PH26390A - Pharmaceutical compositions - Google Patents
Pharmaceutical compositions Download PDFInfo
- Publication number
- PH26390A PH26390A PH39561A PH39561A PH26390A PH 26390 A PH26390 A PH 26390A PH 39561 A PH39561 A PH 39561A PH 39561 A PH39561 A PH 39561A PH 26390 A PH26390 A PH 26390A
- Authority
- PH
- Philippines
- Prior art keywords
- composition according
- ether
- polyoxyethylene glycol
- ester
- alcohol
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- -1 polyoxyethylene Polymers 0.000 claims abstract description 55
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 50
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 23
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000010521 absorption reaction Methods 0.000 claims description 53
- 239000000203 mixture Substances 0.000 claims description 34
- 230000002708 enhancing effect Effects 0.000 claims description 30
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 claims description 23
- 229960004755 ceftriaxone Drugs 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002552 dosage form Substances 0.000 claims description 10
- 150000001735 carboxylic acids Chemical class 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 229960005480 sodium caprylate Drugs 0.000 claims description 6
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 claims description 6
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 claims description 4
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims description 4
- 239000006186 oral dosage form Substances 0.000 claims description 4
- 229940071160 cocoate Drugs 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 20
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 17
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 229940127557 pharmaceutical product Drugs 0.000 abstract 1
- 230000003115 biocidal effect Effects 0.000 description 22
- WMPGRAUYWYBJKX-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO WMPGRAUYWYBJKX-UHFFFAOYSA-N 0.000 description 19
- 210000002381 plasma Anatomy 0.000 description 18
- 239000000463 material Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 239000002775 capsule Substances 0.000 description 13
- 239000003623 enhancer Substances 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 10
- 239000002702 enteric coating Substances 0.000 description 10
- 238000009505 enteric coating Methods 0.000 description 10
- 239000003242 anti bacterial agent Substances 0.000 description 9
- FDRNWTJTHBSPMW-GNXCPKRQSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical class [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C FDRNWTJTHBSPMW-GNXCPKRQSA-L 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 229940088710 antibiotic agent Drugs 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 235000011187 glycerol Nutrition 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000004166 bioassay Methods 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 229960001139 cefazolin Drugs 0.000 description 5
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 5
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 4
- 241001551177 Markhamia Species 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 4
- 229960003012 cefamandole Drugs 0.000 description 4
- 229960002682 cefoxitin Drugs 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000011928 denatured alcohol Substances 0.000 description 4
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 229940056360 penicillin g Drugs 0.000 description 4
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 3
- 229930182566 Gentamicin Natural products 0.000 description 3
- 241001504519 Papio ursinus Species 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 108010059993 Vancomycin Proteins 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 3
- UIMOJFJSJSIGLV-JNHMLNOCSA-N carumonam Chemical compound O=C1N(S(O)(=O)=O)[C@H](COC(=O)N)[C@@H]1NC(=O)C(=N/OCC(O)=O)\C1=CSC(N)=N1 UIMOJFJSJSIGLV-JNHMLNOCSA-N 0.000 description 3
- 229960000662 carumonam Drugs 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 229960002518 gentamicin Drugs 0.000 description 3
- 125000005456 glyceride group Chemical group 0.000 description 3
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 229960000433 latamoxef Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229960000198 mezlocillin Drugs 0.000 description 3
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229960003165 vancomycin Drugs 0.000 description 3
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 3
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 3
- 239000002132 β-lactam antibiotic Substances 0.000 description 3
- 229940124586 β-lactam antibiotics Drugs 0.000 description 3
- 150000003952 β-lactams Chemical class 0.000 description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000006136 alcoholysis reaction Methods 0.000 description 2
- 125000003460 beta-lactamyl group Chemical group 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 229960004261 cefotaxime Drugs 0.000 description 2
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 2
- SRZNHPXWXCNNDU-RHBCBLIFSA-N cefotetan Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CS[C@@H]21)C(O)=O)=O)C(=O)C1SC(=C(C(N)=O)C(O)=O)S1 SRZNHPXWXCNNDU-RHBCBLIFSA-N 0.000 description 2
- 229960005495 cefotetan Drugs 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052901 montmorillonite Inorganic materials 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane 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](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- VNSZBSPSHVNRAB-UHFFFAOYSA-N C(C(=C)C)(=O)O.C(C(=C)C)(=O)O.C(C=1C(C(=O)O)=CC=CC1)(=O)O.C(C)(=O)O Chemical class C(C(=C)C)(=O)O.C(C(=C)C)(=O)O.C(C=1C(C(=O)O)=CC=CC1)(=O)O.C(C)(=O)O VNSZBSPSHVNRAB-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 240000001817 Cereus hexagonus Species 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000282520 Papio Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
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- 150000002367 halogens Chemical class 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- 150000002398 hexadecan-1-ols Chemical class 0.000 description 1
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- 230000000968 intestinal effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
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- 239000000314 lubricant Substances 0.000 description 1
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 1
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- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 230000003606 oligomerizing effect Effects 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 150000002943 palmitic acids Chemical class 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002961 penems Chemical class 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- PFZCOWLKXHIVII-UHFFFAOYSA-N pyridin-1-ium-1-amine Chemical compound N[N+]1=CC=CC=C1 PFZCOWLKXHIVII-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007886 soft shell capsule Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 229960001114 temocillin Drugs 0.000 description 1
- BVCKFLJARNKCSS-DWPRYXJFSA-N temocillin Chemical compound N([C@]1(OC)C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C=1C=CSC=1 BVCKFLJARNKCSS-DWPRYXJFSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
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- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
Pharmaceutical product containing (a) a compound with antibacterial activity, and (b) an effective amount of an absorption-promoting 2-component system which contains as first component (b 1) an ether composed of a C6-C18-alcohol and polyoxyethylene glycol and as second component either (b 2-1) a polyoxyethylene glycol C6-C18-carboxylic acid glyceride ester, or (b 2-2) a C6-C18-carboxylic acid or a pharmaceutically utilisable salt thereof, or (b 2-3) an ester composed of two or more C6-C18-carboxylic acids, glycerol and a polyoxyethylene glycol.
Description
2 ! D
PHARMACEUTICAL COMPOSITION
The present invention relates to pharmaceutical compositions comprising (a) an antibacterial compound and ‘+ (b) an absorption enhancing amount of a two-component absorption enhancing system made up of a first component which is (1) an ether of a Ce to Cig alcohol and a polyoxyethylene glycol (PEG) and a second component selected from among (2)(i) a polyoxyethylene glycol - Ce to Cis carboxylic acid glyceride ester, (2)(ii) a Ce to Cis carboxylic acid or pharmaceutically acceptable salt thereof, and (2)(iii) an ester of two or more Ce to Ca carboxylic acids, glycerol and a polyoxyethylene glycol.
