CN100581586C - 一种快速起效的药物组合物 - Google Patents
一种快速起效的药物组合物 Download PDFInfo
- Publication number
- CN100581586C CN100581586C CN200480003272A CN200480003272A CN100581586C CN 100581586 C CN100581586 C CN 100581586C CN 200480003272 A CN200480003272 A CN 200480003272A CN 200480003272 A CN200480003272 A CN 200480003272A CN 100581586 C CN100581586 C CN 100581586C
- Authority
- CN
- China
- Prior art keywords
- compositions
- composition
- bio
- pharmaceutically acceptable
- cellulose
- 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.)
- Expired - Fee Related
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 117
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 35
- 239000002245 particle Substances 0.000 claims abstract description 27
- 230000035587 bioadhesion Effects 0.000 claims abstract description 20
- 230000001154 acute effect Effects 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 208000035475 disorder Diseases 0.000 claims abstract description 17
- 239000013543 active substance Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims description 31
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical group O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 claims description 24
- 229960002428 fentanyl Drugs 0.000 claims description 24
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 23
- 239000000853 adhesive Substances 0.000 claims description 16
- 230000003213 activating effect Effects 0.000 claims description 15
- 230000001070 adhesive effect Effects 0.000 claims description 14
- 208000002193 Pain Diseases 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 229920002472 Starch Polymers 0.000 claims description 10
- 239000008107 starch Substances 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 8
- 239000008187 granular material Substances 0.000 claims description 8
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 8
- -1 hydroxypropyl Chemical group 0.000 claims description 8
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 7
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 7
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 7
- 230000003232 mucoadhesive effect Effects 0.000 claims description 7
- 239000011347 resin Substances 0.000 claims description 7
- 229920005989 resin Polymers 0.000 claims description 7
- 239000004094 surface-active agent Substances 0.000 claims description 7
- 239000008180 pharmaceutical surfactant Substances 0.000 claims description 6
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 5
- 235000010413 sodium alginate Nutrition 0.000 claims description 5
- 239000000661 sodium alginate Substances 0.000 claims description 5
- 229940005550 sodium alginate Drugs 0.000 claims description 5
- 208000000003 Breakthrough pain Diseases 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- FEBUJFMRSBAMES-UHFFFAOYSA-N 2-[(2-{[3,5-dihydroxy-2-(hydroxymethyl)-6-phosphanyloxan-4-yl]oxy}-3,5-dihydroxy-6-({[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-4-yl)oxy]-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl phosphinite Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(OC2C(C(OP)C(O)C(CO)O2)O)C(O)C(OC2C(C(CO)OC(P)C2O)O)O1 FEBUJFMRSBAMES-UHFFFAOYSA-N 0.000 claims description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920002305 Schizophyllan Polymers 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 229920006037 cross link polymer Polymers 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 210000004400 mucous membrane Anatomy 0.000 claims description 3
- 229920005615 natural polymer Polymers 0.000 claims description 3
- 229950008882 polysorbate Drugs 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000003833 bile salt Substances 0.000 claims description 2
- 239000000084 colloidal system Substances 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 239000000230 xanthan gum Substances 0.000 claims description 2
- 235000010493 xanthan gum Nutrition 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 229940082509 xanthan gum Drugs 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims 3
- 239000004531 microgranule Substances 0.000 claims 3
- 208000005298 acute pain Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 14
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 239000011859 microparticle Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 description 21
- 230000000202 analgesic effect Effects 0.000 description 20
- 229940079593 drug Drugs 0.000 description 15
- 210000004877 mucosa Anatomy 0.000 description 14
- 102000002723 Atrial Natriuretic Factor Human genes 0.000 description 13
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 12
- NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 description 12
- 238000010521 absorption reaction Methods 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 10
- 229930195725 Mannitol Natural products 0.000 description 10
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 206010022437 insomnia Diseases 0.000 description 10
- 239000000594 mannitol Substances 0.000 description 10
- 235000010355 mannitol Nutrition 0.000 description 10
