OA17358A - Pediatric oral liquid compositions containing nepadutant. - Google Patents
Pediatric oral liquid compositions containing nepadutant. Download PDFInfo
- Publication number
- OA17358A OA17358A OA1201500012 OA17358A OA 17358 A OA17358 A OA 17358A OA 1201500012 OA1201500012 OA 1201500012 OA 17358 A OA17358 A OA 17358A
- Authority
- OA
- OAPI
- Prior art keywords
- nepadutant
- tpgs
- pharmaceutical composition
- composition according
- aqueous
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 91
- NPSVXOVMLVOMDD-SXRVEDALSA-N (2S)-2-[[(3S,6S,9S,12S)-12-[[(2S)-4-[[(2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]amino]-2-amino-4-oxobutanoyl]amino]-6-benzyl-9-(1H-indol-3-ylmethyl)-5,8,11,14-tetraoxo-1,4,7,10-tetrazacyclotetradecane-3-carbonyl]amino]-4-methyl Chemical compound C([C@H](N)C(=O)N[C@H]1CC(=O)NC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C3=CC=CC=C3NC=2)NC1=O)C(=O)N[C@@H](CC(C)C)C(O)=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O NPSVXOVMLVOMDD-SXRVEDALSA-N 0.000 title claims abstract description 76
- 229950000640 Nepadutant Drugs 0.000 title claims abstract description 76
- 239000007788 liquid Substances 0.000 title claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 239000002738 chelating agent Substances 0.000 claims abstract description 18
- 208000008665 Gastrointestinal Disease Diseases 0.000 claims abstract description 9
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical group OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 229940075582 Sorbic Acid Drugs 0.000 claims description 16
- 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 16
- 239000008121 dextrose Substances 0.000 claims description 16
- 239000008213 purified water Substances 0.000 claims description 16
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 claims description 16
- 235000010199 sorbic acid Nutrition 0.000 claims description 16
- 239000004334 sorbic acid Substances 0.000 claims description 16
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 15
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 14
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 14
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 239000008203 oral pharmaceutical composition Substances 0.000 claims description 7
- 229960001484 Edetic Acid Drugs 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 230000000996 additive Effects 0.000 claims description 5
- 239000000546 pharmaceutic aid Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 235000003599 food sweetener Nutrition 0.000 claims description 3
- 239000003765 sweetening agent Substances 0.000 claims description 3
- 230000002335 preservative Effects 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 229940095629 edetate calcium disodium Drugs 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000003963 antioxidant agent Substances 0.000 description 23
- 235000006708 antioxidants Nutrition 0.000 description 22
- 238000009472 formulation Methods 0.000 description 22
- 230000003078 antioxidant Effects 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- 108010040722 Neurokinin-2 Receptors Proteins 0.000 description 10
- 102100020227 TACR2 Human genes 0.000 description 10
- 239000011261 inert gas Substances 0.000 description 10
- 229920000136 polysorbate Polymers 0.000 description 10
- 239000000796 flavoring agent Substances 0.000 description 9
- 102000003141 Tachykinins Human genes 0.000 description 8
- 108060008037 Tachykinins Proteins 0.000 description 8
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 8
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 8
- 229940068968 Polysorbate 80 Drugs 0.000 description 7
- 229930003427 Vitamin E Natural products 0.000 description 7
- 229940046009 Vitamin E Drugs 0.000 description 7
- 229920000053 polysorbate 80 Polymers 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 235000019165 vitamin E Nutrition 0.000 description 7
- 239000011709 vitamin E Substances 0.000 description 7
- 150000003712 vitamin E derivatives Chemical class 0.000 description 7
- 230000003042 antagnostic Effects 0.000 description 6
- 230000000111 anti-oxidant Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 235000019634 flavors Nutrition 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 229950008882 Polysorbate Drugs 0.000 description 5
- 229940068965 Polysorbates Drugs 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- -1 polyethylen Polymers 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical class O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 4
- 229920000881 Modified starch Polymers 0.000 description 4
- 229940100688 Oral Solution Drugs 0.000 description 4
- 229940044519 Poloxamer 188 Drugs 0.000 description 4
- 229940075579 Propyl Gallate Drugs 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012456 homogeneous solution Substances 0.000 description 4
- 230000000968 intestinal Effects 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229920001993 poloxamer 188 Polymers 0.000 description 4
- 239000000473 propyl gallate Substances 0.000 description 4
- 235000010388 propyl gallate Nutrition 0.000 description 4
- 235000019640 taste Nutrition 0.000 description 4
- 230000035917 taste Effects 0.000 description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 235000011034 Rubus glaucus Nutrition 0.000 description 3
- 235000009122 Rubus idaeus Nutrition 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- CONXGOYCVNRCCT-UHFFFAOYSA-F [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O.[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O.[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O CONXGOYCVNRCCT-UHFFFAOYSA-F 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 235000019658 bitter taste Nutrition 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 230000004899 motility Effects 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- ZTHYODDOHIVTJV-UHFFFAOYSA-N propyl 3,4,5-trihydroxybenzoate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229940086735 succinate Drugs 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 3
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 3
- 229960000984 tocofersolan Drugs 0.000 description 3
- 239000011732 tocopherol Substances 0.000 description 3
- 125000002640 tocopherol group Chemical group 0.000 description 3
- 235000019149 tocopherols Nutrition 0.000 description 3
- 229930003799 tocopherols Natural products 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 230000036912 Bioavailability Effects 0.000 description 2
- ACTIUHUUMQJHFO-UPTCCGCDSA-N Coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 2
- 229940119017 Cyclosporine Drugs 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-α-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 2
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 2
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 2
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 2
- 208000004454 Hyperalgesia Diseases 0.000 description 2
- 208000007999 Hyperesthesia Diseases 0.000 description 2
- 210000000936 Intestines Anatomy 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 240000003497 Rubus idaeus Species 0.000 description 2
- HYHCSLBZRBJJCH-UHFFFAOYSA-M Sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 2
- 229940035936 Ubiquinone Drugs 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229960001452 alpha-Tocopherol Acetate Drugs 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 230000035514 bioavailability Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 235000017471 coenzyme Q10 Nutrition 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000004030 hiv protease inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 230000003033 spasmogenic Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000087 stabilizing Effects 0.000 description 2
- CIWBSHSKHKDKBQ-DUZGATOHSA-N (+)-Ascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 1
- PUSNGFYSTWMJSK-GSZQVNRLSA-N (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan- Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](OC)O[C@@H]1COC.CC(O)CO[C@@H]1[C@@H](OCC(C)O)[C@H](OCC(C)O)[C@@H](COCC(O)C)O[C@H]1O[C@H]1[C@H](OCC(C)O)[C@@H](OCC(C)O)[C@H](OCC(C)O)O[C@@H]1COCC(C)O PUSNGFYSTWMJSK-GSZQVNRLSA-N 0.000 description 1
- 244000020998 Acacia farnesiana Species 0.000 description 1
- 206010061590 Blood disease Diseases 0.000 description 1
- YBYCBEQAZWHDPG-UHFFFAOYSA-K C(N(CC(=O)[O-])CC(=O)O)CN(CC(=O)[O-])CC(=O)[O-].C(N(CC(=O)O)CC(=O)O)CN(CC(=O)O)CC(=O)O.[Na+].[Ca+2] Chemical compound C(N(CC(=O)[O-])CC(=O)O)CN(CC(=O)[O-])CC(=O)[O-].C(N(CC(=O)O)CC(=O)O)CN(CC(=O)O)CC(=O)O.[Na+].[Ca+2] YBYCBEQAZWHDPG-UHFFFAOYSA-K 0.000 description 1
- 229940063834 Carboxymethylcellulose Sodium Drugs 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 210000000981 Epithelium Anatomy 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021746 Infantile colic Diseases 0.000 description 1
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 229940040461 Lipase Drugs 0.000 description 1
- 208000005135 Methemoglobinemia Diseases 0.000 description 1
- 210000004080 Milk Anatomy 0.000 description 1
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 1
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 1
- CVZWMOALRGVDCH-UHFFFAOYSA-N O.O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O Chemical compound O.O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O CVZWMOALRGVDCH-UHFFFAOYSA-N 0.000 description 1
- 229940054534 Ophthalmic Solution Drugs 0.000 description 1
- 229960000502 Poloxamer Drugs 0.000 description 1
- 229940113116 Polyethylene Glycol 1000 Drugs 0.000 description 1
- 240000007651 Rubus glaucus Species 0.000 description 1
- 108010072901 Tachykinin Receptors Proteins 0.000 description 1
- 102000007124 Tachykinin Receptors Human genes 0.000 description 1
- MIJPAVRNWPDMOR-ZAFYKAAXSA-N [(2R)-2-[(1S)-1,2-dihydroxyethyl]-3-hydroxy-5-oxo-2H-furan-4-yl] dihydrogen phosphate Chemical compound OC[C@H](O)[C@H]1OC(=O)C(OP(O)(O)=O)=C1O MIJPAVRNWPDMOR-ZAFYKAAXSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 1
- 229940087168 alpha Tocopherol Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 201000002393 blood protein disease Diseases 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
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- 239000000839 emulsion Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 201000002146 gastrointestinal system disease Diseases 0.000 description 1
- 201000002138 hematopoietic system disease Diseases 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
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- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 102000004882 lipase Human genes 0.000 description 1
- 108090001060 lipase Proteins 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 235000021056 liquid food Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 239000002746 neurokinin 2 receptor antagonist Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000001590 oxidative Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer 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
- 239000000843 powder Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000019613 sensory perceptions of taste Nutrition 0.000 description 1
- 230000003381 solubilizing Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000002195 synergetic Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000035923 taste sensation Effects 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 231100000730 tolerability Toxicity 0.000 description 1
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Abstract
Oral liquid pharmaceutical compositions containing as active ingredient nepadutant, PGS as solubilizer and optionally a chelating agent. Such compositions are found to be very stable and suitable for paediatric use in the treatment of gastro-intestinal diseases.
Description
Summary
Oral liquid pharmaceutical compositions containing as active ingrédient Nepadutant, PGS as solubilizer and optionally a chelating agent. Such compositions are found to be very stable and suitable for paediatric use in the treatment of gastro-intestinal diseases.
Field of the invention
The présent invention relates to novel pharmaceutical compositions containing an antagonist of tachykinin NK2 receptor, i.e. Nepadutant, very slightly soluble in aqueous solutions.
These pharmaceutical compositions are stable solutions, designed for oral administration of the active ingrédient and preferably intended for use in neonates and infants for paediatric gastrointestinal diseases. The high stability of the compositions is due to the use of TPGS as a solubilizer additive optionally with the addition of a chelating agent.
Background
Contrary to what happens in most préparations of animal tissues where it is necessary to block both NK1 and NK2 receptors to obtain a more efficient antagonism against the spasmogenic effect induced by tachykinins, in other préparations, including préparations of isolated human intestine, the antagonists of NK2 receptor are already fully effective against the spasmogenic effect induced by exogenous or endogenous tachykinins.
In addition to the stimulation rôle in the régulation of intestinal motility, the activation of tachykinin NK2 receptors, also triggers both intrinsic and extrinsic inhibitory mechanisms to the intestinal wall (Giuliani et al. J. Pharmacol. Exp Ther. 246:322-327 (1988)). Moreover NK2 tachykinin receptors regulate intestinal permeability (Hallgren et al. Am. J. Physiol. 273: G1077-G1086 (1997)) and are also involved in the régulation of the sécrétion of water and ions in the gut epithelium in rats and in humans (Tough et al. Naunyn-Schmiedeberg's Arch Pharmacol. 367:104-108 (2003), and in the modulation of viscéral sensitivity (Julia et al. Gastroenterology 107:94-102 (1994)), especially when altered by an active or previous inflammatory state or by a stressful situation.
These pharmaceutical aspects of tachykinins hâve suggested the assessment of sélective antagonists of the tachykinin NK2 receptor in the development of drugs directed against gastrointestinal diseases characterized by gut motility disorders and viscéral hypersensitivity such as, for example, irritable bowel syndrome in adults (Lecci et al. Curr. Opin. Invest. Drugs 3:589-601 (2002)).
Nepadutant is a sélective antagonist of the tachykinin NK2 receptor with formula (I), originally described in EP815126. It is bicyclic hexapeptide, with an excellent safety profile and tolerability.
The NK2 antagonist, Nepadutant, can be identified as [N4-(2acetylamino-2-deoxy-p-D-glucopyranosyl)-L-asparaginyl-L-a-triptophan-Lphenylalanyl-L-2,3-diaminopropio-nil-L-leucil]-C-4.2-N-3.5-lattame-C-1.6-N2.1 -lattame or cyclic[3-amino-L-alanil-L-leucil-N-[2-(acetylamino)-2-deoxy-pD-glucopyranosyl]-L-asparaginyl-L-a,-aspartyl-L-triptophan-Lphenylalanyl](4->1)-lattame (9CI) (CAS RN: 183747-35-5)) (altematively known as MEN11420).
d)
Nepadutant has shown good activity in various in vitro and in vivo models and in humans in reversing the side effects of the activation of NK2 receptors in the intestine, such as viscéral hyperalgesia or alterations of the intestinal motility.
It has been recently discovered that Nepadutant is absorbed when administered orally in new born animais (rats or mice), contrary to what is found in adult animais. Furthermore, the oral administration of Nepadutant in new born rats is able to block, up to 24 hours after its administration, the increase in intestinal transit induced by the activation of NK2 receptors, without altering the basal parameters. In addition Nepadutant has proven effective in a model of hyperalgesia in new born rats.
These results suggest the oral potential bioavailability even in newborns and therefore the clinical use of Nepadutant in the symptomatic treatment of gastrointestinal disorders (e.g. infantile colic), as claimed in W02006045820.
The EMA recommends the use of oral solutions for newborns and infants (nurslings) (from 28 days to 23 months) as the preferred dosage form (EMEA/CHMP/PEG/194810/2005). On the other hand the parentéral formulations (e.g. intravenous) are strongly contraindicated especially for not life-threatening diseases. Thus, it was essential to develop an oral solution of Nepadutant for paediatric use in the gastrointestinal disorders.
Nepadutant is poorly soluble in aqueous medium and has a bitter taste. Furthermore, it is stable in the dried state but the solutions of Nepadutant are sensitive to oxidative dégradation.
In W02006045820 pharmaceutical compositions containing paediatric Nepadutant in liquid form are described (pages 7-8, Examples 1-4), and such compositions are characterized by the use of polysorbate as solubilizer; such compositions appear to be not completely satisfactory for their storage limited duration at room température or at a high température.
EP1464341 describes an ophthalmic solution/emulsion comprising TPGS (Vitamin E TPGS 1000 also referred to as d-alpha tocopheryl polyethylen glycol 1000 succinate) and the antioxidant active ingrédient ubiquinone. Combinations of ubiquinone, TPGS and magnésium ascorbyl-2phosphate show synergistic antioxidant effects. It is not described, however, any antioxidant effect on any active ingrédient which is an antagonist of the tachykinin NK2 receptor in solutions containing TPGS.
In WO97/35587 the formation of liquid formulations containing an HIV protease inhibitor, TPGS and a hydrophilic non-aqueous solvent miscible with TPGS is disclosed, preferred for the filling of soft gélatine capsules. The formulations show a higher bioavailability of the HIV protease inhibitor. The non-aqueous solvent is essential for this formulation.
WO99/26607 describes a distribution System based on a liquid crystal structure, in which the drug is dissolved directly in TPGS. In order to maintain the drug in solution the solid structure of cyclosporine with TPGS does not require the presence or absence of emulsifiers, co-solvents, surfactants, or other solubilizer agents. The resulting products, such as controlled release capsules, tablets, pills are solid oral dosage forms. Because TPGS is used as the sole solvent, high amounts of TPGS (50% to 99.9%) are required.
U.S. Patent 5,583,105 describes pre-concentrated émulsion contaîning the active ingrédient cyclosporine in a lipophilie and/or amphiphilic solvent. In this composition TPGS is mentioned as an emulsifier, adjuvant and antioxidant for fat oils. The antioxidant effect on a pharmaceutical active ingrédient, and especially on a NK2 receptor antagonist, is not claimed.
W02006036614 describes materials like surfactants suitable for solid formulations. The TPGS row material of waxy consistency is converted into properly shaped solid that can be incorporated for example into tablets. The use of the solid form for the préparation of solutions and/or émulsions is not described.
EP1216025 describes the use of a wide range of TPGS as a surfactant (from 0.1% to 90%) in solid formulations comprising a dispersant soluble in water and a soluble compound in lipid medium as a lipase inhibitor. The solidified mixture is loaded into HPMC capsules that reveal an increase in the efficiency and power.
Formulations for topical use contaîning TPGS and layers of alphatocopherol to solubilize or emulsify water insoluble drugs are mentioned in WO9531217.
TPGS is described as a stabilizer applied for the formation and stabilization of double-layer liposomes in acid environment (US5, 364.631).
In W09808490 the préparation of solid co-precipitated for oral delivery of lipophilie substances with poor biodisponibility is described. Delivery tests are conducted on dry powders.
DESCRIPTION OF THE INVENTION
The présent invention relates to stable oral, liquid, pharmaceutical compositions contaîning Nepadutant and TPGS, even for paediatric use for the treatment of newborns and infants (nurslings) in the period from birth to one year, and preferably, from birth to six months of âge.
The TPGS is a substance with solubilizer and antioxidant activity therefore acts as a stabilizer of substances which are highly unstable to oxidation. In addition, the TPSG is essentially tasteless and therefore suitable and acceptable for use in neonates and nurslings. Surprisingly the use of TPGS results in a solubilizing and antioxidant action allowing to obtain limpid, stable solutions of Nepadutant and acceptable from an organoleptic point of view. Additional excipients commonly used with TPGS, such as lipophilie or hydrophilic non-aqueous solvents or co-solvents, lipophilie antioxidant phases etc. are therefore not necessary to generate a stable liquid formulation.
Therefore objects of the présent application are liquid aqueous oral pharmaceutical compositions comprising as active ingrédient Nepadutant and TPGS as an additive.
In a spécifie embodiment of the invention, the compositions contain the TPGS as the only solubilizer and / or stabilizing additive.
In another embodiment of the invention the compositions may further comprise a chelating agent.
In a further embodiment of the invention the compositions comprise in addition to the TPGS other pharmaceutically acceptable excipients.
A second object of the invention is the compositions contaîning Nepadutant, TPGS and optionally a chelating agent and other optional excipients for use in a paediatric treatment in neonates or nurslings, in particular for the paediatric treatment of gastrointestinal diseases.
A further object of the présent application is a process for the préparation of the composition of the invention.
Formulations designed for paediatric use should be in liquid dosage forms for oral administration.
The purified water is a solvent appropriate for paediatric formulations. However, due to the poor water solubility of Nepadutant, in order to dissolve a pharmaceutical effective amount, the use of at least one solubilizer, surfactant or emulsifier is essential.
Few solubilizers, surfactants or emulsifiers are suitable for paediatric formulations, since most ofthe solubilizers/surfactants or emulsifiers produce side effects.
Solubilizers which are very used are polymers of Poloxamer type, for example, the Poloxamer 188 ® (Poloxamer 188 termone indicates a copolymer between the polyoxypropilen and polyoxyethylene and polyoxypropilene of an approximately molecular mass of 1800 g / mol with a content of 80% w / w of polyoxyethylene). However, it has not been possible to obtain the necessary solubilisation of Nepadutant in water with Poloxamer 188 (Tablel).
Table 1) Solubility in water of Nepadutant with different concentrations of solubilizer at 25 0 C.
% of Poloxamer 188 in water | soluble nepadutant [mg/mL] |
— | 0,13 |
0,50% | 0,20 |
1,00% | 0,21 |
2,00% | 0,28 |
2,50% | 0,31 |
Polysorbates are widely used such as solubilizers, in oral, topical formulations and even in parentéral ones. The polysorbates are also accepted as a food additive in Europe (E433). Typical examples of compositions of Nepadutant with polysorbate 80 are those described in W02006045820 (e.g. 1-4 on page 7-8). A disadvantage of polysorbates is the bitter taste of the excipient. The use of flavourings and / or sweeteners to mask the bitter taste of active ingrédients and/or excipients is the approach mostly used in paediatric oral formulations, with raspberry and cream aromas frequently identified as possible excipients masking the flavour, that generate the preferred taste sensation. However, the formulations containing polysorbates Nepadutant proved poorly stable at room température.
In order to increase the stability of solutions containing Nepadutant, the packaging of the formulation and procedures for filling multiple doses containers must be conducted under conditions of deaeration in the presence of inert gases such as nitrogen and argon. These conditions represent an additional problem in the industrial process of packaging, an increasing of total costs and are insufficient to completely prevent the instability of formulations containing polysorbates.
A potential alternative to the conditions of deaeration may be the use of an antioxidant. Thus, various compositions containing different antioxidants hâve been studied.
It has been assayed the effect of different standard antioxidants and their mixtures on the stability of the paediatric formulation in oral solution of Nepadutant 0.4 mg / mL containing polysorbate 80 as a solubilizer (Table 2).
Table 2
Ingrédient | |||||||||||
A | B | C : | D | E | F | G | H | r | J | K | |
Nepadutant | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 |
Polysorbate 80 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 |
Dextrose | 400.0 | 400.0 | 400.0 | 400.0 | 400.0 | 400.0 | 400.0 | 400.0 | 400.0 | 400.0 | 400.0 |
Sorbic acid | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
Sodium carboxymethylc ellulose | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 |
Raspberry flavour | 0.035 | 0.035 | 0.035 | 0.035 | 0.035 | 0.035 | 0.035 | 0.035 | 0.035 | 0.035 | 0.035 |
Cream flavour | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 | 0.015 |
Citric acid | 20 | - | - | 20 | 20 | - | - | 20 | - | - | - |
Propyl gallate | - | 0.1 | - | 0.1 | - | 0.1 | - | - | 0.1 | - | - |
Edetate sodium | - | - | 0.1 | - | 0.1 | 0.1 | - | - | - | 0.1 | - |
Bis-sodium Bisulphite | - | - | - | - | - | - | 10 | 10 | 10 | 10 | - |
Purified water | ad 1.0 ml | ad 1.0 ml | ad 1.0 ml | ad 1.0 ml | ad 1.0 ml | ad 1.0 ml | ad 1.0 ml | ad 1.0 ml | ad 1.0 ml | ad 1.0 ml | ad 1.0 ml |
After storage for 2 months at accelerated conditions (40° C/75% RH) the content of Nepadutant was determined (Table 3, 4). Surprisingly, the formulations containing citric acid showed a significant decrease in
Nepadutant content compared to a reference formulation without the addition of antioxidant (Table 3). These results could be caused by a significant decrease in the formulation pH from pH 5 to ca. pH 3.
No effect on the increased stability on the Nepadutant content has been found for the formulations containing edetate sodium. However, formulations containing propyl gallate, the so-called super antioxidant, and a mixture of propyl gallate and edetate sodium showed a significant increase in the stability of Nepadutant.
However, the propyl gallate is not allowed in foods for infants and 5 young children, because of the known tendency to cause the blood disorder methemoglobinemia.
Incompatibilities hâve been found with sodium bisulfide and sodium bisulfide mixtures containing antioxidants. The initial concentration of the formulations of Nepadutant was found to be ca. 20% of the declared 10 Nepadutant content (Table 4).
Table 3
The Nepadutant content in paediatric formulations in oral solution containing different amounts of antioxidants and their mixtures after storage at 40° C/75% RH (in percentage of the initial Nepadutant content).
Months | Antioxidant | ||||||
illill | iiiiiii | iiiiiii | Illill! | Iiiiiii | llllllïi | ||
0 | 100,0 | 100,0 | 100,0 | 100,0 | 100,Ô | 100,0 | 100,0 |
1 | 68,5 | 97,5 | 89,0 | 92,5 | 80,7 | 101,5 | 82,9 |
2 | 51,1 | 95,2 | 79,0 | 82,7 | 65,1 | 99,8 | 70,3 |
Table 4
The Nepadutant content in paediatric formulations in oral solution containing different amounts of antioxidants and their mixtures after storage 20 at 40° C/75% RH (in percentage of the initial Nepadutant content).
Months | Antioxidant | ||||
liiiiliii | |||||
Ô | 21,5 | 21,7 | 17,6 | 19,6 | 100,0 |
1 | n,t, | n,t, | n,t, | n,t, | 84,2 |
2 | n,t, | n,t, | n,t, | n,t, | 79,2 |
The use of TPGS according to the présent invention offers solution to ail the problème related to the compositions of the prior art, specifically connected to the difficult solubilisation of Nepadutant, to its instability to oxidation and the need to achieve the organoleptic characteristics of the composition also acceptable from the paediatric population.
The purpose of comparing the effect of water-soluble antioxidant additives based on Vitamin E selected from the group: TPGS (Vitamin E TPGS 1000 or d-alpha tocopheryl polyethylen glycol 1000 succinate), Lascorbic acid dl-alpha-tocopherol phosphate potassium sait and dispersible pre-formulated such as dried mixtures of tocopherols at 30% (vitamin E finely dispersed in a matrix of modified food starch) and vitamin E dried at 15% CC 10 (alpha tocopherol acetate finely dispersed in a matrix of modified food starch), were added to a typical pharmaceutical composition containing polysorbate (example 2) to study the increase in the stability of dissolved Nepadutant (table 5). During packaging and the subséquent filling process no deaeration with inert gases such as nitrogen or argon has been used.
Table 5
Nepadutant recovery after storage of solutions at 40° C/75% RH
Formulations | Antioxidant | Time [months] | [%] recovered nepadutant |
Example 1 (formulation K) | none | 0 | 100.0 |
1 | 82.9 | ||
2 | 70.3 | ||
Example 2 | TPGS 3 mg/ml | 0 | 100.0 |
1 | 94.4 | ||
2 | 89.5 | ||
Example 2 | Dry mixed tocopherols 30% 1.8 mg/ml | 0 | 100.0 |
1 | 93.2 | ||
2 | 87.8 | ||
Example 2 | L-ascorbic acid dl-alfatocoferol phosphate potassium sait 2.3 mg/ml | 0 | 100.0 |
1 | 83.5 | ||
2 | 77.3 | ||
Example 2 | Dry vitamin E 15% 3.9 mg/ml | 0 | 100.0 |
1 | 83.5 | ||
2 | 77.1 |
An interesting increase in stability has been achieved with TPGS.
Surprisingly, the composition with TPGS as antioxidant proves to be very stable, making unnecessary the addition of antioxidants as well as the procedure of deaeration with inert gases.
Moreover, equally surprisingly it was found that TPGS can also function as a powerful and efficient solubilizer for Nepadutant to get the preferred concentrations in aqueous solutions (Table 6).
Table 6
Solubility of Nepadutant in aqueous solutions of TPGS at 25° C
Solubilizer concentration [%] | Nepadutant concentration [mg/ml] |
0.5 | 1.60 |
1.0 | 3.39 |
2.0 | 3.59 |
2.5 | 3.59 |
Consequently TPGS can be used as solubilizer instead of polysorbate 80 giving rise to a composition in solution form with a substantially better taste even when formulated without flavouring (Example 3).
The formulation containing TPGS shows a better acceptance from the 15 organoleptic point of view.
Table 7) organoleptic rank for different Nepadutant formulations
The compositions were tasted, in double-blind, by six researchers who hâve expressed a qualitative judgment on three possibilities:
*Bad: slightly unpleasant taste, or bitter or presence of unpleasant 20 aftertaste **lndifferent: no appréciable taste ***Good: pleasant taste
Formulation | Flavour | Organoleptic rank |
based on Polysorbate | no | * |
based on Polysorbate | yes | ★* |
based on TPGS | yes | |
based on TPGS | no | *** |
*Bad, “Indifferent, “*Good
The stability ofthe formulations (Table 8) can be further increased if a chelating agent is added (Example 4).
Table 8
Recovery of Nepadutant after maintenance of solutions at
40°C/75% RH
Formulation | Solubilizer | Chelating agent | Time [months] | [%] recovered nepadutant |
Example 3 | TPGS | none | 0 | 100.0 |
1 | 95.7 | |||
2 | 91.4 | |||
Example 4 | TPGS | sodium diedetate | 0 | 100.0 |
1 | 99.2 | |||
2 | 96.5 |
A preferred composition, in the form of aqueous solution, according to the présent invention, comprises:
a) from 0.01% to 1% w/v (i.e. from 0.1 mg/ml to 10 mg/ml) of nepadutant
b) from 0.1 % to 20% w/v (i.e. from 1 mg/ml to 200 mg/ml) of TPGS
c) optionally from 0.001% to 0.1% w/v (i.e. from 0.01 mg/ml to 1 mg/ml) of a chelating agent
d) one or more pharmaceutically acceptable excipients.
According to the présent invention, the liquid oral pharmaceutical composition comprises the active ingrédient Nepadutant in an amount from 0.01 % to 1 % w/v and preferably from 0.025% to 0.5% w/v.
The composition comprises as solubilizer and / or stabilizing the TPGS in an amount of at least 0.1% w/v, preferably from 0.1% to 20% w/v, for 20 example from 0.5% to 5% w/v.
In the composition the weight ratio between Nepadutant and the solubilizer TPGS is in the range from 1:1 to 1:50, preferably in the range from 1:2 to 1:40 for example in the range from 1:4 to 1:30.
The composition according to the présent invention can possibly comprise a chelating agent selected from the group of ethylenediaminetetraacetic acid (EDTA), disodium (ethylendinitrile) tetraacetate dihydrate (disodium edetate), and disodium-[(ethylenedinitryl) tetraacetate] hydrocalcium (calcium sodium diedetate). The chelating agent may be présent in the composition in an amount of from 0.001 % to 0.1 % w/v, preferably from 0.005% to 0.05%, or from 0.005% to 0.02% w/v.
Other pharmaceutically acceptable excipients for paediatric use may be présent, such as sweeteners (such as sugars, including dextrose), additîonal solubilizer agents (such as polyvinylpyrrolidone, sodium carboxymethylcellulose) and preservatives (e.g. Sorbic acid and ascorbic acid).
Examples of compositions according to the invention include:
a) Nepadutant 0:40 mg / ml, TPGS 10:00 mg / ml, dextrose 400.00 mg/ml, sorbic acid 1:00 mg/ml, sodium carboxymethylcellulose 20:00 mg/ml, purified water qs 1.0 ml.
b) Nepadutant 0:40 mg / ml, TPGS 10:00 mg/ml, diedetate sodium 0.100 mg/ml, dextrose 400.00 mg/ml, sorbic acid 1:00 mg/ml, sodium carboxymethylcellulose 20:00 mg/ml, purified water qs 1.0 ml.
c) Nepadutant 2:00 mg/ml, TPGS 10:00 mg/ml, diedetate sodium 0.100 mg/ml, dextrose 400.00 mg/ml, sorbic acid T.00 mg/ml, sodium carboxymethylcellulose
20.0 mg/ml, purified water qs 1.0 ml.
In order to administer these compositions to the patient, they may be added to foods used for the nutrition of infants, particulariy to milk, in beverages or liquid foods.
The composition may be administered in a single or multiple daily dose, depending on doctor's advice, for the treatment of gastrointestinal disease in neonates and infants aged from birth to one year, and preferably, from birth to six months.
The présent invention further relates to a process for the préparation of pharmaceutical compositions such as those described above, which process comprises mixing Nepadutant with TPGS, and optionally a chelating agent, with one or more pharmaceutically acceptable excipients.
Some examples of aqueous solutions packaged in accordance with the formulation described are shown below.
EXAMPLES
Formulations containing polysorbate 80as solubilizer.
Example 1 (comparative example)
The formulation is quite similar to that described in W02006045820 and was prepared in an inert atmosphère.
A dry premix consisting of dextrose, sorbic acid, sodium carboxymethylcellulose, and flavourings was prepared. Such a premix is dissolved in purified water (ca. 60% of the total amount) to a température of 35° C- 40° C while stirring and homogenizing in a spécial machine for mixing.
Subsequently, the solution is cooled to a température of 20° 0-25° C and polysorbate 80, Nepadutant and the remaining amount of water (40% of the total quantity) is added by shaking and homogenising in an inert gas atmosphère. The formulation is stirred until obtaining a limpid and homogeneous solution.
Ingrédient | Amount [mg / ml] |
Nepadutant | 0.40 |
Polysorbate 80 | 12.50 |
Dextrose | 400.00 |
Sorbic Acid | 1.00 |
sodium carboxymethylcellulose | 20.00 |
Raspberry flavour | 0.035 |
Cream flavour | 0.015 |
Purified Water | qs 1.0 ml |
Inert Gas | q.s. |
This formulation also corresponds to the formulation K in the Table 2, 3 and 4.
Examole 2 (comparative example)
Compositions similar to those of Example 1 with in addition an antioxidant are prepared in accordance with Example 1, containing in addition an antioxidant. The presence of antioxidant makes the deaeration with inert gas not required.
by A dry premix consisting of dextrose, sorbic acid, sodium carboxymethylcellulose, and flavourings is prepared. Such a premix is dissolved in purified water (ca. 60% of the total amount) to a température of 35 0 C - 40 ° C while stirring and homogenizing in a spécial machine for mixing.
Subsequently, the solution is cooled to a température of 20 0 C - 25 ° 25 C and to it is added polysorbate 80, the antioxidant, Nepadutant and the remaining amount of water (40% of the total quantity) by stirring and homogenizing. The formulation is stirred until obtaining a limpid and homogeneous solution.
The antioxidant used is selected from the group: TPGS (vitamin E polyethylene glycol 1000 succinate or Vitamin E TPGS NF grade) 3 mg/ml, Lascorbic acid dl-alpha-tocopherol phosphate potassium sait 2.3 mg/ml, vitamin E dried to 15% CC (alpha tocopherol acetate finely dispersed in a matrix of modified food starch) 3.9 mg/ml, mixtures of tocopherols dried to 30% (vitamin E finely dispersed in a matrix of modified food starch) 1.8 10 mg/ml.
Formulations contaîning TPGS as solubilizer
Example 3
This example illustrâtes a liquid formulation comprising aqueous Nepadutant TPGS as solubilizer. This formulation was packaged without 15 deaeration with inert gas.
by A dry premix consisting of dextrose, sorbic acid and sodium carboxymethylcellulose is prepared. Such a premix is dîssolved in purified water (ca. 60% of the total amount) to a température of 35° C-40° C while stirring and homogenizing in a spécial machine for mixing, in an inert gas 20 atmosphère.
Subsequently, the solution is cooled to a température of 20° C- 25° C and to it is added 20% w/v solution of TPGS, Nepadutant and the remaining amount of water (40% of the total quantity) by stirring and homogenizing. The formulation is stirred until obtaining a limpid and homogeneous solution.
Ingrédient | Amount [mg / ml] |
Nepadutant | 0.40 |
TPGS | 10.00 |
Dextrose | 400.00 |
Sorbic Acid | 1.00 |
carboxymethylcellulose sodium | 20.00 |
Purified Water | qs 1.0 ml |
Example 4
This example illustrâtes a liquid formulation comprising aqueous Nepadutant TPGS as solubilizer. This formulation was packaged without deaeration with inert gas and comprises in addition edetate disodium as a 5 chelating agent.
A dry premix consîsting of dextrose, sorbic acid and sodium carboxymethylcellulose is prepared. Such a premix is dissolved in purified water (ca. 60% of the total amount) to a température of 35 ° C - 40 ° C while stirring and homogenizing in a spécial machine for mixing.
Subsequently, the solution is cooled to a température of 20° C-25° C and to it is added 20% w/v solution of TPGS, edetate sodium, Nepadutant and the remaining amount of water (40% of the total amount) by stirring and homogenizing in an inert gas atmosphère.
The formulation is stirred until obtaining a limpid and homogeneous solution.
Ingrédient | Amount [mg/ml] |
Nepadutant | 0.40 |
TPGS | 10.00 |
Sodium diedetate | 0.10 |
Dextrose | 400.00 |
Sorbic Acid | 1.00 |
sodium carboxymethylcellulose | 20.00 |
Purified Water | qs 1.0 ml |
Example 5
At the same manner as in Example 4, the following composition can be prepared
Ingrédient | Amount [mg / ml] |
Nepadutant | 2.00 |
TPGS | 10.00 |
Sodium diedetate | 0.10 |
Dextrose | 400.00 |
Sorbic Acid | 1.00 |
sodium carboxymethylcellulose | 20.00 |
Purified Water | qs 1.0 ml |
Claims (19)
1. A liquid aqueous oral pharmaceutical composition comprising nepadutant as active ingrédient and an additive and optionally a chelating agent and optionally other pharmaceutical acceptable excipients, characterized in that the selected additive is TPGS.
2. The pharmaceutical composition according to claim 1, wherein nepadutant is présent in an amount from 0.01% to 1% weight/volume of the total composition.
3. The aqueous pharmaceutical composition according to claim 2, wherein nepadutant is présent in an amount from 0.025% to 0.5% weight/volume on the total composition.
4. The aqueous pharmaceutical composition according to any one of claims 1-3, wherein TPGS is présent in an amount of at least 0.1% weight/volume of the total composition.
5. The aqueous pharmaceutical composition according to claim 4, wherein TPGS is présent in an amount from 0.1% to 20% weight/volume on the total composition.
6. The aqueous pharmaceutical composition according to claim 5, wherein TPGS is présent in an amount from 0.5% to 5% weight/volume of the total composition.
7. The aqueous pharmaceutical composition according to any one of claims from 1 to 6, wherein the ratio between nepadutant and TPGS is from 1:1 to 1:50.
8. The aqueous pharmaceutical composition according to any one of claims from 1 to 7, wherein the ratio between nepadutant and TPGS is from 1:2 to 1:40.
9. The aqueous pharmaceutical composition according to any one of claims from 1 to 8, wherein the ratio between nepadutant and TPGS is from 1:4 to 1:30.
10. The aqueous pharmaceutical composition according to any one of claims from 1 to 9, further comprising a chelating agent selected from the group: EDTA, edetate disodium, and edetate calcium disodium.
11. The aqueous pharmaceutical composition according to claim 10, wherein the chelating agent is présent in an amount comprised from 0.001% to 0.1% w/v of the total composition.
12. The aqueous pharmaceutical composition according to claim 11, wherein the chelating agent is présent in an amount comprised from 0.005 % to 0.05 % w/v of the total composition.
13. The aqueous pharmaceutical composition according to claim 11, wherein the cheating agent is présent in an amount comprised from 0.005% to 0.02% w/v of the total composition.
14. The aqueous pharmaceutical composition according to any one of claims from 1 to 13, further comprising pharmaceutical acceptable excipients such as sweeteners, preservatives, or solubilizers.
15. The liquid aqueous oral pharmaceutical composition according to any one of claims from 1 to 14, comprising:
a) from 0.01 % to 1 % w/v of nepadutant
b) from 0.1 % to 20% w/v of TPGS
c) optionally from 0.001 % to 0.1 % w/v of chelating agent
d) one or more pharmaceutically acceptable excipients
16. The aqueous oral pharmaceutical composition according to claim 14, selected from the group:
a) nepadutant 0.40 mg/ml, TPGS 10.00 mg/ml, dextrose 400.00 mg/ml, sorbic acid 1.00 mg/ml, sodium carboxymethyl cellulose 20.00 mg/ml, purified water qs 1.0 ml;
b) nepadutant 0.40 mg/ml, TPGS 10.00 mg/ml, edetate disodium 0.100 mg/ml, dextrose 400.00 mg/ml, sorbic acid 1.00 mg/ml, sodium carboxymethylcellulose 20:00 mg / ml, purified water qs 1.0 ml;
c) nepadutant 2.00 mg/ml, TPGS 10.00 mg/ml, edetate disodium
0.100 mg/ml, dextrose 400.00 mg/ml, sorbic acid 1.00 mg/ml, sodium carboxymethylcellulose 20.00 mg/ml, purified water qs 1.0 ml.
5
17. The aqueous oral pharmaceutical composition according to any one of claims 1 to 16 for use in the paediatric treatment of newborns and nurslings.
18. The aqueous oral pharmaceutical composition according to claim
10 17 for use in the paediatric treatment of gastrointestinal diseases.
19. A process for the préparation of the compositions according to any one of claims from 1 to 18, comprising a step wherein nepadutant is mixed with TPGS, and optionally with a chelating agent.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITRM2012A000331 | 2012-07-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA17358A true OA17358A (en) | 2016-09-21 |
Family
ID=
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