CA2053005A1 - Emulsifier-free emulsion polymers - Google Patents
Emulsifier-free emulsion polymersInfo
- Publication number
- CA2053005A1 CA2053005A1 CA002053005A CA2053005A CA2053005A1 CA 2053005 A1 CA2053005 A1 CA 2053005A1 CA 002053005 A CA002053005 A CA 002053005A CA 2053005 A CA2053005 A CA 2053005A CA 2053005 A1 CA2053005 A1 CA 2053005A1
- Authority
- CA
- Canada
- Prior art keywords
- polymer
- active substance
- emulsion
- release
- dispersion
- 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.)
- Abandoned
Links
- 239000004908 Emulsion polymer Substances 0.000 title claims abstract description 33
- 239000013543 active substance Substances 0.000 claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 32
- 238000002360 preparation method Methods 0.000 claims abstract description 29
- 230000003111 delayed effect Effects 0.000 claims abstract description 7
- 229920000642 polymer Polymers 0.000 claims description 27
- 239000003995 emulsifying agent Substances 0.000 claims description 23
- 239000006185 dispersion Substances 0.000 claims description 16
- 238000000605 extraction Methods 0.000 claims description 13
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 10
- 229960002896 clonidine Drugs 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 6
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229960001117 clenbuterol Drugs 0.000 claims description 3
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical group CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 claims description 3
- 238000007796 conventional method Methods 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 230000008014 freezing Effects 0.000 claims description 3
- 238000007710 freezing Methods 0.000 claims description 3
- 239000005062 Polybutadiene Substances 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims description 2
- 238000000502 dialysis Methods 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920002857 polybutadiene Polymers 0.000 claims description 2
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 2
- 239000011118 polyvinyl acetate Substances 0.000 claims description 2
- 229920001289 polyvinyl ether Polymers 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000005185 salting out Methods 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims 1
- 239000004815 dispersion polymer Substances 0.000 claims 1
- 238000007720 emulsion polymerization reaction Methods 0.000 claims 1
- 229920002239 polyacrylonitrile Polymers 0.000 claims 1
- 238000006116 polymerization reaction Methods 0.000 claims 1
- 229920002223 polystyrene Polymers 0.000 claims 1
- 229920001290 polyvinyl ester Polymers 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000003860 storage Methods 0.000 description 34
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 12
- 239000011159 matrix material Substances 0.000 description 12
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 11
- 230000000968 intestinal effect Effects 0.000 description 11
- 238000001035 drying Methods 0.000 description 8
- 229920000058 polyacrylate Polymers 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000007669 thermal treatment Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 229920003163 Eudragit® NE 30 D Polymers 0.000 description 3
- 229920003153 Eudragit® NE polymer Polymers 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 210000004051 gastric juice Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- -1 ni~edipine Chemical compound 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005496 tempering Methods 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 229920003134 Eudragit® polymer Polymers 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 2
- 229960002576 amiloride Drugs 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000009997 thermal pre-treatment Methods 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- WCVOGSZTONGSQY-UHFFFAOYSA-N 2,4,6-trichloroanisole Chemical compound COC1=C(Cl)C=C(Cl)C=C1Cl WCVOGSZTONGSQY-UHFFFAOYSA-N 0.000 description 1
- BUXRLJCGHZZYNE-UHFFFAOYSA-N 2-amino-5-[1-hydroxy-2-(propan-2-ylamino)ethyl]benzonitrile Chemical compound CC(C)NCC(O)C1=CC=C(N)C(C#N)=C1 BUXRLJCGHZZYNE-UHFFFAOYSA-N 0.000 description 1
- QBQMXWZTRRWPGK-UHFFFAOYSA-N 5-[[4-(dimethylamino)-3,5-dimethoxyphenyl]methyl]pyrimidine-2,4-diamine Chemical compound COC1=C(N(C)C)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 QBQMXWZTRRWPGK-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- UMSGKTJDUHERQW-UHFFFAOYSA-N Brotizolam Chemical compound C1=2C=C(Br)SC=2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl UMSGKTJDUHERQW-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- YAVZHCFFUATPRK-YZPBMOCRSA-N Erythromycin stearate Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 YAVZHCFFUATPRK-YZPBMOCRSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- 150000000996 L-ascorbic acids Chemical class 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- GQWNECFJGBQMBO-UHFFFAOYSA-N Molindone hydrochloride Chemical compound Cl.O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 GQWNECFJGBQMBO-UHFFFAOYSA-N 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- XQCFHQBGMWUEMY-ZPUQHVIOSA-N Nitrovin Chemical compound C=1C=C([N+]([O-])=O)OC=1\C=C\C(=NNC(=N)N)\C=C\C1=CC=C([N+]([O-])=O)O1 XQCFHQBGMWUEMY-ZPUQHVIOSA-N 0.000 description 1
- TURHTASYUMWZCC-UHFFFAOYSA-N Olaquindox [BAN:INN] Chemical compound C1=CC=C2N([O-])C(C)=C(C(=O)NCCO)[N+](=O)C2=C1 TURHTASYUMWZCC-UHFFFAOYSA-N 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 241001387976 Pera Species 0.000 description 1
- 229920002845 Poly(methacrylic acid) Chemical class 0.000 description 1
- 239000004189 Salinomycin Substances 0.000 description 1
- KQXDHUJYNAXLNZ-XQSDOZFQSA-N Salinomycin Chemical compound O1[C@@H]([C@@H](CC)C(O)=O)CC[C@H](C)[C@@H]1[C@@H](C)[C@H](O)[C@H](C)C(=O)[C@H](CC)[C@@H]1[C@@H](C)C[C@@H](C)[C@@]2(C=C[C@@H](O)[C@@]3(O[C@@](C)(CC3)[C@@H]3O[C@@H](C)[C@@](O)(CC)CC3)O2)O1 KQXDHUJYNAXLNZ-XQSDOZFQSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 229950008338 aditoprim Drugs 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 238000010936 aqueous wash Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- OTKPPUXRIADSGD-PPRNARJGSA-N avoparcina Chemical compound O([C@@H]1C2=CC=C(C(=C2)Cl)OC=2C=C3C=C(C=2O[C@H]2C([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2O[C@@H](C)[C@H](O)[C@H](N)C2)OC2=CC=C(C=C2)[C@@H](O)[C@H](C(N[C@H](C(=O)N[C@H]3C(=O)N[C@H]2C(=O)N[C@@H]1C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)C=1C=CC(O)=CC=1)=O)NC(=O)[C@H](NC)C=1C=CC(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)=CC=1)[C@H]1C[C@@H](N)[C@@H](O)[C@H](C)O1 OTKPPUXRIADSGD-PPRNARJGSA-N 0.000 description 1
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 description 1
- 229960003870 bromhexine Drugs 0.000 description 1
- 229960003051 brotizolam Drugs 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 229960000427 carbadox Drugs 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229950010971 cimaterol Drugs 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- CHCISLOJADQUNQ-UHFFFAOYSA-N climazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1Cl CHCISLOJADQUNQ-UHFFFAOYSA-N 0.000 description 1
- 229950001490 climazolam Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001193 diclofenac sodium Drugs 0.000 description 1
- SEALOBQTUQIVGU-QNIJNHAOSA-N dihydroergocornine Chemical compound C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1 SEALOBQTUQIVGU-QNIJNHAOSA-N 0.000 description 1
- 229960004290 dihydroergocornine Drugs 0.000 description 1
- UOOWRCRLTSXSAV-GSZJWLEYSA-N dihydroergocornine mesylate Chemical compound CS(O)(=O)=O.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1 UOOWRCRLTSXSAV-GSZJWLEYSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- FDRNWTJTHBSPMW-BBJOQENWSA-L disodium;(6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino-1-oxidoethylidene]amino]-3-[(2-methyl-5,6-dioxo-1h-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [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-BBJOQENWSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229960004142 erythromycin stearate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 1
- 229960004135 idebenone Drugs 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- IMSSROKUHAOUJS-MJCUULBUSA-N mestranol Chemical compound C1C[C@]2(C)[C@@](C#C)(O)CC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 IMSSROKUHAOUJS-MJCUULBUSA-N 0.000 description 1
- 229960001390 mestranol Drugs 0.000 description 1
- BPMVRAQIQQEBLN-OBPBNMOMSA-N methyl n-[(e)-(1-hydroxy-4-oxidoquinoxalin-4-ium-2-ylidene)methyl]iminocarbamate Chemical compound C1=CC=C2N(O)C(=C/N=NC(=O)OC)/C=[N+]([O-])C2=C1 BPMVRAQIQQEBLN-OBPBNMOMSA-N 0.000 description 1
- 229960001300 metoprolol tartrate Drugs 0.000 description 1
- GAOZTHIDHYLHMS-KEOBGNEYSA-N monensin A Chemical compound C([C@@](O1)(C)[C@H]2CC[C@@](O2)(CC)[C@H]2[C@H](C[C@@H](O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C[C@@]21C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(O)=O)O2 GAOZTHIDHYLHMS-KEOBGNEYSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229940053934 norethindrone Drugs 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 229950010210 olaquindox Drugs 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
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 235000019378 salinomycin Nutrition 0.000 description 1
- 229960001548 salinomycin Drugs 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 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
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F6/00—Post-polymerisation treatments
- C08F6/14—Treatment of polymer emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Polymers & Plastics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Abstract
Abstract The invention relates to emulsifier-free emulsion polymers, processes for their preparation and their use in pharmaceutical preparations giving a delayed release of active substance.
