離子阻斷劑的一種，具有增加冠狀動脈 血"M·里與心肌氧氣供應，及擴張末稍血管減低阻力的作用 =在6m床上廣泛應用於狹心症及高血壓的治療，在治療上 ::碰到的困擾是病人忘了服藥；另一方面則是對夜間至 ’月晨這段時間病發作的抑制亦感困難。 依我國第7_234號專利案（公告〇97677號）係有關 延長㈣之新醫藥製劑’其特徵是將極低溶解度之活性化 &物尤其經取代之二氫卩ϋ啶，如費洛狄平，將其溶於 分散於半固態或液態非離子助溶劑，其助溶劑之重量至一 等於活性化合物之量，使其具有高生物利用率。 基於以上所述，本發明之目的係為了製造一種費 千口服持續性釋放錠’其可使㈣狄平在長時間緩緩釋 二:需間隔24小時服用一錠即可，不僅減少忘記服藥 可此，亦能控制夜間至清晨這段時間疾病的發作。 基於以上所述，本發明的目的在於提高藥物溶出率， 達成持續釋放之效果，解決f用技術在製程上之困難。 上述本發明之目的係由以下完成：以親水離子㈣面活㈣#助關，與水純極低的費1 、’elodlpine)混合或濕式製粒，來增加藥物溶出之 少 出 的 (請先閱讀背面之注意事*8^填寫本頁) ι·ί 丨裝 訂‘ 國家#?規格⑽x 297公爱了 !252758 B7 五、發明說明（/)2速率，再加人親水性凝膠、疏水 緩釋劑，來混合或濕式製粒。 H貝物質當 圖式之簡單說明： Q)圖一 ⑵圖二 費洛狄平溶離率比較。 費洛狄平溶離率比較。 ⑶圖三：人體血液中含費洛狄平之濃度曲線。 發明之詳細說明： 本發明之主要製程為：以親水性高分子化合物 『二面活性劑：助溶劑，與水溶性極低的費 Wd聊e)混合或濕式製粒；再加人親水性凝膠、於水 、纖維素純質物質當緩釋劑，來混合或濕式製粒，以 成一具有持續性緩釋費洛狄平成份之藥物，其中各成份 主要含量範圍為:費洛狄平：〇·5_5%重量百分比；助溶 :4〇’%重量百分比；與緩釋劑：10-40%重量百分比： 更詳細地說，本發明之費洛狄平口服持續性釋放鏡的 I法如下：首先將費洛狄平與離子型界面活性劑或親水性 尚分子化合物之助溶劑，及親水性凝膠、疏水性纖維素或 «物質之緩釋劑混合均勻。必要時可再加人稀釋劑，、如 微結晶纖維素、乳糖或二氧切等混合均自，必要時此組 =物可再混以潤滑劑，經打键機壓製成錠劑或充填在硬 囊内；或用水或有機溶#丨以濕式製粒法煉合製成顆粒，… 顆粒經乾燥後，再混以潤滑劑後，經打錠機壓製成錠劑或 充填在硬膠囊内，必要時可於包衣锅（⑽ting _)内 頁 形 之劑 膠此 錠劑被覆一層具阻光作用的膜衣。 為 本紙張尺度適用中關家標準f NS)A4規格咖χ挪公爱「 Ϊ252758 A7 --------E_______ 五、發明說明（汐） *本發明所用離子型界面活性劑之助溶齊1，其佔總助溶 ^中之合里| 3G-9G%重量百分，並可為：續基琥拍酸二 辛酯鈉或硫酸月桂酯納。 本發明所用親水性高分子化合物之助溶劑，其佔總助 岭剡中之含^為40-90%重量百分比，並可為：乙烯四氫 W略酮（pvp)、乙基纖維素⑽c)、經丙基纖維素（Hpc) 、羥丙基曱基纖維素（HPMC)或聚乙烯醇（PVA)。 本發明所用緩釋劑可為：明膠、蟲膠、羥丙基曱基纖 維素（HPMC)、甲基纖維素（Mc)、乙基纖維素（Ec)、羥丙基 曱基纖維笨一甲酸鹽（HPMCP)、乙酸苯二曱基纖維素（CAp) 、甲基丙烯酸/甲基丙烯酸曱酯共聚物、聚乙烯乙酸苯二 甲酸（PVAP)、二十二酸甘油酯（glyceryl behenate)、石蠟 (paraffin wax)或棕櫚 4 鼠（carnauba wax)。 本1¾明所用稀釋劑可為：微結晶纖維素、殺粉、乳糖 、一氧化碎、碟酸氫詞、鱗酸妈、碳酸齊、碳酸鎮、石夕酸 鋁、矽酸鎂或甘露醇。 本發明所用溶劑可為：水、乙醇、丙酮、異丙醇、二 氯甲烷或其混合溶媒。 本發明所用潤滑劑可為：滑石粉、硬脂酸、硬脂酸鹽 、延胡索硬脂酸鈉（sodium stearyl fumarate)或二十二酸 甘油醋（glycery behenate)。 本發明所用阻光作用之膜衣為··羥丙基甲基纖維素、 聚乙二醇、二氧化鈦與氧化鐵。 以下實施例作為舉例說明本發明，惟本發明之專利保 5 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） ---1 I I L I I I - — — — 1111 ^ ^--I I ί I I I (請先閱讀背面之注意事項再填寫本頁) 1252758 A7 五、發明說明（^/) 護範圍並非侷限於此等實施例 圍為主。 實例一： 而應以後附之申請專 利範 費洛狄平（felodipine) lg 羥丙基纖維素 72g 一十^一酸甘油自旨 15g 步驟： 將費洛狄平（felodipine)lg、羥丙基纖維素72呈方 十二酸甘油酯15g混合均勻，經迴轉式打錠機壓製成片、厂 11.0mm，硬度3-8kgf之圓形雙凸面錠劑。 也 實例二： 費洛狄平（felodipine) 羥丙基曱基纖維素 二十二酸甘油酯 乳糖 二氧化矽 步驟： 將費洛狄平（felodipine) lg、幾 十二酸甘油酯24g、乳糖8g與二氧化矽Hg混合均 經迴轉式打錠機壓製成片徑lh〇mm，硬度3_8Kgf之 圓形雙凸面旋劑。 實例三： 費洛狄平（felodipine) \g 乙烯四氫毗咯酮 62g lg44g24g8gHg 丙基甲基纖維素44gV. INSTRUCTIONS OF THE INVENTION (The present invention relates to a method for producing a drug containing felodipine orally, a drug for releasing a sputum, and in particular to a method for slowly releasing felodipine over a long period of time in order to reduce A method for the manufacture of oral sustained-release drugs containing felodipine that forgets the possibility of taking the drug and can control the onset of the disease from night to morning. Gufelopipine is a calcium blocker with increased coronary blood flow. "M·Li and myocardial oxygen supply, and the effect of dilating the last vascular reduction resistance = widely used in the treatment of angina and hypertension in the 6m bed, in