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 8
- 229920000642 polymer Polymers 0.000 description 8
- 210000000214 mouth Anatomy 0.000 description 7
- 210000003296 saliva Anatomy 0.000 description 7
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 6
- 229960000381 omeprazole Drugs 0.000 description 6
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 208000026935 allergic disease Diseases 0.000 description 5
- 230000007815 allergy Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000036571 hydration Effects 0.000 description 5
- 238000006703 hydration reaction Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229940127240 opiate Drugs 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 206010037423 Pulmonary oedema Diseases 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 229940127219 anticoagulant drug Drugs 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229960005181 morphine Drugs 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 208000005333 pulmonary edema Diseases 0.000 description 4
- 230000009747 swallowing Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- 239000002934 diuretic Substances 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229940121819 ATPase inhibitor Drugs 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010058019 Cancer Pain Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229920000896 Ethulose Polymers 0.000 description 2
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 208000000913 Kidney Calculi Diseases 0.000 description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010029148 Nephrolithiasis Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 241000282894 Sus scrofa domesticus Species 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 239000000227 bioadhesive Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 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 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 229960000482 pethidine Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 description 1
- UVOIBTBFPOZKGP-CQSZACIVSA-N 1-[10-[(2r)-2-(dimethylamino)propyl]phenothiazin-2-yl]propan-1-one Chemical compound C1=CC=C2N(C[C@@H](C)N(C)C)C3=CC(C(=O)CC)=CC=C3SC2=C1 UVOIBTBFPOZKGP-CQSZACIVSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- VQGWUEFARIAFPF-UHFFFAOYSA-N 5-hydroxy-7-(2-hydroxy-4-methoxyphenyl)-2,2-dimethyl-10-(3-methylbut-2-enyl)pyrano[3,2-g]chromen-6-one Chemical compound OC1=CC(OC)=CC=C1C(C(C1=C2O)=O)=COC1=C(CC=C(C)C)C1=C2C=CC(C)(C)O1 VQGWUEFARIAFPF-UHFFFAOYSA-N 0.000 description 1
- CKLBXIYTBHXJEH-UHFFFAOYSA-J 75881-23-1 Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Cu+2].[N-]1C(N=C2C3=CC=C(CSC(N(C)C)=[N+](C)C)C=C3C(N=C3C4=CC=C(CSC(N(C)C)=[N+](C)C)C=C4C(=N4)[N-]3)=N2)=C(C=C(CSC(N(C)C)=[N+](C)C)C=C2)C2=C1N=C1C2=CC(CSC(N(C)C)=[N+](C)C)=CC=C2C4=N1 CKLBXIYTBHXJEH-UHFFFAOYSA-J 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 101800000407 Brain natriuretic peptide 32 Proteins 0.000 description 1
- 102400000667 Brain natriuretic peptide 32 Human genes 0.000 description 1
- 101800002247 Brain natriuretic peptide 45 Proteins 0.000 description 1
- YWDQMNKEXHFLDJ-UHFFFAOYSA-N C(CC)(=O)NC1=CC=CC=C1.C1(=CC=CC=C1)C(C)N1CCC(CC1)N(C1=CC=CC=C1)C(CC)=O Chemical compound C(CC)(=O)NC1=CC=CC=C1.C1(=CC=CC=C1)C(C)N1CCC(CC1)N(C1=CC=CC=C1)C(CC)=O YWDQMNKEXHFLDJ-UHFFFAOYSA-N 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000003870 Drug Overdose Diseases 0.000 description 1
- 244000024675 Eruca sativa Species 0.000 description 1
- 235000014755 Eruca sativa Nutrition 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000167880 Hirundinidae Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- ALFGKMXHOUSVAD-UHFFFAOYSA-N Ketobemidone Chemical compound C=1C=CC(O)=CC=1C1(C(=O)CC)CCN(C)CC1 ALFGKMXHOUSVAD-UHFFFAOYSA-N 0.000 description 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical group C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010033296 Overdoses Diseases 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- FQXZITIIHQHGBC-UHFFFAOYSA-N UNPD773 Natural products CC(C)=CCC1=CC(C(=O)OCC2C3CCCN3CC2)=CC(CC=C(C)C)=C1OC1OC(CO)C(O)C(O)C1O FQXZITIIHQHGBC-UHFFFAOYSA-N 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 241000792914 Valeriana Species 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960003792 acrivastine Drugs 0.000 description 1
- PWACSDKDOHSSQD-IUTFFREVSA-N acrivastine Chemical compound C1=CC(C)=CC=C1C(\C=1N=C(\C=C\C(O)=O)C=CC=1)=C/CN1CCCC1 PWACSDKDOHSSQD-IUTFFREVSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229960001391 alfentanil Drugs 0.000 description 1
- HXBPYFMVGFDZFT-UHFFFAOYSA-N allyl isocyanate Chemical compound C=CCN=C=O HXBPYFMVGFDZFT-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- HUSUHZRVLBSGBO-UHFFFAOYSA-L calcium;dihydrogen phosphate;hydroxide Chemical compound O.[Ca+2].OP([O-])([O-])=O HUSUHZRVLBSGBO-UHFFFAOYSA-L 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000012461 cellulose resin Substances 0.000 description 1