Description
2~3~
S0125~.23 Emulsifier-free emulsion poly~rs The present invention relates to emulsion polymers which are free from emulsifi~rs, processes for their preparation and their use in pharmaceutical preparations giving a delayed release of active suhstance.
Certain emulsion polymers~ such as, for example, emulsion-polymerised estexs of acrylic or methacrylic acid, have in recent years become indispensable adjuvants in the preparation of pharmaceuticals in which the intention is to provide a preparation with delayed release oE the active substance [H~ Dekermann und R.
Lotz, Pharmazeutische Industrie 32 (1970) 469].
Delayed-rel~ase forms o~ this kind allow the active substance to be rele~sed constantly over a fairly long period and thus make it possible to reduce the number of doses of the drug to be administered each day and thereby simplify the therapy plan.
In the course of the development o~ these delayed release forms, in addition to numerous tablets and capsules, plasters which contain active substance with controlled release of the substance have also been described, inter alia.
Numerous methods are also known from the prior art for preparing delayed release forms of this kind.
For example, they may be prepared by ~reeing the emulsion polymer from the suspension agent, dissolving the polymer isolated in this way with the active substance in a suitable organic solvent, then evaporating off the solvent and grinding the ~olid polyacrylate, which contains the active substance, at a temperature below the glass transition temperature o~
i the polymer, and processing the active subskance-containing polyacrylate powder either by using tablet-making excipients tQ form tablets or in some other way, e.g. ~y introducing the powder into capsules.
" '~ " . ~ ' ' .
' :, ' ' ~ ' ' .
,, ~ ' ' , .
.
20~3~
The preparation oE plasters which contain active substance is also known from the prior art, for example by processes described in European Patent No. 20 905.
Suitable emulsion polymers for producing such preparations include, as already mentioned hereinbefore, esters of acrylic or methacrylic acid, e g. the commercially available products under the general product name of Eudragit made by Rohm GmbH of Darmstadt, Germany.
Emulsion polymers of this kind are generally produced by emulsifying the water-insoluble monomer in water with the aid of emulsifiers or surfactants and initiating or performing polymerisation with the use of con~entional initiators. The polymer dispersions obtained by this kind of polymerisation can, in numerous instances, be used directly and are available in the form of dispersions. Active substance release systems produced on the basis of emulsion polymers o~ this kind do, however, have the disadvantage that the rate of release of the active substance may depend on the thermal treatment of the active substance release system during the manufacturing process and may also depend on the storage conditions.
The aim of the present invention is therefore to provide acti~e substance release systems based on emulsion polymers - more particularly based on polyacrylic acid esters or polymethacrylic acid esters -which do not have the dependency described above and which also have substantially identical release characteristics even after lengthy storage under various storage conditions.
It has now been found, surprisingly, that the dependency of the rate of release on the thermal pretreatment during the manufacturing process, observed in the release charaoteristics of active substance release systems, can be traced back to the presence of the emulsifier.
. `
." .
~ ~ .
. ,. ~: :
~3~3~
A further aim of the present invention is to provide emulsifier-free emulsion polymers and a process ; for producing them.
According to the present invention, there is provided an emulsion polymer, which is substantially free from emulsifiers or surfactants and other adjuvants used in the preparation o~ said polymer.
According to a further aspect of the present invention there is provided a process for the preparation of an emulsion polymer as defined ab~ve wherein a dispersion of an emulsion polymer i5 first produced by conventional methods and in which the emulsifier, surfactant and other adjuvants used in the conventional preparation method (the extractable ; 15 excipients) are subsequently substantially removecl from ~ said polymer dispers`ion.
; There are varlous possible ways of removing the emulsifier and/or the other e~tractable excipients. In ~` a preferred process according to the present invention, the emulsion polymer dispersion is treated with an extraction agent in which the polymer itself is insoluble and the extractable excipients are soluble.
Preferably, water is used for the extraction methods according to the invention. However, depending on the type of polymer used, it is also possible to use other solvents o~ mixtures of solvents in which the polymer itself is insoluble.
For carrying out the extraction one may eliminate ~` the emulsifier from the standard commercial emulsion by precipitating the polymer. This can be done by conventional methods, e.g. by precipitation with a suitable solvent or an acid, or by salting out, freezing out or extraction.
Another possibility is to remove the emulsifer or the other excipientts~ from the polymer after separation of the dispersing agent. The following methods would appear appropriate, for example:
:;
: ., ',:
:
: ~ , ..
:: : : :
equilibrium extraction, Soxleth extraction, column extraction or dialysis~
Alternatively, other methods of separation of the polymer such as centrifugation are suitable.
It is preferred to carry out extraction of the polymer, in particular the dried acrylate (Eudragit NE
30 D~)-In a preferred process according to the present invention, the dried acrylate is comminuted or ground in a suitable apparatus and extracted with water, which is constantly renewed. Preferably, the emulsifier is eliminated by freezing the corresponding emulsion polymer and subsequently thawing it and washing with a suitable solvent, preferably waterO
The emulsion polymers of the present inventioll may be used in the produ~tion of active substance release systems which use comprises a further feature of the present invention. The emulsifier-free active substance release systems are produced thereProm~ by methods known Per se.
According to a further aspect o~ the pressnt invention there is provided an active substance release system based on an emulsion polymer which contains an emulsion polymer as defined above. A preferred release system according to the present invention is one which provides delayed release of the active substance.
According to a yet further aspect of the present invention there is provided a process for the preparation of an acti~e substance release system as defined above, wherein one or more emulsion polymers as defined above is or are charged with one or more active substances in a manner known ~ se.
As already mentioned, t~e preparation of the active substance release systems is known from ths prior art and described, inter alia, in German Offenlegungsschrift ;l 33 14 003 and in European Patent 0 086 997, the contents I of which are referred to here.
:?. ~ :
: ` ~ ` ' .
2~3~
Suitable carriers, in addition to the polymers mentioned hereinbefore, are those polymers which can be prepared by the emulsion polymerisation method, e.g.
PVC, polylactides, poly~tyrene, polyvinylacetate, polybutadiene, polyacrylonitrilel polyvinylpyrr~lidone, polyvinylaster, polyvinylether and copolymers thereof.
Polymers based on esters of acrylic and/or methacrylic acid are preferred.
Emulsion-polymerised copolymers of methyl and/or ethylesters of acrylic and methacrylic acid are particularly preferred.
Examples of pharmaceutical active substances include, as well as clonidine, ranitidine, cimetidine, atenolol, enalapril, captopril, ni~edipine, naproxene, diclofenac, diclofenac sodium, piroxicam, cefaclor, diltiazem, ketotifene, ketotifene-hydrogen fumarate, salbutamol, propranolol, amoxicillin, triamterene, ~ norethisterone, mestranol, cefotoxamine, cefotoxamine-`~ sodium, ceEtriaxone, ceftriaxone-disodium, cefalexin, dipyridamole, alprazolam, cefoxitin, cyclosporin, metoprolol tartrate, acyclovir, sulindac, cla~ulanic acid, me.thyldopa, nicardipine, pentoxifylline, glycerol trinitrate, timolol, idebenone, terfenadine, tamoxifen-dihydroyen citrate, prazosine, doxorubicine, amiloride, amiloride.HCl, hydrochlorothiazide, dihydroergocornine, dihydroergocornine methanesulphonate, erythromycin, erythromycin stearate, triazolam, latamoxefl cromoglycic acid, ceftazidime, clenbuterol, bromhexine ox~tetracycline, dexamethason-21-isonicotinate, sulfadiazine, cimaterol, aditoprim, mederantil, climazolam, carprofen, caffeine and acetylsalicyclic acid - or vitamins - such as vitamin A~ A1~ A2, B1, B2, B4, B6, Bl2, C (ascorbic acid), ascorbylpalmitate and other pharmacologically acceptable derivatives of ascorbic acid, D, D1, Dz, D3, D4, E, H, K, K1, K2, P and Q
- or active substances such as avoparcine, ~lavopholipol, monensine, monensine-sodium, salinomycin, ~:
2~
carbadox, nitrovin and olaquindox, and active substances such as those mentioned in the Red List 1990 (Editio Cantor Verlag fur Medizin und Naturwissenschaften GmbH
und Co. KG, Aulendorf/Wurttemb.3 the contents of which S are hereby referred to.