Optionally, a pharmaceutically inert carrier can also be included.
The term "polyoxyethylene glycol-C. to Cie carboxylic acid glyceride ester" as used in connection with this invention refers to those reaction products derived from the co-reaction of polyoxyethylene glycol (or polymerizable precursor thereof, such as ethylene oxide) ‘with a Ce-C1p carboxylic acid and glycerol or with a
Ce~C18 carboxylic acid glyceride or glycerides.
Resulting from such reactions are, typically, mixtures of a polyoxyethylene glycol-Cg to Cig carboxylic acid glyceride ester (e.g., PEG-glycerol-caprate, PEG-glycerol- caprylate or PEG-glycerol-caprylate/caprate), a
Polyoxyethylene glycol-Cg to Cig carboxylic acid ester (e.g., PEG-caprate, PEG-caprylate or PEG-caprylate/caprate), and a glyceryl-Cg to Cig carboxylic acid ester (e.g.. glyceryl mono-, di- or tricaprylate, glyceryl mono-, di- or tricaprate or glyceryl mono-, di- or tricaprylate/ caprate), ' 35
Grn/13.9.89
, ql
BE ow” - 2 _ as the principal components. : 1t has been found that the above-identified absorption enhancing system functions to increase the extent of absorption of antibacterial compounds through mucosal tissue and into the bloodstream. This invention thus promotes the 1 absorption and, concomitantly, the bioavailability of antibacterial compounds which, when administered without the absorption enhancer by means other than parenteral, are only
Poorly absorbed or not absorbed to any appreciable degree.
The preparation and use of a greater variety of dosage forms for such compounds are thus enabled. The pharmaceutical compositions of the present invention also promote the greater absorption and bioavailability of antibacterial compounde which are otherwise only moderately absorbed through mucosal tissue, thue enhancing the effectiveness of such therapeutic compounds also.
This invention encompasses the aforementioned pharmaceutical composition for administration in virtually any dosage form suitable for oral or rectal administration.
Embraced within its scope are oral and rectal types of pharmaceutical preparations containing effective amounts of “an antibacterial compound and an absorption enhancing system } 25 in accordance with the present description, with or without an inert carrier and pharmaceutically acceptable adjuvants. i The terms "antibacterial" and "antibiotic" are used interchangeably throughout this disclosure to refer to bactericidal or bacteriostatic compounds which have been metabolically derived from a microorganism, synthetically prepared by chemical means, or prepared by a combination of microbial and chemical procedures (semi-synthetic). ‘ 35 Contemplated for utilization in the practice of this invention is virtually any antibiotic substance which is useful for combatting a bacterial infection in a host,
J 1° 596390 including those antibiotice which are only moderately absorbed upon non-injected or non-infused administration.
However, thie invention finds ite greatest usefulness when employed to enhance the absorption and bioavailability of antibiotics which, for the most part, can be effectively administered only by injection or infusion due to non- or » poor absorbability via other routes of administration.
Among the most preferred antibacterial compounds suitable for use as the therapeutic substance in the practice of this invention are beta-lactam antibiotics, particularly compounds having a beta-lactam ring as the central structure, that is, the structure
N
0 which can be substituted at various positions on the ring and/or fused with other ring systems which themselves can be substituted or unsubstituted. Exemplary of such beta-lactam ‘antibiotics are penicillins, cephalosporins, penems, ’ 25 carbapenems and monocyclic beta-lactams. ’ Especially preferred beta-lactam antibiotics for use in this invention are compounds of the formula
R
- : N
N . 0 Ra ol hl * . . Ga ) - 4 - in which R, is hydrogen or optionally substitutes alkyl,
R, is 50, -M+ where M+ is a proton or cation, R, is an ’ acylamino group or hydroxyalkyl, or R, and R, together with the beta-lactam (azetidinone) ring to which they are bonded represent
Rs x ' | i
N———e ¥ o in which X is -s-, -0, -SO-, -80,, -CH,, or -CH(CH,) and Y is group ya x or or
CHa z \\ COOE ™
COOE
J h
COOE
’ in which R, igs a substituted thio group such as ethylthio, ~SCH_CH_NH_,
Cn Wo -SCH,, CH, NHCH, -SCH,CH,OCNH,,, -s—( yr conwe, as NH
. Wr co = 2639 or an optionally substituted lower alkyl group such as aminomethyl, acylaminomethyl, + J 0 or a substituted oxy group such as carbamoyloxy (-OCNH,), » the carbon atom which carries the -COOE group is bonded to the nitrogen atom of the beta-lactam ring, Z is hydrogen, halogen, alkoxy or CH,T. with T denoting hydrogen, alkyl ’ 10 -CO0-0-, pyridinium, carboxamidopyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxyl, the group -S-phenyl which can be substituted or the group -S-het wherein "het” is an optionally substituted 5- or 6-membered heterocyclic ring, and E is hydrogen, a pharmaceutically acceptable ester group or a galt-forming cation.
Examples of the 5- or 6-membered heterocyclic rings encompassed within "het" above are the following:
N—-N N-—N N—N
LN, /\, I \, } CHy CH,-CHy-N(CH3);
H
N—N N—N CHa, _N 0
LY [ 1
N
’
Ss NT x
N 0
CH,CO.H . 35 Especially preferred beta-lactam antibiotics and their pharmaceutically acceptable salts, esters and hydrates include ceftriaxone, a cephalosporin described in U.S.
V7 v . _ 6 -
Patent No. 4,327,210 (Montavon et al.): carumonam, a monocyclic beta-lactam described in European Patent No. EP : 73061: piperacillin, a penicillin described in U.S. Patent
No. 4,112,090; cefamandole, a cephalosporin described in
U.S. Patent No. 3.641,021; mezlocillin, a penicillin described in U.S. patent No. 3,974,142; and cefazolin, a ‘ cephalosporin described in U.S. Patent No. 3,516,997, the - disclosures of all of which are incorporated herein by reference. Further included are cefoxitin, cefmetazole, cefotetan, moxalactam, cefuroxime, ceforamide, cefoperazone, ceftizoxime, cefotaxime, cefmenoxime, ceftazidime, cefsulodin, cefazolin, cephalexin, azlocillin, penicillin G, temocillin, gulbenicillin, ticarcillin, mecillinam, amoxicillin, methicillin, carbenicillin, thienamycin,
N-formimidoylthienomycin, gulbactam and azthreonam.
Another preferred beta-lactam antibiotic for use in thie invention is the compound, (E)-2-(1sobutoxy carbonyl) 5. pentenyl (6R,7R)-7-[ (2)-2- (2-amino-4-thiazoly})
CE ethoxyimino)acetamido]-3- (azidomethyl)-8-oxo-5- hia _1.azabicyclo[4.2.0]oct-2-ene-2-carboxylate which is described in European Patent publication AZ2-0318767.