- JXPCRJDMUSNASY-WEMUOSSPSA-N chembl150283 Chemical compound C1CN(/C=N/CCCCCCCC)CCC1C(C=1C=CC=CC=1)C1=CC=CC=C1 JXPCRJDMUSNASY-WEMUOSSPSA-N 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000007799 cork Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- UVKZSORBKUEBAZ-UHFFFAOYSA-N cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 1
- 229960003564 cyclizine Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 231100000725 drug overdose Toxicity 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- KWORUUGOSLYAGD-YPPDDXJESA-N esomeprazole magnesium Chemical compound [Mg+2].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-YPPDDXJESA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229950010805 fenoctimine Drugs 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960003029 ketobemidone Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- VRQVVMDWGGWHTJ-CQSZACIVSA-N methotrimeprazine Chemical compound C1=CC=C2N(C[C@H](C)CN(C)C)C3=CC(OC)=CC=C3SC2=C1 VRQVVMDWGGWHTJ-CQSZACIVSA-N 0.000 description 1
- 229940042053 methotrimeprazine Drugs 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 239000000479 mixture part Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- CQJHTZPBHIZIPT-UHFFFAOYSA-N n-(3,4-dichlorophenyl)quinolizin-5-ium-2-amine;bromide Chemical compound [Br-].C1=C(Cl)C(Cl)=CC=C1NC1=CC=[N+](C=CC=C2)C2=C1 CQJHTZPBHIZIPT-UHFFFAOYSA-N 0.000 description 1
- ITNLONMDUMHEOK-UHFFFAOYSA-N n-methyl-2-pyridin-2-ylthiolane-2-carbothioamide Chemical compound C=1C=CC=NC=1C1(C(=S)NC)CCCS1 ITNLONMDUMHEOK-UHFFFAOYSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- HPNRHPKXQZSDFX-OAQDCNSJSA-N nesiritide Chemical compound C([C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CO)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 HPNRHPKXQZSDFX-OAQDCNSJSA-N 0.000 description 1
- 229950005892 nolinium bromide Drugs 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- AQNQGBUEVCAVML-UHFFFAOYSA-N oxazepane Chemical compound C1CCNOCC1 AQNQGBUEVCAVML-UHFFFAOYSA-N 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- FIADGNVRKBPQEU-UHFFFAOYSA-N pizotifen Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CCC2=C1C=CS2 FIADGNVRKBPQEU-UHFFFAOYSA-N 0.000 description 1
- 229960004572 pizotifen Drugs 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229960005036 propiomazine Drugs 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 235000017468 valeriana Nutrition 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 229960000820 zopiclone Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Zoology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Otolaryngology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pain & Pain Management (AREA)
- Molecular Biology (AREA)
- Neurology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
描述了一种用于治疗急性紊乱的药物组合物。该组合物包含微粒形式的至少一种药学活性剂的基本上不含水的有序混合物,其粘附于显著大于活性剂微粒的载体颗粒表面,并且基本不溶于或微溶于水,且与粘附于所述载体颗粒表面的生物粘附和/或粘膜粘附促进剂组合。该组合物主要用于舌下或鼻内给药。本发明还涉及该组合物的制备方法和使用该组合物治疗剂型紊乱的方法。
Description
技术领域
本发明涉及用于舌下或鼻内给予药物试剂的快速起效的药物组合物,涉及所述组合物的制备方法,并涉及应用所述组合物治疗急性紊乱的方法。
发明背景
急性和/或严重的紊乱通常导致急诊或住院治疗。该类型中最常见的紊乱之一是急性或突破性(breakthrough)疼痛。在癌症患者中,通常单独或组合使用非甾类消炎药(NSAIDs)和阿片制剂治疗。对需要阿片样物质的癌症疼痛患者通常给予缓释阿片制剂(缓释的吗啡或凯托米酮或透皮芬太尼)。癌症疼痛的特征在于周期性的不充分止痛(突破性疼痛)。它们最常起因于患者身体活力的增加。但是,治疗突破性疼痛时,增加应急剂量的长效镇痛药的给药时间,会引起了不良副作用比如过度镇静作用、恶心以及便秘。
其它需要快速起效治疗的紊乱和病情例如肺水肿、胃食管反流、失眠症和肾结石。
现有的口腔、直肠、鼻内或舌下制剂具有相对冗长的起效时间或不稳定的吸收特性,不太适于控制急性紊乱。
急性手术/术后或创伤/创伤后疼痛以及严重疾病(例如心肌梗塞、肾结石等)引起的疼痛等病情通常经胃肠外给予(经静脉注射或肌肉注射给药)阿片样物质镇痛药治疗从而达到速效的止痛。在此情况下,速效的口服替换物具有相当大的治疗意义。对于治疗其它急性紊乱,提供了快速起效的口服或经鼻内途径给药而非胃肠外或直肠给药的治疗组合物,也具有重要意义。
但是,许多本该有利于口服给予的药物活性剂却不适于吞服。它们例如可能被胃-肠内液体失活、由于在水媒质中的低溶解度而起效缓慢、或高度易于被胃-肠内酶代谢并具有弱的吸收性质,例如肽类激素。因此,更优选使该活性组分通过口腔或鼻腔粘膜吸收。对于口腔而言,最优选的给药方式是经由舌下途径。在该给药方式中,剂量单位的药物组合物置于舌下,活性组分通过周围粘膜被吸收。但是,使用这一给药方式时,患者吞咽唾液而吞服药物的风险为大家所熟知。
对于治疗剧痛可以使用芬太尼、N-(1-苯乙基-4-哌啶基)-丙酰苯胺(propioanilide)或其一种药学上可接受的盐。该化合物是阿片类激动剂并共具有阿片制剂比如吗啡和哌替啶的许多药效作用。但是,与这些阿片制剂相比,芬太尼基本不表现出催眠活性,很少诱发组胺释放,并且其呼吸抑制更加短暂。已有商品销售的用于静脉注射、颊内(锭剂-转化粘液质)以及透皮给药的芬太尼。
肠胃外给予芬太尼后,止痛作用比吗啡和哌替啶更加迅速且很少延迟。静脉内给药后迅速开始止痛。在几分钟内达到止痛峰值。使用锭剂透颊(transbucchal)给药之后,该锭剂通常在30分钟内彻底消耗并在约20分钟后出现血浆浓度峰值,如Farrar等,J.Natl.Cancer Inst.,1998,90(8),p.611-616中所描述的。在5~15分钟内止痛明显且峰值出现在大约20~50分钟。虽然相对口服给药以胃肠吸收所进行的改进,但更快的止痛起效将对患者具有实质的益处。此外,相当大量的锭剂给药的芬太尼被患者吞咽。这不是所希望的并导致该药物的给药过量,可能引起副作用。
发明目的
本发明的一个目的是提供一种对急性紊乱的治疗,其以在给药后短期内达到所述药物的药理学有效血浆水平的方式经口或鼻内给药。
本发明的另一目的是提供一种适于上述目的的药物组合物。
本发明的另一目的是提供这种组合物的制备方法。
本发明的另一目的是提供一种舌下或鼻内给药的药物的制备方法,其包含生理学有效剂量的可用于治疗急性紊乱的至少一种药学活性化合物。
附图简介
唯一的附图显示了根据本发明的组合物的生物粘附强度(bio-adhesivestrength)的测试结果。它是显示浓度-最大张力的曲线图。
发明简介
根据本发明,急性紊乱的经口治疗包括舌下给予包含药理学有效量的至少一种药学活性剂的有序混合物。所述活性剂组合生物粘附和/或粘膜粘附促进化合物舌下给药。同样地,相同的组合物还可用于鼻内给药。
此外根据本发明,还有提供了用于舌下或鼻内给药的单一剂量药物组合物,包含药理学上有效量的至少一种药学活性剂。所述组合物还包含生物粘附剂或粘膜粘附促进化合物。该组合物减少了因吞咽唾液引起的不稳定药物吸收并使少量所述活性剂的给予成为可能。因此,它显著地减少了副作用的危险和患者内以及患者间对治疗响应的变化。由此减少了药物累积的危险,使得该药物制剂很适于重复给予患急性紊乱的患者。
具体地,本发明提供了一种用于经舌下或鼻内给药治疗急性紊乱的药物组合物,包含粘附于载体颗粒表面至少一种药学活性剂微粒的基本上不含水的有序混合物,以及粘附于该载体颗粒表面的生物粘附和/或粘膜粘附促进剂,所述颗粒显著大于所述微粒且不溶于或微溶于水。
在本发明的组合物,其中生物/粘膜粘附促进剂选自交联聚合物、丙烯酸聚合物、纤维素衍生物、具有生物/粘膜粘附性质的天然聚合物,及其混合物。
在本发明的组合物,其中载体颗粒包含至少一种下列物质:药学上可接受的聚合物、药学上可接受的无机盐以及这些材料的混合物或共-加工物质。
进一步地,在根据本发明的舌下组合物中,该组合物包含至少一种药学上的崩解剂,其促进与活性剂混合的载体颗粒在舌下粘膜上的分散。所述的崩解剂选自交联聚乙烯吡咯烷酮、羧甲基淀粉、天然淀粉、微晶纤维素、纤维素树脂,及其混合物。崩解剂的含量为该组合物的1至10重量百分比。