the treatment: the trouble encountered is that the patient forgot to take the medicine; On the other hand, it is also difficult to suppress the onset of the disease from night to month. According to China Patent No. 7_234 (Announcement No. 97677), the new pharmaceutical preparations related to extension (4) are characterized by extremely low Solubility activation & the substance, especially substituted dihydroacridine, such as valopidine, is dissolved in a semi-solid or liquid nonionic cosolvent, the weight of the cosolvent is equal to one The amount of the compound is such that it has a high bioavailability. Based on the above, the object of the present invention is to produce a thousand oral sustained release ingots, which can make (iv) Diping slowly release for a long time: need to be separated Taking one tablet for 24 hours can not only reduce the forgetting to take the medicine, but also control the onset of the disease from night to early morning. Based on the above, the object of the present invention is to improve the dissolution rate of the drug and achieve the effect of sustained release. f The difficulty in using the technique in the process. The above object of the present invention is accomplished by the following: mixing with hydrophilic ions (four) surface (four) # assisting off, mixing with water purely low cost 1, 'elodlpine' or wet granulation, Increase the amount of drug dissolution (please read the note on the back *8^ fill this page) ι·ί 丨 装 ' Country #? Specifications (10) x 297 public! 252758 B7 V, invention description (/) 2 rate, A hydrophilic gel or a hydrophobic slow release agent is added for mixing or wet granulation. H shell material as a brief description of the pattern: Q) Figure 1 (2) Figure 2 Comparison of the dissolution rate of felotidipine. Comparison of the dissolution rate of felodipine. (3) Figure 3: Concentration curve of felotidipine in human blood. DETAILED DESCRIPTION OF THE INVENTION: The main process of the present invention is: mixing or wet granulation with a hydrophilic polymer compound "two-sided active agent: co-solvent, and extremely low water solubility"; Gel, water, cellulose pure substance as a sustained release agent, mixed or wet granulation, to form a sustained sustained release of the drug of the composition of the ingredients, the main content of each component is: Ferodi Flat: 〇·5_5% by weight; solubilization: 4 〇 '% by weight; and sustained release agent: 10-40% by weight: In more detail, the felodipine oral sustained release lens of the present invention I The method is as follows: First, the homodipine is mixed with an ionic surfactant or a hydrophilic molecular compound, and a hydrophilic gel, a hydrophobic cellulose or a substance sustained release agent. If necessary, a thinner may be added, such as microcrystalline cellulose, lactose or dioxo, etc., if necessary, the group can be mixed with a lubricant, pressed into a tablet by a key press or