JPH03246233A - Drug composition for transmucosal administration - Google Patents
Drug composition for transmucosal administrationInfo
- Publication number
- JPH03246233A JPH03246233A JP2043921A JP4392190A JPH03246233A JP H03246233 A JPH03246233 A JP H03246233A JP 2043921 A JP2043921 A JP 2043921A JP 4392190 A JP4392190 A JP 4392190A JP H03246233 A JPH03246233 A JP H03246233A
- Authority
- JP
- Japan
- Prior art keywords
- drug
- hyaluronic acid
- composition
- salt
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 46
- 229940079593 drug Drugs 0.000 title claims abstract description 44
- 239000000203 mixture Substances 0.000 title claims abstract description 20
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 28
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 28
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 28
- 229960003726 vasopressin Drugs 0.000 claims abstract description 20
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 claims abstract description 18
- 108010004977 Vasopressins Proteins 0.000 claims abstract description 18
- 102000002852 Vasopressins Human genes 0.000 claims abstract description 18
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 claims abstract description 18
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 claims abstract description 17
- 229960004281 desmopressin Drugs 0.000 claims abstract description 17
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims abstract description 8
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims abstract description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 230000000694 effects Effects 0.000 abstract description 9
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000813 peptide hormone Substances 0.000 abstract description 3
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 abstract description 3
- 108060001064 Calcitonin Proteins 0.000 abstract description 2
- 102000055006 Calcitonin Human genes 0.000 abstract description 2
- 108090001061 Insulin Proteins 0.000 abstract description 2
- 102000004877 Insulin Human genes 0.000 abstract description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 abstract description 2
- 229960004015 calcitonin Drugs 0.000 abstract description 2
- 229940125396 insulin Drugs 0.000 abstract description 2
- 210000004877 mucosa Anatomy 0.000 abstract 2
- 238000013329 compounding Methods 0.000 abstract 1
- 239000012528 membrane Substances 0.000 abstract 1
- 238000010521 absorption reaction Methods 0.000 description 21
- 239000008363 phosphate buffer Substances 0.000 description 14
- 230000002686 anti-diuretic effect Effects 0.000 description 11
- XASIMHXSUQUHLV-UHFFFAOYSA-N camostat Chemical compound C1=CC(CC(=O)OCC(=O)N(C)C)=CC=C1OC(=O)C1=CC=C(N=C(N)N)C=C1 XASIMHXSUQUHLV-UHFFFAOYSA-N 0.000 description 6
- 229960000772 camostat Drugs 0.000 description 6
- 210000002700 urine Anatomy 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 210000004400 mucous membrane Anatomy 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000002850 nasal mucosa Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229940010747 sodium hyaluronate Drugs 0.000 description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 2
- 108010037003 Buserelin Proteins 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 1
- 208000035859 Drug effect increased Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010021717 Nafarelin Proteins 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003688 hormone derivative Substances 0.000 description 1
- 239000000815 hypotonic solution Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 description 1
- 229960002333 nafarelin Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は経粘膜投与用薬剤組成物、特に主たる薬効成分
の吸収改善に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a pharmaceutical composition for transmucosal administration, particularly to improving the absorption of a main medicinal ingredient.
［従来技術］
従来、全身効果を期待する医薬品は経口投与製剤または
注射剤が中心であった。しかし、新たに医薬品として注
目されつつあるペプチドホルモンやプロスタグランジン
のような生理活性物質は、消化管や肝臓で分解または代
謝を受けるため経口投与では全く効果がない。しかも生
物学的半減期が短く、注射では頻回投与が必要となる。[Prior Art] Conventionally, pharmaceuticals expected to have systemic effects have mainly been oral preparations or injections. However, physiologically active substances such as peptide hormones and prostaglandins, which are newly attracting attention as pharmaceuticals, are completely ineffective when administered orally because they are degraded or metabolized in the gastrointestinal tract and liver. Moreover, it has a short biological half-life and requires frequent injections.
そこで、薬物が肝臓を経ることなく直接血中に入る投与
方法として経皮・経粘膜投与が注目されるようになって
きた。Therefore, transdermal/transmucosal administration has been attracting attention as an administration method in which drugs directly enter the blood without passing through the liver.