Also included within the scope of this jnvention are : 25 antibiotics other than the beta-lactams, for example, vancomycin and gentamicin, the absorption and bioavailability of which are improved by use with the described absorption enhancing systems.
Absorption enhancing system component (b)(1) is the product of an etherification reaction between an alcohol, gpecifically, an acyclic Ce to Cig gtraight or branched chain alkanol and a polyoxyethylene glycol (PEG) - Examples of alcohols guitable for the preparation of component (bY (1) ’ a5 include n-hexyl, n-heptyl, n-octyl, n-decyl, n-dodecyl (lauryl), n-tetradecyl (myristyl), n-hexadecyl (cetyl),
————————— eee 7 - 7 - n-octadecyl, and so forth. Lauryl alcohol is preferred.
The polyoxyethylene glycol is, typically, a medium to high molecular weight material which preferably has a number average molecular weight in the range from about 200 to about 1500, and more usually from about 400 to about 600. !
Component (b)(l) can be prepared by known procedures.
Especially favored for use as component (b)(l) is the material known as Laureth-12 (CTFA designation). A suitable commercially available material is MACOL LA-12, manufactured by Mazer Chemicals Company, Gurnee, Illinois.
Absorption enhancing system component (b)(2)(i), may be the product of an esterification reaction between a polyoxyethylene glycol, glycerol and one or more straight or branched chain Ce to Cig carboxylic acids, preferably a monofunctional acid or acids. Alternatively, component o0 (b)(2)(i) may be prepared by oligomerizing or polymerizing ethylene oxide in the presence of an ester of glycerol and one or more of such Ce to Cig carboxylic acide (glyceride esters). Still another route, and the preferred one, is by 'co-reacting the glyceride ester or esters with a fully ’ o5 pre-formed polyoxyethylene glycol under conditions sufficient to achieve alcoholysis.
According to a particular preferred procedure, involving alcoholysis, a reaction vessel is charged with a0 stoichiometric quantities of a glyceryl-fatty acid ester or esters and a polyethylene glycol. The vessel is closed and heated at atmospheric pressure to 200°C, with continuous stirring commenced at 70°C, for a period of 12 to 24 hours or until the reaction is completed. The vessel is allowed ’ 35 to cool and the reaction product is then separated from the reaction mixture by filtration.
. yO
Co 0 - B -
Examples of Ce to Cig carboxylic acids, saturated or unsaturated, which are useful for the preparation of absorption enhancing system component (b)(2)(i) are caproic, caprylic, capric, lauric, myristic, oleic, palmitic and stearic. Especially preferred for this invention are capric and caprylic acids, individually or together.
The polyoxyethylene glycol (PEG) used in the formation of absorption enhancing system component (b)(2)(i) is,
Co 10 typically, a medium to high molecular weight material, preferably having a number average molecular weight in the range from about 200 to about 1500, and more preferably from about 300 to about 600.
A material which is suitable for use as absorption enhancing system component (b)(2)(i) will most preferably have the following characteristics:
Organoleptic Properties: . 20
Appearance: clear oily liquid odor: faint
Color: pale vellow to yellow ’ 25 Physical and Chemical Properties:
Acid value: 0.2 - 0.6
Sulfated ash: less than 0.05% saponification index: 85 - 105 lodine index: less than 2
Moisture content: less than 0.05%
Free glycerin content: approx. 2%
Monoglyceride content: approx. 6 to 8% . 35 Density (3%): 1.062 - 1.068 g/cc
Refractive index (n°: 1.458 - 1.462
. pT - 9 _
Suitable absorption enhancing system components for use in this invention which are commercially available are - LABRASOL, produced by Gattefosse Corporation, Paris, France (PEG-B caprylate/caprate glyceride esters), and SOFT1GEN 767, produced by Dynamit Nobel, West Germany (PEG-6 caprylate/caprate glyceride esters).
The Ce to Cig carboxylic acid or its salt which constitutes absorption enhancing system component (b) (2) (il) ie derived from an acyclic carboxylic acid, which may be straight or branched chain. Examples include caproic, caprylic, capric, lauric, myristic, oleic, palmitic and stearic. Most favored for the purposes of this invention are caprylic and capric acids. :
These salts can be prepared in a conventional manner and using known techniques by reacting the acid with a base having a non-toxie, pharmacologically and pharmaceutically acceptable cation. 1In general, any base which will form a op Balt with a carboxylic acid and the pharmacological properties of which will not cause an adverse physiological effect when ingested by or otherwise administered to a warm-blooded animal is suitable. Such bases thus include, ‘for example, alkali metal and alkaline earth metal : 25 hydroxides or carbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, and the like. Particularly preferred for this invention are sodium salts, chiefly because of their ready availability.
Absorption enhancing system component (b)(2) (iii) is derived from a mixture of two or more carboxylic acids of 6 to 18 carbon atoms, glycerol and a polyoxyethylene glycol.
The acids may be straight or branched chain, and saturated or unsaturated. ’ 35 suitable acids include saturated carboxylic acids such as n-hexyl, n-heptyl, n-octyl, n-decyl, lauryl, myristyl,
Co i» yf10 - 10 - cetyl and n-octadecyl, and unsaturated enoic (e.g., oleic) and dienoic (e.g., linoleic) acids.
Preferred are mixtures comprised of several Ce to
Cig fatty acids, such as found in vegetable oils and fats, and most preferably coconut oil, which is composed of major + amounts of saturated and minor amounts of ungaturated fatty acids of up to 18 carbon atoms.
Preferably, the polyoxyethylene glycol employed for absorption enhancing system component (b)(2)(iii) is characterized by a number average molecular weight in the range from about 200 to about 1500, and more usually from about 300 to about 600.
Absorption enhancing agents useful as absorption enhancing system component (b)(2)(iii) can be prepared by those skilled in the art using conventional esterification procedures. A suitable material is available commercially og from Capital City Products, Janesville, wisconsin under the trade designation ACCONON CON (a PEG glycerol cocoate).
The relative proportions of the two components which ‘comprise the absorption enhancing system can be varied to ’ 25 achieve optimum results for a particular embodiment of the invention. Preferably, the weight ratio of (b)(1l) to (b)(2)(i), (b)(2)(ii) or (b)(2)(iii) is in the range from about 1:50 to about 50:1, more preferably from about 1:10 to about 10:1, and most preferably from about 1:4 to about 4:1. -
The effective amount of the absorption enhancing system, component (b), in the composition of this invention will vary depending on such factors as the particular antibacterial compound being employed and ite amount, as ‘ as well as the age of the subject being treated.