本发明药物组合物中所包含的活性剂的量显然取决于许多因素,其将由治疗医师评价。这些因素中,可以提及的包括所用的特定药物和所治疗的紊乱类型、患者的医学状态等等。
当芬太尼用于治疗急性或突破性疼痛时,本发明组合物将包含从0.05直到20wt%的芬太尼或其一种药学上可接受的盐。更优选地,该组合物包含从0.05至5wt%的芬太尼,并且尤其是从0.1到1wt%。该含量还可以用芬太尼在该组合物剂量单位比如片剂中的量来表示。在这种情况下,剂量单位将包含从0.025至10mg,并且优选0.05到2mg的芬太尼。当使用盐形式的芬太尼时,这些百分比和量应该相应地重新计算。
进一步根据该发明,该舌下或鼻内组合物包含一种或多种生物粘附和/或粘膜粘附载体物质的有序混合物,其包衣有细颗粒形式的药学上的活性剂。根据本发明,载体物质在水中不溶或微溶(sparingly soluble)。术语“有序混合物”意在表示应用细颗粒性质的活性成分密切地与较粗糙的赋形剂颗粒混合。然后,该细药物颗粒基本上为粘附在赋形剂(载体)颗粒表面上的主要颗粒。在本文中,“交互混合物”(interactive mixture)或“粘附混合物”等术语可以交互使用。
优选对欧洲专利EP0324725中公开的配制快速溶解的有序-组合物的工艺进行改变,从而用来配制根据本发明的组合物。在这些组合物中,细分散状态的药物覆盖明显更大的、水溶性载体颗粒的表面。这些组合物在水中快速地崩解,由此分散它们包含的微小药物颗粒。
细颗粒药物从有序混合物中的溶出与可溶性载体的应用有关。这一方法的特征在于载体的快速溶解,由此快速释放细药物颗粒。这些药物颗粒,现在作为离散单位存在,由于有利的流体力学(hydrodynamics)而将快速地溶解。这一方法以前被局限用于使用大体积的溶解液体。已知晓只有当药物颗粒释放到较大量溶解液体时溶解才不被饱和现象或不利的流体力学阻碍。
但是,在公开的PCT申请WO 00/16750中,具有可溶性载体的有序组合物已用于舌下给药。尽管口腔中溶解液体(唾液)的体积有限,但已发现可以实现快速溶解以及随后的药物吸收。出乎意料地,现已实现了可以使用不溶或微溶载体获得相同的结果。据相信较粗糙载体颗粒表面上离散药物颗粒(即非聚集形式)的最佳暴露代表了快速溶解的决定因素。因为药物位于主片剂组分的表面上,参与溶解的大表面面积将提供快速的溶解,尽管事实上在溶解前这些药物颗粒没有从不溶性载体上释放。由此,只要药物是非常细微的颗粒形式并以离散的、非聚集单位存在,就可从附着于载体的药物颗粒中快速地溶解。另一先决条件是药物以低比例使用。优选地,剂量应低于10mg且更优选低于2mg。
不溶性载体较可溶性载体的优势在于包被上更细的、生物/粘膜-粘附组分后它们粘附于粘膜的倾向改善了。已发现可溶性载体在给药后不久,将开始溶解并由此降低粘膜粘附。另一方面,涂有生物粘附颗粒的不溶性载体将在较长时间内持续附着于粘膜并将导致粘膜粘附的改善。这将在实施例1中进一步解释。
还将生物粘附和/或粘膜粘附促进剂加入到根据本发明的载体颗粒中。该生物粘附和/或粘膜粘附促进剂在制备粘附于口腔或鼻粘膜的活性剂中起效,此外,与水接触时还可具有膨胀和扩张的性质。该生物/粘膜粘附促进剂必须存在于载体颗粒的表面上。
术语“粘膜粘附”意在表示粘附于被比如口腔中粘液覆盖的粘膜,而术语″生物粘附″意在表示粘附于含义更广义的生物表面,包括不被粘液覆盖的粘膜。作为定义这些术语通常重叠,并且通常可交互使用,虽然术语“生物粘附”具有较宽的范围。在本说明书和权利要求书中,考虑到本发明的目的,两术语用于相同的目的,且其还被表达为通用的术语“生物/粘膜粘附”。
适当地,载体颗粒包含从基于总组合物0.1直到40重量百分比的生物/粘膜粘附促进化合物。实践中,已发现含量低于1重量百分比无法提供足够的生物/粘膜粘附作用。生物/粘膜粘附促进剂优选的含量范围为2至25重量百分比。
优选的生物/粘膜粘附促进剂是聚合物,优选平均分子量高于5,000(重均)的物质。粘膜粘附促进剂界面的水合水平对于生物/粘膜粘附力的形成是很重要的。因此,聚合物膨胀得越快,生物/粘膜粘附就出现得越早。生物粘附化合物的水合还使得适于用作本发明的吸附增强剂。
优选地,载体颗粒小于750μm,更优选从50至500μm。尽管可以使用指定范围以外的颗粒大小,但使用具有这样大小的颗粒配制药物制剂时在存在操作困难。所用载体可以包含任何药学上可接受的物质,其不溶于或微溶于水,并可配制成适于加入生物/粘膜粘附促进剂的颗粒。本领域技术人员已知大量这样的物质。合适例子可提及聚合物比如纤维素(例如微晶纤维素)、纤维素衍生物、淀粉、淀粉衍生物、基于例如淀粉或纤维素的交联聚合物和聚乙烯吡咯烷酮。此外,可以使用无机盐比如磷酸钙、磷酸氢钙水合物、磷酸氢钙二水合物、磷酸三钙、碳酸钙和硫酸钡。还可使用上述材料的混合物或共-加工物质(co-processed qualities)。
根据本发明的一个特别优选方面,该载体还具有破碎行为。破碎行为意指该载体是具有一定程度脆性的材料,当其构成药物组合物的一部分而被压制成片剂时,该材料易于压碎或分裂。当生物/粘膜粘附促进剂还起崩解剂作用时,这一效果尤其显著。磷酸氢钙(dicalcium phosphate)已经被认为特别适合作为破碎促进剂。
向该组合物中加入药学上可接受的表面活性剂也是本发明优选的特征。表面活性剂的增湿作用增强了载体颗粒的润湿,导致更快地引起生物/粘膜粘附。表面活性剂应为细分散形式并与活性剂密切地混合。表面活性剂的量应为组合物的0.5到5重量百分比,并且优选0.5到3重量百分比。
合适的表面活性剂的例子可以提及月桂基硫酸钠、聚山梨酯(polysorbate)、胆汁酸盐及其混合物。
本领域已知的多种聚合物可用作生物/粘膜粘附促进剂。除它们的聚合性质之外,它们的膨胀能力也是重要的。另一方面,同样重要的是它们基本上不溶于水。当接触到水或唾液时它们的体积膨胀系数应优选至少10,且更优选至少20。这些生物/粘膜粘附促进剂的例子包括纤维素衍生物比如羟丙基甲基纤维素(HPMC),羟乙基纤维素(HEC),羟丙基纤维素(HPC),甲基纤维素,羟乙基纤维素乙基醚,乙基羟乙基纤维素(ethyl hydroxyethylcellulose),羧甲基纤维素和羧甲基纤维素钠(NaCMC),修饰的纤维素树脂;淀粉衍生物比如适度交联的淀粉,修饰的淀粉;丙烯酸类聚合物比如卡波姆和其衍生物(Polycarbophyl,等等);聚氧乙烯(polyethylene oxide,PEO);壳聚糖(聚-(D-葡糖胺));天然聚合物比如明胶、藻酸钠、胶质(pectin);硬葡聚糖(scleroglucan);黄原胶;瓜尔胶;聚共-(甲基乙烯基醚/马来酐);以及交联羧甲基纤维素(crosscaramellose)。还可以使用两种或多种生物/粘膜粘附聚合物的组合。一般地说,任何显示生物/粘膜粘附特性的生理可接受试剂均可成功地加入该载体中。生物/粘膜粘附剂可在体外确定,例如根据G.Sala等Proceed.Int.Symp.Contr.Release.Bioact.Mat.16:420,1989。
代表性的生物/粘膜粘附聚合物的一些合适的商业来源包括:
HPMC-Dow Chemical Co.,Midland,),MI,USA;
NEC(Natrosol)-Hercules Inc.,Wilmington,DE.,USA;
HPC-Dow Chemical Co.,Midland,MI,USA;NaCMC-Hercules Inc.Wilmington,DE.,USA;PEO-Aldrich Chemicals,USA;藻酸钠,-Edward Mandell Co.,Inc.,Carmel,NY,USAi胶质-BF Goodrich Chemical Co.,Cleveland,OH,USA.′Ac-Di-(具有高膨胀性的改性纤维素树脂)-FMC Corp.,USA;Actigum,-Mero-Rousselot-Satia,Baupte,France;Satiaxane-Sanofi BioIndustries,Paris,France;
-ISP,Milan,Italy;
壳聚糖-Sigma,St Louis,MS,USA;
取决于所用生物/粘膜粘附促进剂的类型以及比例,生物/粘膜粘附的速率和强度可以改变。根据本发明一个优选的方面,优选具有高且快速膨胀能力的物质。
当向其加入生物/粘膜粘附促进剂时,为了保证本发明的药物组合物合适地发挥作用,该试剂必需分布于载体颗粒的表面。生物/粘膜粘附促进剂可以与载体颗粒以若干种方式混合。在本发明的优选实施方案中,细颗粒性质的生物/粘膜粘附促进剂与粗糙载体一起混合足够长时间以生成有序混合物,其中较细的颗粒以粘附于载体颗粒表面的主要离散颗粒存在。由此,生物/粘膜粘附促进剂以与欧洲专利号0324725中描述的活性化合物相同的方式混合。
生物/粘膜粘附促进剂的颗粒大小合适地在1至100μm之间。当该试剂的颗粒与载体颗粒混合形成有序混合物时,其大小在该大小区间的下部分,且它们的大小合适地低于10μm。
本发明特别涉及给予用于治疗需要快速且短暂作用的医学病情的药物,比如疼痛、失眠症、变应性病情和肺水肿。这些药物的非限制性例子可以提及吗啡(止痛剂)、芬太尼(止痛剂)、alfentanyl(止痛剂)、舒芬太尼(止痛剂)、丁丙诺啡(止痛剂)、苯噻啶(止痛剂)、舒马曲坦(止痛剂)、消炎痛(止痛剂)、舒林酸(止痛剂)、双氯芬酸(止痛剂)、酮咯酸(止痛剂)、吡罗昔康(止痛剂)、替诺昔康(止痛剂)、布洛芬(止痛剂)、萘普生(止痛剂)、酮洛芬(止痛剂)、苯基丁氮酮(止痛剂)、苯基保泰松(止痛剂)、安定(失眠症)、去甲羟基安定(失眠症)、吡嗪哌酯(失眠症)、唑吡坦(失眠症)、丙酰马嗪(失眠症)、valeriana(失眠症)、左旋甲丙嗪(失眠症)、赛克力嗪(变态反应)、西替立嗪(变态反应)、特非那定(变态反应)、阿伐斯汀(变态反应)、非索非那定(变态反应)和呋塞米(利尿剂)。
受益于增强的吸收以及可用于需要快速起效的医学病情的其它药物包括,但没有任何的限制含义,各种肽和酶比如心钠素(ANP、ANF、心耳素)(利尿剂)、脑钠素(利尿剂)、血小板聚集抑制物(抗凝血剂)、链激酶(抗凝血剂)、肝素(抗凝血剂)、尿激酶(抗凝血剂)、肾素抑制剂(高血压)、胰岛素(抗糖尿病药)以及睡眠诱导肽(失眠症)。
可通过本制剂的生物/粘膜粘附性质减少避免接触胃酸以及所吞咽的包含唾液的活性药物的其它药物例子包括,但没有任何限制的含义,用作H+,K+和ATP酶抑制剂的苯并咪唑类(减少胃酸)比如奥美拉唑、泮托拉唑、吡帕拉唑和兰索拉唑。其它的H+,K+和ATP酶抑制剂包括异氰酸烯丙酯、trifluorperazide、溴苯胺嗪、RP 40749和苯辛替明。
本发明特别适合芬太尼及其药学上可接受的盐比如柠檬酸盐或马来酸盐的给药,这些盐不易溶于水。芬太尼或其盐颗粒的最大粒径合适地约为24μm但优选不大于约10μm。例如通过在足够长时间内干法混合各成分使得芬太尼粘附于载体颗粒。该时间长短可以根据所用的混合设备而改变。本领域熟练技术人员通过实验将轻易地确定对于给定的活性物质、生物/粘膜粘附促进剂和载体的组合以及使用具体混合设备的合适搅拌时间。
本发明另一优选方面包括在本发明组合物中加入崩解剂。这样的试剂将加速载体颗粒的分散。根据本发明的崩解剂的例子包括交联聚乙烯吡咯烷酮、羧甲基淀粉、天然淀粉、微晶纤维素、纤维素树脂及其混合物。崩解剂的优选含量为该组合物的1%至10%。可以看出,崩解剂与生物/粘膜粘附促进剂的定义有些重叠,可以优选两种作用由同一物质提供。但是,需要着重指出的,这两种赋形剂并非等价,有些功能有效的崩解剂却不具有生物/粘附的性质,反之亦然。
根据本发明制备的有序混合物可用于例如鼻内给药。通常,粉末混合物在某一类型的给药装置辅助下被吹入鼻腔。还可将该有序混合物加到用于舌下给药的各种制剂中。不论该制剂的形式,重要的是该制剂基本上无水,因为其生物/粘膜粘附促进特性来自于其接触到水或唾液时几乎瞬时发生的水合作用。过早的水合将显著地降低粘膜粘附促进性质并导致活性物质过早溶解。