［本発明が解決しようとする課題］
しかしながら、皮膚や粘膜は本来外界からの侵襲を防止
するための器官であって、薬物の吸収は必ずしも十分で
はない。とりわけ親水性の高い薬物や高分子量の薬物は
吸収されに＜＜、その吸収性改善が望まれていた。[Problems to be Solved by the Present Invention] However, the skin and mucous membranes are originally organs for preventing invasion from the outside world, and absorption of drugs is not necessarily sufficient. In particular, highly hydrophilic drugs and high molecular weight drugs are difficult to absorb, and it has been desired to improve their absorption.
本発明は前記従来技術の課題に鑑みなされたものであり
、その目的は良好な薬剤吸収性を有し、安全性の高い経
粘膜投与用薬剤組成物を提供することにある。The present invention has been made in view of the problems of the prior art, and its purpose is to provide a drug composition for transmucosal administration that has good drug absorption and is highly safe.
［課題を解決するための手段］
前記目的を達成するために本発明者らが鋭意研究をかさ
ねた結果、経粘膜投与用薬剤にヒアルロン酸ないしその
塩を加えることにより薬剤吸収性が解決されることを見
出した。[Means for Solving the Problem] In order to achieve the above object, the present inventors have made extensive research, and as a result, drug absorption has been solved by adding hyaluronic acid or a salt thereof to a drug for transmucosal administration. I discovered that.
すなわち、本出願の請求項１記載の経粘膜投与用薬剤組
成物は、薬剤とヒアルロン酸及び／またはその塩を含有
することを特徴とする
請求項２記載の経粘膜投与用薬剤組成物は、薬剤がペプ
チド性薬剤からなり、蛋白分解酵素阻害剤を含むことを
特徴とする
請求項３記載の経粘膜投与用薬剤組成物は、薬剤がバソ
プレッシンからなり、ｐＨが略４に調整されたことを特
徴とする
請求項４記載の経粘膜投与用薬剤組成物は、薬剤がデス
モプレッシンからなり、ｐＨが略４に調整されたことを
特徴とする。That is, the pharmaceutical composition for transmucosal administration according to claim 1 of the present application contains a drug and hyaluronic acid and/or a salt thereof. The drug composition for transmucosal administration according to claim 3, wherein the drug is a peptide drug and contains a protease inhibitor, the drug composition is characterized in that the drug consists of vasopressin and the pH is adjusted to approximately 4. The drug composition for transmucosal administration according to claim 4 is characterized in that the drug consists of desmopressin and the pH is adjusted to approximately 4.
以下本発明の構成について詳しく説明する。The configuration of the present invention will be explained in detail below.
本発明に用いるヒアルロン酸はヒアルロン酸まはたはそ
の塩であればよく、その塩としてはＮａ塩、Ｋａ塩など
をあげることができる。本発明は上記に限定されるもの
ではないが、その中で特にＮａ塩が好ましい。The hyaluronic acid used in the present invention may be hyaluronic acid or a salt thereof, and examples of the salt include Na salt and Ka salt. Although the present invention is not limited to the above, Na salt is particularly preferred.
本発明に用いるヒアルロン酸またはその塩の配合量は、
薬剤組成物全量中０．０００１〜２重量％であり、好ま
しくは０．１〜１．５重量％の範囲を挙げる事ができる
。０．０００１重量％未満では本発明の効果が十分に期
待できない。また２重量％をこえると粘性が大きすぎて
製剤上不都合であり、コスト的にも不利である。The amount of hyaluronic acid or its salt used in the present invention is:
The amount is 0.0001 to 2% by weight, preferably 0.1 to 1.5% by weight based on the total amount of the pharmaceutical composition. If the amount is less than 0.0001% by weight, the effects of the present invention cannot be fully expected. Moreover, if it exceeds 2% by weight, the viscosity is too high, which is inconvenient in terms of formulation and also disadvantageous in terms of cost.
また、本発明に用いるヒアルロン酸またはその塩の分子
量は特に限定されるものではないが８５万以上が好まし
い。なお、分子量が余りに小さいと製剤が投与部位から
流出しやすく、粘膜への付着性が不十分である。Further, the molecular weight of hyaluronic acid or its salt used in the present invention is not particularly limited, but is preferably 850,000 or more. Note that if the molecular weight is too small, the preparation will easily flow out from the administration site and will have insufficient adhesion to mucous membranes.