filled in In the hard capsule; or by water or organic solvent #丨 by wet granulation method to make granules,... After the granules are dried, and then mixed with a lubricant, they are pressed into a tablet by a tableting machine or filled in a hard capsule. If necessary, the tablet may be coated with a film having a light blocking effect in a coating pan ((10) ting _). For the paper scale, the standard of the national standard is adopted. f NS) A4 specification χ χ χ 「 Ϊ Ϊ 758 758 758 758 758 758 758 758 758 758 758 758 758 758 758 758 758 758 758 758 Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Ϊ Qi1, which accounts for 3G-9G% by weight of the total solubilization solution, and can be: sodium succinate or sodium lauryl sulfate. The hydrophilic polymer compound used in the present invention The co-solvent, which accounts for 40-90% by weight of the total sorghum, can be: ethylene tetrahydro W-ketone (pvp), ethyl cellulose (10) c), propyl cellulose (Hpc) Hydroxypropyl decyl cellulose (HPMC) or polyvinyl alcohol (PVA). The sustained release agent used in the present invention may be: gelatin, shellac, hydroxypropyl decyl cellulose (HPMC), methyl cellulose (Mc) ), ethyl cellulose (Ec), hydroxypropyl fluorenyl fiber monomethylate (HPMCP), phenylenediphenyl cellulose (CAp), methacrylic acid / methacrylate copolymer, polyethylene Phthalic acid phthalate (PVAP), glyceryl behenate, paraffin wax or carnauba wax. It may be: microcrystalline cellulose, powdered powder, lactose, oxidized slag, hydrogen sulphuric acid word, scaly mother, carbonated carbonate, carbonated acid, aluminum alumite, magnesium citrate or mannitol. The solvent used in the present invention may be : water, ethanol, acetone, isopropanol, dichloromethane or a mixed solvent thereof. The lubricant used in the present invention may be: talc, stearic acid, stearate, sodium stearyl fumarate or Glycerin behenate. The filming agent for the light blocking effect used in the present invention is hydroxypropylmethylcellulose, polyethylene glycol, titanium oxide and iron oxide. The following examples illustrate the invention by way of example. However, the patent of this invention is 5 The paper size applies to the Chinese National Standard (CNS) A4 specification (210 297 297 mm) ---1 IILIII - — — — 1111 ^ ^--II ί III (Please read the note on the back first) 1252758 A7 V. INSTRUCTIONS (^/) The scope of protection is not limited to these examples. Example 1: The patent application should be attached to the patent felodipine lg hydroxypropyl Cellulose cellulose 72g Glycerin from the purpose of 15g Steps: Felotipine (felodipine) lg, hydroxypropyl cellulose 72 is 15g of quaternary acid monoglyceride, evenly mixed, compressed into a tablet by a rotary tableting machine, plant 11.0mm, hardness 3- 8kgf round biconvex lozenge. Also example 2: felodipine hydroxypropyl decyl cellulose glutaric acid glyceride lactose cerium oxide step: felodipine lg, several 24 g of dodecyl glyceride, 8 g of lactose and Hg of cerium oxide were compressed by a rotary tableting machine into a circular double convex surface spinning agent having a diameter of lh 〇 mm and a hardness of 3_8 Kgf. Example 3: felodipine \g ethylene tetrahydropyrrolidone 62g lg44g24g8gHg propylmethylcellulose 44g