In general, for oral dosage form compositions of this
Co 0 / - 11 - invention, it is preferred to employ from about 50 to about 1000 milligrams (mg), and more preferably from about 100 to about 500 mg of the absorption enhancing system, for each unit dose of the composition. These compositions will § usually contain the antibacterial compound in amounts from about 10 to about 500 mg, and more usually from about 50 to , about 250 mg, per unit dose. }
Rectal dosage form compositions in accordance with this invention will usually contain from about 50 to about 1500 mg, more preferably from about 75 to about 600 mg of the absorption enhancing system, for each unit dose of the composition. Such compositions will usually contain the antibacterial compound in amounts from about 10 to about 3000 mg, and more usually from about 100 to about 1500 mg, per unit dose.
The term "unit dose" is used here in the conventional sense to mean a single application or administration of the sp drug to the subject being treated in an amount as stated : above, but it should be understood that the amount can be given in the form of a single pill, tablet, capsule, suppository, etc., or alternatively, in multiples of two or . more of such dosage units with the total adding up to the ~ 25 stated amount of drug.
The described antibacterial compound and absorption enhancing system, components (a) and (b), respectively, can be incorporated into a vehicle, if desired. As the vehicle, there can be used any pharmaceutically acceptable solid, gemi-solid or liquid carrier in which these components are soluble or readily dispersible. Some examples include but are not limited to cocoa butter, polyethylene glycols, polypropylene glycols, methylcellulose, carboxymethyl- . 35 cellulose and suppocire® semi-synthetic bases (Gattefosse Corp., Paris, France). Preferably, the vehicle is a solid. Favored as a solid vehicle for the compositions
. nV i og’ - 12 - of this invention are mixtures of mono-, di- and triglycerides of Cz to Cig natural saturated fatty : acids, preferably vegetable fatty acids having an even number of carbon atoms (Crp Cigar Ci6° etc.).
Especially suitable and preferred are the pharmaceutical bases of Dynamit Nobel having the trade designation \ "WITEPSOL". still other pharmaceutically compatible carrier ‘ 10 materials may be employed as desired and depending upon particular requirements, the selection of which is within the knowledge of those skilled in the art. 1f utilized, the vehicle will generally be present in those amounts which are conventional for pharmaceutical carrier materials and which can be reasonably and safely administered.
The preferred method of orally administering the combination of antibacterial compound and absorption enhancing system in accordance with this invention is in the form of an enteric coated entity, and more specifically, an enteric coated solid dosage form. The formulation can be © filled into a hard- or soft-shell capsule or, if the formulation is a liquid, absorbed onto a suitable carrier to make a free flowing powder and then filled into the capsule or, alternatively, compressed into a pill or tablet. still other possible dosage forms include microcapsule or beadlet forms of the antibacterial compound mixed with the absorption enhancing system which may thereafter be encapsulated in an enteric coated capsule. “Usage of enteric coating materials in this manner serves to protect the antibacterial compound from the gastric fluid ‘ a5 and to achieve optimum delivery of the antibacterial compound together with the absorption enhancing system to the intestine. The enteric coating material is, for the
Co yi? - 13 - v most part, resistant to the gastric fluid and is unaffected by it but dissolves in the intestinal fluid to cause release : of the drug.
The effectiveness of particular enteric coating materials can be measured using known USP procedures. By , way of illustration, suitable enteric coating materials for purposes of this invention include but are not limited to the following: cellulose acetate phthalate cellulose acetate trimellitate hydroxypropyl methylcellulose phthalate hydroxypropyl methylcellulose phthalate succinate polyvinyl acetate phthalate methacrylic acid methacrylic acid esters
These enteric coating materials may be applied with or without plasticizers, such as acetylated glycerides or diethylphthalate, using methods known to those skilled in the art. : The percentage of enteric coating applied is usually
Y 25 between about 1 and about 10 percent by weight, or more, and most desirably from about 2 to about 8 percent by weight, based on the total weight of the unit dosage form, i.e., the total capsule or tablet weight. Examples of guitable enteric coating formulations are glven below.
. / ; xl . * ~Y / - 14 - - Enteric Coating Formulations , ee
Ingredients tT w/w
Preparation A:
Hydroxypropyl methylcellulose phthalate (HPMCP) 5.0
Triacetin 0.5%
Methylene chloride 47.25
Denatured alcohol 47.25
Preparation B:
HPMCP 10.0
Titanium dioxide 0.2
Dimethyl polysiloxane 0.05 og Acetone 44.87%
Denatured alcohol 44.875
Preparation C: o5 Cellulose acetate phthalate (CAP) 8.5 \ Diethyl phthalate 1.5
Titanium dioxide 0.2 3) Acetone 44.9
Denatured alcohol 44.9 "
Preparation D:
Polyvinyl acetate phthalate : 5.0
Acetylated glycerides 0.8 ‘ 35 Methylene chloride 47.1
Denatured alcohol 47.1 ee ———————————————————————————— ee —_—
VY
Vv - 15 - ; Preparation E: 2 0 3 9 0 : Methacrylic acid or methacrylic acid ester (Eudragit S or L, 8.0
Rohm Pharma, GMBH, Wetterstadt,
West Germany) ' Acetone 46.0 }
Anhydrous alcohol 46.0
Plasticizer q.8.
Oral dosage form compositions in accordance with this invention can algo be formulated to additionally contain conventional additives or supplementary ingredients, in the usual amounts for such materials. By way of fllustration, such additives or supplements include thickening agents, guch as silicic acid (for instance, the trade designated "Aerosil"” products): bentonites; colloidal clay: carboxymethyl celluloses; modified montmorillonites, such as alkyl ammonium salts of montmorillonites (for instance, the og commercial products known as "Bentone"): organic thickening and structure-forming agents, such as saturated higher fatty acids and alcohols containing from 12 to 20 carbon atoms (for instance, stearic or palmitic acids, or stearic or “cetyl alcohols); waxes; monoglycerides of gaturated or o5 unsaturated high fatty acids such as stearic acid, palmitic acid or oleic acid: gelling agents, such as aluminum stearate; dispersing agents, such as ionic, non-ionic or ) cationic surfactants: emulsifying agents, such as lecithin, and so forth. "
The compositions of this invention can also contain pharmaceutically acceptable adjuvants, such as binders or lubricants for tabletting, stabilizing agents, ‘antioxidants, flowing agents (to enhance pourability or flowability during ‘ 35 processing), preservatives, flavoring agents, coloring agents and buffering agents. Any of these can be selected from among materials known for such purposes and used in nV j wv - 16 - > conventional amounts.
In vivo tests were utilized to evaluate the enhanced mucoegal tissue absorption of antibiotics administered in accordance with this invention. ' IN VIVO (RATS) - ENTERAL t
Adult Sprague-Dawley female rats (Charles River Breeding
Laboratories, Kingston, New York), weighing about 250 grams each, were fasted overnight and anesthetized with metofane.