本発明の薬剤組成物のｐＨは用いる薬剤の特性により異
なるが、ヒト粘膜の生理的環境及びヒアルロン酸の安定
性の点からｐＨ４〜ｐＨ８が好ましく、特にｐＨ４近傍
で優れた薬剤吸収促進効果が得られる。The pH of the pharmaceutical composition of the present invention varies depending on the characteristics of the drug used, but from the viewpoint of the physiological environment of human mucous membranes and the stability of hyaluronic acid, it is preferably pH 4 to pH 8. In particular, an excellent drug absorption promoting effect can be obtained near pH 4. It will be done.
本発明の薬剤組成物に配合する薬効成分は、ヒアルロン
酸またはその塩と不都合な反応をおこさないものであれ
ばいずれでもよく、バソプレッシン、カルシトニン、イ
ンスリン、オキシトシンなどのペプチドホルモン、ある
いはデスモプレッシン、ブセレリン、ナファレリンなど
のホルモン誘導体を挙げることができる。The medicinal ingredients to be incorporated into the pharmaceutical composition of the present invention may be any ingredients that do not cause any unfavorable reactions with hyaluronic acid or its salts, such as peptide hormones such as vasopressin, calcitonin, insulin, and oxytocin, or desmopressin and buserelin. , and hormone derivatives such as nafarelin.
本発明の薬剤組成物は上記必須成分に加えて、本発明の
効果をそこなわない範囲でブチルヒドロキシトルエン（
Ｂ）ＩＴ）、ブチルヒドロキシアニソール（ＢＨＡ）、
ｌ−コフェロールなどの酸化防止剤、燐酸水素二ナトリ
ウム、燐酸二水素ナトリウム、塩酸、水酸化ナトリウム
などのｐＨ調整剤、メシル酸カモスタットなどの蛋白分
解酵素阻害剤など他の有効成分を配合することができる
。In addition to the above-mentioned essential ingredients, the pharmaceutical composition of the present invention contains butylated hydroxytoluene (
B) IT), butylhydroxyanisole (BHA),
Other active ingredients such as antioxidants such as l-copherol, pH adjusters such as disodium hydrogen phosphate, sodium dihydrogen phosphate, hydrochloric acid, and sodium hydroxide, and protease inhibitors such as camostat mesylate may be added. can.
特にペプチド性の薬物を使用する際には、蛋白質分解酵
素阻害剤を配合することにより、さらにその効果が増す
。Particularly when using a peptide drug, its effectiveness is further enhanced by incorporating a protease inhibitor into the drug.
［発明の効果］
本発明の経粘膜投与用薬剤組成物は、ヒアルロン酸また
はその塩を含むので、薬物の粘膜がらの吸収性を著しく
高め、しかも生体への適合性に優れ、高い安全性を示す
。[Effects of the Invention] Since the pharmaceutical composition for transmucosal administration of the present invention contains hyaluronic acid or its salt, it significantly increases the absorption of the drug through mucous membranes, has excellent biocompatibility, and has high safety. show.
また、ペプチド性の薬物を使用する際には、蛋白質分解
酵素阻害剤を配合することによりさらに効果が増す。Furthermore, when using a peptide drug, the effect is further enhanced by incorporating a protease inhibitor.
さらに組成物のｐＨを略４に調整することにより、究め
て高い薬剤吸収性が得られる。Furthermore, by adjusting the pH of the composition to about 4, extremely high drug absorption can be obtained.
［実施例］
以下に実施例を挙げて本発明を詳述する。なお本発明は
これによって限定されるものではない。[Example] The present invention will be described in detail with reference to Examples below. Note that the present invention is not limited to this.
（粘膜吸収試験）
具体的な実施例の説明に先立ち、粘膜吸収試験の方法に
ついて説明する。なお、ここでは薬剤として抗利尿効果
を有する生理活性ペプチドであるバソプレッシン及びそ
の誘導体であるデスモプレッシンを例にとり説明する。(Mucosal absorption test) Prior to explaining specific examples, the method of mucosal absorption test will be explained. Here, vasopressin, which is a physiologically active peptide having an antidiuretic effect, and desmopressin, which is a derivative thereof, will be used as an example of the drug.
