AU1607595A - Process for solubilizing difficultly soluble pharmaceutical actives - Google Patents
Process for solubilizing difficultly soluble pharmaceutical activesInfo
- Publication number
- AU1607595A AU1607595A AU16075/95A AU1607595A AU1607595A AU 1607595 A AU1607595 A AU 1607595A AU 16075/95 A AU16075/95 A AU 16075/95A AU 1607595 A AU1607595 A AU 1607595A AU 1607595 A AU1607595 A AU 1607595A
- Authority
- AU
- Australia
- Prior art keywords
- peg
- polyethylene glycol
- difficultly soluble
- process according
- solution
- 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
- 238000000034 method Methods 0.000 title claims description 23
- 230000003381 solubilizing effect Effects 0.000 title description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 61
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 39
- 229920001223 polyethylene glycol Polymers 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 229960005489 paracetamol Drugs 0.000 claims description 24
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 15
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- 229960003908 pseudoephedrine Drugs 0.000 claims description 12
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 11
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 claims description 9
- 229960001985 dextromethorphan Drugs 0.000 claims description 9
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 claims description 8
- -1 fenbuprofen Chemical compound 0.000 claims description 8
- 229960002146 guaifenesin Drugs 0.000 claims description 8
- KBAUFVUYFNWQFM-UHFFFAOYSA-N Doxylamine succinate Chemical compound OC(=O)CCC(O)=O.C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 KBAUFVUYFNWQFM-UHFFFAOYSA-N 0.000 claims description 7
- 229960005008 doxylamine succinate Drugs 0.000 claims description 7
- 239000008346 aqueous phase Substances 0.000 claims description 5
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 claims description 4
- 229940046978 chlorpheniramine maleate Drugs 0.000 claims description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 4
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 claims description 2
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 claims description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 2
- 229960000520 diphenhydramine Drugs 0.000 claims description 2
- 229960001419 fenoprofen Drugs 0.000 claims description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 2
- 229960001680 ibuprofen Drugs 0.000 claims description 2
- 229960000905 indomethacin Drugs 0.000 claims description 2
- 229960002009 naproxen Drugs 0.000 claims description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 2
- 229960001128 triprolidine Drugs 0.000 claims description 2
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 claims description 2
- 230000000063 preceeding effect Effects 0.000 claims 5
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims 2
- AKWFJQNBHYVIPY-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO AKWFJQNBHYVIPY-UHFFFAOYSA-N 0.000 claims 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims 1
- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 claims 1
- YZUUTMGDONTGTN-UHFFFAOYSA-N nonaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCO YZUUTMGDONTGTN-UHFFFAOYSA-N 0.000 claims 1
- 108010010803 Gelatin Proteins 0.000 description 34
- 229920000159 gelatin Polymers 0.000 description 34
- 235000019322 gelatine Nutrition 0.000 description 34
- 235000011852 gelatine desserts Nutrition 0.000 description 34
- 239000008273 gelatin Substances 0.000 description 33
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 25
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 24
- 239000007788 liquid Substances 0.000 description 20
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 20
- 239000004615 ingredient Substances 0.000 description 15
- 239000008194 pharmaceutical composition Substances 0.000 description 14
- 239000007903 gelatin capsule Substances 0.000 description 13
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- 239000004014 plasticizer Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 239000002826 coolant Substances 0.000 description 7
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 7
- 229940057847 polyethylene glycol 600 Drugs 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 238000005538 encapsulation Methods 0.000 description 6
- 229920003072 Plasdone™ povidone Polymers 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 2
- WYUYEJNGHIOFOC-VVTVMFAVSA-N 2-[(z)-1-(4-methylphenyl)-3-pyrrolidin-1-ylprop-1-enyl]pyridine;hydrochloride Chemical compound Cl.C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C\CN1CCCC1 WYUYEJNGHIOFOC-VVTVMFAVSA-N 0.000 description 2
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 2
- VUNOFAIHSALQQH-UHFFFAOYSA-N Ethyl menthane carboxamide Chemical group CCNC(=O)C1CC(C)CCC1C(C)C VUNOFAIHSALQQH-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920003079 Povidone K 17 Polymers 0.000 description 2
- 229920003080 Povidone K 25 Polymers 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000000686 essence Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 2
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 229960001593 triprolidine hydrochloride Drugs 0.000 description 2
- WFXURHIXPXVPGM-LREBCSMRSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-methyl-9-phenyl-1,3,4,9-tetrahydroindeno[2,1-c]pyridine Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(C)CCC(C2=CC=CC=C22)=C1C2C1=CC=CC=C1 WFXURHIXPXVPGM-LREBCSMRSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- MDVYIGJINBYKOM-UHFFFAOYSA-N 3-[[5-Methyl-2-(1-methylethyl)cyclohexyl]oxy]-1,2-propanediol Chemical group CC(C)C1CCC(C)CC1OCC(O)CO MDVYIGJINBYKOM-UHFFFAOYSA-N 0.000 description 1