With each rat, an incision was made on the ventral surface to expose the intestine. Administration of an antibiotic was carried out using a solution dosage form. The solutions
Were prepared by dissolving 5 mg of antibiotic in water with or without absorption enhancer and diluting to the desired concentration.
Each solution of antibiotic in water was administered op enterally by injecting with a syringe into the duodenum below the pyloric valve. For purposes of comparison, the solution was alternatively administered intravenously by injecting with a syringe into a tail vein. o5 Plasma Levels of Antibiotic in Rats
The concentration of antibiotic in rat plasma was 3 determined at various time intervals after intravenous or enteral administration. Blood samples were collected from the tail of each test animal prior to administration of the antibiotic and at 5, 10, 20, 40, 60, 120, 240 and 360 minutes after administration, then centrifuged at 3200 rpm for 5 to 10 minutes, after which the plasma was withdrawn and frozen until assayed.
av i Ww - 17 - ’ Biocaggay of Plasma Samples 9 6 3 9 §) ‘ Most of the antibiotics tested had exhibited some degree of protein binding when drug-spiked rat plasma was assayed against drug in H,0. Any antibiotic not bound by plasma was diluted in H,0 and assayed against standards prepared : in HO.
For bound antibiotics, the influence of protein binding was negated by diluting all standards and samples in pooled rat plasma.
In the case of ceftriaxone and cefazolin, the effect of binding was accounted for by deproteinizing plasma samples with acetonitrile with a dilution factor of 1:12 and assaying against a standard curve diluted in H,0. Antibiotic levels were assayed on nunc plates employing the appropriate agar seeded with bacteria, as listed below.
x yl V / - 18 - 8”
Assay Range o” Standard Bioassay Volume
Antibiotic Organism Curves (mcg/ml) Media (mc)
Carumonam E. coli. 1346 32-1 ran’ 20
Ampicillin' M. lutea ATCC 934) 8-0.25 AAR) 20 cefamandole’ M. lutea ATCC 934) 32-1 AAR) 20 ] 10 cefotaxime €. coli. 1346 8-0.25 or 16-0.5 AAS 20
Cefoxitin S. aureus MB2786 64-4 BHI 20
Ceftriaxone’ E. coli. 1346 4-0.125 AAR) 20 cefazolin’ S. aureus ATCC 25923 32-1 aan 50
B. subtilis spores 32-2 AAR 50
Moxalactam’ E. coli. 1346 50-1.56 AAS] S0
Penicillin G' M. lutea ATCC 934) 8-0.5 AAR] 20
Mezlocillin' M. lutea ATCC 934) 16-1 AANY 50
Gentamicin K. pneumoniae A 80-2.5 wm 50
Vancomycin’ B. cereus ATCC 11778 64-2 AArE® 50 ! Antibiotics protein bound in rat plasma.
Zant = antibiotic agar ¥1 (Difco).
San = Brain Heart Infusion Media (Difco). . ™ = Mueller Hinton Agar (Difco).
Saar = antibiotic agar #8 (Difco). mcg/m] = micrograms per milliliter mcl = microliters 3 o
The plates were incubated -overnight at 37° C and the zones of inhibition were read to the nearest 0.1 mm. Calculations were made using an autoassay machine (Giles Scientific,
Inc., New York). For reference, see J. V. Befinett et al.,
Applied Microbiology 14, 170-177 (1966).
The results were as follows:
f1V / - 19 -
TABLE 1
TABLE 1
ENTERAL ABSORPTION IN RATS - ! With and Without Absorption Enhancers
Dose = 5 mg/0.5 m}
Onax_(micrograms per milliliter) (Control) Acconon Con Labraso) Sodium Caprylate (301) + + +
Antibiotic Water Laureth-12* Laureth-12* Laureth-12%
Carumonam 0.0+£00 7.2% 1.4 11.7% 38 63% 2.4
Cefamandole 1.3 ¢£ 2.5 6.4 + 0.6 g.4¢t 2.6 18.1% 3.7
Cefazolin 0.0 + 0.0 42.9 t+ 3.0 62.2 + 25.2 40.7 + 1.2
Cefoxitin 0.0 £ 0.0 1.7+ 2.8 9.1 + 3.4 16.2 tt 46
Cefotetan 0.0 £ 0.0 9.5 + 2.8 21.2 + 5.8 26.1 + 11.4
Gentamicin 3.9 15.4 + 2.3 9.6 £+ 1.9 14.1 + 6.9
Mezlocillin 0.0 £ 0.0 0.6 + 1.0 1.4 + 1.4 6.7 + 1.7
Moxalactam 0.0 £ 0.0 9.6 + 2.2 16.2 + 1.8 19.9 + 45
Penicillin G 0.5 t£ 0.) 3.5% 1.0 5.2 + 1.6 7.4 + 2.4 05 Vancomycin 294406 00% 0.0 69+ 1.0 9.8% 3.5
Ceftriaxone 2.44+1.9 3884+ 22.6 105.5 ¢£ 23.0 53.7 + 13.3 *Weight Ratio of Other Absorption Enhancer Component to Laureth-12 was 8:1 0 i jab j B - 20 -
IN VIVO (DOGS) - ENTERAL - Six male beagle dogs, weighing about 10 to 16 kilograms each, were chronically fitted with a modified Thomas cannula implanted in the distal duodenum. Each dog received 2 hard shell gelatin capsules containing 210 mg of ceftriaxone , sodium salt in 280 mg of a bage (WITEPSOL HIS), with : absorption enhancer (157.5 mg of Labrasol and 52.5% mg of
Laureth-12). Administration of the capsules in each lnstance was enteral through the modified Thomas cannula into the proximal jejunum. Drug dosage was 20 to S50 mg of ceftriaxone per kilogram of dog body weight.
Blood plasma concentrations of ceftriaxone were determined prior to administration and at lo, 20, 40, so, 120, 180 and 240 minutes after administration. Measurements te were made by withdrawing blood at these time intervals, - } centrifuging, separating the plasma and assaying by High
Performance Liquid Chromatography (HPLC), reverse phase } 20 method, or by bioassay (the Bame procedure as previously described for the Bioassay of Plasma Samples).
To establish a standard curve, ceftriaxone was diluted : with normal dog plasma, then deproteinized in the same manner as described previously. calculations were conducted using a Waters 840 Computer System. Through the use of an appropriate computer program, the area under the curve (AUC)
OD was determined for each route of administration. From these - determinatione, the bicavailability was computed using the following equation: - 0% Bioavailability = r-fnterall x 100
Whenever intravenous (1.V.) data were not avallable for ’ 35 the same dose level uged enterally, the following equation was employed:
0 ~U - 21 - t+ Bioavailability = lang Entetall x ee x 100 ’ The results were 45.4 + 18.2% Biocavailability and 19.% + 6.5 mcg/ml Cmax for the absorption enhanced formulation, compared to 0% Bioavailability and 0.5 mcg/ml
Cmax for the control (a golution of ceftriaxone in water ' equivalent to 25 mg/kg, no absorption enhancers).