すなわち、バソプレッシン及びデスモプレッシンの鼻粘
膜吸収に及ぼすヒアルロン酸ナトリウムの効果を調べる
ため、以下の実験を行った。That is, the following experiment was conducted to examine the effect of sodium hyaluronate on nasal mucosal absorption of vasopressin and desmopressin.
ラットはｆｉｓｔ訂系雄外系雄性ラット：２００〜２３
０ｇ 、 １群４匹）を用い、−夜絶食した後エタノー
ルで麻酔し、気道確保用・経鼻投与用にそれぞれカニュ
レーションを行った。また尿量確保のため股動脈より低
張溶液（１，７％Ｗ／ｖグルコース、０．３％Ｗ／Ｖ
ＮａＣ１，１，２％Ｗ／Ｖ エタノール）を持続注入（
０，５ｍｌ／ｍｉｎ／ｋｇ） した。Rats are fist type male rats: 200-23
After fasting overnight, the mice were anesthetized with ethanol and cannulated for securing the airway and for nasal administration. In addition, hypotonic solution (1.7% W/v glucose, 0.3% W/V
Continuous injection of NaCl (1, 1, 2% W/V ethanol) (
0.5ml/min/kg).
尿量の安定したラット鼻腔内に、以下の実施例１〜６及
び比較例１〜２にしたがって調整した薬剤組成物を投与
した。Pharmaceutical compositions prepared according to Examples 1 to 6 and Comparative Examples 1 to 2 below were administered intranasally to rats with stable urine output.
投与前１０分間および投与後１０分毎に採尿を行った。Urine was collected 10 minutes before administration and every 10 minutes after administration.
バソプレッシンおよびデスモプレッシンの吸収はその薬
理作用である抗利尿効果（投与後１０分毎の尿量／投与
前１０分間の尿量Ｘ １００）により評価した。The absorption of vasopressin and desmopressin was evaluated based on its pharmacological action, antidiuretic effect (urine volume every 10 minutes after administration/urine volume 10 minutes before administration x 100).
ヒアルロン と
まず、ヒアルロン酸の濃度と薬剤吸収性を調べるため、
以下の各実施例、比較例により粘膜吸収試験を行なった
。First, to examine the concentration of hyaluronic acid and drug absorption,
Mucosal absorption tests were conducted using the following Examples and Comparative Examples.
実Ｕよ
ヒアルロン酸を燐酸緩衝液（ｐＨ７，０）で膨潤させ、
０．５重量％とした溶液中にバソプレッシン（０゜０２
５ＩＵ／Ｋｇ）を加え薬剤組成物とする。Swell the hyaluronic acid with a phosphate buffer (pH 7.0),
Vasopressin (0°02
5 IU/Kg) to prepare a pharmaceutical composition.
実１１汁！
ヒアルロン酸を燐酸緩衝液（ｐＨ７，０）で膨潤させ、
１．０重量％とした溶液中にバソプレッシン（０゜０２
５ＩＵ／Ｋｇ）を加え薬剤組成物とする。Fruit 11 juice! Hyaluronic acid is swollen with phosphate buffer (pH 7.0),
Vasopressin (0°02
5 IU/Kg) to prepare a pharmaceutical composition.
実１叩旦
ヒアルロン酸を燐酸緩衝液（ｐＨ７，０）で膨潤させ、
１．５重量％とした溶液中にバソプレッシン（０゜０２
５１Ｕ／Ｋｇ）を加え薬剤組成物とする。Swelling hyaluronic acid with a phosphate buffer (pH 7.0)
Vasopressin (0°02
51 U/Kg) to prepare a pharmaceutical composition.
ル較勇１
燐酸緩衝液（ｐＨ７，０）にバソプレッシンＩＵ／Ｋｇ
）を加え比較組成物とする。Vasopressin IU/Kg in phosphate buffer (pH 7,0)
) was added to prepare a comparative composition.