(請先閱讀背面之注意J 事 填寫本頁j •裝 勻 6 1252758 A7 ________B7__ 五、發明說明（；） 二十二酸甘油g旨 12g 碟酸氫妈 1 Og 乳糖 3g 步驟：將費洛狄平（felodipine)lg、乙烯四氫p比咯酮62g、 二十二酸甘油酯12g、構酸氫妈10g與乳糖3g混合均勻 ，經迴轉式打錠機壓製成片徑11· Omm，硬度3-8Kgf之圓 形雙凸面錠劑。 實例四·· ⑴費洛狄平（felodipine) lg 硫酸月桂S旨納 44g 二十二酸甘油醋 24g 二氧化矽 1.6g 乳糖 17g ⑵水 適量 ⑶硬脂酸鎂 〇. 4g 步驟： 將⑴項物質費洛狄平（felodine)lg、硫酸月桂酯鈉 44g、二十二酸甘油酯24g、二氧化矽1.6g與乳糖17g混 合均勻；以⑵項之水加入煉合製粒，濕粒經5 0 °C定溫乾 燥至含水率在〇· 4〜6%(w/w)後再與⑶項物質硬脂酸鎂 0.4g混合均勻，充填在硬膠囊内。 實例五： ⑴費洛狄平（felodipine) lg 本紙張尺度適用中國國家標準（CNS)A4規格（210x297公釐） (請先閱讀背面之注意事_填寫本頁) l»i ，裝 訂· # 1252758 A7 ______— B7 五、發明說明（^) 硫酸月桂酯鈉 lg 羥丙基曱基纖維素 48g 微結晶維維素 2g 二氧化矽 30g 乳糖 4g ⑵酒精 適量 ⑶延胡索硬脂酸鈉（s〇dium stearyl fumarate) 2g ⑷羥丙基甲基維維素 4. 39g 聚乙二醇 0.79g 二氧化鈦 〇.21g 純水 適量 95%酒精 適量 步驟： (請先閱讀背面之注意事項_填寫本頁) 丨裝 .Γ訂· 將⑴項物質費洛狄平（fel〇dipine)lg、硫酸月桂酯鈉 、羥丙基曱基纖維素48g、微結晶纖維素2g、二氧化矽 3〇g與乳糖4g首先混合均勻；以⑵項之酒精加入煉合製 粒，濕粒經45°C定溫乾燥至含水率在〇.4〜6%(w/w)後； 再與⑶項物質延胡索硬脂酸鈉（s〇dium stearyl fumarate)2g混合均勾，經迴轉式打錠機壓製成片徑 11.0mm，硬度3〜8Kgf之圓形雙凸面錠劑；此錠劑再於包 衣鍋内被覆上含⑷項物質羥丙基甲基纖料4 39g、聚乙 二醇〇.79g、二氧化鈦〇.21g與氧化鐵〇.叫之膜衣。 實例六： 8 本紙張尺度適用中國國家標準（CNS)A4規格（2l〇T^7i^-—~ ----- 1252758 A7 B7 五、發明說明（y ) 費洛狄平（felodipine) ig 微結晶纖維素 24g 一氧化石夕 30g 乳糖 3g 一'十二酸甘油酷 30g 步驟： 將⑴項物質費洛狄平（fel〇dipine) lg、微結晶纖維素 2½、二氧化矽30g、乳糖3g與二十二酸甘油酯3吆混合 均勻，經迴轉式打錠機壓製成徑u〇mm，硬度3〜8Kgf之 圓形雙凸面錠劑，當做未加助溶劑之對照組。 >谷離試驗： 將K Μ例一至實施例六含藥製品與市售已知含等量之 費洛狄平持續釋放鍵，用符合美國藥典規範圍2 4版之溶 =試驗機來做溶離試驗，取G1N鹽酸溶液（含油酸 來醇山梨酯）9〇〇mL當作溶離試驗液，倒入溶離試驗槽中 ，加熱至37±0.5t，用裝置n之騎槳（paddle)，調整 轉速在5〇rpm，測其溶離率對時間之曲線圖。 其結果列於表一、圖一及圖二。 由表一得知實施例一至實施例五含藥劑製品，與市售 已知含等量之費洛狄平持續釋放錠，在^謂鹽酸溶液 0·1%油酸聚醇山梨醋）中，都有持續釋放效果，且在2〇小 時其溶離率都在75%以上，對照組之實施例六含藥製品， 在20小日守只有6, 6%溶出率，表示本發明製品可提高㈣ 浴出率，並達持續釋放之效果。 本紙張尺;ΐ適用中ϋ標準_(.CNS)A4規格⑵Q χ 297公髮)---------_ (請先閱讀背面之注意事*^填寫本頁) 丨裝_ ! #_ -ϋ ϋ κι · 1252758 A7 五、發明說明（y 等二；示以實例一及實例二之旋劑，與市售已知含 洛狄平持續釋放錠，m鹽酸㈣（含〇,1% …來醇山梨_)巾的f洛狄平溶離率比較。 酸、容【Γ人:顯示以實例三至實施例六之錠劑，在〇.in鹽 r液G 0.1%油酸聚醇山梨醋）中的費洛狄平溶離率比 季父。 體内人體試驗： 士，將貝％例五含藥製品與市售已知含等量之費洛狄平持 續釋放錠，測試在人體血中濃度變化，在服下含10mg費 洛狄平含藥製品後，其結果列於表二及圖三。 (請先閱讀背面之注意事項#(填寫本頁) ι·ΐ 裝 表一：在0· 1N鹽酸溶液（含〇· 1%油酸聚醇山梨酯） 雙間(小時) 市售產品 實施例一 實施例二 實施例三 實施例四 實施例五 實施例六 0 -—----- 0 0 0 0 0 0 7^* v w 1 1 0 _0· 25 7.31 0.20 2.32 0. 98 48. 39 2. 53 0. 94__ 0. 50 — 8. 24 0.20 3. 68 1· 57 51. 69 4. 62 1.76一 0. 75 — 9. 60 0. 00 4. 59 2. 16 54.55 6. 52 1. 76_ —1 10. 69 1.38 6· 01 2. 95 56. 55 8. 47 2.85__ —2 15. 93 3. 36 11. 97 14. 74 61. 31 16. 96 3. 58_ 一 4 28. 08 11.45 26. 05 35. 56 64. 93 35. 26 4.43 6 -—-— 41. 40 22. 51 42. 98 51.86 67. 10 55. 38 4. 43一 8 --- 53. 83 32. 79 57. 06 66. 01 70. 51 70.81 4.66_ 10 *— 65. 78 43. 26 68. 02 75. 45 73. 09 81. 91 5. _ 12 77. 29 53. 52 74. 42 80. 76 74. 24 84. 93 5. 51 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 訂· #· 1252758 A7 B7 五、發明說明（f ) 14 84. 13 61.42 78. 21 83. 71 74. 66 85. 76 5. 51 16 89. 