- NFLLKCVHYJRNRH-UHFFFAOYSA-N 8-chloro-1,3-dimethyl-7H-purine-2,6-dione 2-(diphenylmethyl)oxy-N,N-dimethylethanamine Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Cl)=N2.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 NFLLKCVHYJRNRH-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical class OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229920003085 Kollidon® CL Polymers 0.000 description 1
- IJHNSHDBIRRJRN-UHFFFAOYSA-N N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 IJHNSHDBIRRJRN-UHFFFAOYSA-N 0.000 description 1
- ISFHAYSTHMVOJR-UHFFFAOYSA-N Phenindamine Chemical compound C1N(C)CCC(C2=CC=CC=C22)=C1C2C1=CC=CC=C1 ISFHAYSTHMVOJR-UHFFFAOYSA-N 0.000 description 1
- SSOXZAQUVINQSA-BTJKTKAUSA-N Pheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 SSOXZAQUVINQSA-BTJKTKAUSA-N 0.000 description 1
- DYWNLSQWJMTVGJ-KUSKTZOESA-N Phenylpropanolamine hydrochloride Chemical compound Cl.C[C@H](N)[C@H](O)C1=CC=CC=C1 DYWNLSQWJMTVGJ-KUSKTZOESA-N 0.000 description 1
- 229920003075 Plasdone™ K-29/32 polymer Polymers 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920003078 Povidone K 12 Polymers 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000008406 cosmetic ingredient Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 229960001583 diphenhydramine citrate Drugs 0.000 description 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- MZNZKBJIWPGRID-UHFFFAOYSA-N diphenylphosphorylmethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)CP(C=1C=CC=CC=1)C1=CC=CC=C1 MZNZKBJIWPGRID-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960005178 doxylamine Drugs 0.000 description 1
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 229960004842 ephedrine sulfate Drugs 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000036074 healthy skin Effects 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003534 phenindamine Drugs 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- 229960001339 pheniramine maleate Drugs 0.000 description 1
- 229960002305 phenylpropanolamine hydrochloride Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007905 soft elastic gelatin capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000005496 tempering Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
PROCESS FOR SOLUBILIZING DIFFICULTLY SOLUBLE PHARMACEUTICAL ACTIVES
TECHNICAL FIELD The present invention relates to a process for enhancing the solubility of difficultly soluble pharmaceutical actives in a mixture of polyethylene glycol, polyvinylpyrrolidone, and propylene glycol.
BACKGROUND OF THE INVENTION Liquid, and especially concentrated liquid pharmaceutical compositions offer several advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Moreover, liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Likewise, concentrated liquid compositions offer certain distinct advantages. These compositions are ideally suited for incorporation into easy-to-swallow soft, flexible capsules. Encapsulation of this nature permits the accurate and uniform delivery of unit dose amounts of a pharmaceutical active, encompassing even those instances where relatively small amounts of a pharmaceutical active are to be delivered. In addition, soft gelatin capsules are aesthetically appealing (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors. These advantages notwithstanding, it is often difficult to prepare such com¬ positions using the desired pharmaceutical active however. Many pharmaceutical actives are poorly soluble and, therefore, require relatively large volumes of solvent for dissolution, resulting in impractically large doses. Also, encapsulating such large volumes into easy-to-swallow gelatin capsules presents obvious difficulties, suggesting the immediate importance of concentrated liquid compositions. Furthermore, the situation becomes even more complicated when multiple pharmaceutical actives are involved, and particularly where the difficultly soluble pharmaceutical active is in combination with a water soluble pharmaceutical active(s).
The current approach to this solubility problem is to force solubility into small volumes of solvent by means of a step-wise process incorporating heat. This step-wise process consists of dissolving the difficultly soluble pharmaceutical active in polyethylene
glycol with heat, followed by the addition of any additional pharmaceutical actives. As a separate admixture, polyvinylpyrrolidone is dissolved in a solution of water and propylene glycol. Finally, the polyvinylpyrrolidone solution is then added to the original batch solution to complete the process. Because the resultant concentrated liquid (or fill) is a supersaturated solution of the difficultly soluble pharmaceutical active, it is even more difficult to increase the resultant composition's concentration of the difficultly soluble active.
The present inventor has discovered that by using a polyvinylpyrrolidone with a specific viscosity average molecular weight of from about 5,000 to about 25,000 provides dissolution of significantly higher levels of the difficultly soluble pharmaceutical active.
It is, therefore, an object of the present invention to describe a process which provides for increased solubility of difficultly soluble pharmaceutical actives. A further object of the present invention is to enhance stability of the resultant composition by reducing the tendency of the difficultly soluble pharmaceutical active to precipitate out of solution. These and other objects of this invention will become apparent in light of the following discussion.