IN VIVO (BABOONS) - ORAL
B 10 : Adult baboons (Papio anubis and Papilio hamadryas). ranging in weight from 12 to 30 kilograms, were used in this study. The baboons were fasted overnight, then sedated with ketamine hydrochloride by intramuscular injection prior to administration of the antibiotic. Each baboon received four hard shell gelatin capsules through a gastric tube. Each capsule contained the following: i
Ceftriaxone sodium salt 300 mg
Labrasol 225 mg
Laureth-12 75 mg
Witepsol HLS 380 mg 980 mg
Enteric coating: polyvinyl acetate phthalate (approximately 8% of total capsule weight)
VD one-milliliter blood samples were taken from the femoral region of each baboon using a heparinized 3-ml syringe.
Samples were taken prior to ceftriaxone administration and at 15, 30, 60, 120, 240, 360, 480, 600 and 720 minutes following ceftriaxone administration. The samples were centrifuged at 12,000 rpm for one minute and the plasma was separated and bloassayed for antibiotic content after ’ 35 deproteinization with acetonitrile, using the same procedure described previously for the Bioassay of Plasma samples.
pf" j - 22 -
The results were 10.0 + 6.5% Bioavailability and 5.5-59.8 mcg/ml Cmax range, compared to 0% Bioavailability and 0 meg/ml Cmax for the control (ceftriaxone sodium salt, 300 mg, in the same enteric coated capsule, no absorption enhancers). ' Absorption was also evaluated using a formulation composed of 300 mg of ceftriaxone sodium salt, 200 mg of sodium caprylate, 7% mg of Laureth-12 and 415 mg of Witepsol j0 H15. The Bioavailability of this formulation was 15.7 + 9.9% and 15.0-66.3 mcg/ml Cmax range, compared to 0% Bioavailability and 0 mcg/ml Cmax for the control (same as above). .
IN VIVO (DOGS) - ORAL
Male beagle dogs weighing approximately 10-14 kilograms were used in this study. The dogs received 2 or 3 hard shell capsules through a gastric tube. Each capsule o0 contained the following:
Ceftriaxone sodium salt 300 mg
Labrasol 22% mg
Laureth-12 7% mg
Witepsol HLS 380 mg 980 mg
Enteric coating: polyvinyl acetate phthalate (approximately 8% of total capsule weight) -
Blood plasma concentrations of ceftriaxone were determined prior to administration and at lo, 20, 40, 60, 120, 180 and 240 minutes after administration.’ Measurements were made by withdrawing blood at these time intervals, ‘ 35 separating the plasma, deproteinizing, and assaying by High
Performance Liquid Chromatography (HPLC), reverse phase method, or by the previously described Bioassay of Plasma y 10 ; i - 23 - ‘ samples method. 9 6 3 0
The results were 34.2 ¢ 14.0% Bioavailability and 21.6 + 7.6 mcg/ml Cmax for the above formulation, and 0%
Bioavailability and 0 mcg/ml Cmax for the control (ceftriaxone sodium salt, 300 mg, in the same enteric coated ‘ capsule, no absorption enhancers}.
Absorption was also evaluated using a formulation composed of 300 mg of ceftriaxone sodium salt, 200 mg of sodium caprylate, 75 mg of Laureth-12 and 415 mg of Witepsol
H15. Bioavailability was 22.4 + 13.5% and Cmax was 14.4 + 8.4 mcg/ml, compared to O% and O mcg/ml, respectively, for the control (same as above). 15 .
IN VIVO (BABOONS) - RECTAL
Male and female adult baboons (Papio anubis and Papio hamadryas), ranging in weight from 12 to 27 kilograms, were ) 20 used in this study. The baboons were fasted for 24 hours prior to administration of antibiotic, then sedated with ketamine hydrochloride by intramuscular injection prior to administration of the antibiotic. suppositories made up of " the formulations shown below were administered to the baboons and the rectal openings were then taped closed to prevent expulsion and leakage of the suppository mass.
Lo Antibiotic 500 mg
Laureth-12 125 mg
Labrasol - 250 mg
Witepsol 15 1125 mg . Total: 2000 mg ' ' a5 To measure antibiotic absorption into the bloodstream, blood samples were taken from the femoral region of each baboon, using heparinized 3-ml syringes, prior to antibiotic lk - 24 - : administration and at 15, 30, 60, 120, 240, 360 and 480 minutes after antibiotic administration. The withdrawn ‘ samples were centrifuged at 12,000 rpm for one minute and bicassayed by the previously described Bioassay of Plasma
Samples method. The results were as follows: ; TABLE 2
Antibiotic Bioavailability and Cmax Range in Baboons
After Rectal Administration
With Absorption Enhancer Control-No Absorption
System Enhancer System * Bioavail- Cmax Range * Bioavail- Cmax Range
Antibiotic ability mcq/ml ability meg/ml
Ceftriaxone 31.5 + 13.1 18.2-49.6 4.3 + 2.8 0.3-9.0
Cefamandole 46.5 + 16.6 5.9-16.4 6.0 + 2.3 2.3-4.6
Cefoxitin 77.0 t+ 22.5 4.7-10.8 0 0
Penicillin G 38.2 + 26.1 2.0-11.1 17.4 + 8.0 1.2-2.4
Absorption was also evaluated using a formulation composed of 600 mg of ceftriaxone sodium salt, 200 mg of © godium caprylate, 125 mg of Laureth-12 and 1075 mg of o5 Witepsol H15 (total: 2000 mg). The Bioavailability was . 49.3 + 13.7% and the Cmax range was 68.1-102.8 mcg/ml, compared to 4.3% Bioavailability and 0.3-9.0 mcg/ml Cmax range for the control (600 mg of ceftriaxone sodium salt in suppository vehicle with no absorption enhancers). -
By way of illustration, some suitable formulations for various dosage forms in accordance with this invention are set forth below. While ceftriaxone, the preferred antibiotic for this invention, is used to illustrate these ‘ 35 formulations, it should be understood that other antibiotics may be substituted in appropriate amounts.