45 67. 93 81. 26 86. 07 75. 51 86. 63 5. 75 18 93. 36 74. 05 83. 99 87. 64 76. 08 87. 02 6. 60 20 95. 88 79. 18 85. 65 88. 62 76. 79 87. 98 6. 60 22 97. 14 82. 54 87. 05 88. 43 77. 21 87. 65 6. 60 24 98. 34 85. 30 88. 84 88. 82 77. 64 87. 99 6. 83 表二：在人體血液中含費洛狄平濃度（ng/mL) 時間（小時） 市售產品 實施例五 0 0 0 0· 5 1. 03 0. 553 1. 0 2. 02 2. 54 1.5 3. 62 3.46 2. 0 4. 16 4. 38 2. 5 4. 09 4. 17 3. 0 4.21 3. 74 3. 5 3.88 3. 51 4. 0 3.28 3. 22 5. 0 3. 20 2.84 6. 0 2.45 2. 23 8. 0 1. 57 1. 57 10. 0 1. 30 1. 23 11 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項#|填寫本頁) 訂·-- 1252758 五 A7 B7(Please read the note on the back first. J. Fill in this page. j • Mix well 6 1252758 A7 ________B7__ V. Invention description (;) Twenty-two acid glycol g 12g Dissolved hydrogen hydrogen mother 1 Og Lactose 3g Step: Will be adipine (felodipine) lg, ethylene tetrahydropyrrolidone 62g, dodecanoic acid glyceride 12g, phytic acid hydrogen mother 10g and lactose 3g mixed evenly, compressed by a rotary tableting machine to a diameter of 11·Omm, hardness 3- 8Kgf round biconvex lozenge. Example 4· (1) Felodidipine lg Sulfate Laurel S. Na. 44g Twenty-two acid glycerin vinegar 24g Ceria 1.6g Lactose 17g (2) Water amount (3) Magnesium stearate g. 4g Step: Mix the substance (1), felodine lg, sodium lauryl sulfate 44g, glutaric acid ester 24g, cerium dioxide 1.6g and lactose 17g; add water according to item (2) The granules were prepared, and the wet granules were dried at a temperature of 50 ° C until the water content was 〇·4 to 6% (w/w), and then uniformly mixed with 0.4 g of magnesium stearate (3), and filled in a hard capsule. Example 5: (1) felodipine lg This paper scale applies to China National Standard (CNS) A4 specification (210x297 public) (Please read the note on the back _ fill out this page) l»i, binding · # 1252758 A7 ______— B7 V. Description of invention (^) Sodium lauryl sulfate lg Hydroxypropyl fluorenyl cellulose 48g Microcrystalline Vivi 2g bismuth dioxide 30g lactose 4g (2) alcohol amount (3) sodium stearyl fumarate 2g (4) hydroxypropyl methyl vecnene 4. 39g polyethylene glycol 0.79g titanium dioxide 〇.21g pure water amount Steps for 95% alcohol: (Please read the notes on the back _ fill out this page) 丨装.Γ定· (1) Substance felodipine (fel〇dipine) lg, sodium lauryl sulfate, hydroxypropyl sulfhydryl 48g of cellulose, 2g of microcrystalline cellulose, 3〇g of cerium oxide and 4g of lactose are firstly mixed uniformly; the alcohol of (2) is added to the smelting granulation, and the wet granule is dried at 45 ° C until the water content is 〇.4 After ~6% (w/w); and then mixed with (2) substance 2, sodium stearyl stearate (s〇dium stearyl fumarate) 2g, pressed by a rotary tableting machine to make a diameter of 11.0mm, hardness 3~8Kgf Round double convex lozenge; the lozenge is then coated with the (4) substance hydroxypropyl in the coating pan Methyl fiber material 4 39g, polyethylene glycol 〇.79g, titanium dioxide 〇.21g and iron oxide 〇. Called