SUMMARY OF THE INVENTION The present invention relates to a process for enhancing the solubility of difficultly soluble pharmaceutical actives by combining and mixing until dissolved from about 1% to about 40% of at least one difficultly soluble pharmaceutical active in a solution comprising: i) from about 20% to about 70% of a polyethylene glycol; ii) from about 4% to about 20% of a polyvinylpyrrolidone having a viscosity average molecular weight from about 5,000 to about 25,000; and iii) from about 1% to about 10% of a propylene glycol.
The process preferably further comprises combining and mixing until dissolved the above solution with a separate admixture of from about 0.5% to about 20% of at least one additional pharmaceutical active in from about 1% to about 50% of an aqueous phase.
All percentages and ratios used herein are by weight and all measurements are at 25°C, unless otherwise indicated.
DETAILED DESCRIPTION OF THE INVENTION
The term "difficultly soluble pharmaceutical active", as used herein, describes an active having a solubility of less than or equal to 1% by weight in water at 25°C. This term is defined to also include the descriptive terms "sparingly soluble"; "slightly soluble"; "very slightly soluble"; "practically insoluble, or insoluble"; and their equivalents as defined
in the USP XXII. p.8 ( 1990), this reference being incorporated herein by reference in its entirety.
Concentrated Liquid Pharmaceutical Compositions
The highly concentrated liquid pharmaceutical compositions of the present invention comprise the following essential, as well as optional, components. Polyethylene Glycol
An essential component of the present compositions is a polyethylene glycol. Polyethylene glycols generally are clear, viscous liquids or white solids which are soluble in water and many organic solvents. These polymers correspond to the general formula:
H(OCH2CH2)nOH where n is greater than or equal to 4. Polyethylene glycols are described in G.M. Powell, III in Handbook of Water-Soluble Gums & Resins. R.L. Davidson, Ed. (McGraw-Hill, New York, 1980) pp. 18/1-18/3 1, this reference being incorporated herein by reference in its entirety. Polyethylene glycols, which are also known as "PEGs" or "polyoxyethylenes", are designated by both their average molecular weight range and their average "n" value as in the above designated formula. For example, polyethylene glycol 400, which is also known by the CTFA designation, PEG-8, has an average molecular weight range from 3SO-420 and an average value of n between 8.2 and 9. 1. See CTFA Cosmetic Ingredient Dictionary. Third Edition (1982), pp. 201-203; and The Merck Index. Tenth Edition, entry 7441, p. 1092 (1983); these two references being incorporated herein by reference in their entirety.
Polyethylene glycols useful herein are mixtures of those which are liquids at room temperature or have a melting point slightly thereabove. Preferred mixtures include those polyethylene glycols having a molecular weight range of from about 300 to about 1000 and corresponding n values of from about 6 to about 20. More preferred are those of polyethylene glycols having a molecular weight range of from about 400 to about 1000 and corresponding n values of from about 8 to about 20. Most preferred are those of polyethylene giycols having a molecular weight range of from about 600 to about 1000 and corresponding n values of from about 12 to about 20. Liquid and low-melting poly¬ ethylene glycols are commercially available from Union Carbide (Danbury, CT) under the Carbowax® trademark. See "Carbowax® Polyethylene Glycols", Union Carbide Technical Bulletin f-4772M-ICD 1 1/86-20M, this reference being incorporated herein by reference in its entirety
Polyethylene glycols having an average molecular weight below about 300 are not desirable for use in the instant invention since such polyethylene glycols tend to diffuse into, plasticize, and ultimately disrupt the soft gelatin shells which can be employed to encapsulate the compositions described herein.