（０，０２５
１１週Ａ
ヒアルロン酸を燐酸緩衝液（ｐＨ７，０）で膨潤させ、
０，５重量％とした溶液中にデスモプレッシン（９ｎｇ
／Ｋｇ）を加え薬剤組成物とする。(0,025 11 weeks A Hyaluronic acid is swollen with phosphate buffer (pH 7,0),
Desmopressin (9 ng
/Kg) to prepare a pharmaceutical composition.
実ｍ旦
ヒアルロン酸を燐酸緩衝液（ｐＨ７，０）で膨潤させ、
１．０重量％とじた溶液中にデスモプレッシン（９ｎｇ
／Ｋｇ）を加え薬剤組成物とする。Actually, hyaluronic acid is swollen with phosphate buffer (pH 7,0),
Desmopressin (9 ng
/Kg) to prepare a pharmaceutical composition.
寒ｍ旦
ヒアルロン酸を燐酸緩衝液（ｐＨ７，０）で膨潤させ、
１．５重量％とした溶液中にデスモプレッシン（９ｎｇ
／Ｋｇ）を加え薬剤組成物とする。On a cold day, hyaluronic acid is swollen with a phosphate buffer (pH 7.0),
Desmopressin (9 ng
/Kg) to prepare a pharmaceutical composition.
比ｆｆｆｌλ
燐酸緩衝液（ｐＨ７，０）にデスモプレッシン（９ｎｇ
／Ｋｇ）を加え比較組成物とする。Desmopressin (9 ng) in phosphate buffer (pH 7,0)
/Kg) to prepare a comparative composition.
（ここで用いたヒアルロン酸ナトリウムは分子量８５万
〜１６０万：資生堂社製のものを使用した。(The sodium hyaluronate used here had a molecular weight of 850,000 to 1,600,000 and was manufactured by Shiseido.
またバソプレッシン及びデスモプレッシンは［Ａｒｇ”
］−Ｖａｓｏｐｒｅｓｓｉｎ、 ［ｄｅａｍｉｎｏ−
Ｃｙｓ”、 Ｄ−Ａｒｇ”］−Ｖａｓｏｐｒｅｓｓｉｎ
：いずれもシグマ社製を用いた。）以上の結果を第１
図、第２図及び表−１，２に示す。Also, vasopressin and desmopressin are [Arg”
]-Vasopressin, [deamino-
Cys”, D-Arg”]-Vasopressin
: All products manufactured by Sigma were used. ) The above results are the first
It is shown in Figure 2, Figure 2, and Tables 1 and 2.
表−１
ＡＡＣ：
Ｐ、Ａ、 ：
Ａｒｅａ ａｂｏｖｅ ｔｈｅ ＣｕｒｖｅＰｈａ
ｒｍａｃｏｌｏｇｉｃ Ａｖａｉｌａｂｉｌｉｔｙ表−
２
ＡＡＣ：
Ａｒｅａ ａｂｏｖｅ ｔｈｅ
ｕｒｖｅ
Ｐ、Ａ、 ：
Ｐｈａｒｍａｃｏｌｏｇｉｃ Ａｖａｉｌａｂｉｌｉｔ
ｙここでＡＡＣとは抗利尿効果を時間で積算したもの、
すなわち第１図及び第２図で得られた曲線から１００％
ラインまでの面積を求め総合的な抗利尿効果の指標とし
たものである。Table-1 AAC: P, A, : Area above the CurvePha
Rmacologic Availability Table-
2 AAC: Area above the urve P, A, : Pharmacologic Availability
yHere, AAC is the cumulative antidiuretic effect over time.
That is, 100% from the curves obtained in Figures 1 and 2.
The area up to the line was determined and used as an index of the overall antidiuretic effect.
Ｐ、Ａ、は静脈内投与効果を１００とした薬学的利用率
である。P and A are the pharmaceutical utilization rates with the intravenous administration effect set as 100.
表−１及び２から明らかなように、本発明の薬剤組成物
は比較例に対し著しい抗利尿効果を示し、しかもその効
果は配合されるヒアルロン酸の濃度に依存的であった。As is clear from Tables 1 and 2, the pharmaceutical composition of the present invention exhibited a significant antidiuretic effect compared to the comparative example, and the effect was dependent on the concentration of hyaluronic acid blended.