film coating. Example 6: 8 This paper scale applies to China National Standard (CNS) A4 specifications (2l 〇 T ^ 7i^--~ ----- 1252758 A7 B7 V. Description of invention (y) felodipine ig microcrystalline cellulose 24g nitric oxide eve 30g lactose 3g a 'dodecanoic acid cool 30g Step: The substance (1), fel〇dipine, lg, microcrystalline cellulose 21⁄2, cerium oxide 30g, lactose 3g, and glutaric acid glyceride are uniformly mixed, and pressed into a diameter u by a rotary tableting machine. 〇mm, round double convex lozenge with a hardness of 3~8Kgf, as a control group without added solvent. > Deviation test: K Μ 例 例 例 Example 6 drug-containing products and commercially available known sustained-release bonds of the same amount of felodipine, using a solution = 24 test machine in accordance with the scope of the United States Pharmacopoeia regulations For the dissociation test, take 9 〇〇mL of G1N hydrochloric acid solution (containing oleic acid sorbate) as the dissolution test solution, pour into the dissolution test tank, heat to 37±0.5t, and adjust with the paddle of the device n. The rotation speed was measured at 5 rpm, and the elution rate versus time was measured. The results are shown in Table 1, Figure 1 and Figure 2. From Table 1, it is known that the pharmaceutical preparations of the first embodiment to the fifth embodiment are commercially available with an equal amount of the sustained release tablet of felopimine, in the case of hydrochloric acid solution 0.1% oleic acid sorbitol vinegar, It has a sustained release effect, and its dissolution rate is above 75% at 2 hours. In the control group, the six drug-containing products have a dissolution rate of only 6% at 20 days, indicating that the product of the present invention can be improved (4) Bathing rate and the effect of sustained release. This paper ruler; ΐApplicable to the Chinese standard _(.CNS)A4 specification (2)Q χ 297 cc)---------____ (Please read the note on the back*^fill this page) 丨 _ ! #_ -ϋ ϋ κι · 1252758 A7 V. Inventive Note (y, etc.; showing the spinners of Example 1 and Example 2, and commercially available Ledipine sustained release ingots, m hydrochloric acid (4) (including bismuth, 1 % ... to the alcohol Yamanashi _) towel flodidine dissolution rate comparison. Acid, capacity [Γ人: shows the tablet of Example 3 to Example 6, in 〇.in salt r liquid G 0.1% oleic acid polyalcohol The dissolution rate of felodipine in sorbet is higher than that of the season father. In vivo human test: Shi, the sample containing five parts of the five drug-containing products and the commercially available isoproterenol tablets containing sustained release tablets, test the concentration changes in human blood, under the service containing 10mg of felopidine After the pharmaceutical products, the results are shown in Table 2 and Figure 3. (Please read the precautions on the back # (fill in this page) ι·ΐ Packing Table 1: in 0·1N hydrochloric acid solution (containing 〇·1% oleic acid sorbitan) Double room (hour) Commercial product example Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5 Embodiment 6 0 ------ 0 0 0 0 0 0 7^* vw 1 1 0 _0· 25 7.31 0.20 2.32 0. 