用于优选的舌下给药路线的药物组合物可通过组合前述有序混合物与舌下制剂领域常规的药物添加剂和赋形剂而获得。本领域技术人员公知适当的配制方法;参见,例如Pharmaceutical Dosage Forms:Tablets.1卷,第2版,Lieberman H A等;Eds.;Marcel Dekker,New York and Basel 1989,p.354-356,以及其中所引用的文献。适宜的添加剂包括其它载体试剂、防腐剂、润滑剂、崩解剂、调味剂和染料。
因此,本发明提供了易于制备且成本低廉的剂型,其可快速释放活性物质,促进活性剂通过口腔或鼻腔粘膜快速吸收,且增强了难以溶解的物质比如肽的吸收。低剂量活性剂用于提供短期的作用,同时可对于需要治疗的一再发生的急性紊乱重复给予预定剂量。
本发明现将参照实施例进行详细说明。
实施例1
材料
低水溶性的磷酸氢钙二水合物(DCP)(Emcompress,Edward Mendell Co,Inc,USA)和高水溶性的甘露醇(颗粒状,Roquette,France)用作制备有序混合物的非生物粘附载体材料。通过干法过筛(Retsch,German)得到各材料的180-355μm大小部分。
交联羧甲基纤维素钠(Ac-Di-Sol,FMC,Cork,Ireland)以细粉形式使用,以代表具有粘膜粘附/生物粘附性质的材料。Ac-Di-Sol的细颗粒部分通过在砂浆碾磨机(Retsch,Germany)中碾磨随后经空气分级(100MZR,Alpine,Germany)而得到。
测试材料的基本特征
所有粉末在40%RH和室温下贮存至少48小时后再进行表征以及混合。使用Friedrich透过测粒法(n=3)(Eriksson等1990)测定甘露醇和DCP中较粗糙部分(180-355μm)的外表面积。Blaine透过测粒法用于测定Ac-Di-Sol粉末的外表面积(Alderbom等1985)(表1)。
有序/交互混合物的制备
将碾磨的Ac-Di-Sol(表1)以各种比例加至甘露醇或DCP(均为180-355μm)中以得到不同浓度的Ac-Di-Sol。在2L涡流搅拌器(W.A.Bachofen AG,Basel,Switzerland)中在玻璃罐内以120rpm混合粉末24小时。根据先前的研究(Westerberg 1992;Sundell-Bredenberg and2001)进行混合并通过目视确定混合均匀性。
生物粘附/粘膜粘附性质的测量
粘膜材料和表征
在屠宰室(Swedish Meat AB,Uppsala,Sweden)内收集新鲜的猪肠,新鲜使用或冷冻备用。使用前,冷冻的肠在4℃缓冲液中解冻过夜。所用的缓冲液为pH 7.4的Krebs-Ringer Bicarbonate(Sigma-Aldrich Chemie GmbH,Steinheim,Germany)。
为了测试粘膜层的质量以及粘膜的处理效果,部分地根据Corne等的方法(1974)使用阿辛蓝对几种组织样本染色。然后将新鲜和冷冻的组织均在含有阿辛蓝8GX(Certistain,Merck,Germany)(1mg/ml)并以蔗糖溶液(Sigma-Aldrich Chemie GmbH,Steinheim,Germany)缓冲的TRIS(TRIZMAHydrochloride,Sigma-Aldrich Chemie GmbH,Steinheim,Germany)中浸泡两小时。在TRIS/蔗糖缓冲液中清洗该组织并经肉眼观察。通过评价粘液层的质量和对该组织的处理作用,注意到解冻过程(在4℃的缓冲液中)或处理过程均不影响粘膜的质量,即,该粘膜层保持完好,因此新鲜和冷冻的粘膜均可用于该研究。
粘附测试
具有5kg测压元件和相关软件的TA-HDi纹理分析仪(Stable MicroSystems,Haslemere,UK)用于该生物粘附研究。猪肠被切成大约2cm2的小片并置于组织固定器中。将粉末混合物[使用双面带(Scotch,3M Svenska AB,Sollentuna,Sweden)]粘附于探头上端。通过将该探头浸在粉末层中而应用该粉末,为了获得单层颗粒,探头浸入后轻微地振荡以除去任何的过量,这通过视觉确证。使用吸液管在粘膜上涂布30μl缓冲液从而使得水合作用标准化后,使得所研究的物质在0.5N压力下接触粘膜30秒。然后以0.1mm/s恒速升高探头,并将分开力记录为位移的函数。在测量周期内,以25次测量/秒的采样率测量分开力。使用计算机软件Texture Expert Exceed(StableMicrosystems,Haslemere,UK)确定所检测的最大力,即断裂力。该分开力除以探头面积得到张力(N/cm2)。
关于应用有序/交互混合物(加入细生物粘附颗粒)以提高载体材料生物粘附性质的结果
一定量生物粘附/粘膜粘附组分的作用
当粗糙DCP或甘露醇与细颗粒大小的Ac-Di-Sol混合时,粘膜和非生物粘附载体颗粒之间的张力得到改善(p<0.0001)(附图1)。最初随着Ac-Di-Sol浓度的增加,生物粘附性质开始改善(p<0.05)。
包含两个最高浓度Ac-Di-Sol(28.2和39.9%w/w)的DCP有序混合物产生了显著高于纯Ac-Di-Sol粉末的张力值(p<0.05)(附图1)。这一作用却未显示于包含甘露醇的混合物中(p>0.1),可能是由于甘露醇较高的水溶性,如下所讨论。如附图1所示,直至加入Ac-Di-Sol的量达到一定程度,生物粘附强度显著地增加(p<0.01)。当该量超过大约20%w/w时,张力显著增加。
载体溶解性的作用
DCP混合物具有明显高的(p<0.02)生物粘附性(较甘露醇混合物具有更高的张力)。这可能是由于甘露醇较高的水溶性引起的。由此,甘露醇混合物部分可能已溶解了交互混合物的外周区域但无法完全溶解粘膜层。
表1.测试材料的基本特征。均值(±s.d.)
a使用氦比重计(AccuPyc 1330Pycnometer,Micromeritics,USA)测量(n=3)。
b使用Friedrich透过测粒法(Eriksson等1990)或Blaine透过测粒法(Alderborn等1985)测量(n=3)。
结论
当与细颗粒的Ac-Di-Sol混合时,粘膜和较粗糙甘露醇或DCP粉末间的张力改善了(p<0.0001)。这显示加入具有较高粘附倾向的材料将增加另一种较差的生物粘附材料比如载体材料的粘附。应用生物粘附粉末与水不溶载体的交互混合物较水溶性载体具有预料不到的优越性,特别是以接近单颗粒表面覆盖的比例应用时。因此,得出的结论为,使用微溶载体的这种交互混合物是开发生物粘附制剂比如舌下给药的速释制剂的有利配制工具。
实施例2.具有生物/粘膜粘附促进性质的快速崩解片的制备
根据下列组成批量生产1000片剂:82.5g粒径约为250至450微米的磷酸氢钙二水合物(DCP),与500mg微粉化的芬太尼混合50小时。所得混合物与10.0g微粉化的藻酸钠(生物/粘膜促进剂)混合5小时。此后,将5.0gPh 101(用作粘附剂)和2.0g Ac-Di-(修饰过的纤维素树脂用作有效的崩解剂)混合60分钟。所得混合物与0.5g硬脂酸镁(润滑剂)混合2分钟,最终的片材在200Mpa压制力下压制成片,各片重量为100mg,包含0.5mg芬太尼。
实施例3.给予心钠素(ANP)的快速崩解片的制备
根据实施例2制备了具有生物/粘膜粘附性质的快速崩解片,其还增强了舌下给药时大分子的吸收,各片包含0.7mg ANP。但在该组合物中,除去了藻酸钠并将加入的Ac-Di-增加至5.0g,其既作为崩解剂又作为生物粘附成分。与常规经口制剂相比,该片剂显示了快速释放ANP并增强了通过口腔粘膜对ANP的吸收。该制剂可用于治疗肺水肿。
实施例4.给予奥美拉唑的快速崩解片的制备
根据实施例3制备了具有生物/粘膜粘附性质的用于舌下给药的快速崩解片,各片包含10mg奥美拉唑。与常规经口制剂相比,该片剂显示了快速释放奥美拉唑并增强了通过口腔粘膜对奥美拉唑的吸收,以及减少了吞咽的唾液中的奥美拉唑。该制剂可用于治疗胃食管反流。
实施例5.心钠素(ANP)鼻内粉剂的制备
根据实施例2制备了具有生物/粘膜粘附性质的用于鼻内给药的有序组合物,各剂量体积的粉末混合物包含0.7mg的ANP。与实施例2的组合物相比,不必压制成片因此也不必加入粘附剂(Ph 101)、崩解剂(Ac-Di-)或润滑剂(硬脂酸镁)。吹入鼻腔后,与常规剂型相比,该粉末显示了快速溶解ANP并增强了通过鼻腔粘膜对ANP的吸收。该制剂可用于治疗肺水肿。
在前述说明书中,已参考各种实施例各优选实施方案描述了本发明。但是,对于本领域技术人员而言,显然本发明的范围不限于这些实施例和实施方案,可以在不偏离本发明思想下进行进一步的修改和变化。因此,本发明的范围仅由权利要求书限定。
参考文献
Alderborn,G.,Pasanen,K.,Nystrom,C.(1985)Studies on directcompression of tablets.XI.Characterization of particle fragmentation duringcompaction by permeametry measurements of tablets.Int.J.Pharm.23:79-86
Corne,S.J.,Morrisey,S.M.,Woods,R.J.(1974)A method for thequantitative estimation of gastric barrier mucus.J.Physiol.242:116P-117P
Eriksson,M.,Nystrom,C.,Alderborn,G.(1990)Evaluation of apermeametry technique for surface area measurements of coarse particulatematerials.Int.J.Pharm.63:189-199
Sundell-Bredenberg,S.,Nystrom,C.(2001)The possibility of achieving aninteractive mixture with high dose homogeneity containing an extremely lowproportion of a micronised drug.Eur.J.Pharm.Sci.12:285-295
Westerberg,M.(1992)Studies on ordered mixtures for fast release anddissolution of drugs with low aqueous solubility.Ph.D.Thesis.UppsalaUniversity,Reprocentralen,HSC,Uppsala,Sweden
Claims (31)
1.一种用于经舌下或鼻内给药治疗急性紊乱的药物组合物,包含粘附于载体颗粒表面至少一种药学活性剂微粒的有序混合物,以及粘附于该载体颗粒表面的生物粘附和/或粘膜粘附促进剂,所述颗粒显著大于所述微粒且不溶于或微溶于水,其中载体颗粒为磷酸氢钙二水合物。
2.根据权利要求1的组合物,其中所述活性剂微粒基于重量的平均直径小于10μm。
3.根据权利要求1的组合物,其中载体颗粒的平均过筛直径不大于750μm。
4.根据权利要求3的组合物,其中载体颗粒的平均过筛直径为从50μm至500μm。
5.根据权利要求1的组合物,其中载体颗粒包含基于总组合物0.1至40重量百分比的生物/粘膜粘附促进剂。
6.根据权利要求2的组合物,其中载体颗粒包含基于总组合物0.1至40重量百分比的生物/粘膜粘附促进剂。
7.根据权利要求3的组合物,其中载体颗粒包含基于总组合物0.1至40重量百分比的生物/粘膜粘附促进剂。
8.根据权利要求5的组合物,其中载体颗粒包含基于总组合物2至25重量百分比的生物/粘膜粘附促进剂。