また第１図、第２図のように最大抗利尿効果は水溶液に
よる投与と比較してバソプレッシンで約１．５〜２０倍
、デスモプレッシンで約１．０〜１５倍であった。Furthermore, as shown in FIGS. 1 and 2, the maximum antidiuretic effect was about 1.5 to 20 times greater for vasopressin and about 1.0 to 15 times greater for desmopressin than when administered with an aqueous solution.
すなわち、本発明の薬剤組成物は薬剤の吸収を著しく高
めることが示唆された。In other words, it was suggested that the drug composition of the present invention significantly enhances drug absorption.
且旦ｍ町１収性
次に組成物のｐＨと薬剤吸収性の関係を以下の実施例の
粘膜吸収試験を行なうことにより調べた。Next, the relationship between the pH of the composition and drug absorption was investigated by conducting the mucosal absorption test in the following example.
実ＪＬ（汁ヱ
ヒアルロン酸を燐酸緩衝液（ｐＨ７，０）で膨潤させ、
１．０重量％とした溶液中にデスモプレッシン（９ｎｇ
／Ｋｇ）を加え薬剤組成物とする。JL (juice) swell hyaluronic acid with phosphate buffer (pH 7,0),
Desmopressin (9 ng
/Kg) to prepare a pharmaceutical composition.
実１１旦
ヒアルロン酸を燐酸緩衝液（ｐＨ５，０）で膨潤させ、
１．０重量％とした溶液中にデスモプレッシン（９ｎｇ
／Ｋｇ）を加え薬剤組成物とする。Fruit 11: Swell hyaluronic acid with phosphate buffer (pH 5,0),
Desmopressin (9 ng
/Kg) to prepare a pharmaceutical composition.
実ＩＬ旦
ヒアルロン酸を燐酸緩衝液（ｐＨ４，０）で膨潤させ、
１．０重量％とした溶液中にデスモプレッシン（９ｎｇ
／Ｋｇ）を加え薬剤組成物とする。During actual IL treatment, hyaluronic acid is swollen with phosphate buffer (pH 4,0),
Desmopressin (9 ng
/Kg) to prepare a pharmaceutical composition.
前記実施例７〜９の抗利尿効果を調査した結果、第３図
に示すようにｐＨ５とｐＨ７とでは差が見られなかった
が、ｐＨ４で最大抗利尿効果が増大した。As a result of investigating the antidiuretic effects of Examples 7 to 9, as shown in FIG. 3, no difference was observed between pH 5 and pH 7, but the maximum antidiuretic effect increased at pH 4.
と
次に蛋白分解酵素阻害剤の添加と薬剤吸収性の関係を、
以下の実施例の粘膜吸収試験により調べた。Next, we investigated the relationship between the addition of protease inhibitors and drug absorption.
It was investigated by the mucosal absorption test in the following example.
実１劃［旦
ヒアルロン酸をリン酸緩衝液（ｐＨ７，０）で膨潤させ
、１．０重量％とした溶液中にバソプレッシン（０００
５１Ｕ／Ｋｇ）、メシル酸カモスタットを５０ｍＭとな
るように加え、薬剤組成物とする。First, hyaluronic acid was swollen with phosphate buffer (pH 7.0), and vasopressin (000
51 U/Kg) and camostat mesylate were added to give a concentration of 50 mM to prepare a pharmaceutical composition.
実ｍ
ヒアルロン酸をリン酸緩衝液（ｐ）１５．０）で膨潤さ
せ、１．０重量％とじた溶液中にバソプレッシン（００
０５１Ｕ／Ｋｇ）、メシル酸カモスタットを５０ｍＭと
なるように加え、薬剤組成物とする。Hyaluronic acid was swollen with phosphate buffer (p) 15.0) and vasopressin (00