98 48. 39 2 53 0. 94__ 0. 50 — 8. 24 0.20 3. 68 1· 57 51. 69 4. 62 1.76 — 0. 75 — 9. 60 0. 00 4. 59 2. 16 54.55 6. 52 1. 76_ —1 10. 69 1.38 6· 01 2. 95 56. 55 8. 47 2.85__ —2 15. 93 3. 36 11. 97 14. 74 61. 31 16. 96 3. 58_ A 4 28. 08 11.45 26 05 35. 56 64. 93 35. 26 4.43 6 ---- 41. 40 22. 51 42. 98 51.86 67. 10 55. 38 4. 43-8 --- 53. 83 32. 79 57. 06 66. 01 70. 51 70.81 4.66_ 10 *— 65. 78 43. 26 68. 02 75. 45 73. 09 81. 91 5. _ 12 77. 29 53. 52 74. 42 80. 76 74. 24 84 93 5. 51 The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). · # 1252758 A7 B7 V. Inventions (f) 14 84. 13 61.42 78. 21 83. 71 74 66 85. 76 5. 51 16 89. 45 67. 93 81. 26 86. 07 75. 51 86. 63 5. 75 18 93. 36 74. 05 83. 99 87. 64 76. 08 87. 02 6. 60 20 95. 88 79. 18 85. 65 88. 62 76. 79 87. 98 6. 60 22 97. 14 82. 54 87. 05 88. 43 77. 21 87. 65 6. 60 24 98. 34 85. 30 88. 84 88. 82 77. 64 87. 99 6. 83 Table 2: Condotripine concentration (ng/mL) in human blood Time (hours) Commercial product example 5 0 0 0· 5 1. 03 0. 553 1 0 2. 02 2. 54 1.5 3. 62 3.46 2. 0 4. 16 4. 38 2. 5 4. 09 4. 17 3. 0 4.21 3. 74 3. 5 3.88 3. 51 4. 0 3.28 3 . 22 5. 0 3. 20 2.84 6. 0 2.45 2. 23 8. 0 1. 57 1. 57 10. 0 1. 30 1. 23 11 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back #|fill this page) Order·- 1252758 V A7 B7
由表二得知實施例五含藥製品與市售已知含等量之費 :狄平持續釋放錠’在人體可用率都可錢24小時高活 、發明說明（/C)) 圖三：顯示以實例五之錠劑與市售已知含等量之 狄平持續釋放錠，在人體血液中含費 甘士 η , 5 W /口狄十之濃度曲線； 并T Reference Tab.為市售之費洛狄孚 τ , ^ _ 買，合狄十持績釋放錠，Test iab.為實例五之錠劑。 本發明之費洛狄平口服持續性釋访 項優點： “性釋放樂物’具有下列幾 (1)由於可使費洛狄平持續性釋出 ^ κ1怦可減少服用次數及 病人1¾忘醫嘱的可能。 ⑵持續性釋放之費洛狄W液巾的濃度變動較小， 有較好的病人忍受性。 综^述，本案實具有新穎性並為_具有高度創作之 电明’為此具文中請發明專利，懇請責審查委員早賜專 利，至感公便。From Table 2, it is known that the five parts of the drug-containing products and the commercially available products contain the same amount of fees: Diping continuous release ingots can be used for 24 hours in the human body, and the invention instructions (/C)) Shows the tablet of Example 5 and the commercially available equivalent of Diping continuous release ingot, containing the concentration curve of Fagans η, 5 W / Di Di 10 in human blood; and T Reference Tab. The Froudefu τ, ^ _ buy, He Di ten sustained release ingot, Test iab. For example five lozenges. Advantages of oral sustained release of the felodipine of the present invention: "Sexual release music" has the following (1) because the sustained release of pedopalin can reduce the number of administrations and the patient's medical treatment (2) The sustained release of the Ferodi W liquid towel has a small change in concentration and has better patient tolerance. In summary, the case is novel and is highly creative. In the article, please invent the patent, and ask the reviewing committee to give the patent as soon as possible.