9.根据权利要求5的组合物,其中生物/粘膜粘附促进剂选自交联聚合物、丙烯酸聚合物、羟丙基甲基纤维素,羟乙基纤维素,羟丙基纤维素,羧甲基纤维素钠,甲基纤维素,羟乙基纤维素乙基醚,羧甲基纤维素和修饰的纤维素树脂;交联羧甲基纤维素、具有生物/粘膜粘附性质的天然聚合物,及其混合物。
10.根据权利要求5的组合物,其中生物/粘膜粘附促进剂选自羟丙基甲基纤维素,羟乙基纤维素,羟丙基纤维素,羧甲基纤维素钠,甲基纤维素,羟乙基纤维素乙基醚,羧甲基纤维素和修饰的纤维素树脂;交联羧甲基纤维素;丙烯酸聚合物;聚氧乙烯;壳聚糖;明胶;藻酸钠;胶质;硬葡聚糖;黄原胶;瓜尔胶;聚-共-(甲基乙烯基醚/马来酐);及其混合物。
12.根据权利要求1的组合物,还包含药学上可接受的表面活性剂,其为细分散形式并与活性剂密切地混合。
13.根据权利要求2的组合物,还包含药学上可接受的表面活性剂,其为细分散形式并与活性剂密切地混合。
14.根据权利要求3的组合物,还包含药学上可接受的表面活性剂,其为细分散形式并与活性剂密切地混合。
15.根据权利要求5的组合物,还包含药学上可接受的表面活性剂,其为细分散形式并与活性剂密切地混合。
16.根据权利要求10的组合物,还包含药学上可接受的表面活性剂,其为细分散形式并与活性剂密切地混合。
17.根据权利要求12的组合物,其中表面活性剂的量为该组合物的0.5至5重量百分比。
18.根据权利要求17的组合物,其中表面活性剂的量为该组合物的0.5至3重量百分比。
19.根据权利要求12的组合物,其中表面活性剂选自月桂基硫酸钠、聚山梨酯、胆汁酸盐及其混合物。
20.根据权利要求1-19任一项的组合物,其中所述的组合物为舌下组合物的形式,并且该组合物包含至少一种药学上的崩解剂,其促进与活性剂混合的载体颗粒在舌下粘膜上的分散。
21.根据权利要求20的组合物,其中崩解剂选自交联聚乙烯吡咯烷酮、羧甲基淀粉、天然淀粉、微晶纤维素、纤维素树脂,及其混合物。
22.根据权利要求20的组合物,其中崩解剂的含量为该组合物的1至10重量百分比。
23.根据权利要求1-19任一项的组合物,其中药学活性剂是芬太尼或其药学上可接受的盐。
24.根据权利要求20的组合物,其中药学活性剂是芬太尼或其药学上可接受的盐。
25.根据权利要求21的组合物,其中药学活性剂是芬大尼或其药学上可接受的盐。
26.根据权利要求22的组合物,其中药学活性剂是芬太尼或其药学上可接受的盐。
27.权利要求1~26中任一项的组合物在制备用于治疗急性紊乱的药物中的用途。
28.根据权利要求27的用途,其中药学活性剂是芬太尼或其药学上可接受的盐。
29.根据权利要求28的用途,其中芬太尼以每剂量单位0.025至10mg的量给药。
30.根据权利要求29的用途,其中芬太尼以每剂量单位0.05至2mg的量给药。
31.根据权利要求27的用途,其中所述的急性紊乱为急性或突破性疼痛。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US44385703P | 2003-01-31 | 2003-01-31 | |
US60/443,857 | 2003-01-31 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1744898A CN1744898A (zh) | 2006-03-08 |
CN100581586C true CN100581586C (zh) | 2010-01-20 |
Family
ID=32825385
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200480003272A Expired - Fee Related CN100581586C (zh) | 2003-01-31 | 2004-01-15 | 一种快速起效的药物组合物 |
Country Status (21)
Country | Link |
---|---|
US (2) | US20060216352A1 (zh) |
EP (1) | EP1587514B3 (zh) |
JP (1) | JP2006516616A (zh) |
KR (1) | KR20050096950A (zh) |
CN (1) | CN100581586C (zh) |
AT (1) | ATE329594T1 (zh) |
AU (1) | AU2004208644B2 (zh) |
CA (1) | CA2512559A1 (zh) |
CY (1) | CY1106154T1 (zh) |
DE (1) | DE602004001209T3 (zh) |
DK (1) | DK1587514T3 (zh) |
ES (1) | ES2270335T7 (zh) |
HK (1) | HK1080387A1 (zh) |
MX (1) | MXPA05008140A (zh) |
NO (1) | NO20053277L (zh) |
NZ (1) | NZ541167A (zh) |
PL (1) | PL211224B1 (zh) |
PT (1) | PT1587514E (zh) |
RU (1) | RU2345791C2 (zh) |
SI (1) | SI1587514T1 (zh) |
WO (1) | WO2004067004A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10143706B2 (en) | 2016-06-29 | 2018-12-04 | Cannscience Innovations, Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
Families Citing this family (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030091629A1 (en) | 1998-03-27 | 2003-05-15 | Cima Labs Inc. | Sublingual buccal effervescent |
US6974590B2 (en) | 1998-03-27 | 2005-12-13 | Cima Labs Inc. | Sublingual buccal effervescent |
US7638138B2 (en) | 2003-02-21 | 2009-12-29 | Translational Research, Ltd. | Compositions for nasal administration of pharmaceuticals |
AU2003220808B2 (en) | 2003-03-27 | 2008-08-21 | Bioactis Limited | Powder medicine applicator for nasal cavity |
GB0329918D0 (en) * | 2003-12-24 | 2004-01-28 | West Pharm Serv Drug Res Ltd | Intranasal compositions |
JP5244318B2 (ja) | 2003-12-31 | 2013-07-24 | シーマ・ラブス、インコーポレイテッド | 発泡性経口アヘン薬投薬形態およびアヘン薬の投与方法 |
KR101184138B1 (ko) | 2003-12-31 | 2012-09-19 | 시마 랩스 인크. | 일반적인 선형 발포성 경구 펜타닐 투약 제형 및 투여 방법 |
US7858121B2 (en) | 2003-12-31 | 2010-12-28 | Cima Labs, Inc. | Effervescent oral fentanyl dosage form and methods of administering fentanyl |
US7658945B2 (en) * | 2004-02-17 | 2010-02-09 | Transcept Pharmaceuticals, Inc. | Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof |
JP4922762B2 (ja) | 2004-08-10 | 2012-04-25 | 株式会社新日本科学 | 速効性でかつ高い吸収性を可能とする経鼻投与用組成物 |
KR20070111497A (ko) * | 2005-02-10 | 2007-11-21 | 오렉쏘 에이비 | 약의 경점막 투여에 유용한 새로운 약학 조성물 |
FR2883179B1 (fr) * | 2005-03-18 | 2009-04-17 | Ethypharm Sa | Comprime enrobe |
AU2006228296B2 (en) * | 2005-03-28 | 2011-08-04 | Orexo Ab | New pharmaceutical compositions useful in the treatment of Parkinson's disease |
EP1863456A1 (en) * | 2005-03-28 | 2007-12-12 | Orexo AB | New pharmaceutical compositions useful in the treatment of pain |
US20080193526A1 (en) * | 2005-03-28 | 2008-08-14 | Anders Pettersson | Pharmaceutical Compositions Useful in the Treatment of Pain |
US20070287740A1 (en) * | 2005-05-25 | 2007-12-13 | Transcept Pharmaceuticals, Inc. | Compositions and methods of treating middle-of-the night insomnia |
AU2006249761A1 (en) * | 2005-05-25 | 2006-11-30 | Transcept Pharmaceuticals, Inc. | Solid compositions and methods for treating middle-of-the night insomnia |
US20070225322A1 (en) * | 2005-05-25 | 2007-09-27 | Transoral Pharmaceuticals, Inc. | Compositions and methods for treating middle-of-the night insomnia |
SE530184C2 (sv) | 2005-12-23 | 2008-03-18 | Kjell Stenberg | Bioadhesiv farmaceutisk filmkomposition innehållande lågviskösa alginater |
US8535714B2 (en) | 2006-01-06 | 2013-09-17 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US8865743B2 (en) | 2006-01-06 | 2014-10-21 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US8357114B2 (en) | 2006-01-06 | 2013-01-22 | Acelrx Pharmaceuticals, Inc. | Drug dispensing device with flexible push rod |
US8252329B2 (en) | 2007-01-05 | 2012-08-28 | Acelrx Pharmaceuticals, Inc. | Bioadhesive drug formulations for oral transmucosal delivery |
US8753308B2 (en) | 2006-01-06 | 2014-06-17 | Acelrx Pharmaceuticals, Inc. | Methods for administering small volume oral transmucosal dosage forms using a dispensing device |
US8202535B2 (en) | 2006-01-06 | 2012-06-19 | Acelrx Pharmaceuticals, Inc. | Small-volume oral transmucosal dosage forms |
US8252328B2 (en) * | 2006-01-06 | 2012-08-28 | Acelrx Pharmaceuticals, Inc. | Bioadhesive drug formulations for oral transmucosal delivery |
US9289583B2 (en) | 2006-01-06 | 2016-03-22 | Acelrx Pharmaceuticals, Inc. | Methods for administering small volume oral transmucosal dosage forms using a dispensing device |
US9066847B2 (en) * | 2007-01-05 | 2015-06-30 | Aceirx Pharmaceuticals, Inc. | Storage and dispensing devices for administration of oral transmucosal dosage forms |
EP1837020A1 (en) * | 2006-03-24 | 2007-09-26 | Bioalliance Pharma | Mucosal bioadhesive slow release carrier for delivering active principles |
US20070260491A1 (en) * | 2006-05-08 | 2007-11-08 | Pamela Palmer | System for delivery and monitoring of administration of controlled substances |
US20100233257A1 (en) * | 2006-06-09 | 2010-09-16 | Ethypharm | Low dose sublingual tablets of opioid analgesics and preparation process |
US20070286900A1 (en) * | 2006-06-09 | 2007-12-13 | Catherine Herry | Low dose tablets of opioid analgesics and preparation process |
US20070299687A1 (en) * | 2006-06-23 | 2007-12-27 | Pamela Palmer | Inpatient system for patient-controlled delivery of oral transmucosal medications dosed as needed |
TW200824693A (en) | 2006-08-28 | 2008-06-16 | Jazz Pharmaceuticals Inc | Pharmaceutical compositions of clonazepam and methods of use thereof |
US20080132535A1 (en) * | 2006-11-30 | 2008-06-05 | Transcept Pharmaceuticals, Inc. | Stabilized Zolpidem Pharmaceutical Compositions |
US8470361B2 (en) | 2006-12-04 | 2013-06-25 | Orexo Ab | Non-abusable pharmaceutical composition comprising opioids |
GB0625322D0 (en) * | 2006-12-19 | 2007-01-24 | Pharmakodex Ltd | Pharmaceutical compositions |
ES2652415T3 (es) | 2006-12-26 | 2018-02-02 | Shin Nippon Biomedical Laboratories, Ltd. | Preparación para aplicación transnasal |
CA2673837C (en) * | 2007-01-05 | 2015-11-24 | Acelrx Pharmaceuticals, Inc. | Storage and dispensing devices for administration of oral transmucosal dosage forms |
EP2168573A1 (en) * | 2008-09-30 | 2010-03-31 | LEK Pharmaceuticals D.D. | Formulations comprising ezetimibe |
US8945592B2 (en) | 2008-11-21 | 2015-02-03 | Acelrx Pharmaceuticals, Inc. | Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same |
WO2010107761A1 (en) | 2009-03-18 | 2010-09-23 | Acelrx Pharmaceuticals, Inc. | Improved storage and dispensing devices for administration of oral transmucosal dosage forms |
JP2012526726A (ja) * | 2009-05-15 | 2012-11-01 | 株式会社新日本科学 | 薬物動態が改善された鼻腔内用薬学的組成物 |
WO2011013003A2 (en) * | 2009-07-31 | 2011-02-03 | Shin Nippon Biomedical Laboratories, Ltd. | Intranasal granisetron and nasal applicator |
SG10201912526TA (en) | 2009-10-01 | 2020-02-27 | Adare Pharmaceuticals Inc | Orally administered corticosteroid compositions |
MY150626A (en) | 2009-10-30 | 2014-02-07 | Ix Biopharma Ltd | Fast dissolving solid dosage form |
US20110150993A1 (en) | 2009-12-22 | 2011-06-23 | Fmc Corporation | Fine Particle Croscarmellose and Uses Thereof |
WO2012106058A2 (en) | 2011-01-31 | 2012-08-09 | New Market Pharmaceuticals | Animal treatments |
AU2012311293B2 (en) | 2011-09-19 | 2014-02-20 | Orexo Ab | New abuse-resistant pharmaceutical composition for the treatment of opioid dependence |
BR112014027352B1 (pt) * | 2012-05-02 | 2022-10-25 | New Market Pharmaceuticals | Composições farmacêuticas para a introdução sistêmica direta |
US10064849B2 (en) | 2012-05-02 | 2018-09-04 | New Market Pharmaceuticals | Pharmaceutical compositions for direct systemic introduction |
PE20142444A1 (es) | 2012-05-02 | 2015-01-09 | Orexo Ab | Nueva composicion de alfentanilo para el tratamiento del dolor agudo |
MX2015011624A (es) | 2013-03-04 | 2015-12-17 | Besins Healthcare Lu Sarl | Composiciones farmaceuticas secas que comprenden nanoparticulas de agente activo ligadas a particulas portadoras. |
WO2015034678A2 (en) | 2013-09-06 | 2015-03-12 | Aptalis Pharmatech, Inc. | Corticosteroid containing orally disintegrating tablet compositions for eosinophilic esophagitis |
AU2015369710B2 (en) | 2014-12-23 | 2020-09-17 | Vertical Pharmaceuticals, Llc | Systems, devices and methods for dispensing oral transmucosal dosage forms |
CN105147721A (zh) * | 2015-08-28 | 2015-12-16 | 施康培医疗科技(武汉)有限公司 | 一种抑菌清洗剂及其使用方法 |
JP7017849B2 (ja) * | 2015-09-11 | 2022-02-09 | シムライズ アーゲー | 経口投与剤形 |
CN106822007B (zh) * | 2015-09-11 | 2021-12-31 | 西姆莱斯股份公司 | 口服制剂 |
TWI728172B (zh) | 2016-08-18 | 2021-05-21 | 美商愛戴爾製藥股份有限公司 | 治療嗜伊紅性食道炎之方法 |
US11744967B2 (en) | 2017-09-26 | 2023-09-05 | Shin Nippon Biomedical Laboratories, Ltd. | Intranasal delivery devices |
IT202100010802A1 (it) * | 2021-05-03 | 2022-11-03 | Alfasigma Spa | Formulazione solida mucoadesiva comprendente probiotici per uso nella prevenzione e nel trattamento di disbiosi orale. |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE8800080L (sv) | 1988-01-13 | 1989-07-14 | Kabivitrum Ab | Laekemedelskomposition |
JP3414539B2 (ja) * | 1994-05-11 | 2003-06-09 | 有限会社ドット | 経鼻吸収用組成物 |
JP3197221B2 (ja) * | 1996-02-27 | 2001-08-13 | 帝人株式会社 | 吸収性が改善された粉末状経鼻投与組成物 |
US6391452B1 (en) * | 1997-07-18 | 2002-05-21 | Bayer Corporation | Compositions for nasal drug delivery, methods of making same, and methods of removing residual solvent from pharmaceutical preparations |
JPH11322582A (ja) * | 1998-05-06 | 1999-11-24 | Dot:Kk | 経鼻吸収用鼻粘膜付着・滞留型キャリヤ |
SE9803239D0 (sv) * | 1998-09-24 | 1998-09-24 | Diabact Ab | Composition for the treatment of acute pain |
SE9803240D0 (sv) * | 1998-09-24 | 1998-09-24 | Diabact Ab | A pharmaceutical composition having a rapid action |
CA2396381A1 (en) * | 2000-01-20 | 2001-07-26 | Akira Yanagawa | Nasally administrable cyclic peptide compositions |
US20020106407A1 (en) * | 2000-12-11 | 2002-08-08 | Dennis Coleman | Method and apparatus for treating breakthrough pain |
JP2004043479A (ja) * | 2002-07-11 | 2004-02-12 | Taiho Yakuhin Kogyo Kk | 経鼻吸収用組成物 |
-
2004
- 2004-01-15 CN CN200480003272A patent/CN100581586C/zh not_active Expired - Fee Related
- 2004-01-15 RU RU2005127353/15A patent/RU2345791C2/ru not_active IP Right Cessation
- 2004-01-15 DE DE602004001209T patent/DE602004001209T3/de not_active Expired - Lifetime
- 2004-01-15 SI SI200430055T patent/SI1587514T1/sl unknown
- 2004-01-15 CA CA002512559A patent/CA2512559A1/en not_active Abandoned
- 2004-01-15 AT AT04702472T patent/ATE329594T1/de not_active IP Right Cessation
- 2004-01-15 NZ NZ541167A patent/NZ541167A/en not_active IP Right Cessation
- 2004-01-15 US US10/543,818 patent/US20060216352A1/en not_active Abandoned
- 2004-01-15 KR KR1020057013534A patent/KR20050096950A/ko not_active Application Discontinuation
- 2004-01-15 AU AU2004208644A patent/AU2004208644B2/en not_active Ceased
- 2004-01-15 PL PL378051A patent/PL211224B1/pl not_active IP Right Cessation
- 2004-01-15 WO PCT/SE2004/000037 patent/WO2004067004A1/en active IP Right Grant
- 2004-01-15 DK DK04702472T patent/DK1587514T3/da active
- 2004-01-15 PT PT04702472T patent/PT1587514E/pt unknown
- 2004-01-15 MX MXPA05008140A patent/MXPA05008140A/es active IP Right Grant
- 2004-01-15 EP EP04702472A patent/EP1587514B3/en not_active Expired - Lifetime
- 2004-01-15 ES ES04702472T patent/ES2270335T7/es active Active
- 2004-01-15 JP JP2006502771A patent/JP2006516616A/ja active Pending
-
2005
- 2005-07-05 NO NO20053277A patent/NO20053277L/no not_active Application Discontinuation
-
2006
- 2006-01-19 HK HK06100858A patent/HK1080387A1/xx not_active IP Right Cessation
- 2006-09-04 CY CY20061101249T patent/CY1106154T1/el unknown
-
2011
- 2011-06-30 US US13/173,566 patent/US20110256229A1/en not_active Abandoned
Non-Patent Citations (2)
Title |
---|
口服生物粘附性给药系统. 魏淑波.镇江医学院学报,第11卷第1期. 2001 |
口服生物粘附性给药系统. 魏淑波.镇江医学院学报,第11卷第1期. 2001 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10143706B2 (en) | 2016-06-29 | 2018-12-04 | Cannscience Innovations, Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
US10383892B2 (en) | 2016-06-29 | 2019-08-20 | CannScience Innovations Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
US10537592B2 (en) | 2016-06-29 | 2020-01-21 | CannScience Innovations Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
Also Published As
Publication number | Publication date |
---|---|
PL378051A1 (pl) | 2006-02-20 |
KR20050096950A (ko) | 2005-10-06 |
NO20053277D0 (no) | 2005-07-05 |
RU2345791C2 (ru) | 2009-02-10 |
ES2270335T3 (es) | 2007-04-01 |
ES2270335T7 (es) | 2012-03-16 |
RU2005127353A (ru) | 2006-06-10 |
EP1587514B3 (en) | 2011-06-22 |
CY1106154T1 (el) | 2011-06-08 |
DE602004001209T3 (de) | 2012-03-15 |
EP1587514A1 (en) | 2005-10-26 |
US20060216352A1 (en) | 2006-09-28 |
CA2512559A1 (en) | 2004-08-12 |
AU2004208644B2 (en) | 2009-07-23 |
EP1587514B1 (en) | 2006-06-14 |
DE602004001209T2 (de) | 2007-04-26 |
US20110256229A1 (en) | 2011-10-20 |
DK1587514T3 (da) | 2006-10-16 |
AU2004208644A1 (en) | 2004-08-12 |
ATE329594T1 (de) | 2006-07-15 |
PT1587514E (pt) | 2006-09-29 |
NZ541167A (en) | 2008-07-31 |
PL211224B1 (pl) | 2012-04-30 |
CN1744898A (zh) | 2006-03-08 |
WO2004067004A1 (en) | 2004-08-12 |
MXPA05008140A (es) | 2005-09-30 |
JP2006516616A (ja) | 2006-07-06 |
HK1080387A1 (en) | 2006-04-28 |
SI1587514T1 (sl) | 2006-10-31 |
NO20053277L (no) | 2005-07-15 |
DE602004001209D1 (de) | 2011-01-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100581586C (zh) | 一种快速起效的药物组合物 | |
EP2236133B1 (en) | Pharmaceutical composition comprising fentanyl for the treatment of acute or breakthrough pain by sublingual administration | |
KR100760531B1 (ko) | 급성 통증 치료용 펜타닐 조성물 | |
JP2006516616A5 (zh) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100120 Termination date: 20130115 |
|
CF01 | Termination of patent right due to non-payment of annual fee |