yv ; PW - 25 -
ORAL DOSAGE FORMS 2 6 3 9 0 : per capsule
A) Ceftriaxone (sodium) 60 mg 120 mg 210 mg 300 mg
Labrasol 225% mg 225 mg 225 mg 22% mg
Laureth-12 75 mg 75 mg 75 mg 75 mg ' Witepsol H15 340 mg 340 mg 340 mg 340 mg : B) Ceftriaxone (sodium) 60 mg 120 mg 210 mg 300 mg
Sodium caprylate 200 mg 200 mg 200 mg 200 mg
Laureth-12 75 mg 75 mg 75 mg 75 mg
Witepsol H15 365 mg 365 mg 365 mg 365 mg
C) Ceftriaxone (sodium) 60 mg 120 mg 210 mg 300 mg
Acconon Con 225 mg 225 mg 225 mg 225 mg
Laureth-12 75 mg 75 mg 75% mg 75 mg
Witepsol H15 340 mg 340 mg 340 mg 340 mg
D) Ceftriaxone (sodium) 60 mg 120 mg 210 mg 300 mg
Softigen 767 22% mg 225 mg 225 mg 225 mg
Laureth-12 75 mg 75 mg 75 mg 7% mg
Witepsol HLS 340 mg 340 mg 340 mg 340 mg
RECTAL DOSAGE FORMS per suppository
A) Ceftriaxone (sodium)180 mg 300 mg 600 mg 1200 mg
Labrasol 250 mg 250 mg 250 mg 500 mg
Laureth-12 12% mg 12% mg 125 mg 250 mg
Witepsol HI15 1445 mg 1325 mg 1025 mg 2050 mg
B) Ceftriaxone (sodium)1B80 mg 300 mg 600 mg 1200 mg
Sodium caprylate 200 mg 200 mg 200 mg 400 mg
Laureth-12 125 mg 125 mg 125 mg 250 mg ’ 35 Witepsol H1S5 1495 mg 1375 mg 1075 mg 2150 mg pf i —- 26 - ) Cc) Ceftriaxone (sodium)180 mg 300 mg 600 mg 1200 mg
Acconon Con 250 mg 250 mg 250 mg 500 mg : Laureth-12 125 mg 12% mg 125 mg 250 mg
Witepsol H15 1445 mg 1325 mg 1025 mg 2050 mg
Dp) Ceftriaxone (sodium)180 mg 300 mg 600 mg 1200 mg \ softigen 767 250 mg 250 mg 250 mg 500 mg
Laureth-12 12% mg 125 mg 125 mg 250 mg witepsol HLS 1445 mg 1325 mg 1025 mg 2050 mg
The above dosage forms can be prepared as follows:
PROCEDURES oral
The base (Witepsol H15) ig warmed to 55°C and the absorption enhancer system components are added to the melt with mixing. The melt is then cooled to 45°C and the drug (ceftriaxone godium) is added to the molten mass and mixed until uniformly distributed and free of any aggregates. The mass is homogenized, if necessary, to obtain a uniform suspension. The suspension is filled into gelatin capsules, gealed if necessary, and the capsules are enteric coated.
Rectal
The base (Witepsol H1S) ig warmed to 55°C and the absorption enhancer system components are added to the melt with mixing. The melt is then cooled to 45°C and the drug (ceftriaxone sodium) is added to the molten mass and mixed until uniformly distributed and free of any aggregates. The mass is homogenized, if necessary, to obtain a: uniform suspension. The suspension is then filled into suppository ‘ a5 shelle and allowed to cool and congeal.
Claims (9)
- : nv yr —- 27 - . . ‘ CLAIMS: 2 6 3 9 0Co. A pharmaceutical composition comprising (a) ceftriaxone or a ceftriazone or a pharmaceutically acceptable salts. ester or hydrate thereof and (b) an ' absorption enhancing amount of a two—-companent absorption enhancing system made up of a first component which is (1) an ether of a Cs to Cie alcohol and a polyoxyethylene glycol and a second component selected from among {2Y(i) a polyoxyethylene glycol (PEG) - Cs to Cie glyceride ester, (2)(ii) a Cs to Cia carboxylic acid or pharmaceutically acceptable salt thereof, and (2) (iii) an ester of two or more Ce to Cais carboxylic acids. glycerol and a polyoxyethylene glycol, with or without (c) a pharmaceutically acceptable inert carrier.
- 2. A composition according to claim 1, in which the absorption enhancing system is composed of (b) (1) an ether of a Ce to Cie alcohol and a polyoxyethyl- ene glycol and (b)(2)(i) a polyoxyethylene glycol - Ce to Cim carboxylic acid glyceride ester.
- 3. A composition according to claim 2, in which (b) (1) is an ether of lauryl alcohol and polyoxyethyl- ene glycol and (b) (2) (i) is a PEG-8 caprylate/caprate ! glyceride ester.
- 4. A composition according to claim 1, in wich the absorption enhancing system is composed of (Db) (1) an ether of a Ce to Cis alcohol and a polyoxy- ethylene glycol and (b) (2) (ii) a Cs to Cie ' carboxylic acid or pharmaceutically acceptable salt thereof.
- 5. A composition according to claim 4, in which (b) (1) is an ether of lauryl alcohol and Co polyoxyethylene glycol and (bY (2) (ii) is sodium caprylate. :D 0 = 26390
- 6. A composition according to claim 1, in which the absorption enhancing system is composed of (b) (1) an ether of a Cs to Cy,e alcohol and a polyoxy- ethylene glycol and (b)(2)(iii) an ester of two or more Ce to Cie carboxylic acids, glycerol and a ' polyoxyethylene glycol.
- : 7. A composition according to claim 6, in which (b) (1) is an ether of lauryl alcohol and polyoxyethyl- ene glycol and (b)(2)(iii) is a PEG glycerol cocoate.
- 8. A composition according to claim 1 which is in an enteric coated oral dosage form.
- 9. A composition according tc claim 1 which is in a rectal dosage form. MARIA OKSANA BACHYNSKY MARTIN HOWARD INFELD NAVNIT SHAH JOEL UNOWSKY (Inventors)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27459088A | 1988-11-22 | 1988-11-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
PH26390A true PH26390A (en) | 1992-07-02 |
Family
ID=23048828
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PH39561A PH26390A (en) | 1988-11-22 | 1989-11-21 | Pharmaceutical compositions |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0370481B1 (en) |
JP (1) | JPH0774165B2 (en) |
KR (1) | KR900007412A (en) |
AT (1) | ATE94765T1 (en) |
AU (1) | AU625276B2 (en) |
CA (1) | CA2003340A1 (en) |
DE (1) | DE58905681D1 (en) |
DK (1) | DK585889A (en) |
HU (1) | HU205713B (en) |
IE (1) | IE63119B1 (en) |
IL (1) | IL92357A (en) |
NZ (1) | NZ231447A (en) |
PH (1) | PH26390A (en) |
YU (1) | YU221889A (en) |
ZA (1) | ZA898331B (en) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4115849A1 (en) * | 1991-05-15 | 1992-11-19 | Lohmann Therapie Syst Lts | PENETRATION PROMOTING SUBSTANCE |
GB9405304D0 (en) * | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
SI9400338A (en) * | 1994-08-31 | 1996-04-30 | Lek D D | Vancomycin hydrochloride suspensions for peroral use and for filling into soft ,gelatine capsules. |
IT1275802B1 (en) * | 1994-11-03 | 1997-10-17 | Hoffmann La Roche | INTERFERONE COMPOSITION |
FR2775188B1 (en) * | 1998-02-23 | 2001-03-09 | Lipha | IMMEDIATE RELEASE ORAL EXTENDED RELEASE GALENIC FORM COMPRISING AN ABSORPTION PROMOTING AGENT AND USE OF THE ABSORPTION PROMOTING AGENT |
IL125244A (en) * | 1998-07-07 | 2002-12-01 | Yissum Res Dev Co | Pharmaceutical compositions containing low-melting waxes |
US8119159B2 (en) | 1999-02-22 | 2012-02-21 | Merrion Research Iii Limited | Solid oral dosage form containing an enhancer |
DE60038097T2 (en) * | 1999-02-22 | 2009-02-12 | Merrion Research I Ltd. | SOLID ORAL DOSAGE FORM CONTAINING A RESORPTION AMPLIFIER |
US7658938B2 (en) | 1999-02-22 | 2010-02-09 | Merrion Reasearch III Limited | Solid oral dosage form containing an enhancer |
US20030176379A1 (en) | 2001-05-11 | 2003-09-18 | Raoof Araz A. | Antisense permeation enhancers |
BRPI0710503A2 (en) | 2006-04-07 | 2011-08-16 | Merrion Res Iii Ltd | use of a pharmaceutical composition, pharmaceutical composition, and oral dosage form |
MX2010012201A (en) | 2008-05-07 | 2011-05-30 | Merrion Res Iii Ltd | Compositions of peptides and processes of preparation thereof. |
BRPI0918652B1 (en) | 2008-09-17 | 2021-10-19 | Chiasma, Inc. | PHARMACEUTICAL COMPOSITION INCLUDING A HYDROPHOBIC MEDIUM AND A SOLID FORM WHICH INCLUDES POLYPEPTIDE AND MEDIUM CHAIN FATTY ACID SALT, PRODUCTION PROCESS AND ORAL DOSAGE FORM |
WO2011120033A1 (en) | 2010-03-26 | 2011-09-29 | Merrion Research Iii Limited | Pharmaceutical compositions of selective factor xa inhibitors for oral administration |
EP2661273A4 (en) | 2011-01-07 | 2014-06-04 | Merrion Res Iii Ltd | Pharmaceutical compositions of iron for oral administration |
EP3250191B1 (en) | 2015-01-29 | 2024-01-17 | Novo Nordisk A/S | Tablets comprising glp-1 agonist and enteric coating |
EP3253401A4 (en) | 2015-02-03 | 2018-11-21 | Chiasma Inc. | Method of treating diseases |
US11141457B1 (en) | 2020-12-28 | 2021-10-12 | Amryt Endo, Inc. | Oral octreotide therapy and contraceptive methods |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1168949A (en) * | 1979-08-13 | 1984-06-12 | William G. Gorman | Cleansing compositions |
US4525339A (en) * | 1982-10-15 | 1985-06-25 | Hoffmann-La Roche Inc. | Enteric coated oral dosage form |
EP0126348A2 (en) * | 1983-05-19 | 1984-11-28 | Kyoto Pharmaceutical Industries, Ltd. | Composition for rectal administration and method of promoting rectal drug absorption |
JPS59212427A (en) * | 1983-05-19 | 1984-12-01 | Kyoto Yakuhin Kogyo Kk | Composition for rectum administration |
CA1256799A (en) * | 1984-02-22 | 1989-07-04 | Walter Fuller | Suppositories |
EP0179583A1 (en) * | 1984-10-04 | 1986-04-30 | Merck & Co. Inc. | A system for enhancing the water dissolution rate and solubility of poorly soluble drugs |
-
1989
- 1989-11-01 ZA ZA898331A patent/ZA898331B/en unknown
- 1989-11-20 IL IL9235789A patent/IL92357A/en not_active IP Right Cessation
- 1989-11-20 NZ NZ231447A patent/NZ231447A/en unknown
- 1989-11-20 CA CA002003340A patent/CA2003340A1/en not_active Abandoned
- 1989-11-21 JP JP1300926A patent/JPH0774165B2/en not_active Expired - Lifetime
- 1989-11-21 AT AT89121548T patent/ATE94765T1/en not_active IP Right Cessation
- 1989-11-21 DE DE89121548T patent/DE58905681D1/en not_active Expired - Fee Related
- 1989-11-21 KR KR1019890016872A patent/KR900007412A/en not_active Application Discontinuation
- 1989-11-21 AU AU45384/89A patent/AU625276B2/en not_active Ceased
- 1989-11-21 IE IE371889A patent/IE63119B1/en not_active IP Right Cessation
- 1989-11-21 PH PH39561A patent/PH26390A/en unknown
- 1989-11-21 DK DK585889A patent/DK585889A/en not_active Application Discontinuation
- 1989-11-21 EP EP89121548A patent/EP0370481B1/en not_active Expired - Lifetime
- 1989-11-22 HU HU896123A patent/HU205713B/en not_active IP Right Cessation
- 1989-11-22 YU YU02218/89A patent/YU221889A/en unknown
Also Published As
Publication number | Publication date |
---|---|
AU4538489A (en) | 1990-05-31 |
HU205713B (en) | 1992-06-29 |
IE893718L (en) | 1990-05-22 |
ATE94765T1 (en) | 1993-10-15 |
DK585889D0 (en) | 1989-11-21 |
EP0370481A2 (en) | 1990-05-30 |
ZA898331B (en) | 1990-07-25 |
JPH02180837A (en) | 1990-07-13 |
IL92357A0 (en) | 1990-07-26 |
CA2003340A1 (en) | 1990-05-22 |
HU896123D0 (en) | 1990-02-28 |
KR900007412A (en) | 1990-06-01 |
HUT52374A (en) | 1990-07-28 |
IL92357A (en) | 1994-10-07 |
NZ231447A (en) | 1992-09-25 |
EP0370481A3 (en) | 1991-01-16 |
YU221889A (en) | 1992-05-28 |
AU625276B2 (en) | 1992-07-09 |
DK585889A (en) | 1990-05-23 |
EP0370481B1 (en) | 1993-09-22 |
DE58905681D1 (en) | 1993-10-28 |
IE63119B1 (en) | 1995-03-22 |
JPH0774165B2 (en) | 1995-08-09 |
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