For the preparation of the active substance release system according to the pre~ent invention, the emulsion polymer as defined above is usually dissolved with the active substance in a suitable organic solvent, the solvent is evaporated off and the solid, active substance-containing polyacrylate is further processed depending on the planned use.
The measured values of the particular rates of release found were recorded after the following treatment of the samples: the first measured value was racorded after treat~ent of the samples with artificial gastric ~uice at pH : 1.2 over a period of one or two hours - all the subsequently measured values were - recorded after treatment of the samples with artiPicialintestinal juice at pH : 6.5 after the periods of time respectively indicated.
` The present invention is further illustrated by reference to Figures 1 to 13. These Figures will now be discussed and their relevance explained:
~; Figs. 1 to 10 show the influence of the thermal pretreatment and storage time on the rates of release o~
active substance from emulsifier-containiny ~r emulsifier-free active substance release systems produced on the hasis of polyacrylate (Eudragit~. In each case the active substance is clonidine.
' Figs. 1 to 5, 8 and 10 show the release characteristics of various active substance preparations consisting of 1.00 wt.-% of clonidine and ~9.00 wt.-% of acrylate. Figs. 6, 7 and 9 show the release characteristics of corresponding polyvinylpyrrolidone-.
, . .
. , , . , , : .
2~3~
containing active substance release systems.
In each particular case, the acrylate used was an untreated polyacrylate, or a polyacrylate freed from dispersant, the acrylate being of the make Eudragit NE 30 D~ of Rohm GmbH o~ Darmstadt, Germany. The particle size of the preparation in question is in the range from 315-400 ~m. The quantity of active substance contained therein amounts to 130 ~g.
Fig. 11 and Fig. 12 show the dependency of the diffusion coefficient on the charge, on the one hand using a non-extracted matrix (Fig. 11) and on the other hand using an extracted matrix (Fig. 12~.
Fig. 13 shows the rates of release of an active substance release sy$tem charged with clenbuterol (8 wt.-%). (Matrix: Eudragit NE 30 D).
In the Figures 1 to 9, the various symbols used denote the following:-~` Ch 20/U represents an untempered sample measured after drying at 20C.
.
Ch 40/U represents an untempered sample measured afterdrying at 4'0C.
Ch 20/T represents a sample which is tempered for a period of 1 hour (Figs. 8a and 9a) or 3 hours (remaining Figures) at 70C after drying at 20C and then measured.
Ch ~0/T represents a sample which i5 tempered for a period of 1 hour (Figs. 8a and 9a~ or 3 hours at 70C
after drying at 40C and then measured.
Ch 20/0 represents a sample dried at 20C and tempered for a period of 15 hours at 70C and subsequently ' .
.
, ,, ~ . , , -~ -~J~ 3 measured.
Ch 20/0.5/20 represents a sample dried at 20OC and tempered at 70C for a period of 15 hours and measured after a storage time of half a month, at 20C.
Ch 20/1/20 represents a sample dried at 20C and tempered at 70C for a period of 15 hours and measured after a storage time of one month at 20C.
Ch 20/2/20 represents a sample dried at 20C and tempered at 70c over a period of 15 hours and measured after a storage time of two months at 20C.
Ch 20/4.5/20 represents a sample dried at 20C and tempered at 70C ove~ a period of 15 hours and measured after a storage time of four and a half months at 20C.
., .
Ch 20/6/20 represents a sample dried at 20C and tempered at 70C over a period of 15 hours and measured a~ter a storage time of six months at 20C.
Ch 20/7/40 represents a sample dried at 20C and ~ tempered at 70C for a period of 15 hours and measured .' 25 after a storage time of 7 days at 40C.
.' Ch 20/14/40 represents a sample dried at 20C and tempered at 70C for a period of 15 hours and measured after a storage time of 14 days at 40C.
Ch 20/30/40 represents a sample dried at 20C and tempered at 70C over a period of 15 hours and measured after a storage time o~ 30 days at 40~C.
,~, Ch 20/60/40 represents a sample dried at 20C and tempered at 70C over a period of 15 hours and measured after a storage time of 60 days at 40C.
~ .
~:!
~'~: . , ' ' ' .:
?~ 3 63 ~ ~
Ch 20/180/40 represents a sample dried at 20C and tempered at 70~ over a period of 15 hours and measured after a storage time of 180 days at 40C.
Ch 40/O represents a sample dried at 40C and tempered for a period of 15 hours at 70C and subse~uently measured.
Ch 40/0.5/20 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured after a storage kime of half a month at 20C.
Ch 40/1/20 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured a*ter a storage time of one month at 20C.
Ch 40/2/20 represents a sample dried at 40C and tempered at 70C for a period o~ 15 hours and measured after a storage time of two months at 20C.
~ Ch 40/6/20 represents a sample dried at 40C and : tempered at 70C for a period o~ 15 hours and measured after a storage time of six months at 20~C.
Ch ~0/0.5/40 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured a~ter a storage time of half a month at 40C.
Ch 40~1/40 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured after a storage time of one month at 40C.
Ch 40/2/40 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured after a storage time of two months at 40C.
Ch 40/6/~0 represents a sample dried at 40C and ::;
: .
.:
,., :
-`" 2 ~
tempered at 70~C for a period of 15 hours (Fig. 5) or 3 hours (Fig. 7b) and measured after a storage time of six months at 40C.
Ch 20/6/40 represents a sample which was dried at 20C, tempered for 3 hours at 70C, stored for six months at 40C and measured.
Ch 40/T/3/40 represents a sample which had been heated to a tèmperature of 70C for 3 hours and was measured ; after 3 months storage at 40C.
Ch 40~U/3/40 represents an untempered sample which was measured after 3 months storage at 40C.
In Figure 10 the symbols used denote the following:-:, .
Ch W represents an untempered sample, prepared direct}y 20 from the aqueous dispersion, which had been dried at a temperature of 20C and measured immedi.ately Ch W/3/20 represents an untempered sample prepared directly from the aqueous dispersion, which had been 25 stored for a period of three months at a te~pera~ure of 20C after manufacture and then measured.
Ch W/3/40 represents an untempered sample prepared directly from the aqueous dispersion, which had been 30 stored for a period o~ three months at a temperature of 40C after manufacture and then measured.
As previously indicated, for Figures 6, 7 and 9, the ~amples contain polyvinylpyrrolidone.
Fia. l shows the rates of release of preparations containing emulsifier which have not been tempered or '~
:'~
, : :. , ,~ . , . : -:, , . .:
- ~ , 2 ~
have been tempered for 3 hours at 70C (melting of the emulsifier) and have been dried at temperatures of 20C
or 40C, respectively, as a function of time. Fig. 1 clearly shows that the rates of release of untempered matrices containing emulsifier assume their maximum values, with a given time span, whilst the rates of release of the preparation dried at 20C are comparatively higher than those of the active substance preparation dried at 40C. By contrast, the rates of release of the tempered samples show significantly lower levels.
Fiq. 2 shows the rates of release of emulsifier~
containing active substance preparations which have been dried at 20C and tempered for 15 hours at 70C and stored for various lèngths of time at a temperature of 20C.
: .
It can be seen from Fig. 2 that the rates of release of the merely tempered sample show the lowest values, whilst the rates of release of samples stored for a longer period at 20C are significantly higher than the values for the completely untreated matrix or the merely tempered matrix.
Fiq. 3 shows the rates of release of active substance preparations containing emulsifier which have been dried at 20C and tempered for 15 hours at 70C and, unlike Fig. 2, stored for various lengths of time at a temperature of 40C.
In principle, Fig. 3 shows that the various active substance preparations behave analogously.
