TW201417841A - 促進經皮吸收、具有消炎止痛噴霧凝膠的安定醫藥組合物 - Google Patents
促進經皮吸收、具有消炎止痛噴霧凝膠的安定醫藥組合物 Download PDFInfo
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- TW201417841A TW201417841A TW101141957A TW101141957A TW201417841A TW 201417841 A TW201417841 A TW 201417841A TW 101141957 A TW101141957 A TW 101141957A TW 101141957 A TW101141957 A TW 101141957A TW 201417841 A TW201417841 A TW 201417841A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 239000007921 spray Substances 0.000 title claims abstract description 7
- 238000010521 absorption reaction Methods 0.000 title claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 title claims description 5
- 230000000202 analgesic effect Effects 0.000 title claims description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims abstract description 16
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940041616 menthol Drugs 0.000 claims abstract description 16
- 229960001193 diclofenac sodium Drugs 0.000 claims abstract description 15
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims abstract description 15
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 239000000787 lecithin Substances 0.000 claims description 12
- 229940067606 lecithin Drugs 0.000 claims description 12
- 235000010445 lecithin Nutrition 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 3
- 235000010469 Glycine max Nutrition 0.000 claims description 3
- 244000068988 Glycine max Species 0.000 claims description 3
- 239000002738 chelating agent Substances 0.000 claims description 2
- 230000001737 promoting effect Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 230000036407 pain Effects 0.000 abstract description 3
- 230000000699 topical effect Effects 0.000 abstract description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 2
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
- 229940035676 analgesics Drugs 0.000 abstract 1
- 239000000730 antalgic agent Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 7
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- -1 latexes Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 239000003961 penetration enhancing agent Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000001760 anti-analgesic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 2
- 229960004134 propofol Drugs 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000033309 Analgesic asthma syndrome Diseases 0.000 description 1
- 208000025978 Athletic injury Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000000604 anti-edema agent Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 229940052354 dibasic sodium phosphate heptahydrate Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- PYLIXCKOHOHGKQ-UHFFFAOYSA-L disodium;hydrogen phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O PYLIXCKOHOHGKQ-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- 229960002288 procaterol Drugs 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
雙氯芬酸鈉(Diclofenac Sodium)為目前止痛藥市場上使用最普遍及廣泛之成分。本發明係關於一種含雙氯芬酸鈉(Diclofenac sodium)4%重量百分比及薄荷醇(Menthol)1~5%之重量百分比噴霧凝膠的安定醫藥組合物，應用於局部外用消炎止痛。
Description
本發明為含雙氯芬酸鈉(Diclofenac sodium)4%重量百分比及薄荷醇(Menthol)1~5%之重量百分比噴霧凝膠的安定醫藥組合物，其安定性試驗及加速試驗結果推估其有效期限達兩年以上。其安定之醫藥組合物另含薄荷醇(Menthol)1~5%重量百分比及卵磷脂(SOYBEAN LETHICIN)5~10%重量百分比，用以促進雙氯芬酸鈉(Diclofenac sodium)滲透皮膚，達到局部外用消炎止痛。。
雙氯芬酸鈉(Diclofenac Sodium)係I965年瑞士Ciba-Geigy藥廠，利用Phenylacetic Acid誘導體所開發的一種非類固醇消炎劑(NSAID)，作用機轉為抑制前列腺素的生合成。
臨床上證實對各種疼痛性炎症，有相當卓越的效果。市面上最常見的雙氯芬酸鈉(Diclofenac Sodium)藥品劑型除錠劑、膠囊、注射劑，尚可製成軟膏、乳膠、凝膠及栓劑。其軟膏、乳膠或凝膠供局部使用時，觸感清涼不油膩，主成分可迅速滲入皮膚並分佈於皮下組織中，有效對抗急、慢性發炎反應，緩解因關節炎或運動傷害所造成之發炎腫脹及疼痛現象。
由於雙氯芬酸鈉(Diclofenac Sodium)首次通過肝臟時，有半數會被代謝掉(首度效應)，口服或以栓劑投予後之血漿濃度曲線下面積(AUC)，約為注射投予相等劑量時的一半。雙氯芬酸鈉(Diclofenac Sodium)口服製劑之禁忌為：消化性潰瘍患者、重症之血液異常患者、重症之肝障害患者、重症之腎障害患者、患有Aspirin氣喘或曾有該病史之患者。
將它製成栓劑由肛門直腸深處給藥，可避免在肝臟被分解，並防止雙氯芬酸鈉(Diclofenac Sodium)在口服時產生胃腸障礙之副作用，更因特選之基劑可在直腸內快速溶解而能加速主成分之吸收，發揮療效。
雙氯芬酸鈉(Diclofenac Sodium)4% Spray為方便之外用止痛噴劑更具有以下優點：
1.標靶性傳遞(Targeted delivery)治療，沒有全身性(NO system)治療：選擇性的治療，只限於受傷面積為200平方厘米之單關節或肌肉的炎症和疼痛，不會讓整個身體吸收的非類固醇消炎劑(NSAID)。
2.雙氯芬酸鈉(Diclofenac Sodium)4% Spray不會讓整個身體吸收雙氯芬酸鈉(Diclofenac Sodium)，沒有非類固醇消炎劑(NSAID)的系統性起源胃、腎和心血管副作用，是一個更安全的替代口服非類固醇消炎劑(NSAID)的藥物，它可提高效益/風險比，耐受性等同於安慰劑，所以治療時併用胃藥以防護胃病的副作用是沒有必要，所以使用本品除了可以減少副作用外還可減少健保及病人之支出。
本發明係利用卵磷脂(Lecithin)及薄荷醇(Menthol)來促進主成分吸收。卵磷脂被商業化使用為皮膚滲透增強劑，已發表於US patent 4,783,450，其主要Claim藥物為procaterol，作為Transmucosal或transdermal administration，其lecithin在藥劑中含量為2~40%；利用VIT-E及Lecithin作成奈米級乳化劑以促進外用皮膚製劑之安定，發表於US patent 6,780,430，該製劑應於以下之產品：antihiotics、anti-tumor
agent、anti-inflammatory agent、antipyretic、analgesia、anti-edema agent、anti-tussive agent、expectorant、depressant、muscle relaxant、antiepileptic、anti-ulcer agent等產品；另有Compressed Lecithin preparations發表於US patent 6,312,703，其組成含有20% and 100% Lecithin，該製劑應的組成是一形狀和質地適合作為化妝品的滋潤肌膚。另lecithin早已應用於liposome，發表於US patent 5,569,464及5,962,015，lecithin組成liposome使製劑可以安定。Lecithin亦應用於propofol emulsion solution，使propofol能於靜脈注射劑中乳化安定，發表於US patent7,468,394 6,743,436 6,399,087 6,326,406。而根據文獻報導(許衛銘，王暉，鄭麗燕.薄荷醇及其二組分系統對雙氯芬酸鈉的促透作用〔J〕.中國醫院藥學雜誌，2002，22(3)：160.)，對國內外近5年來薄荷醇(Menthol)在促進藥物透過皮膚、鼻腔粘膜、胃腸和口腔粘膜以及其促滲透機理的研究作了綜述，認為薄荷醇是一種很有價值的藥品滲透促進劑，具有良好的應用前景。
本發明為含雙氯芬酸鈉(Diclofenac sodium)4%重量百分
比及薄荷醇(Menthol)1-5%重量百分比之消炎止痛的安定醫藥組合物，其安定性試驗及加速試驗結果推估其有效期限達兩年以上(結果如下)：
另其安定之醫藥組合物另含卵磷脂(SOYBEAN LETHICIN)5~10%重量百分比及薄荷醇(Menthol)1-5%重量百分比用以藥品滲透促進劑，少量ASCORBYL PALMITATE抗氧化劑、MONOBASIC SODIUM PHOSPHATE MONOHYDRATE為緩衝劑、少量DIBASIC SODIUM PHOSPHATE HEPTAHYDRATE為緩衝劑、乙二胺四乙酸二鈉(EDTA-2Na)0.02~0.06%重量百分比為螯合劑、溶劑為少量ALCOHOL、丙二醇(PROPYLENE GLYCOL)10~20%重量百分比、異丙醇(ISOPROPYL
ALCOHOL)10~20%重量百分比及水加至100%重量百分比，並以鹽酸(Hydrochloric acid)10%重量百分比及氫氧化鈉(Sodium hydroxide)10%重量百分比調整其pH值為6.5~8.0。
本發明將進一步經由下列實施例而更加明確，其欲纯粹作為本發明之例證。
Claims (4)
- 一種促進經皮吸收、具有消炎止痛噴霧凝膠的安定醫藥組合物，其包括雙氯芬酸鈉(Diclofenac sodium)4%重量百分比；薄荷醇(Menthol)1~5%重量百分比；溶劑丙二醇(PROPYLENE GLYCOL)10~20%重量百分比、異丙醇(ISOPROPYL ALCOHOL)10~20%重量百分比及水加至100%重量百分比。
- 如申請專利範圍第1項，其促進經皮吸收物質為薄荷醇(Menthol)1~5%重量百分比及卵磷脂(SOYBEAN LETHICIN)5~10%重量百分比。
- 如申請專利範圍第1項，其pH值為6.5~8.0。
- 如申請專利範圍第1項，進一步包括乙二胺四乙酸二鈉(EDTA-2Na)0.02~0.06%重量百分比當螯合劑。
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