The process for preparing the highly concentrated liquid compositions of the present invention comprises adding from about 20% to about 70% polyethylene glycol, more preferably from about 30% to about 60%, and most preferably from about 35% to about 55%. Polwinylpyrrolidone
An essential component of the present compositions is polyvinylpyrrolidone ("PVP"), which is a polymer of N-vinyl-2-pyrrolidone having the following formula:
Polyvinylpyrrolidones are described in L. Blecher et al. in Handbook of
Water-Soluble Gums & Resins. R.L. Davidson, Ed. (McGraw-Hill, New York, 1980) pp. 21/1-21/21, this reference being incorporated herein by reference in its entirety. Polyvi¬ nylpyrrolidone has different solubility characteristics based on its polymeric structure. Long-chain polyvinylpyrrolidone, which is also known as povidone, has good solubility in water and a number of organic solvents. Cross-linked polyvinylpyrrolidone, which is also known as crospovidone, is insoluble in virtually all common solvents. Both the soluble and insoluble forms of polyvinylpyrrolidone are commercially available from GAF Chemicals Company (Wayne, NJ) under the Plasdone® and Polyplasdone® trademarks, respectively, and from BASF Aktiengesellschaft (Ludwigshafen, Germany) under the Kollidon® trademark. Soluble forms of polyvinylpyrrolidone include Plasdone® K-25,
Plasdone® K-26/28, Plasdone® K-29/32, Plasdone® C- 15, Plasdone® C-30, Plasdone® C-90, Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30, and Kollidon® 90. Insoluble forms of polyvinylpyrrolidone include Polyplasdone XL®, Polyplasdone XL ®10, Kollidon® CL, and Kollidon® CL-M. See "Tableting With Plasdone®", GAF Technical Bulletin 2302- 1 1 OR 1 ( 1986); "Polyplasdone XL®, Polyplasdone XL® 10", GAF Technical Bulletin 2302-099 R2 (1984); and "Kollidon® Grades, Polyvinylpyrrolidone for the Pharmaceutical Industry", BASF Technical Bulletin MEF 129e, Register 2, May 1986 (Bn); these references being incorporated herein by reference in their entirety.
The soluble forms of polyvinylpyrrolidone are preferred for use in the present inven- tion. Preferred are soluble polyvinyl- pyrrolidones having an viscosity average molecular weight in the range from about 5000 to about 25,000; more preferred are those having an viscosity average molecular weight in the range from about 5000 to about 15,000; and most preferred are those having an viscosity average molecular weight from about 5,000 to about 10,000. Moreover, mixtures of two or more soluble polyvinylpyrrolidones of different average molecular weight can be employed.
The process for preparing the highly concentrated liquid compositions of the instant invention comprises adding from about 1% to about 28% of a soluble polyvi¬ nylpyrrolidone, more preferably from about 1% to about 15%, and most preferably from about 2% to about 10%. Preferably, the ratio of the total amount of polyethylene glycol to polyvinylpyr¬ rolidone should be at least about 2.5: 1. Propylene Glycol
Propylene glycol, which is represented by the formula:
CH3CHOHCH2OH is well known in the art for its solvent and/or humectant properties. A colorless and viscous liquid, propylene glycol is miscible with water, alcohols and many organic solvents. Propylene glycol is described in Hawlev's Condensed Chemical Dictionary, pp. 970-971, (Revised by Richard J. Lewis, Sr.) (12th ed. 1993, herein incorporated by reference. Propylene glycol suitable for use in the present invention is obtainable from any number of suppliers, Dow Chemical being one. Difficultly Soluble Pharmaceutical Actives
The compositions of the instant invention contain at least one difficultly soluble pharmaceutical active as an essential component. In general, these actives have a solubility less than or equal to about 1 percent by weight in water at 25°C. Useful classes of pharmaceutically-active compounds which can be incorporated into the present
compositions include analgesics, anti-inflammatory agents, anti-pyretics, calcium channel blockers, beta-blockers, antibacterials, antidepressants, antidiabetics, anti-emetics, antihistamines, cerebral stimulants, sedatives, anti-parasitics, expectorants, diuretics, decongestants, antitussives, muscle relaxants, anti-Parkinsonian agents, bronchodilators, cardiotonics, antibiotics, antivirals, nutritional supplements (such as vitamins, minerals, fatty acids, amino acids, and the like), and mixtures thereof. Difficultly soluble pharmaceutical actives selected from the non-narcotic analgesics/nonsteroidal anti-inflammatory drugs are especially useful in the present invention. Examples of such drugs are disclosed in U.S. Patent No. 4,522,828, to Sunshine et al., issued June 1 1, 1985; this patent being incorporated herein by reference in its entirety
Examples of preferred difficultly soluble pharmaceutical actives useful in the present invention include, but are not limited to, acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, naproxen, their p armaceutically-acceptable salts, and mixtures thereof. Acetaminophen is especially preferred for use in the present invention.
The process for preparing the highly concentrated liquid compositions of the instant invention comprises adding from about 1% to about 40% of a difficultly soluble pharma¬ ceutical active, more preferably from about 15% to about 35%, and most preferably from about 25% to about 35%. Additional Pharmaceutical Actives
The compositions of the instant invention can optionally contain one or more additional pharmaceutical actives having a solubility greater than the difficultly soluble pharmaceutical actives described above. In general, these actives have a solubility greater than about 1 percent by weight in water at 25°C. Such additional pharmaceutical actives may also be selected from among the pharmaceutical categories previously mentioned
Specific examples of additional pharmaceutical actives useful in the present in¬ vention include, but are not limited to, pseudoephedrine and its salts such as pseu- doephedrine hydrochloride; dextromethorphan and its salts such as dextromethorphan hydrobromide; doxylamine and its salts such as doxylamine succinate; phenindamine and its salts such as phenindamine hydrogen tartrate; pheniramine and its salts such as pheniramine maleate; chlorpheniramine and its salts such as chlorpheniramine maleate; ephedrine and its salts such as ephedrine sulfate; triprolidine and its salts such as triprolidine hydrochloride; diphenhydramine and it salts such as diphenhydramine hydrochloride, diphenhydramine citrate, and diphenhydramine 8-chlorotheophyllinate; phenyltoxyiamine and its salts; guaifenesin; phenylpropanolamine hydrochloride; and
mixtures thereof Preferred additional pharmaceutical actives are dextromethorphan hydrobromide, doxylamine succinate, pseudoephedrine hydrochloride, chlorpheniramine maleate, guaifenesin, triprolidine hydrochloride, diphenydramine hydrochloride and mixtures thereof A further class of optional actives include those useful in promoting or maintaining healthy skin. Examples of such actives are disclosed in U S Patent 5.073.371. to Turner et al.. issued December 17, 1991, this patent being incorporated herein by reference in its entirety.
The process for preparing the highly concentrated liquid compositions of the instant invention comprises adding one or more of these optionally additional pharmaceutical actives at a concentration of from about 0 5% to about 20% Coolants
In addition, the present invention may optionally incorporate a cooling agent or a combination of cooling agents Suitable cooling agents are those described in U S Patent 4.136.163. January 23, 1979, to Watson et al., U S Patent 4.230.668. October 28, 1980, to Rowsell et al. and U S Patent 4.032.661. to Rowsell et al., all of which are herein incorporated by reference. A particularly preferred cooling agent is N-ethyl-p-menthane- 3-carboxamide (WS-3 supplied by Sterling Organics), taught by the above incorporated U.S. Patent 4.136.163 Another particularly preferred cooling agent is 3-1 - menthoxypropane 1,2-diol (TK- 10 supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan). This material is described in detail in U S Patent 4.459.425. July 10, 1984 to Amano et al. and incorporated herein by reference Other Optional Components
Optional components which can be incorporated into the compositions of the instant invention include coolants, colorings, flavorings, preservatives, lubricants, flow-enhancers, filling aids, anti- oxidants, essences, and other aesthetically pleasing components. Process for Solubilizing Difficultly Soluble Pharmaceutical Actives
The highly concentrated liquid pharmaceutical compositions are prepared using art-recognized principles and methodologies in mixing the ingredients together and in choosing the type of mixing equipment to be used. In a preferred manner of execution, the difficultly soluble pharmaceutical active, polyethylene glycol, propylene glycol and polyvinylpyrrolidone, are combined in the presence of heat and mixed until dissolved to form a homogeneous solution. Upon dissolution of the difficultly soluble pharmaceutical active, additional pharmaceutical actives may then be added to this batch solution or
dissolved separately in an aqueous phase. The process is completed once all additional pharmaceutical actives have been added, whether by direct addition to the original batch solution and/or by indirectly transferring the separately formed admixture to the original batch.
Soft Gelatin Capsules
Preselected amounts of the highly concentrated liquid pharmaceutical compositions of the present invention can also be encapsulated in a soft gelatin shell. Optionally, the soft gelatin shell is essentially transparent so as to enhance the aesthetic qualities of the capsule. The soft gelatin shells comprise the following essential, as well as optional, components. Gelatin
Gelatin is an essential component of the soft gelatin shells of the instant invention. The starting gelatin material used in the manufacture of soft capsules is obtained by the partial hydrolysis of collagenous material, such as the skin, white connective tissues, or bones of animals. Gelatin material can be classified as Type A gelatin, which is obtained from the acid-processing of porcine skins and exhibits an isoelectric point between pH 7 and pH 9; and Type B gelatin, which is obtained from the alkaline-processing of bone and animal (bovine) skins and exhibits an isoelectric point between pH 4.7 and pH 5.2. Blends of Type A and Type B gelatins can be used to obtain a gelatin with the requisite viscosity and bloom strength characteristics for capsule manufacture. Gelatin suitable for capsule manufacture is commercially available from the Sigma Chemical Company, St. Louis, Mo. For a general description of gelatin and gelatin-based capsules, see Remingtons' Pharmaceutical Sciences. 16th ed., Mack Publishing Company, Easton, Pa. ( 1980), page 1245 and pages 1576-1582; and U.S. Patent 4,935,243, to Borkan et al., issued June 19, 1990; these two references being incorporated herein by reference in their entirety.