Fi~. 4 shows the rates of release o~ an active substance preparation which had been treated analogously to the preparation in Fig. 2 but unlike the former had been , :
, : ~ , , .
dried at 40C. Fig. 4 also shows that the rates of release increase~as the storage time of the samples increases, so that the sample which had been stored for 6 months at 20C showed the highest rates of release.
By contrast, the sample which was measured immediately (0 months) showed the smallest release levels.
Fia. 5 shows the rate of release of an active substance preparation which had been treated analogously to the preparation in Fig. 3 but, unlike the former, had been dried at 40C. In principle, the same tendPncies can be found in Fig. 5 as in Fig. 4.
Fia. 6 shows the release characteristics of a polyvinyl-pyrrolidone-containing matrix which contains emulsifier, having the composition: 1 wt.-% clonidine, 20 wt.-%
polyvinylpyrrolidone and 79% acrylate (Eudragit NE 30 DR) which had been dried at 20 or 40C, in tempered or untempered form.
The measurements of the release rates were recorded after the following treatment of the samples:
1) 1 hour in artificial gastric juice pH: 1.2;
2) 1 hour in artificial intestinal juice - pH: 6.5;
S0125~.23 Emulsifier-free emulsion poly~rs The present invention relates to emulsion polymers which are free from emulsifi~rs, processes for their preparation and their use in pharmaceutical preparations giving a delayed release of active suhstance.
Certain emulsion polymers~ such as, for example, emulsion-polymerised estexs of acrylic or methacrylic acid, have in recent years become indispensable adjuvants in the preparation of pharmaceuticals in which the intention is to provide a preparation with delayed release oE the active substance [H~ Dekermann und R.
Lotz, Pharmazeutische Industrie 32 (1970) 469].
Delayed-rel~ase forms o~ this kind allow the active substance to be rele~sed constantly over a fairly long period and thus make it possible to reduce the number of doses of the drug to be administered each day and thereby simplify the therapy plan.
In the course of the development o~ these delayed release forms, in addition to numerous tablets and capsules, plasters which contain active substance with controlled release of the substance have also been described, inter alia.
Numerous methods are also known from the prior art for preparing delayed release forms of this kind.
For example, they may be prepared by ~reeing the emulsion polymer from the suspension agent, dissolving the polymer isolated in this way with the active substance in a suitable organic solvent, then evaporating off the solvent and grinding the ~olid polyacrylate, which contains the active substance, at a temperature below the glass transition temperature o~
i the polymer, and processing the active subskance-containing polyacrylate powder either by using tablet-making excipients tQ form tablets or in some other way, e.g. ~y introducing the powder into capsules.
" '~ " . ~ ' ' .
' :, ' ' ~ ' ' .
,, ~ ' ' , .
.
20~3~
The preparation oE plasters which contain active substance is also known from the prior art, for example by processes described in European Patent No. 20 905.
Suitable emulsion polymers for producing such preparations include, as already mentioned hereinbefore, esters of acrylic or methacrylic acid, e g. the commercially available products under the general product name of Eudragit made by Rohm GmbH of Darmstadt, Germany.
Emulsion polymers of this kind are generally produced by emulsifying the water-insoluble monomer in water with the aid of emulsifiers or surfactants and initiating or performing polymerisation with the use of con~entional initiators. The polymer dispersions obtained by this kind of polymerisation can, in numerous instances, be used directly and are available in the form of dispersions. Active substance release systems produced on the basis of emulsion polymers o~ this kind do, however, have the disadvantage that the rate of release of the active substance may depend on the thermal treatment of the active substance release system during the manufacturing process and may also depend on the storage conditions.
The aim of the present invention is therefore to provide acti~e substance release systems based on emulsion polymers - more particularly based on polyacrylic acid esters or polymethacrylic acid esters -which do not have the dependency described above and which also have substantially identical release characteristics even after lengthy storage under various storage conditions.
It has now been found, surprisingly, that the dependency of the rate of release on the thermal pretreatment during the manufacturing process, observed in the release charaoteristics of active substance release systems, can be traced back to the presence of the emulsifier.
. `
." .
~ ~ .
. ,. ~: :
~3~3~
A further aim of the present invention is to provide emulsifier-free emulsion polymers and a process ; for producing them.
According to the present invention, there is provided an emulsion polymer, which is substantially free from emulsifiers or surfactants and other adjuvants used in the preparation o~ said polymer.
According to a further aspect of the present invention there is provided a process for the preparation of an emulsion polymer as defined ab~ve wherein a dispersion of an emulsion polymer i5 first produced by conventional methods and in which the emulsifier, surfactant and other adjuvants used in the conventional preparation method (the extractable ; 15 excipients) are subsequently substantially removecl from ~ said polymer dispers`ion.
; There are varlous possible ways of removing the emulsifier and/or the other e~tractable excipients. In ~` a preferred process according to the present invention, the emulsion polymer dispersion is treated with an extraction agent in which the polymer itself is insoluble and the extractable excipients are soluble.
Preferably, water is used for the extraction methods according to the invention. However, depending on the type of polymer used, it is also possible to use other solvents o~ mixtures of solvents in which the polymer itself is insoluble.
For carrying out the extraction one may eliminate ~` the emulsifier from the standard commercial emulsion by precipitating the polymer. This can be done by conventional methods, e.g. by precipitation with a suitable solvent or an acid, or by salting out, freezing out or extraction.
Another possibility is to remove the emulsifer or the other excipientts~ from the polymer after separation of the dispersing agent. The following methods would appear appropriate, for example:
:;
: ., ',:
:
: ~ , ..
:: : : :
equilibrium extraction, Soxleth extraction, column extraction or dialysis~
Alternatively, other methods of separation of the polymer such as centrifugation are suitable.
It is preferred to carry out extraction of the polymer, in particular the dried acrylate (Eudragit NE
30 D~)-In a preferred process according to the present invention, the dried acrylate is comminuted or ground in a suitable apparatus and extracted with water, which is constantly renewed. Preferably, the emulsifier is eliminated by freezing the corresponding emulsion polymer and subsequently thawing it and washing with a suitable solvent, preferably waterO
The emulsion polymers of the present inventioll may be used in the produ~tion of active substance release systems which use comprises a further feature of the present invention. The emulsifier-free active substance release systems are produced thereProm~ by methods known Per se.
According to a further aspect o~ the pressnt invention there is provided an active substance release system based on an emulsion polymer which contains an emulsion polymer as defined above. A preferred release system according to the present invention is one which provides delayed release of the active substance.
According to a yet further aspect of the present invention there is provided a process for the preparation of an acti~e substance release system as defined above, wherein one or more emulsion polymers as defined above is or are charged with one or more active substances in a manner known ~ se.
As already mentioned, t~e preparation of the active substance release systems is known from ths prior art and described, inter alia, in German Offenlegungsschrift ;l 33 14 003 and in European Patent 0 086 997, the contents I of which are referred to here.
:?. ~ :
: ` ~ ` ' .
2~3~
Suitable carriers, in addition to the polymers mentioned hereinbefore, are those polymers which can be prepared by the emulsion polymerisation method, e.g.
PVC, polylactides, poly~tyrene, polyvinylacetate, polybutadiene, polyacrylonitrilel polyvinylpyrr~lidone, polyvinylaster, polyvinylether and copolymers thereof.
Polymers based on esters of acrylic and/or methacrylic acid are preferred.
Emulsion-polymerised copolymers of methyl and/or ethylesters of acrylic and methacrylic acid are particularly preferred.
Examples of pharmaceutical active substances include, as well as clonidine, ranitidine, cimetidine, atenolol, enalapril, captopril, ni~edipine, naproxene, diclofenac, diclofenac sodium, piroxicam, cefaclor, diltiazem, ketotifene, ketotifene-hydrogen fumarate, salbutamol, propranolol, amoxicillin, triamterene, ~ norethisterone, mestranol, cefotoxamine, cefotoxamine-`~ sodium, ceEtriaxone, ceftriaxone-disodium, cefalexin, dipyridamole, alprazolam, cefoxitin, cyclosporin, metoprolol tartrate, acyclovir, sulindac, cla~ulanic acid, me.thyldopa, nicardipine, pentoxifylline, glycerol trinitrate, timolol, idebenone, terfenadine, tamoxifen-dihydroyen citrate, prazosine, doxorubicine, amiloride, amiloride.HCl, hydrochlorothiazide, dihydroergocornine, dihydroergocornine methanesulphonate, erythromycin, erythromycin stearate, triazolam, latamoxefl cromoglycic acid, ceftazidime, clenbuterol, bromhexine ox~tetracycline, dexamethason-21-isonicotinate, sulfadiazine, cimaterol, aditoprim, mederantil, climazolam, carprofen, caffeine and acetylsalicyclic acid - or vitamins - such as vitamin A~ A1~ A2, B1, B2, B4, B6, Bl2, C (ascorbic acid), ascorbylpalmitate and other pharmacologically acceptable derivatives of ascorbic acid, D, D1, Dz, D3, D4, E, H, K, K1, K2, P and Q
- or active substances such as avoparcine, ~lavopholipol, monensine, monensine-sodium, salinomycin, ~:
2~
carbadox, nitrovin and olaquindox, and active substances such as those mentioned in the Red List 1990 (Editio Cantor Verlag fur Medizin und Naturwissenschaften GmbH
und Co. KG, Aulendorf/Wurttemb.3 the contents of which S are hereby referred to.
For the preparation of the active substance release system according to the pre~ent invention, the emulsion polymer as defined above is usually dissolved with the active substance in a suitable organic solvent, the solvent is evaporated off and the solid, active substance-containing polyacrylate is further processed depending on the planned use.
The measured values of the particular rates of release found were recorded after the following treatment of the samples: the first measured value was racorded after treat~ent of the samples with artificial gastric ~uice at pH : 1.2 over a period of one or two hours - all the subsequently measured values were - recorded after treatment of the samples with artiPicialintestinal juice at pH : 6.5 after the periods of time respectively indicated.
` The present invention is further illustrated by reference to Figures 1 to 13. These Figures will now be discussed and their relevance explained:
~; Figs. 1 to 10 show the influence of the thermal pretreatment and storage time on the rates of release o~
active substance from emulsifier-containiny ~r emulsifier-free active substance release systems produced on the hasis of polyacrylate (Eudragit~. In each case the active substance is clonidine.
' Figs. 1 to 5, 8 and 10 show the release characteristics of various active substance preparations consisting of 1.00 wt.-% of clonidine and ~9.00 wt.-% of acrylate. Figs. 6, 7 and 9 show the release characteristics of corresponding polyvinylpyrrolidone-.
, . .
. , , . , , : .
2~3~
containing active substance release systems.
In each particular case, the acrylate used was an untreated polyacrylate, or a polyacrylate freed from dispersant, the acrylate being of the make Eudragit NE 30 D~ of Rohm GmbH o~ Darmstadt, Germany. The particle size of the preparation in question is in the range from 315-400 ~m. The quantity of active substance contained therein amounts to 130 ~g.
Fig. 11 and Fig. 12 show the dependency of the diffusion coefficient on the charge, on the one hand using a non-extracted matrix (Fig. 11) and on the other hand using an extracted matrix (Fig. 12~.
Fig. 13 shows the rates of release of an active substance release sy$tem charged with clenbuterol (8 wt.-%). (Matrix: Eudragit NE 30 D).
In the Figures 1 to 9, the various symbols used denote the following:-~` Ch 20/U represents an untempered sample measured after drying at 20C.
.
Ch 40/U represents an untempered sample measured afterdrying at 4'0C.
Ch 20/T represents a sample which is tempered for a period of 1 hour (Figs. 8a and 9a) or 3 hours (remaining Figures) at 70C after drying at 20C and then measured.
Ch ~0/T represents a sample which i5 tempered for a period of 1 hour (Figs. 8a and 9a~ or 3 hours at 70C
after drying at 40C and then measured.
Ch 20/0 represents a sample dried at 20C and tempered for a period of 15 hours at 70C and subsequently ' .
.
, ,, ~ . , , -~ -~J~ 3 measured.
Ch 20/0.5/20 represents a sample dried at 20OC and tempered at 70C for a period of 15 hours and measured after a storage time of half a month, at 20C.
Ch 20/1/20 represents a sample dried at 20C and tempered at 70C for a period of 15 hours and measured after a storage time of one month at 20C.
Ch 20/2/20 represents a sample dried at 20C and tempered at 70c over a period of 15 hours and measured after a storage time of two months at 20C.
Ch 20/4.5/20 represents a sample dried at 20C and tempered at 70C ove~ a period of 15 hours and measured after a storage time of four and a half months at 20C.
., .
Ch 20/6/20 represents a sample dried at 20C and tempered at 70C over a period of 15 hours and measured a~ter a storage time of six months at 20C.
Ch 20/7/40 represents a sample dried at 20C and ~ tempered at 70C for a period of 15 hours and measured .' 25 after a storage time of 7 days at 40C.
.' Ch 20/14/40 represents a sample dried at 20C and tempered at 70C for a period of 15 hours and measured after a storage time of 14 days at 40C.
Ch 20/30/40 represents a sample dried at 20C and tempered at 70C over a period of 15 hours and measured after a storage time o~ 30 days at 40~C.
,~, Ch 20/60/40 represents a sample dried at 20C and tempered at 70C over a period of 15 hours and measured after a storage time of 60 days at 40C.
~ .
~:!
~'~: . , ' ' ' .:
?~ 3 63 ~ ~
Ch 20/180/40 represents a sample dried at 20C and tempered at 70~ over a period of 15 hours and measured after a storage time of 180 days at 40C.
Ch 40/O represents a sample dried at 40C and tempered for a period of 15 hours at 70C and subse~uently measured.
Ch 40/0.5/20 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured after a storage kime of half a month at 20C.
Ch 40/1/20 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured a*ter a storage time of one month at 20C.
Ch 40/2/20 represents a sample dried at 40C and tempered at 70C for a period o~ 15 hours and measured after a storage time of two months at 20C.
~ Ch 40/6/20 represents a sample dried at 40C and : tempered at 70C for a period o~ 15 hours and measured after a storage time of six months at 20~C.
Ch ~0/0.5/40 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured a~ter a storage time of half a month at 40C.
Ch 40~1/40 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured after a storage time of one month at 40C.
Ch 40/2/40 represents a sample dried at 40C and tempered at 70C for a period of 15 hours and measured after a storage time of two months at 40C.
Ch 40/6/~0 represents a sample dried at 40C and ::;
: .
.:
,., :
-`" 2 ~
tempered at 70~C for a period of 15 hours (Fig. 5) or 3 hours (Fig. 7b) and measured after a storage time of six months at 40C.
Ch 20/6/40 represents a sample which was dried at 20C, tempered for 3 hours at 70C, stored for six months at 40C and measured.
Ch 40/T/3/40 represents a sample which had been heated to a tèmperature of 70C for 3 hours and was measured ; after 3 months storage at 40C.
Ch 40~U/3/40 represents an untempered sample which was measured after 3 months storage at 40C.
In Figure 10 the symbols used denote the following:-:, .
Ch W represents an untempered sample, prepared direct}y 20 from the aqueous dispersion, which had been dried at a temperature of 20C and measured immedi.ately Ch W/3/20 represents an untempered sample prepared directly from the aqueous dispersion, which had been 25 stored for a period of three months at a te~pera~ure of 20C after manufacture and then measured.
Ch W/3/40 represents an untempered sample prepared directly from the aqueous dispersion, which had been 30 stored for a period o~ three months at a temperature of 40C after manufacture and then measured.
As previously indicated, for Figures 6, 7 and 9, the ~amples contain polyvinylpyrrolidone.
Fia. l shows the rates of release of preparations containing emulsifier which have not been tempered or '~
:'~
, : :. , ,~ . , . : -:, , . .:
- ~ , 2 ~
have been tempered for 3 hours at 70C (melting of the emulsifier) and have been dried at temperatures of 20C
or 40C, respectively, as a function of time. Fig. 1 clearly shows that the rates of release of untempered matrices containing emulsifier assume their maximum values, with a given time span, whilst the rates of release of the preparation dried at 20C are comparatively higher than those of the active substance preparation dried at 40C. By contrast, the rates of release of the tempered samples show significantly lower levels.
Fiq. 2 shows the rates of release of emulsifier~
containing active substance preparations which have been dried at 20C and tempered for 15 hours at 70C and stored for various lèngths of time at a temperature of 20C.
: .
It can be seen from Fig. 2 that the rates of release of the merely tempered sample show the lowest values, whilst the rates of release of samples stored for a longer period at 20C are significantly higher than the values for the completely untreated matrix or the merely tempered matrix.
Fiq. 3 shows the rates of release of active substance preparations containing emulsifier which have been dried at 20C and tempered for 15 hours at 70C and, unlike Fig. 2, stored for various lengths of time at a temperature of 40C.
In principle, Fig. 3 shows that the various active substance preparations behave analogously.
Fi~. 4 shows the rates of release o~ an active substance preparation which had been treated analogously to the preparation in Fig. 2 but unlike the former had been , :
, : ~ , , .
dried at 40C. Fig. 4 also shows that the rates of release increase~as the storage time of the samples increases, so that the sample which had been stored for 6 months at 20C showed the highest rates of release.
By contrast, the sample which was measured immediately (0 months) showed the smallest release levels.
Fia. 5 shows the rate of release of an active substance preparation which had been treated analogously to the preparation in Fig. 3 but, unlike the former, had been dried at 40C. In principle, the same tendPncies can be found in Fig. 5 as in Fig. 4.
Fia. 6 shows the release characteristics of a polyvinyl-pyrrolidone-containing matrix which contains emulsifier, having the composition: 1 wt.-% clonidine, 20 wt.-%
polyvinylpyrrolidone and 79% acrylate (Eudragit NE 30 DR) which had been dried at 20 or 40C, in tempered or untempered form.
The measurements of the release rates were recorded after the following treatment of the samples:
1) 1 hour in artificial gastric juice pH: 1.2;
2) 1 hour in artificial intestinal juice - pH: 6.5;
3) a further 2 hours in artificial intestinal juice -pH: 6.5;
4~ a further 2 hours in artificial intestinal juice -pH: 6.5.
Fig. 6 also shows that, irrespective of the presence of polyvinylpyrroli~one, the rates of release of the tempered samples are si~nificantly lower than those of the untempered active substance release .
~, .
~ , , ~ , . .
2 ~
systems.
Figures 7a ~nd 7b also show the influence of various drying conditions. The composition of all the samples consists of 1.00% clonidine, 20.00 wt.-%
polyvinylpyrrolidone and 79% acrylate. The samples were all treated analogously to the method given in the description of Fig. 6 in order to record the release characteristics.
Fiq. 7a shows the release characteristics of an untreated sample, a sample which had been melted at ~0C
for 3 hours, and a sample which had been melted for 3 hours at 70C and stored for 6 months at a temperature of 40C. All the samples were dried at a temperature of 20C.
Fi~. ~b shows the release characteristics of samples which had been treated analogously to those in Fig. 7a, except that they were dried at a temperature of 40C.
Fia. 8a shows the rates of release of an active substance release system the matrix of which had been freed from emulsifier.
. .
The release system is made up of 1.00 wt.-%
clonidine and 9g.00 wt.-% emulsifier-free acrylate. The measurements of the release rates were each recorded after the following treatment of the samples-1) 2 hours in artificial gastric juice - pH: 1.2;
2) a further 2 hours in artificial intestinal juice -pH: 6.5;
' ~; 35 3) a further 2 hours in artificial intestinal juice -pH: 6.5;
.
.
.
, , -3~
4) a further 2 hours in artificial intestinal juice -pH: 6.5;
Fig. 6 also shows that, irrespective of the presence of polyvinylpyrroli~one, the rates of release of the tempered samples are si~nificantly lower than those of the untempered active substance release .
~, .
~ , , ~ , . .
2 ~
systems.
Figures 7a ~nd 7b also show the influence of various drying conditions. The composition of all the samples consists of 1.00% clonidine, 20.00 wt.-%
polyvinylpyrrolidone and 79% acrylate. The samples were all treated analogously to the method given in the description of Fig. 6 in order to record the release characteristics.
Fiq. 7a shows the release characteristics of an untreated sample, a sample which had been melted at ~0C
for 3 hours, and a sample which had been melted for 3 hours at 70C and stored for 6 months at a temperature of 40C. All the samples were dried at a temperature of 20C.
Fi~. ~b shows the release characteristics of samples which had been treated analogously to those in Fig. 7a, except that they were dried at a temperature of 40C.
Fia. 8a shows the rates of release of an active substance release system the matrix of which had been freed from emulsifier.
. .
The release system is made up of 1.00 wt.-%
clonidine and 9g.00 wt.-% emulsifier-free acrylate. The measurements of the release rates were each recorded after the following treatment of the samples-1) 2 hours in artificial gastric juice - pH: 1.2;
2) a further 2 hours in artificial intestinal juice -pH: 6.5;
' ~; 35 3) a further 2 hours in artificial intestinal juice -pH: 6.5;
.
.
.
, , -3~
4) a further 2 hours in artificial intestinal juice -pH: 6.5;
5) a further 16 hours in artificial intestinal juice -pH: 6.5.
The rates of release of samples are given which had been dried at diffexent temperatures (20c and 40C) and which had been used untempered or after tempering for : 10 one hour at 70C.
Fiqure 8b shows the release characteristics of an active substance release system (composition as described under Fig. 8a~ based on an emulsifier-free matrix after 3 months storage at a temperature of 40C.
~: .
shows the release characteristics of polyvinyl-pyrrolidone-containing active substance release systems free from emulsifier, made up of 1.00 wt.-% clonidine, 20.00 wt.-% polyvinylpyrrolidone and 79.00 wt.-%
acrylate.
The measurement~ of the release rates in question were recorded after the following treatment of the samples:
11 1 hour in artificial gastric juice - pH: 1.2, 2) a further hour in artificial intestinal juice - pH:
: 30 6.5;
3) a further 2 hours in artificial intestinal juice -pH: 6.5;
4) a further 2 hours in artificial intestinal juice -pH: 6.5;
. , .
~ . ~
:.
~3~
- ~5 -5) ~ further 18 hours in artificial intestinal juice -pH: 6.5.
The rates of release of samples were recorded which had been dried at different temperatures and which were used untempered or after tempering for one hour at 70C.
Fia. 9b shows the release characteristics of an active substance release system (composition as described under 9a) based on an emulsifier-free matrix after three months storage at a temperature of 40C.
Figs. 8 and 9 show that the thermal treatment and storage time have a negligibly slight influence on active substance release systems which are free from emulsi:~ier. `, Fi~. 10 shows the release characteristics of an active substance release system prepared directly from the aqueous dispersion (composition: l wt.-~ clonidine, ` 99 wt.-% acrylate), which had been measured immediately a~ter manufacture and after three months' storage at 20C or 40C, respectively.
As can be seen from the Figures described above, for the emulsifier-containing active substance release systems; the release rates are dependent on the thermal treatment of the active substance release system. Thus, the release ~ates of the untempered samples are significantly~higher than those which have been tempered for three hours at 70C. At the same time, it is apparent that the release rates of the samples (both tempered and untempered) which have been dried at 20C
are higher than the corresponding rates ~or those samples which have been dried at 40C.
The release functions graphically shown in Figs. 2 to 5 indicate that the following trend can be found, :: .
2~3~
irrespective of the drying temperature (20~C or 40C) and storage temperature (20C or 40C) in tempered samples (70C): the release rates oE those samples which were measured immediately after tempering are by far the lowest release rates. They are significantly below the le~els obtained for the corresponding untempered samples. As the storage time increases r the rates of release generally increase at different levels ~depending on the drying and storage temperature.
Figs. 6 and 7 show the influence of the emulsifier on the release rates in a polyacrylate/polyvinyl-pyrrolidone mixture, of a kind which is commercially sold. The findings drawn from Figs. 1 to 5 are also confirmed by the release rates of these systems. Thus, 15 the release rates of the tempered samples are below those of the untempered samples and again there is a dependency on the drying temperature. In these cases, too, the release rates increase after several months' storage.
A completely different picture emerges, on the ~ other hand, when the same investigations are made of I emulsi~ier-free systems for releasing active substance (Figs. 8a and 9a). Independently of the drying conditions, the release rates, both in the PVP-~5 containing system and in the PVP-free system, show only slightly di~ferent values, and in both cases the difference from values of the tempered samples proves to be negligibly slight.
It is also illustrated ~Figs. 8b and 9b) that the 30 active substance release systems prepared according to the invention show better durability, i.e. the release rates remain æubstantially una~fected even by lengthy ~ storage of the active substance release sy~tem.
::, Fiq. 11 shows the dependency of the diffusion coefficient on the load for a non-extracted matrix (Eudragit NE 30 D3.
., ' i ,~
., .
: . . . .. . .
.
2 ~ 5 Fiq. 12 shows this dependency for the corresponding extracted matrix~material. It is clearly visibl~ that, for the purified polymer (Fig. 12) there is substantially smaller scattering with regard to the diffusion coefficient than for the corresponding, non-extracted acrylate.
Fiq. 13 also provides clear evidence that the release from extracted matrices is significantly slower - with less scattering between the curves - than from the corresponding non-extracted matrix.
Thus, in conclusion, by extracting the emulsifier, it can be seen that it is possible to obtain release characteristics which are independent of the thermal treatment of the release system. The aims of the ; present invention mentioned hereinbefore may therefore be achieved.
The process of the present invention is further illustrated in the following Example 1. Various other embodiments of the process will be apparent to the person skilled in the art from the foregoing description. However, it is expressly indicated that the Example and the specific description thereof are provided solely for the purpose of explanation and description and should not be regarded as restricting the scope of the invention.
,~
' :; .
.`; ;
Example 1 30.0 g of the aqueous Eudragit NE 30 dispersion are frozen at -18C and then thawed by simply standing at ambient temperature. After it has thawed completely, demineralised water is added to 300.0 g, with stirring.
As a result of this treatment, the dispersion is broken up completely and a clear supernatant is Eormed over a loose white deposit. (Any slight turbidity present can be clarified by separating suspended particles using a suction device.) The supernatant is decantPd and replaced by the same amount of demineralised water and the residue is washed therewith for about 1 minute.
Separation, topping up and washing are repeated as often (9 times) as is necessary for the last two aqueous wash media separated off to be free from emulsifier.
(Instead of adding io times the amount o~ washing water, it is also possible to wash 15 times with three times the amount of water. The last washing water will then be demonstrably free from emulsifier.) , , :
,1 ,~ .
:`1 ~.
:., .~
The rates of release of samples are given which had been dried at diffexent temperatures (20c and 40C) and which had been used untempered or after tempering for : 10 one hour at 70C.
Fiqure 8b shows the release characteristics of an active substance release system (composition as described under Fig. 8a~ based on an emulsifier-free matrix after 3 months storage at a temperature of 40C.
~: .
shows the release characteristics of polyvinyl-pyrrolidone-containing active substance release systems free from emulsifier, made up of 1.00 wt.-% clonidine, 20.00 wt.-% polyvinylpyrrolidone and 79.00 wt.-%
acrylate.
The measurement~ of the release rates in question were recorded after the following treatment of the samples:
11 1 hour in artificial gastric juice - pH: 1.2, 2) a further hour in artificial intestinal juice - pH:
: 30 6.5;
3) a further 2 hours in artificial intestinal juice -pH: 6.5;
4) a further 2 hours in artificial intestinal juice -pH: 6.5;
. , .
~ . ~
:.
~3~
- ~5 -5) ~ further 18 hours in artificial intestinal juice -pH: 6.5.
The rates of release of samples were recorded which had been dried at different temperatures and which were used untempered or after tempering for one hour at 70C.
Fia. 9b shows the release characteristics of an active substance release system (composition as described under 9a) based on an emulsifier-free matrix after three months storage at a temperature of 40C.
Figs. 8 and 9 show that the thermal treatment and storage time have a negligibly slight influence on active substance release systems which are free from emulsi:~ier. `, Fi~. 10 shows the release characteristics of an active substance release system prepared directly from the aqueous dispersion (composition: l wt.-~ clonidine, ` 99 wt.-% acrylate), which had been measured immediately a~ter manufacture and after three months' storage at 20C or 40C, respectively.
As can be seen from the Figures described above, for the emulsifier-containing active substance release systems; the release rates are dependent on the thermal treatment of the active substance release system. Thus, the release ~ates of the untempered samples are significantly~higher than those which have been tempered for three hours at 70C. At the same time, it is apparent that the release rates of the samples (both tempered and untempered) which have been dried at 20C
are higher than the corresponding rates ~or those samples which have been dried at 40C.
The release functions graphically shown in Figs. 2 to 5 indicate that the following trend can be found, :: .
2~3~
irrespective of the drying temperature (20~C or 40C) and storage temperature (20C or 40C) in tempered samples (70C): the release rates oE those samples which were measured immediately after tempering are by far the lowest release rates. They are significantly below the le~els obtained for the corresponding untempered samples. As the storage time increases r the rates of release generally increase at different levels ~depending on the drying and storage temperature.
Figs. 6 and 7 show the influence of the emulsifier on the release rates in a polyacrylate/polyvinyl-pyrrolidone mixture, of a kind which is commercially sold. The findings drawn from Figs. 1 to 5 are also confirmed by the release rates of these systems. Thus, 15 the release rates of the tempered samples are below those of the untempered samples and again there is a dependency on the drying temperature. In these cases, too, the release rates increase after several months' storage.
A completely different picture emerges, on the ~ other hand, when the same investigations are made of I emulsi~ier-free systems for releasing active substance (Figs. 8a and 9a). Independently of the drying conditions, the release rates, both in the PVP-~5 containing system and in the PVP-free system, show only slightly di~ferent values, and in both cases the difference from values of the tempered samples proves to be negligibly slight.
It is also illustrated ~Figs. 8b and 9b) that the 30 active substance release systems prepared according to the invention show better durability, i.e. the release rates remain æubstantially una~fected even by lengthy ~ storage of the active substance release sy~tem.
::, Fiq. 11 shows the dependency of the diffusion coefficient on the load for a non-extracted matrix (Eudragit NE 30 D3.
., ' i ,~
., .
: . . . .. . .
.
2 ~ 5 Fiq. 12 shows this dependency for the corresponding extracted matrix~material. It is clearly visibl~ that, for the purified polymer (Fig. 12) there is substantially smaller scattering with regard to the diffusion coefficient than for the corresponding, non-extracted acrylate.
Fiq. 13 also provides clear evidence that the release from extracted matrices is significantly slower - with less scattering between the curves - than from the corresponding non-extracted matrix.
Thus, in conclusion, by extracting the emulsifier, it can be seen that it is possible to obtain release characteristics which are independent of the thermal treatment of the release system. The aims of the ; present invention mentioned hereinbefore may therefore be achieved.
The process of the present invention is further illustrated in the following Example 1. Various other embodiments of the process will be apparent to the person skilled in the art from the foregoing description. However, it is expressly indicated that the Example and the specific description thereof are provided solely for the purpose of explanation and description and should not be regarded as restricting the scope of the invention.
,~
' :; .
.`; ;
Example 1 30.0 g of the aqueous Eudragit NE 30 dispersion are frozen at -18C and then thawed by simply standing at ambient temperature. After it has thawed completely, demineralised water is added to 300.0 g, with stirring.
As a result of this treatment, the dispersion is broken up completely and a clear supernatant is Eormed over a loose white deposit. (Any slight turbidity present can be clarified by separating suspended particles using a suction device.) The supernatant is decantPd and replaced by the same amount of demineralised water and the residue is washed therewith for about 1 minute.
Separation, topping up and washing are repeated as often (9 times) as is necessary for the last two aqueous wash media separated off to be free from emulsifier.
(Instead of adding io times the amount o~ washing water, it is also possible to wash 15 times with three times the amount of water. The last washing water will then be demonstrably free from emulsifier.) , , :
,1 ,~ .
:`1 ~.
:., .~
Claims (24)
1. An emulsion polymer, which is substantially free from emulsifiers or surfactants and other adjuvants used in the preparation of said polymer.
2. An emulsion polymer as claimed in claim 1 wherein the polymer is based on esters of acrylic and/or methacrylic acid.
3. An emulsion polymer as claimed in claim 1 or claim 2 wherein the polymer is based on the methyl and/or ethylester of acrylic and/or methacrylic acid.
4. An emulsion polymer as claimed in claim 1 wherein the polymer is selected from the group comprising polylactide, polystyrene, polyvinylacetate, polyvinylpyrrolidone, polybutadiene, polyacrylonitrile, the polyvinylesters, the polyvinylethers and copolymers thereof and mixtures thereof.
5. An emulsion polymer as claimed in any of claims 1 to 4 specifically as described herein.
6. A process for the preparation of an emulsion polymer as claimed in any of claims 1 to 5 wherein a dispersion of an emulsion polymer is first produced by conventional methods and in which the emulsifier, surfactant and other adjuvants used in the conventional preparation method (the extractable excipients) are subsequently substantially removed from said polymer dispersion.
7. A process as claimed in claim 6 wherein the extractable excipients are separated from the emulsion polymer by treating the dispersion with an extraction agent in which the polymer itself is insoluble or substantially insoluble and the extractable excipients are soluble or substantially soluble and either the polymer or the extractable excipients are subsequently removed from the dispersion.
8. A process as claimed in claim 7 wherein the extraction agent is water.
9. A process as claimed in claim 7 or claim 8 wherein the polymer is removed from the dispersion by precipitation.
10. A process as claimed in claim 9 wherein the polymer is precipitated by means of a suitable solvent or acid or by salting out or by freezing.
11. A process as claimed in claim 7 or claim 8 wherein the polymer is removed from the dispersion by centrifugation.
12. A process as claimed in claim 7 or claim 8 wherein the extractable excipients are removed from the dispersion by equilibrium extraction, Soxleth extraction, column extraction or dialysis.
13. A process as claimed in any of claims 6 to 12 substantially as herein described.
14. A process as claimed in any of claims 6 to 12 substantially as herein described and with reference to the Example.
15. An emulsion polymer as claimed in claim 1 whenever prepared by a process as claimed in any of claims 6 to 14.
16. An active substance release system based on an emulsion polymer which contains an emulsion polymer as claimed in any one of claims 1 to 5 or 15.
17. A release system as claimed in claim 15 characterised in that it gives delayed release of the active substance.
18. An active substance release system as claimed in claim 16 or 17 wherein the active substance is clonidine (2-[(2,6-dichlorophenyl)-imino]imidazolidine).
19. An active substance release system as claimed in claim 16 or 17 wherein the active substance is clenbuterol (4-amino-.alpha.-[(tert.-butylamino)-methyl]-3,5-dichlorobenzyl alcohol).
20. The use of a polymer as claimed in any of claims 1 to 5 in an active substance release system as claimed in any one of claims 16 to 19.
21. A process for the preparation of an active substance release system as claimed in any one of claims 16 to 19, wherein one or more emulsion polymers as claimed in any one of claims 1 to 5 or 15 is or are charged with one or more active substances in a manner known per se.
22. A process as claimed in claim 21 substantially as herein described.
23. Each and every novel product, process, method and use herein described.
24. A process for the preparation of an emulsion polymer as claimed in any one of claims 1 to 4, which process comprises subjecting a polymerizable monomer to emulsion polymerization and separating from the obtained polymer all or substantially all of the emulsifier or surfactant used in the polymerization.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19904032096 DE4032096C2 (en) | 1990-10-10 | 1990-10-10 | Use of emulsifier-free emulsion polymers in pharmaceutical preparations with delayed release of the active ingredient |
DEP4032096.0 | 1990-10-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2053005A1 true CA2053005A1 (en) | 1992-04-11 |
Family
ID=6415979
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002053005A Abandoned CA2053005A1 (en) | 1990-10-10 | 1991-10-08 | Emulsifier-free emulsion polymers |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0480391B1 (en) |
JP (1) | JPH04264019A (en) |
AT (1) | ATE132877T1 (en) |
CA (1) | CA2053005A1 (en) |
DE (1) | DE59107240D1 (en) |
DK (1) | DK0480391T3 (en) |
ES (1) | ES2084747T3 (en) |
GR (1) | GR3018795T3 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1777241A1 (en) | 2005-10-19 | 2007-04-25 | Air Products Polymers, L.P. | Vinyl ester based polymer latex composition and process of making the same |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1050546B1 (en) * | 1995-02-06 | 2003-11-26 | E.I. Du Pont De Nemours And Company | Process for isolating polymers of tetrafluoroethylene |
WO2002100382A2 (en) * | 2001-06-08 | 2002-12-19 | Endo Pharmaceuticals, Inc. | Controlled release dosage forms using acrylic polymer, and process for making the same |
SE0201110D0 (en) * | 2002-04-12 | 2002-04-12 | Astrazeneca Ab | New film coating |
US20140323512A1 (en) * | 2011-10-18 | 2014-10-30 | Purdue Pharma L.P. | Acrylic Polymer Formulations |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3204551A1 (en) * | 1982-02-10 | 1983-08-18 | Boehringer Ingelheim KG, 6507 Ingelheim | METHOD FOR PRODUCING A PHARMACEUTICAL PREPARATION IN THE FORM OF A POLYACRYLATE FILM |
-
1991
- 1991-10-08 CA CA002053005A patent/CA2053005A1/en not_active Abandoned
- 1991-10-09 DK DK91117171.8T patent/DK0480391T3/en active
- 1991-10-09 DE DE59107240T patent/DE59107240D1/en not_active Expired - Fee Related
- 1991-10-09 EP EP91117171A patent/EP0480391B1/en not_active Expired - Lifetime
- 1991-10-09 ES ES91117171T patent/ES2084747T3/en not_active Expired - Lifetime
- 1991-10-09 AT AT91117171T patent/ATE132877T1/en active
- 1991-10-11 JP JP3263782A patent/JPH04264019A/en active Pending
-
1996
- 1996-01-25 GR GR960400183T patent/GR3018795T3/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1777241A1 (en) | 2005-10-19 | 2007-04-25 | Air Products Polymers, L.P. | Vinyl ester based polymer latex composition and process of making the same |
US7649067B2 (en) | 2005-10-19 | 2010-01-19 | Wacker Polymers, L.P. | Process of making a vinyl ester based polymer latex composition |
Also Published As
Publication number | Publication date |
---|---|
EP0480391B1 (en) | 1996-01-10 |
EP0480391A3 (en) | 1992-07-29 |
ATE132877T1 (en) | 1996-01-15 |
DK0480391T3 (en) | 1996-04-22 |
JPH04264019A (en) | 1992-09-18 |
ES2084747T3 (en) | 1996-05-16 |
GR3018795T3 (en) | 1996-04-30 |
DE59107240D1 (en) | 1996-02-22 |
EP0480391A2 (en) | 1992-04-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE4032096C2 (en) | Use of emulsifier-free emulsion polymers in pharmaceutical preparations with delayed release of the active ingredient | |
EP0088964B1 (en) | Process for preparing insoluble, only slightly expandable polymers of basic vinyl-heterocyclic compounds, and their use | |
AU611085B2 (en) | Sustained release pharmaceutical preparations | |
KR910001924B1 (en) | Process for preparing delayed releasing tube tablet | |
AU764280B2 (en) | Process for the preparation of pellets with a content of up to 90 wt. per cent of a pharmaceutical active ingredient | |
SI21394A2 (en) | Pharmaceutical pellets containing tamsulosin | |
JPH06504051A (en) | Formulation of stable suspensions for controlled delivery of drug compounds | |
WO2003084513A1 (en) | Controlled release solid dosage carbamazepine formulations | |
FR2510888A1 (en) | NOVEL PHARMACEUTICAL USE COMPOSITIONS WITH PROLONGED EFFECT OF RELEASE OF ACTIVE INGREDIENT | |
JPH05507683A (en) | Polymer drug delivery system | |
JP5394746B2 (en) | Particulate crosslinked polyvinylpyrrolidone as a tablet disintegrant | |
Jeyanthi et al. | Solid tumour chemotherapy using implantable collagen‐poly (HEMA) hydrogel containing 5‐fluorouracil | |
CA2053005A1 (en) | Emulsifier-free emulsion polymers | |
EP0900563B1 (en) | Production of pharmaceutical formulations containing aescin for treatment of edema and venous disorders | |
KR101519612B1 (en) | Process for the preparation of controlled-release solid formulations containing oxcarbazepine, and formulations obtainable by said process | |
Akbugcara | Effect of microsphere size and formulation factors on drug release from controlled-release furosemide microspheres | |
EP1208140B1 (en) | Rapidly decomposing chitosan-based pellets | |
Yunhua et al. | A comparative study on the effect of BCG-PSN and thymopeptides on T-lymphocyte subsets of normal and immunosuppressed mice | |
CA2144500A1 (en) | Pharmaceutical preparation | |
CN101214217A (en) | Hydrogel-hydrogel composite material and preparation thereof and use of medicament sustained-release matrix | |
Nagasree et al. | Design and evaluation of sodium alginate microspheres loaded with gatifloxacin | |
CA2547586A1 (en) | Controlled-release pharmaceutical formulation | |
Wadher et al. | Formulation and evaluation of controlled release matrix tablets using eudragit RSPO and gum copal | |
Singh et al. | Optimization of formulation parameters for controlled drug delivery from metformin hydrochloride loaded chitosan/TPP microspheres | |
Bakre et al. | Development and Evaluation of Metronidazole Microspheres using Starch Isolates of Maize Genotypes as Sustained Release Polymer |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |