CN101541305A - 用以处理口腔炎的包含表皮成长因子的稳定液体组成物 - Google Patents
用以处理口腔炎的包含表皮成长因子的稳定液体组成物 Download PDFInfo
- Publication number
- CN101541305A CN101541305A CNA2007800437524A CN200780043752A CN101541305A CN 101541305 A CN101541305 A CN 101541305A CN A2007800437524 A CNA2007800437524 A CN A2007800437524A CN 200780043752 A CN200780043752 A CN 200780043752A CN 101541305 A CN101541305 A CN 101541305A
- Authority
- CN
- China
- Prior art keywords
- liquid constituent
- handle
- stomatitis
- growth factor
- epidermal growth
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000007788 liquid Substances 0.000 title claims abstract description 85
- 101800003838 Epidermal growth factor Proteins 0.000 title claims abstract description 39
- 208000003265 stomatitis Diseases 0.000 title claims abstract description 39
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 title claims abstract description 39
- 229940116977 epidermal growth factor Drugs 0.000 title claims abstract description 37
- 102000009024 Epidermal Growth Factor Human genes 0.000 title claims abstract 6
- 239000000203 mixture Substances 0.000 title abstract description 16
- -1 inorganic acid salts Chemical class 0.000 claims abstract description 27
- 239000003381 stabilizer Substances 0.000 claims abstract description 26
- 239000007921 spray Substances 0.000 claims abstract description 25
- 239000002998 adhesive polymer Substances 0.000 claims abstract description 24
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 17
- 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 abstract description 16
- 150000001413 amino acids Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000470 constituent Substances 0.000 claims description 77
- 229940024606 amino acid Drugs 0.000 claims description 13
- 229960002885 histidine Drugs 0.000 claims description 10
- 229920001503 Glucan Polymers 0.000 claims description 8
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 8
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 230000001186 cumulative effect Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 229940063675 spermine Drugs 0.000 claims description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 4
- 229920001451 polypropylene glycol Polymers 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 229920002148 Gellan gum Polymers 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- 235000010492 gellan gum Nutrition 0.000 claims description 3
- 239000000216 gellan gum Substances 0.000 claims description 3
- 229920001277 pectin Polymers 0.000 claims description 3
- 239000001814 pectin Substances 0.000 claims description 3
- 235000010987 pectin Nutrition 0.000 claims description 3
- 229920000945 Amylopectin Polymers 0.000 claims description 2
- QYZBCWXZSYTIOY-UHFFFAOYSA-N Mercuric oxide Chemical compound [O-2].[Hg+2] QYZBCWXZSYTIOY-UHFFFAOYSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 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 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 239000003292 glue Substances 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims 2
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims 2
- 206010061218 Inflammation Diseases 0.000 abstract description 7
- 230000004054 inflammatory process Effects 0.000 abstract description 7
- 229920002307 Dextran Polymers 0.000 abstract description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N lysine Chemical compound NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 abstract 2
- 239000004472 Lysine Substances 0.000 abstract 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 33
- 239000003814 drug Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 206010028116 Mucosal inflammation Diseases 0.000 description 7
- 201000010927 Mucositis Diseases 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 230000007774 longterm Effects 0.000 description 7
- 210000000214 mouth Anatomy 0.000 description 7
- 238000002512 chemotherapy Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000002421 anti-septic effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 208000025865 Ulcer Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 210000002200 mouth mucosa Anatomy 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 206010015150 Erythema Diseases 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 235000019658 bitter taste Nutrition 0.000 description 3
- 231100000321 erythema Toxicity 0.000 description 3
- 229920001477 hydrophilic polymer Polymers 0.000 description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000035807 sensation Effects 0.000 description 3
- 235000019615 sensations Nutrition 0.000 description 3
- 230000001953 sensory effect Effects 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- ZNEMGFATAVGQSF-UHFFFAOYSA-N 1-(2-amino-6,7-dihydro-4H-[1,3]thiazolo[4,5-c]pyridin-5-yl)-2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound NC=1SC2=C(CN(CC2)C(CC=2OC(=NN=2)C=2C=NC(=NC=2)NC2CC3=CC=CC=C3C2)=O)N=1 ZNEMGFATAVGQSF-UHFFFAOYSA-N 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 2
- 229960003459 allopurinol Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000035587 bioadhesion Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 229920001992 poloxamer 407 Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000008646 thermal stress Effects 0.000 description 2
- 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 description 1
- FZWBNHMXJMCXLU-UHFFFAOYSA-N 2,3,4,5-tetrahydroxy-6-[3,4,5-trihydroxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxyhexanal Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OCC(O)C(O)C(O)C(O)C=O)O1 FZWBNHMXJMCXLU-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 206010042566 Superinfection Diseases 0.000 description 1
- RXDLGFMMQFNVLI-UHFFFAOYSA-N [Na].[Na].[Ca] Chemical compound [Na].[Na].[Ca] RXDLGFMMQFNVLI-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000015946 suckling behavior Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- 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
- A61K38/18—Growth factors; Growth regulators
-
- 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
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/1808—Epidermal growth factor [EGF] urogastrone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/485—Epidermal growth factor [EGF], i.e. urogastrone
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供一种用以处理口腔炎的包含表皮成长因子的稳定液体组成物,液体组成物包括:表皮成长因子;粘着聚合物;以及至少一种选自由乙二胺四乙酸(EDTA)以及其盐、组胺酸、离胺酸以及其无机酸盐、精胺酸以及其无机酸盐以及葡聚糖所构成的族群的稳定剂。液体组成物包括选自乙二胺四乙酸(或其盐)以及某种胺基酸(或其无机酸盐)的稳定剂,因此可实质上增加表皮成长因子的物化以及生物稳定性。因此,液体组成物可长期储存以及长期分布。稳定组成物包括粘着聚合物,因此,当液体组成物以喷雾剂形式喷入使用者口中时,液体组成物可快速附着至发炎位置且具有长期效用。
Description
技术领域
本发明是关于一种用于处理口腔炎的包括表皮成长因子(epidermalgrowth factor)的稳定液体组成物。
背景技术
口腔炎是影响口腔粘膜(oral mucosa)的疾病。具体而言,口腔炎是由医药处理、尤其由化学疗法或放射性处理所引起或恶化的炎症,且在某些情况下伴有溃疡。口腔炎有轻度至重度的症状。罹患重度口腔炎的患者无法经口进食。同时,在暴露于化学疗法或放射性处理后3天内(通常5-7天内)出现红斑性粘膜炎(erythematous mucositis),其为口腔炎的一种。一般而言,红斑性粘膜炎在暴露于化学疗法处理后7天内可发展成溃疡性粘膜炎(ulcerative mucositis),且某些红斑性粘膜炎会严重到必须完全停止任何药物处理。
虽然罹患粘膜炎的严重程度可能不同,但在用化学疗法处理的患者中,有许多患者罹患粘膜炎。因此,迫切需要开发一种用于处理口腔炎的有效且简单的方法。一般而言,会通过口腔清洁或投予各种维生素来处理口腔炎。具体而言,由化学疗法或放射性处理所引起的口腔炎可由给予包含别嘌呤醇(allopurinol)或海藻酸钠的漱口剂来处理(档案(Archives),第55卷,第1期:28,1995;日本医院药学杂志(JapaneseJournal of Hospital Pharmacy),第18卷,第5期:510,1992;日本护理行为杂志(Japanese Journal of Nursing Acts),第37卷,第15期:44,1991;日本癌症治疗协会杂志(The Journal of Japanese Societyfor Cancer Therapy),第25卷,第6期:1129,1990)。然而,所述漱口剂投药对于减轻症状而言相当有限,对于重度口腔炎几乎无效,且需要长期投药才可能改善症状。基于上述问题,已投注许多精力来开发在短时间内对于处理口腔炎能有高治疗效果的药物或方法。
现有常见的用于处理口腔炎的组成物是含有粘着聚合物的软膏或贴片等形式。举例而言,美国专利第56,578,310号揭露由含有矿物油、羟丙基甲基纤维素以及其类似物的乳液形成的生物粘着软膏;且韩国专利申请公开案第1994-0023469号揭露含有类固醇药物的具有双膜结构的硬膏剂(plaster)以及其制备方法。
除了软膏或贴片的形式外,美国专利申请公开案第2002/0219634号揭露具有50-50,000cps范围内粘度的生物粘着溶液或悬浮液,且韩国专利申请公开案第2005-55858号揭露包括亲水性聚合物(hydrophilicpolymer)和水不溶性聚合物(water-insoluble polymer)的混合物而呈液体或凝胶药物形式的口腔药物传送系统。
同时,国际公开案第WO 03/95637号揭露表皮成长因子可用于处理口腔炎。称为尿抑胃激素(urogastrone)的表皮成长因子是具有53个胺基酸以及3个双硫键且分子量为6045的多肽。表皮成长因子能刺激有丝分裂(mitosis)以及如上皮细胞(epithelial cell)或间质细胞(mesenchymal cell)等细胞的生长,且能阻碍胃酸(gastric acid)分泌,因此,表皮成长因子可有效处理胃溃疡(gastriculcer)、皮肤伤口或角膜伤口(卡彭特,实验细胞研究(Carpenter,Experimental CellResearch),164:1-10,1986)。因此,若将表皮成长因子与如羟丙基甲基纤维素的粘着聚合物一起调配,应该可以在处理口腔炎方面达到高疗效。
然而,因为患者须将含有表皮成长因子以及粘着聚合物的软膏或贴片直接涂覆或附着于口腔炎处或伤口上,所以上述方法不便于执行且可能会引起二次感染。为避免上述问题,表皮成长因子以及粘着聚合物可制备为液体,且以喷雾剂形式来进行调配。然而,由于表皮成长因子在液体介质中具有较高的移动性,因此液体调配方法会使表皮成长因子的稳定性降低。
本申请的发明人发现可使用选自由现有抗氧化剂乙二胺四乙酸(ethylenediaminetetraacetic acid,EDTA)、其盐、葡聚糖(dextran)以及某些胺基酸所构成的族群的稳定剂来制备具有高稳定性的液体调配物。
发明内容
本发明提供一种用于处理口腔炎的稳定液体组成物,其包括:选自EDTA以及其盐、葡聚糖以及某些胺基酸的稳定剂;表皮成长因子;以及粘着聚合物。
本发明还提供一种用于处理口腔炎的包括所述液体组成物的喷雾剂。
根据本发明的一实施例,提供一种用于处理口腔炎的液体组成物,其包括:表皮成长因子;粘着聚合物;以及至少一种选自由乙二胺四乙酸(EDTA)以及其盐、组胺酸、离胺酸以及其无机酸盐、精胺酸以及其无机酸盐以及葡聚糖所构成的族群的稳定剂。
根据本发明的另一实施例,提供一种用于处理口腔炎的包括所述液体组成物的喷雾剂。
具体实施方式
在本发明说明书中,术语“口腔炎”是影响口腔粘膜的炎症,可由医药处理、尤其由化学疗法或放射性处理所引起或恶化,且可伴有溃疡。口腔炎具有由轻度至罹患口腔炎的患者不能经口进食的重度的症状。
本发明的液体组成物包括选自EDTA以及其盐以及某种胺基酸以及其无机酸盐的稳定剂,因此可显著改良表皮成长因子的物化稳定性以及生物稳定性。因此,液体组成物可长期储存或长期散布。液体组成物包括粘着聚合物,因此,当液体组成物以喷雾剂形式喷入使用者口中时,液体组成物可快速附着至发炎位置且具有长期疗效。
本发明的液体组成物包括作为活性组份的表皮成长因子。表皮成长因子可为具有治疗有效量的天然或重组蛋白。即,当液体组成物例如以喷雾剂形式为单位来调配时,表皮成长因子的量可在约0.1至1,000微克/亳升、较佳0.5至500微克/亳升且更佳1.0至100微克/亳升的范围内。以液体组成物的总体积为计量,用以调配为特殊剂型的液体组成物可包括介于0.0001至0.01%(重量/体积)范围内的量的表皮成长因子。
本发明的液体组成物包括至少一种选自由以下各物所构成的族群的稳定剂:EDTA以及其盐,如二钠盐、二钠钙盐或三钠盐;组胺酸;离胺酸以及其无机酸盐,如离胺酸盐酸盐;精胺酸以及其无机酸盐,如精胺酸盐酸盐;以及葡聚糖。稳定剂可为EDTA二钠盐、L-组胺酸、L-离胺酸盐酸盐、L-精胺酸盐酸盐和/或平均分子量在40,000至100,000道尔顿范围内的葡聚糖。较佳地,稳定剂可包括选自由组胺酸、离胺酸以及精胺酸所构成的族群中的至少一个。举例而言,稳定剂可包括EDTA二钠盐和/或L-组胺酸。
根据所使用的稳定剂的种类不同,液体组成物中稳定剂的量也会不同。举例而言,以液体组成物的总体积为计量,稳定剂的量可在0.01至10%(重量/体积)、尤其0.05至5%(重量/体积)的范围内。当稳定剂的量小于0.01%(重量/体积)时,不太容易使表皮成长因子具有稳定性。另一方面,当稳定剂的量大于10%(重量/体积)时,反而可能使表皮成长因子的稳定性降低。
本发明的液体组成物包括粘着聚合物,因此将液体组成物施用于口腔中时,其可快速附着于发炎位置,且可维持恒定的粘度。粘着聚合物可为纤维素,如羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素或羧甲基纤维素钠;可为亲水性聚合物,如玻尿酸钠、卡波姆(carbomer)(例如,卡伯波(Carbopol)940TM(ISP,USA))、三仙胶(xanthan gum)、结冷胶(gellan gum)、支链淀粉(pullulan)、果胶(pectin)或淀粉(例如,玉米淀粉);可为非离子性界面活性剂,如聚氧乙烯与聚氧丙烯的共聚物;或可为其组合。粘着聚合物可为重量平均分子量为7,000至15,000的聚氧乙烯与聚氧丙烯的共聚物,如泊洛沙姆(poloxamer)407TM(BASF,USA)或泊洛沙姆188TM(BASF,USA)。
根据所使用的聚合物种类不同,本发明的液体组成物中粘着聚合物的量可不同。以液体组成物的总体积为计量,粘着聚合物的量可在0.01至20%(重量/体积)、尤其0.1至10%(重量/体积)的范围内。当粘着聚合物的量小于0.01%(重量/体积)时,调配物的粘度较小且粘着效应较弱。另一方面,当粘着聚合物的量大于20%(重量/体积)时,调配物的粘度较高,因此,可能难以将液体组成物制备或调配为(例如)喷雾剂形式。
液体组成物的粘度可在50至10,000cps且尤其500至5,000cps(mPas)的范围内。当液体组成物的粘度小于50cps时,液体组成物的粘度可能太低,因而液体组成物无法停留在伤口位置而可能直接流向食道。另一方面,当液体组成物的粘度大于10,000cps时,液体组成物的粘度可能太高,因而无法将液体组成物调配为可喷射的喷雾剂形式。
本发明的液体组成物可包括医药学上可接受的载剂(carrier)。举例而言,液体组成物可包括水性介质,诸如如水、纯水或注射用水。在某些情况下,液体组成物可另外包括pH控制剂、防腐剂、甜味剂或芳香剂。基于考虑本发明的液体组成物中作为活性组份的表皮成长因子的稳定性,液体组成物的pH值可在5至8且尤其6至7的范围内。控制液体组成物的pH值的pH控制剂可为含有磷酸二氢钠(sodium phosphatemonobasic)、磷酸氢二钠(sodium phosphate bibasic)或柠檬酸钠的缓冲溶液。防腐剂可为对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯甲醇或苯甲酸钠。pH值控制剂、防腐剂、甜味剂以及芳香剂的量可由熟悉此项技术的人者适当控制。举例而言,以液体组成物的总体积为计量,羟基苯甲酸甲酯或对羟基苯甲酸丙酯等防腐剂的量可在而介于0.01至1.0%(重量/体积)的范围内,但不限于此。
本发明的液体组成物可以调配成各种适于以口腔投药的形式、尤其是调配成喷雾剂形式。因此,本发明还提供一种用于处理口腔炎的包括所述液体组成物的喷雾剂。喷雾剂可为气雾剂形式、泵喷雾剂形式或再结合型(reconstitution)喷雾剂形式。泵喷雾剂形式以及再结合型喷雾剂形式可避免推进剂(propallant)造成活性组份的稳定性下降的问题发生。
泵喷雾剂形式是指一种由泵施加负压至容器中而使容器所含的药物溶液(即本发明的液体组成物)喷射的类型。
再结合型喷雾剂是指一种投予包括溶剂单元(即,粘着赋形剂溶液)以及主要组份单元(即,人类成长激素(human growth hormone)与稳定剂的液体混合物组成物)的混合物的类型,其中,在未使用此喷雾剂时,溶剂单元与主要组份单元为分离。举例而言,根据本发明的一实施例,本发明所使用的喷雾剂可为包括以下的再结合型喷雾剂:包括粘着聚合物的溶剂单元以及包括表皮成长因子及稳定剂的主要组份单元,其中所述溶剂单元以及所述主要组份单元放置于不同容器中。
将参考以下实例进一步详细描述本发明。所述实例仅出于说明性目的,而不意欲限制本发明的范畴。
实例1-5以及比较实例1
根据表1中所示的组份以及量来制备液体组成物。在表1中,各组份的量以%(重量/体积)来表示。首先以精制水溶解缓冲液(磷酸二氢钠)以及氯化钠,随后添加适量pH控制剂(磷酸),以将pH值调节为6至7的范围。而后,将所得溶液加热至80℃,以溶解防腐剂(对羟基苯甲酸甲酯),再将所加热的溶液与粘着聚合物泊洛沙姆407TM(BASF,USA)混合。接着,搅拌混合物直至获得均质混合物为止。而后,将稳定剂(EDTA二钠盐、L-组胺酸、盐酸L-精胺酸、L-离胺酸盐酸盐或葡聚糖70)以及表皮成长因子溶解于均质混合物中,且添加水至液体组成物的最终体积达到1公升。比较实例为与上述制备方法皆相同而不添加稳定剂的液体组成物。
【表1】
测试实例1:抵抗热应力的稳定性测试
将以实例1-5以及比较实例1所制备的液体组成物放置于40℃而相对湿度为75%的环境下4周。随后,测量表皮成长因子的量以及活性。使用逆相高效液相层析(reverse phase HPLC)测量表皮成长因子的量,且以酶联免疫吸附剂测定法(ELISA)测量表皮成长因子的活性。所获得的值以相对于初始值的百分比(%)来表示。结果展示于表2中。
【表2】
实例1 | 实例2 | 实例3 | 实例4 | 实例5 | 比较实例1 | |
量% | 89 | 90 | 85 | 86 | 84 | 52 |
活性% | 90 | 92 | 87 | 85 | 84 | 60 |
如表2所示,本发明的液体组成物对热应力展示高稳定性。具体而言,当使用用作抗氧化剂的EDTA或L-组胺酸来制备液体组成物时,液体组成物可具有更高的稳定性。
测试实例2:抵抗物理应力的稳定性测试
为鉴别表皮成长因子对外部物理应力的物理稳定性,以200转/分钟搅拌根据实例1-5以及比较实例1所制备的液体组成物3小时,以鉴别其所产生的凝集作用。在移除所产生的凝集物(0.45微米针筒过滤器,密理博(Millipore))后,定量各液体组成物中的表皮成长因子的量。所得值以相对于初始值的百分比(%)表示。结果展示于表3中。
【表3】
实例1 | 实例2 | 实例3 | 实例4 | 实例5 | 比较实例1 | |
影像 | 洁净且透明 | 洁净且透明 | 微量凝集形态(3至4颗粒子) | 微量凝集形态(1至3颗粒子) | 洁净且透明 | 不透明 |
过滤后的量% | 100.0 | 100.0 | 97.2 | 98.1 | 99.9 | 35.9 |
如表3所示,本发明的液体组成物对物理应力展示极佳稳定性。
实例6-11
根据表4中所展示的组份以及量以与实例1-5中相同的方式来制备液体组成物。在表4中,各组份的量由%(重量/体积)表示。
【表4】
测试实例3:感官测试(sensory test)
以根据实例6-11以及比较实例1所制备的液体组成物来进行感官测试。因为罹患重度口腔炎的患者不能进食,所以用于处理口腔炎的药物应对口腔粘膜不具刺激性且当将药物施用于口腔时,大量药物可停留在病变处。将35位罹患口腔炎的患者以每组5位患者进行分组。将各液体组成物施用于各组的口腔中的发炎位置。施用1小时后,询问患者的敷用感觉(feeling of wearing)以及对舌的刺激为考量的使用感觉(feeling of use)。结果展示于表5中。表5中所示的值是患者感觉的平均值。
【表5】
实例6 | 实例7 | 实例8 | 实例9 | 实例10 | 实例11 | 比较实例1 | |
使用感觉 | 7.5 | 10.0 | 9.5 | 9.5 | 9.0 | 10.0 | 7.0 |
敷用感觉 | 7.0 | 9.0 | 9.5 | 8.0 | 9.0 | 8.5 | 2.0 |
其他 | 苦味以及辛辣味 | 无 | 无 | 无 | 少许苦味 | 无 | 苦味以及辛辣味 |
使用感觉:自10(极佳,无刺激)至1(差,刺激以及疼痛)
敷用感觉:自10(大部分所用药物停留在病变处)至1(大部分所用药物流向食道)
如表5所示,本发明的液体组成物展示良好的使用感觉。具体而言,当使用以纤维素为主的赋形剂制备液体组成物时,可获得更佳的使用感觉。
实例12-16
根据表6中所展示的组份以及量以与实例1-5中相同的方式来制备液体组成物。在表6中,各组份的量由重量/体积%表示。
【表6】
测试实例4:室温稳定性测试
将根据实例12-16所制备的液体组成物放置于25℃而相对湿度为60%的环境下3个月。随后,测量表皮成长因子的量以及活性。使用逆相HPLC测量其量且使用ELISA测量活性。所得值以相对于初始值的百分比(%)表示。结果展示于表7中。
【表7】
实例12 | 实例13 | 实例14 | 实例15 | 实例16 | |
量% | 90.2 | 100.0 | 99.2 | 99.4 | 98.4 |
活性% | 89.3 | 99.1 | 98.3 | 100.5 | 99.1 |
如表7所示,本发明的液体组成物在室温下历时3个月展示极佳稳定性。
本发明的液体组成物包括选自EDTA(或其盐)、葡聚糖以及某些胺基酸(或其无机酸盐)的稳定剂,因此,可实质上增加表皮成长因子的物化稳定性以及生物稳定性。因此,液体组成物可长期储存以及长期散布。稳定组成物包括粘着聚合物,因此,当液体组成物以喷雾剂形式喷入使用者口中时,液体组成物可快速附着至发炎位置且具有长期疗效。
Claims (10)
1、一种用于处理口腔炎的液体组成物,其特征在于包含:表皮成长因子;粘着聚合物;以及至少一种稳定剂,所述稳定剂选自由乙二胺四乙酸以及其盐、组胺酸、离胺酸以及其无机酸盐、精胺酸以及其无机酸盐以及葡聚糖所构成的族群。
2、根据权利要求1所述的用于处理口腔炎的液体组成物,其特征在于所述稳定剂为乙二胺四乙酸二钠盐、L-组胺酸、L-离胺酸盐酸盐、L-精胺酸盐酸盐或平均分子量在40,000至100,000道尔顿范围内的葡聚糖。
3、根据权利要求1所述的用于处理口腔炎的液体组成物,其特征在于所述稳定剂为乙二胺四乙酸二钠盐或L-组胺酸。
4、根据权利要求1所述的用于处理口腔炎的液体组成物,其特征在于以所述液体组成物总体积为计量,所述稳定剂的量介于0.01至10重量/体积%的范围内。
5、根据权利要求1所述的用于处理口腔炎的液体组成物,其特征在于所述粘着聚合物为羟丙基甲基纤维素、羧甲基纤维素钠、玻尿酸钠、卡波姆、聚氧乙烯与聚氧丙烯的共聚物、三仙胶、结冷胶、支链淀粉、果胶或淀粉。
6、根据权利要求1所述的用于处理口腔炎的液体组成物,其特征在于所述粘着聚合物为重量平均分子量为7,000至15,000的聚氧乙烯与聚氧丙烯的共聚物。
7、根据权利要求1所述的用于处理口腔炎的液体组成物,其特征在于以所述液体组成物总体积为计量,所述粘着聚合物的量介于0.01至20重量/体积%的范围内。
8、根据权利要求1所述的用于处理口腔炎的液体组成物,其特征在于以所述液体组成物总体积为计量,所述表皮成长因子的量介于0.0001至0.01重量/体积%的范围内。
9、一种用于处理口腔炎的喷雾剂,其特征在于包含根据权利要求1至8中任一所述的液体组成物。
10、根据权利要求9所述的用于处理口腔炎的喷雾剂,其特征在于所述喷雾剂为包含以下的再结合型喷雾剂:包含粘着聚合物的溶剂单元以及包含表皮成长因子及稳定剂的主要组份单元,其中所述溶剂单元以及所述主要组份单元置放于不同的容器中。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020060097734 | 2006-10-09 | ||
KR1020060097734A KR100784134B1 (ko) | 2006-10-09 | 2006-10-09 | 상피세포성장인자를 함유하는 안정한 구내염 치료용 액상조성물 |
KR10-2006-0097734 | 2006-10-09 | ||
PCT/KR2007/004911 WO2008044852A1 (en) | 2006-10-09 | 2007-10-09 | Stable liquid compositions for treating stomatitis comprising epidermal growth factor |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101541305A true CN101541305A (zh) | 2009-09-23 |
CN101541305B CN101541305B (zh) | 2012-04-11 |
Family
ID=39140442
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2007800437524A Active CN101541305B (zh) | 2006-10-09 | 2007-10-09 | 用以处理口腔炎的包含表皮成长因子的稳定液体组成物 |
Country Status (8)
Country | Link |
---|---|
US (1) | US9155697B2 (zh) |
EP (1) | EP2083797A4 (zh) |
JP (1) | JP2010505942A (zh) |
KR (1) | KR100784134B1 (zh) |
CN (1) | CN101541305B (zh) |
MY (1) | MY144321A (zh) |
TW (1) | TWI370741B (zh) |
WO (1) | WO2008044852A1 (zh) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100190735A1 (en) * | 2006-03-28 | 2010-07-29 | Myrex Pharmaceuticals Inc. | Mouthwash and Method of Using Same for the Treatment of Mucositis or Stomatitis |
US8221994B2 (en) | 2009-09-30 | 2012-07-17 | Cilag Gmbh International | Adhesive composition for use in an immunosensor |
AU2012202981B2 (en) * | 2009-09-30 | 2014-01-23 | Cilag Gmbh International | Adhesive Composition for Use in an Immunosensor |
RS61459B1 (sr) | 2013-11-19 | 2021-03-31 | Aqua Metals Inc | Uređaji i postupci za netopivo recikliranje baterija sa olovnom kiselinom |
WO2016183431A1 (en) | 2015-05-13 | 2016-11-17 | Aqua Metals Inc. | Electrodeposited lead composition, methods of production, and uses |
CN107849634B (zh) | 2015-05-13 | 2019-07-30 | 艾库伊金属有限公司 | 从铅酸电池回收铅的系统和方法 |
UA124142C2 (uk) | 2015-05-13 | 2021-07-28 | Аква Металс Інк. | Системи із замкнутим контуром і способи рециркуляції свинцево-кислотних батарей |
US10316420B2 (en) | 2015-12-02 | 2019-06-11 | Aqua Metals Inc. | Systems and methods for continuous alkaline lead acid battery recycling |
EP3713591A1 (en) * | 2017-11-20 | 2020-09-30 | Just-Evotec Biologics, Inc. | Aflibercept formulations containing a lysine salt as tonicifying agent and uses thereof |
Family Cites Families (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4717717A (en) | 1986-11-05 | 1988-01-05 | Ethicon, Inc. | Stabilized compositions containing epidermal growth factor |
NZ222413A (en) | 1986-11-05 | 1991-06-25 | Ethicon Inc | Compositions containing a polypeptide growth factor and a water-soluble cellulose polymer stabiliser |
US5705485A (en) * | 1987-09-18 | 1998-01-06 | Ethicon, Inc. | Gel formulations containing growth factors |
NZ226171A (en) * | 1987-09-18 | 1990-06-26 | Ethicon Inc | Gel formulation containing polypeptide growth factor |
US5102870A (en) | 1989-04-14 | 1992-04-07 | Schering Ag | Treatment and prevention of oral mucositis with growth factors |
US5130298A (en) * | 1989-05-16 | 1992-07-14 | Ethicon, Inc. | Stabilized compositions containing epidermal growth factor |
US5272135A (en) * | 1991-03-01 | 1993-12-21 | Chiron Ophthalmics, Inc. | Method for the stabilization of methionine-containing polypeptides |
AU670094B2 (en) | 1992-04-23 | 1996-07-04 | Berlex Laboratories, Inc. | Bioadhesive solid mineral oil emulsion |
KR960013439B1 (ko) * | 1993-04-26 | 1996-10-05 | 주식회사 대웅제약 | 안정한 상피세포 성장인자(egf) 조성물 |
SE9400036D0 (sv) * | 1994-01-10 | 1994-01-10 | Pharmacia Ab | Low modecular weight hyaluronic acid |
US5580856A (en) | 1994-07-15 | 1996-12-03 | Prestrelski; Steven J. | Formulation of a reconstituted protein, and method and kit for the production thereof |
TWI240627B (en) | 1996-04-26 | 2005-10-01 | Chugai Pharmaceutical Co Ltd | Erythropoietin solution preparation |
EP1008349A4 (en) * | 1997-08-27 | 2004-01-14 | Mitsubishi Pharma Corp | PROMOTORS OF NEOVASCULARIZATION |
JP2001526239A (ja) | 1997-12-22 | 2001-12-18 | ヒューマン・ジェノム・サイエンシズ・インコーポレイテッド | 角質細胞増殖因子−2製剤 |
JP2000056344A (ja) * | 1998-06-05 | 2000-02-25 | Fuji Xerox Co Ltd | 光導波路素子およびその製造方法 |
WO2000056344A1 (fr) | 1999-03-24 | 2000-09-28 | Seikagaku Corporation | Salive artificielle |
US6458387B1 (en) * | 1999-10-18 | 2002-10-01 | Epic Therapeutics, Inc. | Sustained release microspheres |
EP1255576B1 (en) * | 1999-12-09 | 2003-08-20 | Biosyntech Canada Inc. | Mineral-polymer hybrid composition |
KR100366439B1 (ko) * | 2000-02-21 | 2003-01-09 | 주식회사 대웅 | 상피세포 성장인자를 유효성분으로 하는 안정한 약제학적조성물 |
JP5058404B2 (ja) * | 2000-07-03 | 2012-10-24 | 株式会社シリウス | スロットマシン |
US7998929B2 (en) | 2000-09-01 | 2011-08-16 | Chugai Seikyaku Kabushiki Kaisha | Solution preparations stabilized over long time |
US7544348B2 (en) | 2001-02-15 | 2009-06-09 | Access Pharmaceuticals, Inc. | Liquid formulations for the prevention and treatment of mucosal diseases and disorders |
JP2002255852A (ja) * | 2001-03-01 | 2002-09-11 | Toa Eiyo Ltd | 口内炎用スプレー製剤 |
CN1129452C (zh) * | 2001-04-10 | 2003-12-03 | 王非 | 表皮生长因子口含片 |
US7202066B2 (en) | 2002-01-29 | 2007-04-10 | Carrington Laboratories, Inc. | Combination of a growth factor and a protease enzyme |
WO2004028557A1 (ja) * | 2002-09-26 | 2004-04-08 | Shionogi & Co., Ltd. | 安定化されたタンパク組成物 |
WO2004082590A2 (en) | 2003-02-17 | 2004-09-30 | Sun Pharmaceutical Industries Limited | A low dose corticosteroid composition |
EP1532983A1 (en) * | 2003-11-18 | 2005-05-25 | ZLB Bioplasma AG | Immunoglobulin preparations having increased stability |
KR20050055858A (ko) | 2003-12-09 | 2005-06-14 | 주식회사 엘지생활건강 | 구강 약물 전달 시스템 |
FI20041425A0 (fi) | 2004-11-05 | 2004-11-05 | Orion Corp | Transmukosaalinen veterinäärinen koostumus |
US8304387B2 (en) * | 2004-12-15 | 2012-11-06 | Swedish Orphan Biovitrum Ab (Publ) | Therapeutic formulations of keratinocyte growth factor |
AU2005322019B2 (en) | 2004-12-22 | 2010-08-26 | Ambrx, Inc. | Formulations of human growth hormone comprising a non-naturally encoded amino acid |
NZ560844A (en) | 2005-03-08 | 2008-08-29 | Pharmacia & Upjohn Co Llc | Anti-MAdCAM antibody compositions |
WO2008088922A2 (en) * | 2007-01-19 | 2008-07-24 | Genentech, Inc. | Prevention of hydrogel viscosity loss |
-
2006
- 2006-10-09 KR KR1020060097734A patent/KR100784134B1/ko active IP Right Grant
-
2007
- 2007-10-09 TW TW096137828A patent/TWI370741B/zh active
- 2007-10-09 MY MYPI20091421A patent/MY144321A/en unknown
- 2007-10-09 US US12/444,961 patent/US9155697B2/en active Active
- 2007-10-09 CN CN2007800437524A patent/CN101541305B/zh active Active
- 2007-10-09 EP EP07833222A patent/EP2083797A4/en not_active Withdrawn
- 2007-10-09 WO PCT/KR2007/004911 patent/WO2008044852A1/en active Application Filing
- 2007-10-09 JP JP2009532289A patent/JP2010505942A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
TWI370741B (en) | 2012-08-21 |
EP2083797A1 (en) | 2009-08-05 |
TW200824719A (en) | 2008-06-16 |
CN101541305B (zh) | 2012-04-11 |
MY144321A (en) | 2011-08-29 |
JP2010505942A (ja) | 2010-02-25 |
US20100035809A1 (en) | 2010-02-11 |
KR100784134B1 (ko) | 2007-12-12 |
EP2083797A4 (en) | 2012-10-31 |
WO2008044852A1 (en) | 2008-04-17 |
US9155697B2 (en) | 2015-10-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101541305B (zh) | 用以处理口腔炎的包含表皮成长因子的稳定液体组成物 | |
JP5469777B2 (ja) | 糖尿病性足部潰瘍を処置するための方法 | |
MX2015000541A (es) | Formulaciones de diclofenaco. | |
UA121874C2 (uk) | Порошкова назальна композиція для лікування гіпоглікемії | |
HUE027474T2 (en) | nasal Spray | |
CN105561289A (zh) | 一种用于治疗口腔溃疡的药物制剂 | |
CN101757625A (zh) | 环糊精包合皮质激素和h1受体拮抗剂的鼻用药物组合物 | |
Singh et al. | Oral And Parenteral To Minimize The Nasal Delivery By Thermoreversible Mucoadhesive–A Review | |
JP2009514869A (ja) | ヒト成長ホルモンパッチ製剤 | |
JP6595717B2 (ja) | 骨関節炎治療のための親水化されたスルファサラジンおよびヒアルロン酸を含む組成物およびその製造方法 | |
TW200402307A (en) | Nasal composition | |
CN104338147A (zh) | 一种用于缓控释给药的软膏组合基质 | |
WO2023187116A1 (en) | Mirabegron formulation | |
KR20070027610A (ko) | 2성분 열겔화 조성물 | |
CN111741745A (zh) | 多用托拉塞米组合物 | |
CN102440957B (zh) | 醋酸特利加压素鼻腔喷雾剂及其制备方法 | |
US8367683B2 (en) | Composition and method for treatment of warts | |
US11583495B2 (en) | Nasal composition comprising a mucoadhesive polymer | |
CN112316108B (zh) | 促进及治疗慢性伤口愈合的组合物和方法 | |
KR101697773B1 (ko) | 독소필린을 포함하는 변형 방출 조성물 | |
US20210251886A1 (en) | Oral mucosal delivery systems comprising monophasic concentrate of teriparatide | |
Dattatray et al. | A review on mucoadhesive buccal drug delivery | |
WO2020079299A1 (es) | Microesferas para el tratamiento de enfermedades de la piel o dermatológicas, osteomusculares y vasculares | |
US9750813B2 (en) | Use of heptyl glucoside as skin penetration enhancer in transdermal pharmaceutical compositions | |
CN101919799B (zh) | 缓释透皮给药系统 |
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 |