051 U/Kg) and camostat mesylate were added to give a concentration of 50 mM to prepare a pharmaceutical composition.
実ＪｆＬｆＬＬλ
ヒアルロン酸をリン酸緩衝液（ｐＨ４，０）で膨潤させ
、１．０重量％とした溶液中にバソプレッシン（０゜０
０５１Ｕ／Ｋｇ）、メシル酸カモスタットを５０ｍＭと
なるように加え、薬剤組成物とする。Actual JfLfLLλ Hyaluronic acid was swollen with phosphate buffer (pH 4,0) and vasopressin (0°0
051 U/Kg) and camostat mesylate were added to give a concentration of 50 mM to prepare a pharmaceutical composition.
太ｍ
ヒアルロン酸をリン酸緩衝液（ｐＨ７，０）で膨潤させ
、１０重量％とした溶液中にバソプレッシン（０００５
１Ｕ／Ｋｇ）を加え、薬剤組成物とする。Vasopressin (0005
1U/Kg) to prepare a pharmaceutical composition.
前記実施例１０〜１３の抗利尿効果を調査した結果、第
４図に示すように５０ｍＭメシル酸カモスタットを加え
た場合、カモスタット無添加の薬剤組成物と比較し抗利
尿効果が著しく増大した。As a result of investigating the antidiuretic effect of Examples 10 to 13, as shown in FIG. 4, when 50mM camostat mesylate was added, the antidiuretic effect was significantly increased compared to the drug composition without camostat.
また、その効果はカモスタット添加薬剤組成物のｐＨを
変化させた場合、ｐＨが酸性に傾くほど増大し、特にｐ
Ｈ４附近で優れた抗利尿効果が認められた。In addition, when the pH of the camostat-added drug composition is changed, the effect increases as the pH becomes more acidic;
Excellent antidiuretic effect was observed near H4.
第１図はラット鼻粘膜におけるバソプレッシン投与後の
尿量の変化を示す図、
第２図はラット鼻粘膜におけるデスモプレッシン投与後
の尿量の変化を示す図、
第３図はｐＨと薬剤吸収性の関係を示す説明図、第４図
は蛋白分解酵素阻害剤の添加と薬剤吸収性の関係を示す
説明図である。Figure 1 shows changes in urine volume after administration of vasopressin in rat nasal mucosa. Figure 2 shows changes in urine volume after administration of desmopressin in rat nasal mucosa. Figure 3 shows pH and drug absorption. FIG. 4 is an explanatory diagram showing the relationship between the addition of a protease inhibitor and drug absorption.
Claims (4)
ることを特徴とする経粘膜投与用薬剤組成物。(1) A pharmaceutical composition for transmucosal administration, characterized by containing a drug and hyaluronic acid and/or a salt thereof.
性薬剤からなり、蛋白分解酵素阻害剤を含むことを特徴
とする経粘膜投与用薬剤組成物。(2) The composition for transmucosal administration according to claim 1, wherein the drug is a peptide drug and contains a protease inhibitor.
バソプレッシンからなり、ｐＨが略４に調整されたこと
を特徴とする経粘膜投与用薬剤組成物。(3) A pharmaceutical composition for transmucosal administration according to claim 1 or 2, wherein the pharmaceutical composition comprises vasopressin and has a pH adjusted to approximately 4.
レッシンからなり、ｐＨが略４に調整されたことを特徴
とする経粘膜投与用薬剤組成物。(4) The composition for transmucosal administration according to claim 2, wherein the drug is desmopressin and the pH is adjusted to approximately 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2043921A JP2951681B2 (en) | 1990-02-23 | 1990-02-23 | Pharmaceutical composition for transmucosal administration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2043921A JP2951681B2 (en) | 1990-02-23 | 1990-02-23 | Pharmaceutical composition for transmucosal administration |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03246233A true JPH03246233A (en) | 1991-11-01 |
| JP2951681B2 JP2951681B2 (en) | 1999-09-20 |
Family
ID=12677176
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2043921A Expired - Fee Related JP2951681B2 (en) | 1990-02-23 | 1990-02-23 | Pharmaceutical composition for transmucosal administration |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2951681B2 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08104642A (en) * | 1994-10-04 | 1996-04-23 | Takada Seiyaku Kk | Stabilized composition for injection of sodium hyaluronate |
| JPH09502424A (en) * | 1993-06-29 | 1997-03-11 | フエリング ビー ヴイ | Stabilized pharmaceutical peptide composition |
| JPH09507244A (en) * | 1994-01-10 | 1997-07-22 | ファーマシア アクチボラーグ | Low molecular weight hyaluronic acid with peptides or proteins |
| WO1999059543A1 (en) * | 1998-05-20 | 1999-11-25 | Highchem Company., Ltd. | A pharmaceutical formulation for nasal administration |
| JPH11514967A (en) * | 1995-07-18 | 1999-12-21 | ハイアル ファーマスティカル コーポレイション | Use of hyaluronic acid and NSAIDs for the manufacture of a medicament for the treatment of mucosal inflammation |
| CN1065141C (en) * | 1998-05-20 | 2001-05-02 | 北京金源东和化学有限责任公司 | Medicine preparation administrated through nasal mucosa |
| JP2002193830A (en) * | 1998-10-19 | 2002-07-10 | High Chem Co Ltd | Medicinal preparation for nasal administration |
| DE10064219A1 (en) * | 2000-12-22 | 2002-07-11 | Audit Inst For Medical Service | New pharmaceutical composition of water-soluble or poorly water-soluble active ingredients |
| US9539302B2 (en) | 2009-06-18 | 2017-01-10 | Allergan, Inc. | Safe desmopressin administration |
| JP2019504099A (en) * | 2016-02-03 | 2019-02-14 | インテルジェンクス コーポレーションＩｎｔｅｌｇｅｎｘ Ｃｏｒｐ． | Loxapine film oral dosage form |
-
1990
- 1990-02-23 JP JP2043921A patent/JP2951681B2/en not_active Expired - Fee Related
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09502424A (en) * | 1993-06-29 | 1997-03-11 | フエリング ビー ヴイ | Stabilized pharmaceutical peptide composition |
| JPH09507244A (en) * | 1994-01-10 | 1997-07-22 | ファーマシア アクチボラーグ | Low molecular weight hyaluronic acid with peptides or proteins |
| JPH08104642A (en) * | 1994-10-04 | 1996-04-23 | Takada Seiyaku Kk | Stabilized composition for injection of sodium hyaluronate |
| JPH11514967A (en) * | 1995-07-18 | 1999-12-21 | ハイアル ファーマスティカル コーポレイション | Use of hyaluronic acid and NSAIDs for the manufacture of a medicament for the treatment of mucosal inflammation |
| JP2002515416A (en) * | 1998-05-20 | 2002-05-28 | ハイケム株式会社 | Pharmaceutical preparations for nasal administration |
| CN1065141C (en) * | 1998-05-20 | 2001-05-02 | 北京金源东和化学有限责任公司 | Medicine preparation administrated through nasal mucosa |
| WO1999059543A1 (en) * | 1998-05-20 | 1999-11-25 | Highchem Company., Ltd. | A pharmaceutical formulation for nasal administration |
| US6623732B1 (en) | 1998-05-20 | 2003-09-23 | Highchem Company, Ltd. | Pharmaceutical formulation for nasal administration |
| JP2002193830A (en) * | 1998-10-19 | 2002-07-10 | High Chem Co Ltd | Medicinal preparation for nasal administration |
| DE10064219A1 (en) * | 2000-12-22 | 2002-07-11 | Audit Inst For Medical Service | New pharmaceutical composition of water-soluble or poorly water-soluble active ingredients |
| DE10064219B4 (en) * | 2000-12-22 | 2006-10-12 | Nasalis Pain Relief International Gmbh | Novel use of pharmaceutical compositions containing fentanyl and / or its derivatives |
| DE10064219B9 (en) * | 2000-12-22 | 2009-02-12 | Nasalis Pain Relief International Gmbh | Novel pharmaceutical composition containing fentanyl and / or its derivatives |
| US9539302B2 (en) | 2009-06-18 | 2017-01-10 | Allergan, Inc. | Safe desmopressin administration |
| US11419914B2 (en) | 2009-06-18 | 2022-08-23 | Serenity Pharmaceuticals Llc | Safe desmopressin administration |
| JP2019504099A (en) * | 2016-02-03 | 2019-02-14 | インテルジェンクス コーポレーションＩｎｔｅｌｇｅｎｘ Ｃｏｒｐ． | Loxapine film oral dosage form |
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|---|---|
| JP2951681B2 (en) | 1999-09-20 |
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