The soft gelatin shell of the capsules of the instant invention, as initially prepared, comprises from about 20% to about 60% gelatin, more preferably from about 25% to about 50% gelatin, and most preferably from about 40% to about 50% gelatin. The gelatin can be of Type A, Type B, or a mixture thereof with bloom numbers ranging from about 60 to about 300. Plasticizer
A plasticizer is another essential component of the soft gelatin shells of the instant invention. One or more plasticizers is incorporated to produce a soft gelatin shell. The soft gelatin thus obtained has the required flexibility characteristics for use as an encapsulation agent. Useful plasticizers of the present invention include glycerin, sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures thereof.
The shell of the present invention, as initially prepared, comprises from about 10% to about 35% plasticizer, preferably from about 10% to about 25% plasticizer, and most preferably from about 10% to about 20% plasticizer. A preferred plasticizer useful in the present invention is glycerin.
Water
The soft gelatin shells of the instant invention also comprise water as an essential component Without being limited by theory, the water is believed to aid in the rapid dissolution or rupture of the soft gelatin shell upon contact with the gastrointestinal fluids encountered in the body
The shell of the present invention, as initially prepared, comprises from about 15% to about 50% water, more preferably from about 25% to about 40% water, and most preferably from about 30% to about 40% water Other Optional Components
Other optional components which can be incorporated into the soft gelatin shells in¬ clude colorings, flavorings, preservatives, anti-oxidants, essences, and other aesthetically pleasing components. Soft Gelatin Shell Preparation and Encapsulation
The solubilized pharmaceutical compositions of the present invention can be en¬ capsulated within any conventional soft gelatin shell that is capable of substantially containing the composition for a reasonable period of time The soft gelatin shells of the instant invention can be prepared by combining appropriate amounts of gelatin, water, plasticizer, and any optional components in a suitable vessel and agitating and/or stirring while heating to about 65°C until a uniform solution is obtained This soft gelatin shell preparation can then be used for encapsulating the desired quantity of the solubilized fill composition employing standard encapsulation methodology to produce one-piece, hermetically-sealed, soft gelatin capsules The gelatin capsules are formed into the desired shape and size so that they can be readily swallowed The soft gelatin capsules of the instant invention are of a suitable size for easy swallowing and typically contain from about 100 mg to about 2000 mg of the solubilized pharmaceutical active composition Soft gelatin capsules and encapsulation methods are described in P K Wilkinson et al , "Softgels Manufacturing Considerations", Drugs and the Pharmaceutical Sciences. 41 (Specialized Drug Delivery Systems . P Tyle, Ed (Marcel Dekker, Inc , New York, 1990) pp 409-449, F S Horn et al , "Capsules, Soft", Encyclopedia of Pharmaceutical Technology, vol 2, J Swarbrick and J C Boylan, eds (Marcel Dekker, Inc , New York, 1990) pp 269-284; M S Patel et al , "Advances in Softgel Formulation Technology", Manufacturing Chemist, vol 60, no 7, pp 26-28 (July 1989), M S Patel et al , "Softgel Technology", Manufacturing Chemist, vol 60, no 8, pp 47-49 (August 1989), R F
Jimerson, "Softgel (Soft Gelatin Capsule) Update", Drug Development and Industrial Pharmacy (Interphex '86 Conference , vol 12, no 8 & 9, pp 1 133-1 144 ( 1986), and W.R Ebert, "Soft Elastic Gelatin Capsules A Unique Dosage Form", Pharmaceutical Technology, vol 1, no 5, pp 44-50 ( 1977), these references are incorporated by reference herein in their entirety Methods for tempering soft gelatin capsules are des¬ cribed in U S Patent 5.200.191 to Steele et al , herein incorporated by reference The resulting soft gelatin capsule is soluble in water and in gatrointestinal fluids Upon swallowing the capsule, the gelatin shell rapidly dissolves or ruptures in the gastrointestinal tract thereby introducing the pharmaceutical actives into the physiological system
EXAMPLES
The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLE I Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen in combination with other pharmaceutical actives is prepared from the following ingredients' Ingredients Weight %
Acetaminophen 3 1 25
Pseudoephedrine HC1 2 88
Dextromethorphan HBr 1.44 Doxylamine Succinate 0 60
Polyethylene Glycol 600 24.38
Polyethylene Glycol 1000 22.14
Propylene Glycol 4.33
Polyvinylpyrollidonel 8 17 Water Purified 4 81
1 Available as Kollidon K-17 PF from BASF Chem.Co (Viscosity average molecular weight * 10,000)
A solution of the polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming these compositions to 70°C Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of
nitrogen Once the acetaminophen is dissolved the solution is removed from the heat In a separate container, pseudoephedrine HC1, dextromethorphan HBr and doxylamine succinate are dissolved in water at room temperature by stirring Finally, this separate admixture is combined with the original batch solution and mixed until uniform Examples II-III are further examples of concentrated solutions containing acetaminophen in combination with other pharmaceutical actives and are manufactured in a manner substantially similar to Example I
EXAMPLE II Solubilized Pharmaceutical Composition Ingredients Weight %
Acetaminophen 31 25 Pseudoephedrine HC1 2 88 Dextromethorphan HBr 1 44 Doxylamine Succinate 0 60 Polyethylene Glycol 600 24 38
Polyethylene Glycol 1000 22 14 Propylene Glycol 4 33 Polyvinylpyrollidone 8 17 Water Purified 4 81 * Available as Kollidon K- 12 PF from BASF Chem Co (Viscosity average molecular weight « 5,000)
EXAMPLE III Solubilized Pharmaceutical Composition Ingredients Weight % Acetaminophen 31 25
Pseudoephedrine HC1 2 88 Dextromethorphan HBr 1 44 Chlorpheniramine Maleate 0 19 Polyethylene Glycol 600 24 52 Polyethylene Glycol 1000 22 40
Propylene Glycol 4 33 Polyvinylpyrollidone 1 8 17 Water Purified 4 82
1 Available as Kollidon K- 17 PF from BASF Chem Co (Viscosity average molecular weight a 10,000)
EXAMPLE IV Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen and guaifenesin in combination with other pharmaceutical actives is prepared from the following ingredients Ingredients Weight %
Acetaminophen 3 1 25
Pseudoephedrine HC1 2 88
Dextromethorphan HBr 0 96
Guaifenesin 9.62 Polyethylene Glycol 600 21 12
Polyethylene Glycol 1000 19 26
Propylene Glycol 2 88
Polyvinylpyrollidone 1 8 17
Water Purified 3 86 1 Available as Kollidon K- 17 PF from BASF Chem Co (Viscosity average molecular weight * 10,000)
A solution of polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming to 70°C Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen Once the acetaminophen is dissolved and the solution removed from heat, the guaifenesin is next added and dissolved. In a separate container, pseudoephedrine HC1, dextromethorphan HBr and doxylamine succinate are dissolved in water at room temperature by stirring Finally, this separate admixture is combined with the original batch solution and mixed until uniform. EXAMPLE V
Solubilized Pharmaceutical Composition
Example V is a further example of a concentrated solution containing aceta¬ minophen and guaifenesin in combination with other pharmaceutical actives and is manufactured in a manner substantially similar to Example IV Ingredients Weight %
Acetaminophen 3 1 25
Pseudoephedrine HC1 2 88
Dextromethorphan HBr 0 96
Guaifenesin 9 62 Polyethylene Glycol 600 21. 12
Polyethylene Glycol 1000 19.26
Propylene Glycol 2.88
Polyvinylpyrollidone ' 8. 17
Water Purified 3.86 ' Available as Kollidon K- 12 PF from BASF Chem. Co. (Viscosity average molecular weight = 5,000)
EXAMPLE VI Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen is prepared from the following ingredients
Ingredients Weight %
Acetaminophen 3 1.25
Polyethylene Glycol 600 26.96
Polyethylene Glycol 1000 24.48 Propylene Glycol 4.33
Polyvinylpyrrolidone ' 8. 17
Water Purified 4.81
' Available as Kollidon K-30 from BASF Chem. Co. (Viscosity average molecular weight a 38,000) A solution of the polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming these components to 70°C. Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen gas. Once the acetaminophen is dissolved, the solution is removed from the heat. Finally, a measured quantity of the aqueous phase is combined with the original batch solution and mixed until uniform.
EXAMPLE VII Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen and pseudoephedrine HC1 is prepared from the following ingredients Ingredients Weight %
Acetaminophen 3 1.25 Pseudoephedrine HC1 2.88 Polyethylene Glycol 600 25.45 Polyethylene Glycol 1000 23. 1 1 Propylene Glycol 4.33
Polyvinylpyrrolidone1 8 17
Water Purified 4 81
1 Available as Kollidon K-30 from BASF Chem. Co. (Viscosity average molecular weight « 38,000) A solution of the polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming these components to 70°C. Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen gas. Once the acetaminophen is dissolved, the solution is removed from the heat. In a separate container, pseudoephedrine HC1 is dissolved in water at room temperature by stirring. Finally, this separate admixture is combined with the original batch solution and mixed until uniform.
EXAMPLE VIII Softgel Capsule Containing a Solubilized Pharmaceutical Composition
A soft gelatin capsule is first prepared form the following ingredients: Ingredients Weight %
Gelatin 47.00
Glycerin 1 5.00
Water Purified qs 100
The above ingredients are combined in a suitable vessel and heated with mixing at about 65°C to form a uniform solution. Using standard encapsulation methodology, the resulting solution is used to prepare soft gelatin capsules containing approximately 1040 mg. of the compositions of Examples I-VII. The resulting soft gelatin capsules are suitable for oral administration.
Claims
WHAT IS CLAIMED IS
1 A process to enhance solubility of difficultly soluble pharmaceutical actives by combining and mixing until dissolved from 1% to 40%, preferably from 20% to 40%, more preferably from 25% to 35%, of at least one difficultly soluble pharmaceutical active in a solution comprising i) from 20% to 70%, preferably from 30% to 65%, more preferably from 40%ι to 60%, of a polyethylene glycol, ii) from 4% to 20% of a polyvinylpyrrolidine having a viscosity average molecular weight from 5,000 to 25,000, preferably from 5,000 to 15,000, more preferably from 5,000 to 10,000, and iii) from 1 % to 10% of a propylene glycol
2 A process according to Claim 1 further comprising the step of combining and mixing until dissolved the composition of Claim 1 with from 1% to 50% of an aqueous phases, preferably water
3 A process according to any one of the preceeding claims wherein the ratio of polyethylene glycol to said difficultly soluble pharmaceutical active and said polyvinylpyrrolidine is from 1 0 3 to 1 0 9 and from 1 0 09 to 1 0 3 respectively
4 A process according to any one of the preceeding claims wherein said difficultly soluble pharmaceutical active is selected from the group consisting of acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofen, flubiprofen, indomethacin, naproxen, and mixtures thereof, preferably acetaminophen
5 A process according to any one of the preceeding claims wherein said polyethylene glycol is selected from a group consisting of PEG-6, PEG-8, PEG-9, PEG- 10, PEG- 12, PEG-14, PEG- 16, PEG-18, PEG-20, and mixtures thereof
6. A process according to any one of the preceeding claims wherein said polyethylene glycol is a mixture of PEG- 12 and PEG-20, preferably in a ratio of 1 : 1.
7. A process according to any one of the preceeding claims wherein one or more additional pharmaceutical actives are added to said aqueous phase and wherein said active is selected from the group of pharmaceutical actives consisting of dextromethorphan, HBr, doxylamine succinate, pseudoephedrine HC1, chlorpheniramine maleate, guaifenesin, triprolidine HC1, diphenhydramine HC1, and mixtures thereof.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18557694A | 1994-01-24 | 1994-01-24 | |
| US08/185576 | 1994-01-24 | ||
| PCT/US1995/001018 WO1995019759A1 (en) | 1994-01-24 | 1995-01-24 | Process for solubilizing difficultly soluble pharmaceutical actives |
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| AU706890B2 AU706890B2 (en) | 1999-07-01 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| US5141961A (en) * | 1991-06-27 | 1992-08-25 | Richrdson-Vicks Inc. | Process for solubilizing difficulty soluble pharmaceutical actives |
-
1995
- 1995-01-24 SK SK961-96A patent/SK96196A3/en unknown
- 1995-01-24 MX MX9602955A patent/MX9602955A/en unknown
- 1995-01-24 NZ NZ279443A patent/NZ279443A/en unknown
- 1995-01-24 CZ CZ962104A patent/CZ210496A3/en unknown
- 1995-01-24 WO PCT/US1995/001018 patent/WO1995019759A1/en not_active Application Discontinuation
- 1995-01-24 AU AU16075/95A patent/AU706890B2/en not_active Ceased
- 1995-01-24 CA CA002181241A patent/CA2181241C/en not_active Expired - Fee Related
- 1995-01-24 EP EP95908124A patent/EP0741560A1/en not_active Withdrawn
- 1995-01-24 CN CN95191303.4A patent/CN1138827A/en active Pending
- 1995-01-24 JP JP7519747A patent/JPH09508128A/en active Pending
- 1995-01-24 BR BR9506564A patent/BR9506564A/en not_active Application Discontinuation
- 1995-01-24 PL PL95315635A patent/PL315635A1/en unknown
-
1996
- 1996-07-22 NO NO963052A patent/NO963052L/en not_active Application Discontinuation
- 1996-07-23 FI FI962948A patent/FI962948A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SK96196A3 (en) | 1997-03-05 |
| NZ279443A (en) | 1998-04-27 |
| MX9602955A (en) | 1997-06-28 |
| WO1995019759A1 (en) | 1995-07-27 |
| NO963052D0 (en) | 1996-07-22 |
| AU706890B2 (en) | 1999-07-01 |
| CZ210496A3 (en) | 1996-12-11 |
| JPH09508128A (en) | 1997-08-19 |
| EP0741560A1 (en) | 1996-11-13 |
| CA2181241A1 (en) | 1995-07-27 |
| BR9506564A (en) | 1997-09-02 |
| NO963052L (en) | 1996-09-24 |
| CA2181241C (en) | 2000-04-25 |
| FI962948A0 (en) | 1996-07-23 |
| CN1138827A (en) | 1996-12-25 |
| FI962948A (en) | 1996-07-23 |
| PL315635A1 (en) | 1996-11-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |